TBD Meeting (5111-23)

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

AURORA, COLO. – Several drugs for multiple sclerosis (MS) that are contraindicated during pregnancy nevertheless have not shown concerning safety signals in a series of small studies presented as posters at the annual meeting of the Consortium of Multiple Sclerosis Centers. The industry-sponsored research included an assessment of pregnancy and infant outcomes for cladribine, ocrelizumab, ofatumumab, and ozanimod, all of which are not recommended during pregnancy based primarily on minimal data that suggests, but does not confirm, possible teratogenicity.

“When these new medications hit the market, maternal-fetal medicine physicians and obstetricians are left with very scant data on how to counsel patients, and it’s often based on theory, case reports, or animal studies,” said Teodora Kolarova, MD, a maternal-fetal medicine physician at the University of Washington, Seattle, who was not involved in any of the research. “Although these sample sizes seem small, the population they are sampling from – patients with MS who take immunomodulators who then experience a pregnancy – is much smaller than all pregnant patients.”

Taken together, the findings suggest no increased risk of miscarriage or congenital malformation, compared with baseline risk, Dr. Kolarova said.

“As a whole, these studies are overall reassuring with, of course, some caveats, including timing of medication exposure, limited sample size, and limited outcome data,” Dr. Kolarova said. She noted that embryonic organ formation is complete by 10 weeks gestation, by which time an unplanned pregnancy may not have been recognized yet. “In the subset of patients in the studies that were exposed during the first trimester, there was no increase in congenital malformations from a baseline risk of about 2%-3% in the general population, which is helpful for patient counseling.”
 

Counseling during the childbearing years

That kind of counseling is important yet absent for many people capable of pregnancy, suggests separate research also presented at the conference by Suma Shah, MD, an associate professor of neurology at Duke University, Durham, N.C. Dr. Shah gave 13-question surveys to female MS patients of all ages at her institution and presented an analysis of data from 38 completed surveys. Among those taking disease-modifying therapies, their medications included ocrelizumab, rituximab, teriflunomide, fingolimod, fumarates, interferons, natalizumab, and cladribine.

“MS disproportionately impacts women among 20 to 40 years, and that’s a really big part of their childbearing years when there are big decisions being made about whether they’re going to choose to grow family or not,” said Dr. Shah. The average age of those who completed the survey was 44. Dr. Shah noted that a lot of research has looked at the safety of older disease-modifying agents in pregnancy, but that information doesn’t appear to be filtering down to patients. “What I really wanted to look at is what do our parent patients understand about whether or not they can even think about pregnancy – and there’s a lot of work to be done.”

Just under a third of survey respondents said they did not have as many children as they would like, and a quarter said they were told they couldn’t have children if they had a diagnosis of MS.

“That was a little heartbreaking to hear because that’s not the truth,” Dr. Shah said. She said it’s necessary to have a more detailed conversation looking at tailored decisions for patients. “Both of those things – patients not being able to grow their family to the number that they desire, and not feeling like they can grow a family – I would think in 2023 we would have come farther than that, and there’s still a lot of room there to improve.”

She advised clinicians not to assume that MS patients know what their options are regarding family planning. “There’s still a lot of room for conversations,” she said. She also explicitly recommends discussing family planning and pregnancy planning with every patient, no matter their gender, early and often.
 

Cladribine shows no miscarriage, malformations

Dr. Kolarova noted that one of the studies, on cladribine, had a fairly robust sample size with its 180 pregnancy exposures. In that study, led by Kerstin Hellwig, MD, of Ruhr University in Bochum, Germany, data came from the global surveillance program MAPLE-MS, established to assess cladribine effects on pregnancy and infant outcomes. The researchers analyzed data from 76 mothers and 9 fathers who, at any time from 2017 to 2022, were taking cladribine during pregnancy or up to 6 months before pregnancy. Outcomes included live birth, miscarriage, stillbirth, elective abortion, ectopic pregnancy, and major congenital anomalies.

Just over half the mothers (53.9%) were exposed before pregnancy, and about a quarter (26.3%) were exposed during the first trimester. The timing was unknown for most of the other mothers (18.4%). Among the fathers, two-thirds (66.7%) were exposed before pregnancy, and one-third had unknown timing.

Among the 180 pregnancies in the maternal cohort, 42.2% had known outcomes. Nearly half the women (48.7%) taking cladribine had live births, 28.9% had elective abortions, and 21.1% had miscarriages. Only 9 of the 22 pregnancies in the paternal cohort had known outcomes, which included 88.9% live births and 11.1% miscarriages. None of the pregnancies resulted in stillbirth or in a live birth with major congenital anomalies.

”Robust conclusions cannot be made about the risks of adverse pregnancy outcomes with cladribine tablets, but no increase has been signaled thus far,” the researchers reported. ”It is necessary to counsel patients to prevent pregnancy and to use effective contraception during cladribine tablets intake and for at least 6 months after the last cladribine tablet intake in each treatment year.”

Emily Evans, MD, MBE, medical director at U.S. Neurology and Immunology in Rockland, Mass., speaking on behalf of the findings, said they were fairly encouraging.

“Of course, we don’t encourage patients to get pregnant within 6 months of their last dose of cladribine tablets,” Dr. Evans said, but “within those individuals who have gotten pregnant within 6 months of their last dose of cladribine, or who have fathered a child within 6 months of their last dose of cladribine tablets, we’re seeing overall encouraging outcomes. We’re specifically not seeing any differences in the rates of spontaneous abortions, and we’re not seeing any differences in the rates of congenital malformations.”
 

Ocrelizumab and ofatumumab: No infections so far

Current recommendations for ocrelizumab are to avoid pregnancy for 6 months after the last infusion and stop any breastfeeding during therapy. Yet these recommendations are only because of insufficient data rather than evidence of risk, according to Lana Zhovtis Ryerson, MD, of the NYU Multiple Sclerosis Comprehensive Care Center in New York. She and her colleagues identified all women of childbearing age who had received ocrelizumab within 1 year of pregnancy at their NYU institution. A retrospective chart review found 18 women, with an average age of 35, an average 11 years of an MS diagnosis, and an average 11 months taking ocrelizumab.

Among the 18 pregnancies, four women had a first trimester miscarriage, one had a second trimester miscarriage, and one had an abortion. The miscarriage rate could have been partly influenced by the older maternal population, the authors noted. Of the remaining 12 live births, one infant was premature at 34 weeks, and three infants stayed in NICU but were discharged within 2 weeks.

One patient experienced an MS relapse postpartum, despite receiving ocrelizumab within 45 days of delivery. Of the 16 women who agreed to participate in a Pregnancy Assessment Monitoring System (PRAMS) developed by the CDC, two women chose to breastfeed, and seven said their neurologist recommended against breastfeeding. None of the children’s pediatricians advised delaying vaccinations.

“This small sample observational study has not identified a potential additional risk with ocrelizumab for an adverse pregnancy outcome,” the authors concluded, but they added that ongoing studies, MINORE and SOPRANINO, can help guide future recommendations.

Though still limited, slightly more data exists on ofatumumab during pregnancy, including transient B-cell depletion and lymphopenia in infants whose mothers received anti-CD20 antibodies during pregnancy. However, research has found minimal IgG transfer in the first trimester, though it begins rising in the second trimester, and in utero ofatumumab exposure did not lead to any maternal toxicity or adverse prenatal or postnatal developmental effects in cynomolgus monkeys.

Riley Love, MD, of the University of California, San Francisco, Weill Institute for Neuroscience, and her colleagues both prospectively and retrospectively examined pregnancy and infant outcomes for up to 1 year post partum in women with MS who took ofatumumab during pregnancy or in the 6 months leading up to pregnancy. Their population included 104 prospective cases, most of which (84%) included first trimester exposure, and 14 retrospective cases. One in five of the prospective cases occurred during a clinical trial, while the remaining 80% occurred in postmarketing surveillance.

The prospectively followed women were an average 32 years old and were an average 7 weeks pregnant at the time of reporting. Among the 106 fetuses (including two twin pregnancies), only 30 outcomes had data at the cutoff time, including 16 live births, 9 abortions, and 5 miscarriages. None of the live births had congenital anomalies or serious infections. Another 30 pregnancies were lost to follow-up, and 46 were ongoing.

In the 14 retrospective cases, 57% of women were exposed in the first trimester, and 43% were exposed leading up to pregnancy. Half the cases occurred during clinical trials, and half in postmarketing surveillance. The women were an average 32 years old and were an average 10 weeks pregnant at reporting. Among the 14 pregnancies, nine were miscarriages, one was aborted, and four were born live with no congenital anomalies.

The authors did not draw any conclusions from the findings; they cited too little data and an ongoing study by Novartis to investigate ofatumumab in pregnancy.

“Therapies such as ofatumumab and ocrelizumab can lead to increased risk of infection due to transient B-cell depletion in neonates, but the two studies looking at this did not demonstrate increased infectious morbidity for these infants,” Dr. Kolarova said. “As with all poster presentations, I look forward to reading the full papers once they are published as they will often include a lot more detail about when during pregnancy medication exposure occurred and more detailed outcome data that was assessed.”
 

Ozanimod outcomes within general population’s ‘expected ranges’

The final study looked at outcomes of pregnancies in people taking ozanimod and in the partners of people taking ozanimod in a clinical trial setting. The findings show low rates of miscarriage, preterm birth, and congenital anomalies that the authors concluded were within the typical range expected for the general population.

“While pregnancy should be avoided when taking and for 3 months after stopping ozanimod to allow for drug elimination, there is no evidence to date of increased occurrence of adverse pregnancy outcomes with ozanimod exposure during early pregnancy,” wrote Anthony Krakovich, of Bristol Myers Squibb in Princeton, N.J., and his associates.

Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator whose therapeutic mechanism is not fully understood “but may involve the reduction of lymphocyte migration into the central nervous system and intestine,” the authors wrote. S1P receptors are involved in vascular formation during embryogenesis, and animal studies in rats and rabbits have shown toxicity to the embryo and fetus from S1P receptor modulators, including death and malformations. S1P receptor modulator labels therefore note potential fetal risk and the need for effective contraception while taking the drug.

The study prospectively tracked clinical trial participants taking ozanimod as healthy volunteers or for relapsing MS, ulcerative colitis, or Crohn’s disease. Most of the participants who became pregnant (73%) had relapsing MS, while 18% had ulcerative colitis and 8% had Crohn’s disease.

In female patients receiving ozanimod, 78 pregnancies resulted in 12 miscarriages (including one twin), 15 abortions, and 42 live births, with 6 pregnancies ongoing at the time of reporting and no data available for the remaining 4 pregnancies. Among the 42 live births, 4 were premature but otherwise healthy, 1 had a duplex kidney, and the other 37 infants were typical with no apparent health concerns. These rates of miscarriage, preterm birth, and congenital anomalies were within the expected ranges for the general population, the researchers wrote.

The researchers also assessed pregnancy outcomes for partners of male participants taking ozanimod. The 29 partner pregnancies resulted in 21 live births and one miscarriage, with one pregnancy ongoing and no information available for the other seven. The live births included 5 premature infants (including twins), 13 typical and healthy infants, 1 with Hirschsprung’s disease, 1 with a congenital hydrocele, and 1 with a partial atrioventricular septal defect. Again, the researchers concluded that these rates were within the typical range for the general population and that “no teratogenicity was observed.”

“We often encourage patients with MS, regardless of disease activity and therapies, to seek preconception evaluations with Maternal-Fetal Medicine and their neurologists in order to make plans for pregnancy and postpartum care,” Dr. Kolarova said. “That being said, access to subspecialized health care is not available to all, and pregnancy prior to such consultation does occur. These studies provide novel information that we have not had access to in the past and can improve patient counseling regarding their risks and options.”

The study on cladribine was funded by Merck KGaA, at which two authors are employed. Dr. Hellwig reported consulting, speaker, and/or research support from Bayer, Biogen, Teva, Novartis, Roche, Sanofi, Schering Healthcare, Serono, and Merck, and one author is a former employee of EMD Serono. The study on ocrelizumab was funded by Genentech. Dr. Zhovtis Ryerson reported personal fees from Biogen, Genentech, and Novartis, and research grants from Biogen, Genentech, and CMSC. The other authors had no disclosures. The study on ofatumumab was funded by Novartis. Dr. Bove has received research funds from Biogen, Novartis, and Roche Genentech, and consulting fees from EMD Serono, Horizon, Janssen, and TG Therapeutics; she has an ownership interest in Global Consult MD. Five authors are Novartis employees. Her coauthors, including Dr. Hellwig, reported advisory, consulting, research, speaking, or traveling fees from Alexion, Bayer, Biogen, Celgene BMS, EMD Serono, Horizon, Janssen, Lundbeck, Merck, Pfizer, Roche Genentech, Sanofi Genzyme, Schering Healthcare, Teva, TG Therapeutics, and Novartis. The study on ozanimod was funded by Bristol Myers Squibb. Dr. Krakovich and another author are employees and/or shareholders of Bristol Myers Squibb. The other authors reported consulting, speaking, advisory board, and/or research fees from AbbVie, Almirall, Arena, Biogen, Boehringer Ingelhei, Celgene, Celltrion, EXCEMED, Falk Benelux, Ferring, Forward Pharma, Genentech, Genzyme, Gilead, Janssen, Lilly, Merck, Novartis, Ono Pharma, Pfizer, Prometheus Labs, Protagonist, Roche, Sanofi, Synthon, Takeda, and Teva. Dr. Kolarova had no disclosures. Dr. Shah has received research support from Biogen and VeraSci.
 

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

A version of this article originally appeared on Medscape.com.

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

A version of this article originally appeared on Medscape.com.

DENVER – In the ongoing absence of a reliable biomarker for multiple sclerosis (MS), misdiagnosis is a common and persistent problem that potentially puts patients at prolonged and unnecessary risk. Experts warn that false-negative diagnoses cause treatment delays, while false-positive diagnoses run the risk for potential harm from needless treatment.

“MS has a misdiagnosis problem,” said Patricia Coyle, MD, professor of neurology and vice chair (academic affairs), department of neurology, Stony Brook (N.Y.) University, in presenting on the issue at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“We currently lack a diagnostic biomarker test, yet diagnosis is key. If you get it wrong – that really can be a problem,” Dr. Coyle said. Recent research indicates that MS misdiagnosis is a widespread problem, she added.

For instance, one research paper reported that nearly 20% of patients were misdiagnosed with MS and that more than 50% carried the misdiagnosis for at least 3 years, while 5% were misdiagnosed for 20 years or more.

The misdiagnosis problem is also reflected at large MS referral centers, where 30%-67% of patients turn out not to have the disease, Dr. Coyle noted.

A study from Argentina further highlights some of the key characteristics of misdiagnosis. In this study, examination of a cohort of 572 patients diagnosed with MS revealed that 16% were incorrectly diagnosed with MS and that women were at an 83% greater risk for misdiagnosis than men. Furthermore, the study showed that MS misdiagnosis increased by 8% per year of older age. The most frequent confirmed diagnoses among those who had been initially misdiagnosed as having MS were cerebrovascular disease, radiologically isolated syndrome, and headache.

The majority (83%) of patients incorrectly diagnosed with MS had an atypical presentation that did not indicate demyelination, 70% had an atypical brain magnetic resonance imaging, and 61% received a prescription for a disease-modifying treatment (DMT), despite not having confirmed MS.
 

The dangers of misdiagnosis

Misdiagnosis and incorrect treatment can be particularly dangerous if patients are diagnosed with MS when, in fact, they have neuromyelitis optica spectrum disorder (NMOSD), commonly mistaken for MS, Dr. Coyle noted.

“Several MS DMTs make NMOSD worse. You are also basically giving an unnecessary and inappropriate drug with potential side effects to the misdiagnosed patient,” she said.

There have been some advances in MS diagnosis on MRI. However, there are many caveats, Dr. Coyle noted.

For instance, leptomeningeal enhancement has been considered as an MS diagnostic indicator, but it is not unique to MS, Dr. Coyle noted. In addition, subpial demyelination is MS specific, but it is hard to see and is often missed, she added.

Central vein sign has received significant attention as an important MRI marker for MS, but, Dr. Coyle said, it is “not ready for prime time. It’s somewhat tedious and you need to use special protocols to identify it,” she said.

In the future, artificial intelligence and deep learning may be key to improving some of these technologies, Dr. Coyle noted.
 

Best hope for an accurate diagnosis

In the meantime, Dr. Coyle said she believes spinal fluid evaluation offers the best chance for a reliable MS diagnosis and is her preference. “I personally find spinal fluid to be extremely helpful to support MS diagnosis. Spinal fluid oligoclonal bands are positive in the vast majority of people with MS, and it is an independent finding from MRI to support an MS diagnosis. Added to MRI, it makes you much more comfortable,” she said.

Dr. Coyle said that a comprehensive workup should include:

• A thorough neurologic history and exam.
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist.
• Adding spinal fluid evaluation, especially in any atypical cases.
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4.

“You want to be as certain as possible. Everything starts with a thorough workup,” Dr. Coyle said.

Dr. Coyle’s disclosures include consulting, nonbranded speaker fees, and/or research support with Actelion, Alkermes, Accordant, Biogen, Bristol Myers Squibb, Celgene, CorEvitas LLC, GlaxoSmithKline, Genentech/Roche, Horizon Therapeutics, Janssen, MedDay, Labcorp, Eli Lilly, Mylan, NINDS, Novartis, Sanofi Genzyme, and TG Therapeutics.

A version of this article originally appeared on Medscape.com.

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

DENVER – Taking ozanimod for relapsing multiple sclerosis (MS) at the same time as taking antidepressants that increase serotonin levels does not appear to increase the risk for hypertension or any other adverse events related to serotonin toxicity, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“Depression and anxiety are prevalent comorbidities occurring in up to 54% of patients with multiple sclerosis, and selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line treatments for depression and anxiety disorders,” Robert T. Naismith, MD, of Washington University in St. Louis, and his colleagues reported.

“Coadministration of ozanimod with drugs that increase serotonin could hypothetically lead to serotonin accumulation,” which can increase the likelihood of hypertension. U.S. prescribing information recommends that patients taking both ozanimod and medications that increase norepinephrine or serotonin be monitored for hypertension, an adverse reaction reported in 3.9% of patients receiving ozanimod in the phase 3 trials for relapsing MS.
 

Clarifying the risk

“It’s important to be aware of potential drug interactions and risks from MS disease modifying therapies,” Lauren Gluck, MD, an assistant professor and director of the division of multiple sclerosis at Montefiore Medical Center/Albert Einstein College of Medicine, New York, said in an interview. Dr. Gluck was not involved in this study but described some of the history that revealed the value of this type of research. For example, the first sphingosine-1-phosphate receptor (S1PR) modulator approved for MS, fingolimod (Gilenya), has a risk of cardiac conduction dysfunction with QTc prolongation, so people taking fingolimod with other medications that prolong QTc, such as SSRIs, need additional monitoring.

“Ozanimod is a newer, more selective S1PR modulator that initially raised concerns about interaction with serotonin-increasing drugs based on in vitro studies,” Dr. Gluck said. “This could mean that people on ozanimod and other serotonin-increasing medicine could be at risk for dangerous events like serotonin syndrome. However, in vitro studies do not always translate to how something affects the human body, so it is not clear how much risk truly exists.”
 

Examining open-label extension trial data

The researchers therefore evaluated the safety of taking ozanimod and SSRIs or SNRIs in a subset of patients with relapsing MS who participated in the DAYBREAK open-label extension trial. The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a with 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over one week until all reached 0.92 mg of ozanimod, where they remained for an average of just under 5 years of follow-up. Nearly all the participants (99.4%) were White, and two-thirds (66.5%) were female.

The researchers searched the study data for terms related to serotonin toxicity and compared the rates of adverse events related with those terms and the rates of hypertension in the 274 participants who were and the 2,032 participant who were not taking antidepressants at the same time as ozanimod.

They found that 13.9% of patients taking SSRIs or SNRIs experienced at least one treatment-emergent adverse event related to their search criteria, compared with 17.7% of patients not taking SSRIs or SNRIs. Similarly, 9.2% of trial participants not taking SSRIs or SNRIs had hypertension, compared with 4.7% of participants who were taking antidepressants. The authors further noted that “similar trends were observed when 6 weeks after the end date of concomitant SSRIs/SNRI use were included in the ‘on SSRI/SNRI’ analysis period.”

When the researchers searched specifically for three terms directly related to serotonin toxicity – “serotonin syndrome,” “neuroleptic malignant syndrome,” and “hyperthermia malignant” – they did not find any patients who had treatment-emergent adverse events related to those terms.

“SSRIs/SNRIs were freely allowed as concomitant medications in the DAYBREAK open-label extension, and among the patients from SUNBEAM or RADIANCE who were followed for up to 6 years, there have been no reported safety concerns during the concurrent administration of serotonergic antidepressants and ozanimod in patients with relapsing MS as of the data cutoff,” concluded the authors, though they also noted that the overall rate of SSRI and SNRI use was low in the extension trial.
 

A reassuring finding for clinicians and patients alike

“It is reassuring, if not unexpected, that there were no clinically significant rates of symptoms associated with excess serotonin in patients on ozanimod and SSRI/SNRIs,” Dr. Gluck commented. “These findings are important for both clinicians and patients – they can help [both] feel comfortable considering ozanimod if SSRI/SNRIs are already being used. There is also freedom to use SSRI/SNRIs for symptom management in patients already on ozanimod.”

The research was funded by Bristol Myers Squibb. Dr. Naismith reported consulting for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics. Six other authors reported disclosures for various pharmaceutical companies, and six other authors are employees and/or shareholders of Bristol Myers Squibb. Dr. Gluck has served on advisory boards with Genentech and EMD Serono.
 

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

A version of this article first appears on Medscape.com.

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

A version of this article first appears on Medscape.com.

AURORA, COLO. – Frexalimab, a novel, second-generation anti-CD40L antibody, shows “strikingly positive” effects in the treatment of relapsing multiple sclerosis (MS), significantly reducing disease activity.

“We should be very excited about these results, which are better than expected and fundamentally tackle autoimmunity,” said study investigator Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts, London, and the London School of Medicine and Dentistry. “It will be interesting to see if this treatment reestablishes immune tolerance and induces long-term remission,” he said.

The late-breaking study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
 

Significant lesion reduction

With a variety of disease-modifying therapies available for MS, frexalimab would be unique as a novel second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway. Importantly, the mechanism is believed to potentially modify T- and B-cell activation and innate immune cell function, for an effect of reducing inflammation without depleting B cells.

To investigate the drug’s efficacy and safety, Dr. Giovannoni and his colleagues conducted the phase 2, multicenter trial, in which 129 participants with relapsing MS were randomized to one of four groups – high-dose frexalimab (n = 52); low-dose frexalimab (n = 51); or placebo (n = 12 high-dose, n = 14 low-dose), for the 12-week placebo-controlled period, followed by an open-label extension period that is currently ongoing.

Among 125 participants who completed the study’s 12-week double-blind period, those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions, compared with the pooled placebo group (P = .0004), meeting the study’s primary endpoint. After 24 weeks, as many as 96% of those in the high-dose frexalimab arm were free of gadolinium-enhanced T1 lesions.

The frexalimab low-dose group also had a lower, but significant, reduction in the number of new gadolinium-enhanced T1-lesions of 79% versus the pooled placebo group (P = .0021).

Both of the frexalimab groups also had reductions in enlarging T2-lesions and total gadolinium-enhanced T1-lesions.

In the high-dose group, data on 38 participants with open-label data from week 37 showed no new gadolinium-enhanced lesions.

In terms of safety, frexalimab was well tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants. No serious adverse events were reported.

Looking ahead at safety, Dr. Giovannoni noted that “a known unknown is infections, but this is a problem with all therapies that work via immunosuppressive mechanisms, not only therapies targeting CD40L.” That said, “we didn’t see a big infection signal in the trial, which is reassuring. It also shows the immune system has built-in redundancy and many mechanisms to fight infections,” he added.

In his newsletter, Dr. Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Overall, “these are the first randomized controlled phase 2 data for a CD40L inhibitor in MS and indicate potential for further development of frexalimab as a high-efficacy therapy,” the investigators noted. “Frexalimab led to a pronounced reduction of new gadolinium-enhancing lesions by 3 months and was well-tolerated,” they added.
 

An intriguing mechanism

Commenting on the study, Salim Chahin, MD, an assistant professor of neurology in the John L. Trotter MS Center in the department of neurology at Washington University, St. Louis, said that frexalimab represents an intriguing mechanistic approach to MS.

“In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before,” Dr. Chahin said.

“Therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development,” he said, noting that the drug appears to avoid these side effects, providing good phase 2 efficacy data.

Dr. Chahin agreed that the phase 3 data will be watched closely for further safety and efficacy issues. “Indeed, it is difficult to interpret the occurrence of COVID-19 infections, given the timing of the phase 2 study, or their severity, but based on the mechanism of action, it is possible that this drug will be associated with a more favorable safety profile than some of the currently approved MS treatments,” Dr. Chahin said.

“But phase 3 trial data are much needed to clarify the immunosuppressive risk.”

The study received funding from Sanofi. Dr. Giovannoni’s disclosures include current or recent relationships with AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD, Moderna, Serono, Moderna, Novartis, Sandoz, Sanofi, and Roche/Genentech. Dr. Chahin reports no relevant financial relationships.

A version of this article first appears on Medscape.com.

DENVER – Patients with multiple sclerosis (MS) who switched from anti-CD20 monoclonal antibody therapy to fumarates showed no significant differences in relapse rates or total health care encounters, compared with those who remained on anti-CD20 mAbs, according to a retrospective study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Those who switched did, however, experience a lower rate of inpatient infection-related health care visits per year than those who continued anti-CD20 mAbs.

“As MS is a chronic disease requiring long-term treatment, switching between disease-modifying therapies [DMTs] is a common clinical strategy to optimize individual patient outcomes,” lead author Aliza Ben-Zacharia, PhD, DNP, RN, an assistant professor at the Phillips School of Nursing at Mount Sinai and Hunter College, both in New York, and colleagues reported. They noted that anti-CD20 mAbs are considered high-efficacy DMTs while fumarates are considered moderate-efficacy DMTs.

The researchers used data from the Komodo Health Sentinel Claims Database to track and compare 108 patients who were clinically stable on anti-CD20 mAbs and then switched to fumarates with 540 patients who remained on anti-CD20 mAbs for a follow-up period of approximately 1 year.

The study included adults with a diagnosis of MS between January 2015 and August 2022, and only those with a gap of no more than 9 months between anti-CD20 mAbs and fumarates were included as switchers. The researchers also required that switchers had not had any relapses in the previous year on anti-CD20 mAbs before switching, and had to have been on fumarates for at least 3 months after switching.

Women made up 70% of both groups, and both had an average age of 49 years. The racial/ethnic demographics were similar in both groups, and the average MS severity score was 5.5 in the switching group and 5.6 in the staying group. Most patients had been taking or remained on ocrelizumab (93.5%) with a smaller proportion on rituximab (5.6%). Just over a third of those who switched therapy took diroximel fumarate while 64% took dimethyl fumarate.

The researchers noted that patients who stayed on anti-CD20 mAbs had “slightly higher use of other mAbs prior to anti-CD20 mAbs.” Further, “a higher proportion of patients were DMT naive prior to anti-CD20 mAb initiation, compared with those in the switchers group.”

Patients who switched had been on anti-CD20 mAbs an average 730 days before switching to fumarates, and the average time between their last anti-CD20 mAbs dose and starting fumarates was 274 days. Average exposure to fumarates was 341 days.

The 10.2% of patients who relapsed during follow-up after switching to fumarates was not significantly statistically different than the 6.7% of patients who relapsed while remaining on anti-CD20 mAbs (P = .17). A relapse was considered “an MS-related inpatient claim with a primary diagnosis of MS or an outpatient MS-related diagnosis and a prescription claim for an intravenous steroid, adrenocorticotropic hormone, total plasma exchange, or a high-dose oral corticosteroid 7 days or sooner after the outpatient visit,” the researchers explained. The researchers could not track mild relapses that didn’t involve a health care interaction.

There was also no significant difference in overall average health care encounters between those who switched (7.85 encounters) and those who stayed (8.08; P = .57). Further, average health care costs were statistically similar between those who switched ($22,512) and those who stayed ($20,634; P = 0.59).

The likelihood of having more than one infection-related health care encounter was greater for those who remained on anti-CD20 mAbs, but the difference was not statistically significant. The annual rate of infection-related health care encounters was also not statistically different for outpatient and ED visits, but those who switched did have a statistically lower rate of annual infection-related inpatient visits (P = .03).

Among those who switched, 2.8% were hospitalized for infections, compared with 6.5% who stayed on anti-CD20 mAbs. Urinary tract infections, sepsis, and Escherichia coli were the most common infections among those who switched to fumarates, compared with COVID-19, sepsis, and pneumonia, among those who stayed on anti-CD20 mAbs.

The research was sponsored by and funded by Biogen. Six of the authors are Biogen employees who hold stock options in the company. The other three authors reported combined consulting fees from Biogen, EMD Serono, Greenwich Biosciences, TG Therapeutics, Bristol-Myers Squibb, Horizon, and Novartis; research funding from Genentech and Novartis; and stock options in Pfizer.

DENVER – Patients with multiple sclerosis (MS) who switched from anti-CD20 monoclonal antibody therapy to fumarates showed no significant differences in relapse rates or total health care encounters, compared with those who remained on anti-CD20 mAbs, according to a retrospective study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Those who switched did, however, experience a lower rate of inpatient infection-related health care visits per year than those who continued anti-CD20 mAbs.

“As MS is a chronic disease requiring long-term treatment, switching between disease-modifying therapies [DMTs] is a common clinical strategy to optimize individual patient outcomes,” lead author Aliza Ben-Zacharia, PhD, DNP, RN, an assistant professor at the Phillips School of Nursing at Mount Sinai and Hunter College, both in New York, and colleagues reported. They noted that anti-CD20 mAbs are considered high-efficacy DMTs while fumarates are considered moderate-efficacy DMTs.

The researchers used data from the Komodo Health Sentinel Claims Database to track and compare 108 patients who were clinically stable on anti-CD20 mAbs and then switched to fumarates with 540 patients who remained on anti-CD20 mAbs for a follow-up period of approximately 1 year.

The study included adults with a diagnosis of MS between January 2015 and August 2022, and only those with a gap of no more than 9 months between anti-CD20 mAbs and fumarates were included as switchers. The researchers also required that switchers had not had any relapses in the previous year on anti-CD20 mAbs before switching, and had to have been on fumarates for at least 3 months after switching.

Women made up 70% of both groups, and both had an average age of 49 years. The racial/ethnic demographics were similar in both groups, and the average MS severity score was 5.5 in the switching group and 5.6 in the staying group. Most patients had been taking or remained on ocrelizumab (93.5%) with a smaller proportion on rituximab (5.6%). Just over a third of those who switched therapy took diroximel fumarate while 64% took dimethyl fumarate.

The researchers noted that patients who stayed on anti-CD20 mAbs had “slightly higher use of other mAbs prior to anti-CD20 mAbs.” Further, “a higher proportion of patients were DMT naive prior to anti-CD20 mAb initiation, compared with those in the switchers group.”

Patients who switched had been on anti-CD20 mAbs an average 730 days before switching to fumarates, and the average time between their last anti-CD20 mAbs dose and starting fumarates was 274 days. Average exposure to fumarates was 341 days.

The 10.2% of patients who relapsed during follow-up after switching to fumarates was not significantly statistically different than the 6.7% of patients who relapsed while remaining on anti-CD20 mAbs (P = .17). A relapse was considered “an MS-related inpatient claim with a primary diagnosis of MS or an outpatient MS-related diagnosis and a prescription claim for an intravenous steroid, adrenocorticotropic hormone, total plasma exchange, or a high-dose oral corticosteroid 7 days or sooner after the outpatient visit,” the researchers explained. The researchers could not track mild relapses that didn’t involve a health care interaction.

There was also no significant difference in overall average health care encounters between those who switched (7.85 encounters) and those who stayed (8.08; P = .57). Further, average health care costs were statistically similar between those who switched ($22,512) and those who stayed ($20,634; P = 0.59).

The likelihood of having more than one infection-related health care encounter was greater for those who remained on anti-CD20 mAbs, but the difference was not statistically significant. The annual rate of infection-related health care encounters was also not statistically different for outpatient and ED visits, but those who switched did have a statistically lower rate of annual infection-related inpatient visits (P = .03).

Among those who switched, 2.8% were hospitalized for infections, compared with 6.5% who stayed on anti-CD20 mAbs. Urinary tract infections, sepsis, and Escherichia coli were the most common infections among those who switched to fumarates, compared with COVID-19, sepsis, and pneumonia, among those who stayed on anti-CD20 mAbs.

The research was sponsored by and funded by Biogen. Six of the authors are Biogen employees who hold stock options in the company. The other three authors reported combined consulting fees from Biogen, EMD Serono, Greenwich Biosciences, TG Therapeutics, Bristol-Myers Squibb, Horizon, and Novartis; research funding from Genentech and Novartis; and stock options in Pfizer.

DENVER – Patients with multiple sclerosis (MS) who switched from anti-CD20 monoclonal antibody therapy to fumarates showed no significant differences in relapse rates or total health care encounters, compared with those who remained on anti-CD20 mAbs, according to a retrospective study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Those who switched did, however, experience a lower rate of inpatient infection-related health care visits per year than those who continued anti-CD20 mAbs.

“As MS is a chronic disease requiring long-term treatment, switching between disease-modifying therapies [DMTs] is a common clinical strategy to optimize individual patient outcomes,” lead author Aliza Ben-Zacharia, PhD, DNP, RN, an assistant professor at the Phillips School of Nursing at Mount Sinai and Hunter College, both in New York, and colleagues reported. They noted that anti-CD20 mAbs are considered high-efficacy DMTs while fumarates are considered moderate-efficacy DMTs.

The researchers used data from the Komodo Health Sentinel Claims Database to track and compare 108 patients who were clinically stable on anti-CD20 mAbs and then switched to fumarates with 540 patients who remained on anti-CD20 mAbs for a follow-up period of approximately 1 year.

The study included adults with a diagnosis of MS between January 2015 and August 2022, and only those with a gap of no more than 9 months between anti-CD20 mAbs and fumarates were included as switchers. The researchers also required that switchers had not had any relapses in the previous year on anti-CD20 mAbs before switching, and had to have been on fumarates for at least 3 months after switching.

Women made up 70% of both groups, and both had an average age of 49 years. The racial/ethnic demographics were similar in both groups, and the average MS severity score was 5.5 in the switching group and 5.6 in the staying group. Most patients had been taking or remained on ocrelizumab (93.5%) with a smaller proportion on rituximab (5.6%). Just over a third of those who switched therapy took diroximel fumarate while 64% took dimethyl fumarate.

The researchers noted that patients who stayed on anti-CD20 mAbs had “slightly higher use of other mAbs prior to anti-CD20 mAbs.” Further, “a higher proportion of patients were DMT naive prior to anti-CD20 mAb initiation, compared with those in the switchers group.”

Patients who switched had been on anti-CD20 mAbs an average 730 days before switching to fumarates, and the average time between their last anti-CD20 mAbs dose and starting fumarates was 274 days. Average exposure to fumarates was 341 days.

The 10.2% of patients who relapsed during follow-up after switching to fumarates was not significantly statistically different than the 6.7% of patients who relapsed while remaining on anti-CD20 mAbs (P = .17). A relapse was considered “an MS-related inpatient claim with a primary diagnosis of MS or an outpatient MS-related diagnosis and a prescription claim for an intravenous steroid, adrenocorticotropic hormone, total plasma exchange, or a high-dose oral corticosteroid 7 days or sooner after the outpatient visit,” the researchers explained. The researchers could not track mild relapses that didn’t involve a health care interaction.

There was also no significant difference in overall average health care encounters between those who switched (7.85 encounters) and those who stayed (8.08; P = .57). Further, average health care costs were statistically similar between those who switched ($22,512) and those who stayed ($20,634; P = 0.59).

The likelihood of having more than one infection-related health care encounter was greater for those who remained on anti-CD20 mAbs, but the difference was not statistically significant. The annual rate of infection-related health care encounters was also not statistically different for outpatient and ED visits, but those who switched did have a statistically lower rate of annual infection-related inpatient visits (P = .03).

Among those who switched, 2.8% were hospitalized for infections, compared with 6.5% who stayed on anti-CD20 mAbs. Urinary tract infections, sepsis, and Escherichia coli were the most common infections among those who switched to fumarates, compared with COVID-19, sepsis, and pneumonia, among those who stayed on anti-CD20 mAbs.

The research was sponsored by and funded by Biogen. Six of the authors are Biogen employees who hold stock options in the company. The other three authors reported combined consulting fees from Biogen, EMD Serono, Greenwich Biosciences, TG Therapeutics, Bristol-Myers Squibb, Horizon, and Novartis; research funding from Genentech and Novartis; and stock options in Pfizer.

DENVER – Patients with multiple sclerosis (MS) are significantly more likely to develop herpes zoster infections than immunocompetent individuals, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. “Herpes zoster and its complications are associated with increased health care cost and decreased quality of life,” lead author Nikita Stempniewicz, MSc, director of U.S. Health Outcomes & Epidemiology at GSK Vaccines, Alexandria, Va., reported.

“The take-home finding is that herpes zoster incidence is high among people with MS overall,” Mr. Stempniewicz said in an interview. “We also found that herpes zoster incidence is numerically higher among MS patients with higher levels of baseline immunosuppression, so another conclusion is that herpes zoster prevention may be warranted among this population given the high level of immunosuppression and the high risk of developing herpes zoster infection.” GSK manufactures Shingrix, the only currently approved and recommended herpes zoster vaccine available in the United States

Lawrence Steinman, MD, a professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) Medicine, was not involved in the research but said in an interview that the findings “raise the issue of whether not enough individuals with MS are getting Shingrix, and also whether there is a need for rapid intervention with an antiviral, for those individuals who develop shingles.”
 

Real-world data

For the study, researchers analyzed U.S. administrative claims data from the Optum Research Database between October 2015 and March 2022 to compare shingles infections between adults with MS (and no other immunocompromising conditions) and a random sample of one million people without any immunocompromising conditions. The study excluded anyone who had been vaccinated against herpes zoster or diagnosed with it in the year before October 2015.

Among the 42,185 adults with MS included in the cohort, just over half (53%) were commercially insured, and 47% had Medicare Advantage. Their average age was 53, and 75% were female. Just over half the cohort (55%) had no immunosuppression because of medications while 35% had low immunosuppression from MS therapy and 10% had high immunosuppression from therapy. High suppression meant patients were taking fingolimod, siponimod, ozanimod, ponesimod, cladribine, or a monoclonal antibody except natalizumab. Those with low suppression were taking natalizumab, fumarates, IVIG, glatiramer acetate, interferon beta or a related drug, teriflunomide, azathioprine, methotrexate, or mycophenolate mofetil.

The rate of shingles infections in the MS patient population was 13.8 per 1,000 people per year, compared with 5.6 infections per 1,000 immunocompetent people per year (adjusted incident rate ratio, 1.69; 95% confidenceinterval, 1.58-1.81. When broken down by age, younger adults aged 18-49 with MS were more than three times more likely to develop shingles (incidence rate, 11.6 per 1,000 people per year) than immunocompetent younger adults (IR, 3.5). The gap was narrower for those age 50 and older, where adults with MS had a rate of 15.2 infections per 1,000 people per year versus 8.6 per 1,000 immunocompetent people per year.

Although MS patients with a higher baseline level of immunosuppression from therapy had higher herpes zoster infection rates (18 cases per 1,000 people per year) than those with low immunosuppression (14 cases per 1,000 people per year) or no immunosuppression from medication (13 cases per 1,000 people per year), rates for all three remained higher than for the immunocompetent population.
 

Herpes and MS: Some questions still unanswered

“We’ve known that herpes zoster is more common in people with MS, and we’ve known that it is seen in people on MS therapies,” Robert Fox, MD, a staff neurologist at the Mellen Center for MS and vice-chair for research at the Neurological Institute at the Cleveland Clinic, said in an interview. “What we haven’t known is just how much more common it is in people with MS than the rest of the adult population and whether it truly is more common in people taking MS therapies than people not taking MS therapies. This study puts real, population-based numbers on the incidence rates.”

Dr. Fox, who was not involved in the research, noted that a limitation of the study was the inability to know the risk of shingles according to specific MS therapies since all the therapies were grouped together.

”So I can’t say to a patient that their particular therapy increases their risk,” Dr. Fox said. “Similarly with the MS therapies listed in the ‘high’ immunosuppression category: We don’t know that each of the therapies listed do in fact increase the rate of herpes zoster. We just know that the group of MS therapies bunched into the ‘high’ category, on the whole, increase the rate of herpes zoster.”

The study does not provide any information about the impact of Shingrix vaccination, he added, since vaccinated individuals were excluded from the analysis.
 

Timing the vaccination with MS therapy

Dr. Steinman said in an interview that he recommends herpes zoster vaccination to his patients with MS.

“The mistake that people make with MS is that they don’t want to take the [herpes zoster] vaccine, and they should be taking it,”

Dr. Steinman said. “In a perfect world, they would get it before they went on their [immunosuppressive] drug. But now we’ll have a lot of people who didn’t take the vaccine; they can get it while they’re on their drug.” Although it depends on the particular therapy they’re taking, Dr. Steinman said that most people can get the shingles vaccine while continuing their medication.

The Centers for Disease Control and Prevention recommends that adults who are or will be immunodeficient or immunosuppressed because of a disease or therapy get two doses of the Shingrix vaccine against herpes zoster, regardless of whether they have previously been vaccinated with Zostavax or have ever had shingles. The agency has also issued detailed clinical guidance regarding how to administer the vaccine to individuals taking immunosuppressive therapy, including the option to administer the second dose 1-2 months after the first instead of 2-6 months to “facilitate avoiding vaccination during periods of more intense immunosuppression,” the agency wrote.

The research was sponsored, funded, and analyzed by GSK, which manufactures the shingles vaccine Shingrix, and Mr. Stempniewicz is a GSK employee. Two other authors are GSK employees, and three authors are employees of Optum who received fees from GSK for this study. Dr. Steinman and Dr. Fox reported no relevant disclosures.

DENVER – Patients with multiple sclerosis (MS) are significantly more likely to develop herpes zoster infections than immunocompetent individuals, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. “Herpes zoster and its complications are associated with increased health care cost and decreased quality of life,” lead author Nikita Stempniewicz, MSc, director of U.S. Health Outcomes & Epidemiology at GSK Vaccines, Alexandria, Va., reported.

“The take-home finding is that herpes zoster incidence is high among people with MS overall,” Mr. Stempniewicz said in an interview. “We also found that herpes zoster incidence is numerically higher among MS patients with higher levels of baseline immunosuppression, so another conclusion is that herpes zoster prevention may be warranted among this population given the high level of immunosuppression and the high risk of developing herpes zoster infection.” GSK manufactures Shingrix, the only currently approved and recommended herpes zoster vaccine available in the United States

Lawrence Steinman, MD, a professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) Medicine, was not involved in the research but said in an interview that the findings “raise the issue of whether not enough individuals with MS are getting Shingrix, and also whether there is a need for rapid intervention with an antiviral, for those individuals who develop shingles.”
 

Real-world data

For the study, researchers analyzed U.S. administrative claims data from the Optum Research Database between October 2015 and March 2022 to compare shingles infections between adults with MS (and no other immunocompromising conditions) and a random sample of one million people without any immunocompromising conditions. The study excluded anyone who had been vaccinated against herpes zoster or diagnosed with it in the year before October 2015.

Among the 42,185 adults with MS included in the cohort, just over half (53%) were commercially insured, and 47% had Medicare Advantage. Their average age was 53, and 75% were female. Just over half the cohort (55%) had no immunosuppression because of medications while 35% had low immunosuppression from MS therapy and 10% had high immunosuppression from therapy. High suppression meant patients were taking fingolimod, siponimod, ozanimod, ponesimod, cladribine, or a monoclonal antibody except natalizumab. Those with low suppression were taking natalizumab, fumarates, IVIG, glatiramer acetate, interferon beta or a related drug, teriflunomide, azathioprine, methotrexate, or mycophenolate mofetil.

The rate of shingles infections in the MS patient population was 13.8 per 1,000 people per year, compared with 5.6 infections per 1,000 immunocompetent people per year (adjusted incident rate ratio, 1.69; 95% confidenceinterval, 1.58-1.81. When broken down by age, younger adults aged 18-49 with MS were more than three times more likely to develop shingles (incidence rate, 11.6 per 1,000 people per year) than immunocompetent younger adults (IR, 3.5). The gap was narrower for those age 50 and older, where adults with MS had a rate of 15.2 infections per 1,000 people per year versus 8.6 per 1,000 immunocompetent people per year.

Although MS patients with a higher baseline level of immunosuppression from therapy had higher herpes zoster infection rates (18 cases per 1,000 people per year) than those with low immunosuppression (14 cases per 1,000 people per year) or no immunosuppression from medication (13 cases per 1,000 people per year), rates for all three remained higher than for the immunocompetent population.
 

Herpes and MS: Some questions still unanswered

“We’ve known that herpes zoster is more common in people with MS, and we’ve known that it is seen in people on MS therapies,” Robert Fox, MD, a staff neurologist at the Mellen Center for MS and vice-chair for research at the Neurological Institute at the Cleveland Clinic, said in an interview. “What we haven’t known is just how much more common it is in people with MS than the rest of the adult population and whether it truly is more common in people taking MS therapies than people not taking MS therapies. This study puts real, population-based numbers on the incidence rates.”

Dr. Fox, who was not involved in the research, noted that a limitation of the study was the inability to know the risk of shingles according to specific MS therapies since all the therapies were grouped together.

”So I can’t say to a patient that their particular therapy increases their risk,” Dr. Fox said. “Similarly with the MS therapies listed in the ‘high’ immunosuppression category: We don’t know that each of the therapies listed do in fact increase the rate of herpes zoster. We just know that the group of MS therapies bunched into the ‘high’ category, on the whole, increase the rate of herpes zoster.”

The study does not provide any information about the impact of Shingrix vaccination, he added, since vaccinated individuals were excluded from the analysis.
 

Timing the vaccination with MS therapy

Dr. Steinman said in an interview that he recommends herpes zoster vaccination to his patients with MS.

“The mistake that people make with MS is that they don’t want to take the [herpes zoster] vaccine, and they should be taking it,”

Dr. Steinman said. “In a perfect world, they would get it before they went on their [immunosuppressive] drug. But now we’ll have a lot of people who didn’t take the vaccine; they can get it while they’re on their drug.” Although it depends on the particular therapy they’re taking, Dr. Steinman said that most people can get the shingles vaccine while continuing their medication.

The Centers for Disease Control and Prevention recommends that adults who are or will be immunodeficient or immunosuppressed because of a disease or therapy get two doses of the Shingrix vaccine against herpes zoster, regardless of whether they have previously been vaccinated with Zostavax or have ever had shingles. The agency has also issued detailed clinical guidance regarding how to administer the vaccine to individuals taking immunosuppressive therapy, including the option to administer the second dose 1-2 months after the first instead of 2-6 months to “facilitate avoiding vaccination during periods of more intense immunosuppression,” the agency wrote.

The research was sponsored, funded, and analyzed by GSK, which manufactures the shingles vaccine Shingrix, and Mr. Stempniewicz is a GSK employee. Two other authors are GSK employees, and three authors are employees of Optum who received fees from GSK for this study. Dr. Steinman and Dr. Fox reported no relevant disclosures.

DENVER – Patients with multiple sclerosis (MS) are significantly more likely to develop herpes zoster infections than immunocompetent individuals, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. “Herpes zoster and its complications are associated with increased health care cost and decreased quality of life,” lead author Nikita Stempniewicz, MSc, director of U.S. Health Outcomes & Epidemiology at GSK Vaccines, Alexandria, Va., reported.

“The take-home finding is that herpes zoster incidence is high among people with MS overall,” Mr. Stempniewicz said in an interview. “We also found that herpes zoster incidence is numerically higher among MS patients with higher levels of baseline immunosuppression, so another conclusion is that herpes zoster prevention may be warranted among this population given the high level of immunosuppression and the high risk of developing herpes zoster infection.” GSK manufactures Shingrix, the only currently approved and recommended herpes zoster vaccine available in the United States

Lawrence Steinman, MD, a professor of neurology and neurological sciences, pediatrics, and genetics at Stanford (Calif.) Medicine, was not involved in the research but said in an interview that the findings “raise the issue of whether not enough individuals with MS are getting Shingrix, and also whether there is a need for rapid intervention with an antiviral, for those individuals who develop shingles.”
 

Real-world data

For the study, researchers analyzed U.S. administrative claims data from the Optum Research Database between October 2015 and March 2022 to compare shingles infections between adults with MS (and no other immunocompromising conditions) and a random sample of one million people without any immunocompromising conditions. The study excluded anyone who had been vaccinated against herpes zoster or diagnosed with it in the year before October 2015.

Among the 42,185 adults with MS included in the cohort, just over half (53%) were commercially insured, and 47% had Medicare Advantage. Their average age was 53, and 75% were female. Just over half the cohort (55%) had no immunosuppression because of medications while 35% had low immunosuppression from MS therapy and 10% had high immunosuppression from therapy. High suppression meant patients were taking fingolimod, siponimod, ozanimod, ponesimod, cladribine, or a monoclonal antibody except natalizumab. Those with low suppression were taking natalizumab, fumarates, IVIG, glatiramer acetate, interferon beta or a related drug, teriflunomide, azathioprine, methotrexate, or mycophenolate mofetil.

The rate of shingles infections in the MS patient population was 13.8 per 1,000 people per year, compared with 5.6 infections per 1,000 immunocompetent people per year (adjusted incident rate ratio, 1.69; 95% confidenceinterval, 1.58-1.81. When broken down by age, younger adults aged 18-49 with MS were more than three times more likely to develop shingles (incidence rate, 11.6 per 1,000 people per year) than immunocompetent younger adults (IR, 3.5). The gap was narrower for those age 50 and older, where adults with MS had a rate of 15.2 infections per 1,000 people per year versus 8.6 per 1,000 immunocompetent people per year.

Although MS patients with a higher baseline level of immunosuppression from therapy had higher herpes zoster infection rates (18 cases per 1,000 people per year) than those with low immunosuppression (14 cases per 1,000 people per year) or no immunosuppression from medication (13 cases per 1,000 people per year), rates for all three remained higher than for the immunocompetent population.
 

Herpes and MS: Some questions still unanswered

“We’ve known that herpes zoster is more common in people with MS, and we’ve known that it is seen in people on MS therapies,” Robert Fox, MD, a staff neurologist at the Mellen Center for MS and vice-chair for research at the Neurological Institute at the Cleveland Clinic, said in an interview. “What we haven’t known is just how much more common it is in people with MS than the rest of the adult population and whether it truly is more common in people taking MS therapies than people not taking MS therapies. This study puts real, population-based numbers on the incidence rates.”

Dr. Fox, who was not involved in the research, noted that a limitation of the study was the inability to know the risk of shingles according to specific MS therapies since all the therapies were grouped together.

”So I can’t say to a patient that their particular therapy increases their risk,” Dr. Fox said. “Similarly with the MS therapies listed in the ‘high’ immunosuppression category: We don’t know that each of the therapies listed do in fact increase the rate of herpes zoster. We just know that the group of MS therapies bunched into the ‘high’ category, on the whole, increase the rate of herpes zoster.”

The study does not provide any information about the impact of Shingrix vaccination, he added, since vaccinated individuals were excluded from the analysis.
 

Timing the vaccination with MS therapy

Dr. Steinman said in an interview that he recommends herpes zoster vaccination to his patients with MS.

“The mistake that people make with MS is that they don’t want to take the [herpes zoster] vaccine, and they should be taking it,”

Dr. Steinman said. “In a perfect world, they would get it before they went on their [immunosuppressive] drug. But now we’ll have a lot of people who didn’t take the vaccine; they can get it while they’re on their drug.” Although it depends on the particular therapy they’re taking, Dr. Steinman said that most people can get the shingles vaccine while continuing their medication.

The Centers for Disease Control and Prevention recommends that adults who are or will be immunodeficient or immunosuppressed because of a disease or therapy get two doses of the Shingrix vaccine against herpes zoster, regardless of whether they have previously been vaccinated with Zostavax or have ever had shingles. The agency has also issued detailed clinical guidance regarding how to administer the vaccine to individuals taking immunosuppressive therapy, including the option to administer the second dose 1-2 months after the first instead of 2-6 months to “facilitate avoiding vaccination during periods of more intense immunosuppression,” the agency wrote.

The research was sponsored, funded, and analyzed by GSK, which manufactures the shingles vaccine Shingrix, and Mr. Stempniewicz is a GSK employee. Two other authors are GSK employees, and three authors are employees of Optum who received fees from GSK for this study. Dr. Steinman and Dr. Fox reported no relevant disclosures.

AURORA, COLO. – Long-term use of ozanimod for multiple sclerosis (MS) was well-tolerated across multiple age groups, though risk of certain infections and other treatment-emergent adverse events (TEAE) did increase with age, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Research from the phase 3 DAYBREAK trial had already shown the safety of ozanimod, and the Food and Drug Administration approved the drug as an oral disease-modifying therapy for relapsing forms of MS in 2020.

“In the DAYBREAK study, we already have shown that the clinical and radiological disease was quite low in these patients who received the higher dose of ozanimod, and those who switched from the lower dose of the interferon to this active treatment also had decreases in their annualized relapse rate and their MRI lesion counts,” Sarah Morrow, MD, associate professor of neurology at Western University in London, Ontario, told attendees. She presented the data on behalf of senior author Bruce Cree, MD, PhD, professor of neurology and clinical research director at the University of California, San Francisco, Multiple Sclerosis Center, and the other authors. “But what was not known was whether there’s a difference in efficacy based on age, and we know that disease activity can differ based on age in person with relapsing multiple sclerosis.”
 

Examining efficacy by age

Analysis of data from DAYBREAK and an open-label extension study revealed that respiratory infections were more common in patients younger than 35, and urinary tract infections, dizziness, and treatment-emergent depressive symptoms became were common in patients age 50 and older. “Serious infections did not vary by age, and there were too few serious events to identify any age-related trends by specific TEAE,” the authors reported. During the open-label extension of the study, no new adverse events emerged, “confirming the ozanimod safety profile reported in the parent trials,” SUNBEAM and RADIANCE, the authors reported.

The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a to 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over 1 week until all reached 0.92 mg of ozanimod, where they remained for approximately 5 years of follow-up. The researchers then analyzed TEAEs, serious adverse events, and TEAEs leading to discontinuation in four age categories: 18-25, 26-35, 36-49, and 50 and older.

Respiratory infections occurred more often in those aged 18-25 (10.9%) and 26-35 (6.1%) than in those 36-49 (5.8%) and 50 and older (3.4%). However, UTIs occurred most in those age 50 and older (9.2%), versus occurring in 6.6% of those 36-49, 4.3% of those aged 26-35, and 4.6% of those 18-25.

High cholesterol occurred significantly less often in those 18-25 (1.4%) and 26-35 (2%) than in those 36-49 (5%) and 50 and older (8%), and hypertension showed a similar pattern: 2% in the youngest group, 4.7% in those aged 26-35, 12.8% in those aged 36-49, and 16.7% in those aged 50 and older.

Other TEAEs that occurred more often in older patients included depression/depressive symptoms, dizziness, back pain, joint pain, osteoarthritis, and high gamma-glutamyl transferase (GGT) levels. Overall cardiac and vascular disorders and malignancies were also more common as participants’ age increased.
 

Bigger concerns?

The increase in malignancy risk by age surprised Shailee Shah, MD, assistant professor of neuroimmunology and neurology at Vanderbilt University Medical Center, Nashville, Tenn., who was not involved in the research. This increase in risk was “not expanded upon much in this abstract or compared to population estimates, as this may ultimately be one of the bigger concerns with long-term use of this drug,” Dr. Shah said.

She further noted that “older patients may be at higher risk of infections and multiple cardiovascular risk factors, and so if patients already have comorbid disease, I may be less inclined to use this agent and likely less so in older individuals.”

Dr. Shah said these drugs are often recommended to individuals in their 20s and 30s at time of diagnosis. “If a patient is given this drug and tolerates it and finds it efficacious, we might continue this indefinitely, so looking at how the risk profile of young patients on this drug changes over time will be important,” Dr. Shah said. “I am also concerned about the malignancy risk and would want this elaborated upon.”
 

Overall efficacy across age groups

Serious infections occurred at relatively similar rates across all age groups. Incidence of any serious adverse event was 27 per 1,000 people per year in the youngest group compared with 24 events in the 26-35 group, 35 events in the 36-49 group, and 62 events per 1,000 people per year in those 50 and older.

“Patients in the 50 and older age group had a numerically lower adjusted annualized relapse rate and less gadolinium-enhancing lesions and new or enlarging T2 lesions per scan and were generally more likely to be free of gadolinium-enhancing lesions or new or enlarging T2 lesions than the 25 and younger age group,” Dr. Morrow told attendees, “but we feel that that’s more in keeping with the natural history of disease. And, overall, ozanimod, regardless of the age group, showed decreasing disease activity in the inflammatory part of disease, showing with annualized relapse rate, gad-enhancing lesions, and T2 lesions.”

Older participants were substantially more likely to withdraw from the trial because of adverse events. While 8% of the youngest group and 7.6% of participants aged 26-35 withdrew because of adverse events, 24.5% of those aged 36-49 and 18.5% of those aged 50 and older withdrew because of adverse events.

Dr. Shah said it was reassuring that no new safety signals emerged, “but based on this data, you would be concerned that long-term risk of cardiovascular disease may result in more serious adverse events over a longer period of time and will need to be considered as we see people increasingly on this drug.”

The research was funded by Bristol-Myers Squibb. The authors reported a wide range of financial disclosures, including personal fees, research funding, advisory board, and speakers fees, for multiple pharmaceutical companies, including Bristol-Myers Squibb, and five authors are employees and/or shareholders of the company. Dr. Shah has served on advisory boards for Alexion, Genentech, and Horizon.

AURORA, COLO. – Long-term use of ozanimod for multiple sclerosis (MS) was well-tolerated across multiple age groups, though risk of certain infections and other treatment-emergent adverse events (TEAE) did increase with age, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Research from the phase 3 DAYBREAK trial had already shown the safety of ozanimod, and the Food and Drug Administration approved the drug as an oral disease-modifying therapy for relapsing forms of MS in 2020.

“In the DAYBREAK study, we already have shown that the clinical and radiological disease was quite low in these patients who received the higher dose of ozanimod, and those who switched from the lower dose of the interferon to this active treatment also had decreases in their annualized relapse rate and their MRI lesion counts,” Sarah Morrow, MD, associate professor of neurology at Western University in London, Ontario, told attendees. She presented the data on behalf of senior author Bruce Cree, MD, PhD, professor of neurology and clinical research director at the University of California, San Francisco, Multiple Sclerosis Center, and the other authors. “But what was not known was whether there’s a difference in efficacy based on age, and we know that disease activity can differ based on age in person with relapsing multiple sclerosis.”
 

Examining efficacy by age

Analysis of data from DAYBREAK and an open-label extension study revealed that respiratory infections were more common in patients younger than 35, and urinary tract infections, dizziness, and treatment-emergent depressive symptoms became were common in patients age 50 and older. “Serious infections did not vary by age, and there were too few serious events to identify any age-related trends by specific TEAE,” the authors reported. During the open-label extension of the study, no new adverse events emerged, “confirming the ozanimod safety profile reported in the parent trials,” SUNBEAM and RADIANCE, the authors reported.

The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a to 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over 1 week until all reached 0.92 mg of ozanimod, where they remained for approximately 5 years of follow-up. The researchers then analyzed TEAEs, serious adverse events, and TEAEs leading to discontinuation in four age categories: 18-25, 26-35, 36-49, and 50 and older.

Respiratory infections occurred more often in those aged 18-25 (10.9%) and 26-35 (6.1%) than in those 36-49 (5.8%) and 50 and older (3.4%). However, UTIs occurred most in those age 50 and older (9.2%), versus occurring in 6.6% of those 36-49, 4.3% of those aged 26-35, and 4.6% of those 18-25.

High cholesterol occurred significantly less often in those 18-25 (1.4%) and 26-35 (2%) than in those 36-49 (5%) and 50 and older (8%), and hypertension showed a similar pattern: 2% in the youngest group, 4.7% in those aged 26-35, 12.8% in those aged 36-49, and 16.7% in those aged 50 and older.

Other TEAEs that occurred more often in older patients included depression/depressive symptoms, dizziness, back pain, joint pain, osteoarthritis, and high gamma-glutamyl transferase (GGT) levels. Overall cardiac and vascular disorders and malignancies were also more common as participants’ age increased.
 

Bigger concerns?

The increase in malignancy risk by age surprised Shailee Shah, MD, assistant professor of neuroimmunology and neurology at Vanderbilt University Medical Center, Nashville, Tenn., who was not involved in the research. This increase in risk was “not expanded upon much in this abstract or compared to population estimates, as this may ultimately be one of the bigger concerns with long-term use of this drug,” Dr. Shah said.

She further noted that “older patients may be at higher risk of infections and multiple cardiovascular risk factors, and so if patients already have comorbid disease, I may be less inclined to use this agent and likely less so in older individuals.”

Dr. Shah said these drugs are often recommended to individuals in their 20s and 30s at time of diagnosis. “If a patient is given this drug and tolerates it and finds it efficacious, we might continue this indefinitely, so looking at how the risk profile of young patients on this drug changes over time will be important,” Dr. Shah said. “I am also concerned about the malignancy risk and would want this elaborated upon.”
 

Overall efficacy across age groups

Serious infections occurred at relatively similar rates across all age groups. Incidence of any serious adverse event was 27 per 1,000 people per year in the youngest group compared with 24 events in the 26-35 group, 35 events in the 36-49 group, and 62 events per 1,000 people per year in those 50 and older.

“Patients in the 50 and older age group had a numerically lower adjusted annualized relapse rate and less gadolinium-enhancing lesions and new or enlarging T2 lesions per scan and were generally more likely to be free of gadolinium-enhancing lesions or new or enlarging T2 lesions than the 25 and younger age group,” Dr. Morrow told attendees, “but we feel that that’s more in keeping with the natural history of disease. And, overall, ozanimod, regardless of the age group, showed decreasing disease activity in the inflammatory part of disease, showing with annualized relapse rate, gad-enhancing lesions, and T2 lesions.”

Older participants were substantially more likely to withdraw from the trial because of adverse events. While 8% of the youngest group and 7.6% of participants aged 26-35 withdrew because of adverse events, 24.5% of those aged 36-49 and 18.5% of those aged 50 and older withdrew because of adverse events.

Dr. Shah said it was reassuring that no new safety signals emerged, “but based on this data, you would be concerned that long-term risk of cardiovascular disease may result in more serious adverse events over a longer period of time and will need to be considered as we see people increasingly on this drug.”

The research was funded by Bristol-Myers Squibb. The authors reported a wide range of financial disclosures, including personal fees, research funding, advisory board, and speakers fees, for multiple pharmaceutical companies, including Bristol-Myers Squibb, and five authors are employees and/or shareholders of the company. Dr. Shah has served on advisory boards for Alexion, Genentech, and Horizon.

AURORA, COLO. – Long-term use of ozanimod for multiple sclerosis (MS) was well-tolerated across multiple age groups, though risk of certain infections and other treatment-emergent adverse events (TEAE) did increase with age, according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Research from the phase 3 DAYBREAK trial had already shown the safety of ozanimod, and the Food and Drug Administration approved the drug as an oral disease-modifying therapy for relapsing forms of MS in 2020.

“In the DAYBREAK study, we already have shown that the clinical and radiological disease was quite low in these patients who received the higher dose of ozanimod, and those who switched from the lower dose of the interferon to this active treatment also had decreases in their annualized relapse rate and their MRI lesion counts,” Sarah Morrow, MD, associate professor of neurology at Western University in London, Ontario, told attendees. She presented the data on behalf of senior author Bruce Cree, MD, PhD, professor of neurology and clinical research director at the University of California, San Francisco, Multiple Sclerosis Center, and the other authors. “But what was not known was whether there’s a difference in efficacy based on age, and we know that disease activity can differ based on age in person with relapsing multiple sclerosis.”
 

Examining efficacy by age

Analysis of data from DAYBREAK and an open-label extension study revealed that respiratory infections were more common in patients younger than 35, and urinary tract infections, dizziness, and treatment-emergent depressive symptoms became were common in patients age 50 and older. “Serious infections did not vary by age, and there were too few serious events to identify any age-related trends by specific TEAE,” the authors reported. During the open-label extension of the study, no new adverse events emerged, “confirming the ozanimod safety profile reported in the parent trials,” SUNBEAM and RADIANCE, the authors reported.

The phase 3 parent trials compared 30 mcg once weekly of intramuscular interferon beta-1a to 0.92 mg of once-daily oral ozanimod and 0.46 mg of once-daily oral ozanimod. In the DAYBREAK open-label extension, 2,256 participants underwent a dose escalation over 1 week until all reached 0.92 mg of ozanimod, where they remained for approximately 5 years of follow-up. The researchers then analyzed TEAEs, serious adverse events, and TEAEs leading to discontinuation in four age categories: 18-25, 26-35, 36-49, and 50 and older.

Respiratory infections occurred more often in those aged 18-25 (10.9%) and 26-35 (6.1%) than in those 36-49 (5.8%) and 50 and older (3.4%). However, UTIs occurred most in those age 50 and older (9.2%), versus occurring in 6.6% of those 36-49, 4.3% of those aged 26-35, and 4.6% of those 18-25.

High cholesterol occurred significantly less often in those 18-25 (1.4%) and 26-35 (2%) than in those 36-49 (5%) and 50 and older (8%), and hypertension showed a similar pattern: 2% in the youngest group, 4.7% in those aged 26-35, 12.8% in those aged 36-49, and 16.7% in those aged 50 and older.

Other TEAEs that occurred more often in older patients included depression/depressive symptoms, dizziness, back pain, joint pain, osteoarthritis, and high gamma-glutamyl transferase (GGT) levels. Overall cardiac and vascular disorders and malignancies were also more common as participants’ age increased.
 

Bigger concerns?

The increase in malignancy risk by age surprised Shailee Shah, MD, assistant professor of neuroimmunology and neurology at Vanderbilt University Medical Center, Nashville, Tenn., who was not involved in the research. This increase in risk was “not expanded upon much in this abstract or compared to population estimates, as this may ultimately be one of the bigger concerns with long-term use of this drug,” Dr. Shah said.

She further noted that “older patients may be at higher risk of infections and multiple cardiovascular risk factors, and so if patients already have comorbid disease, I may be less inclined to use this agent and likely less so in older individuals.”

Dr. Shah said these drugs are often recommended to individuals in their 20s and 30s at time of diagnosis. “If a patient is given this drug and tolerates it and finds it efficacious, we might continue this indefinitely, so looking at how the risk profile of young patients on this drug changes over time will be important,” Dr. Shah said. “I am also concerned about the malignancy risk and would want this elaborated upon.”
 

Overall efficacy across age groups

Serious infections occurred at relatively similar rates across all age groups. Incidence of any serious adverse event was 27 per 1,000 people per year in the youngest group compared with 24 events in the 26-35 group, 35 events in the 36-49 group, and 62 events per 1,000 people per year in those 50 and older.

“Patients in the 50 and older age group had a numerically lower adjusted annualized relapse rate and less gadolinium-enhancing lesions and new or enlarging T2 lesions per scan and were generally more likely to be free of gadolinium-enhancing lesions or new or enlarging T2 lesions than the 25 and younger age group,” Dr. Morrow told attendees, “but we feel that that’s more in keeping with the natural history of disease. And, overall, ozanimod, regardless of the age group, showed decreasing disease activity in the inflammatory part of disease, showing with annualized relapse rate, gad-enhancing lesions, and T2 lesions.”

Older participants were substantially more likely to withdraw from the trial because of adverse events. While 8% of the youngest group and 7.6% of participants aged 26-35 withdrew because of adverse events, 24.5% of those aged 36-49 and 18.5% of those aged 50 and older withdrew because of adverse events.

Dr. Shah said it was reassuring that no new safety signals emerged, “but based on this data, you would be concerned that long-term risk of cardiovascular disease may result in more serious adverse events over a longer period of time and will need to be considered as we see people increasingly on this drug.”

The research was funded by Bristol-Myers Squibb. The authors reported a wide range of financial disclosures, including personal fees, research funding, advisory board, and speakers fees, for multiple pharmaceutical companies, including Bristol-Myers Squibb, and five authors are employees and/or shareholders of the company. Dr. Shah has served on advisory boards for Alexion, Genentech, and Horizon.

DENVER – Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” said senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Treatment delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG–positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female, and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups – those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that, after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons versus 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, a clinical data specialist at UT Southwestern Medical Center, told conference delegates. “Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Dr. Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups. “A central theory involves the increased amount of time between treatments,” he said.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Mr. Smith said in his talk, is that, “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions for medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Dr. Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Mr. Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches onto their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Mr. Smith added.

Important research

Commenting on the study, Shailee Shah, MD, an assistant professor in the Neuroimmunology division at Vanderbilt University Medical Center, in Nashville, Tenn., noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Dr. Shah added that in her experience patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Dr. Shah said.

The study was supported by Revert Health, a corporation founded by Dr. Okuda. Dr. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, and research support from Biogen, EMD Serono/Merck, and Novartis. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

A version of this article first appeared on Medscape.com.

DENVER – Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” said senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Treatment delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG–positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female, and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups – those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that, after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons versus 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, a clinical data specialist at UT Southwestern Medical Center, told conference delegates. “Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Dr. Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups. “A central theory involves the increased amount of time between treatments,” he said.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Mr. Smith said in his talk, is that, “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions for medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Dr. Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Mr. Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches onto their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Mr. Smith added.

Important research

Commenting on the study, Shailee Shah, MD, an assistant professor in the Neuroimmunology division at Vanderbilt University Medical Center, in Nashville, Tenn., noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Dr. Shah added that in her experience patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Dr. Shah said.

The study was supported by Revert Health, a corporation founded by Dr. Okuda. Dr. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, and research support from Biogen, EMD Serono/Merck, and Novartis. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

A version of this article first appeared on Medscape.com.

DENVER – Multiple treatment transitions in patients with neuromyelitis optica spectrum disorder (NMOSD) for nonmedical reasons are associated with increased neurological harm, including relapse risk and disease progression, new research shows.

“For the first time, we were able to quantify clinical outcomes associated with treatment transitions in people with NMOSD. Our data highlight that aspects outside of therapeutic efficacy may be remarkably meaningful in the effective suppression of disease advancement,” said senior investigator Darin T. Okuda, MD, professor of neurology and director of the neuroinnovation program at University of Texas Southwestern Medical Center in Dallas.

The findings were presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

Treatment delayed?

NMOSD, an inflammatory syndrome of the central nervous system, can cause irreversible disability. As treatments have improved over time, transitioning from one medication to newer options has become increasingly common.

To better understand the effects of multiple treatment transitions, the researchers conducted a retrospective analysis of electronic medical records of 164 patients with aquaporin-4 IgG–positive NMOSD. Of these individuals, 89 met the study’s inclusion criteria.

Of the participants, 89% were female, and the median disease duration was 10.1 years. Forty-two patients had switched therapies at least once; 26 switched at least twice; 12 switched at least three times; six switched four times; and three switched therapies five times or more for a total of 174 treatment transitions.

Patients were stratified into two groups – those who transitioned for medical reasons (53.4%), and those who switched because of nonmedical/tolerability reasons (46.6%).

Top reasons for transitioning in the medical category included clinical relapse and/or new MRI activity (29.9%), physician-directed transition (11.5%), and increased physical or clinical disability (4.0%). Leading reasons for nonmedical transitions were side effects (16.7%), adherence/persistence (8.1%), and cost/access (5.75%).

A recurrent event survival analysis showed that, after just one transition for nonmedical or tolerability reasons, outcomes significantly improved, with the risk of hospitalization decreasing 40.3% (P = .005), the risk of relapse decreasing by 53.1% (P = .002), and the risk of advancement on MRI decreasing by 65.9% (P = .005).

Conversely, each additional drug discontinuation in the nonmedical group was associated with worse outcomes. These included a 25.2% increased risk of hospitalization (P = .0003), a 24.4% increase in relapse risk (P = .06), and a 41.9% increased risk of MRI advancement (P = .03).

In terms of transitions for medical reasons, there was a significantly increased risk of MRI advancement with the first switch (32.2%; P = .005). However, no significant increases in risk were associated with each additional transition (P = .33).

The median time spent on the first treatment was 306 days in the transition for medical reasons group and 378 days for the nonmedical/tolerability group.

The median duration of time spent between treatments during the initial transition was just 7 days among those transitioning for medical reasons versus 91 days for nonmedical reasons, with the median duration of additional transitions also substantially longer in the nonmedical reasons group, at 22 and 80 days, respectively.

“The median time spent on a first-line therapy regardless of [whether] that first transition was due to a medical or nonmedical tolerability reason was similar; however, the duration of that initial transition was 13 times longer if the transition had to do with a nonmedical or tolerability reason,” first author Alexander D. Smith, a clinical data specialist at UT Southwestern Medical Center, told conference delegates. “Similarly, each additional transition was almost four times longer if it had to do with a nonmedical or tolerability reason,” he said.

Dr. Okuda noted the longer window between treatment transitions may be a key factor in the different outcomes between the groups. “A central theory involves the increased amount of time between treatments,” he said.

“The reasons for the delay in starting a new treatment may be related to a variety of factors, including laboratory testing required to start a new treatment, third-party administrator coverage, time for the resolution of adverse reactions, and/or personal factors from the individual undergoing treatment, etc.”

Another factor, Mr. Smith said in his talk, is that, “when people are left miserable by a prior treatment exposure, they may simply be hesitant to get on the next therapy.”

The finding that only MRI advancement was associated with transitions for medical reasons suggests that worsening disease activity is not necessarily behind increased transitions, with nonmedical reasons often the cause, and more likely to be associated with the worse outcomes.

With the time between treatments a possible culprit, Dr. Okuda said the clinical implications are that “treatment transitions, regardless of the reason, should occur as quickly as possible to reduce the risk for disease progression associated with NMOSD.”

Mr. Smith echoed the suggestion, adding that “it’s important that even if disease activity is not present, complacency should be avoided.”

“Clinicians and third-party administrators should work to ensure that people with NMOSD have accelerated switches onto their next therapy, even if that disease activity is not present. In a sense, rapid treatment transitions may have equitable benefits to the treatments themselves,” Mr. Smith added.

Important research

Commenting on the study, Shailee Shah, MD, an assistant professor in the Neuroimmunology division at Vanderbilt University Medical Center, in Nashville, Tenn., noted the findings are consistent with generally higher concerns around switching treatments for nonmedical reasons.

“In general, if a high-efficacy medication is started, it appears that patients are less likely to require a transition to a different medication. It is a little harder to predict who may have issues with tolerability or nonmedical reasons to transition medications, and many providers would likely agree that these transitions do raise some concerns about the risk of relapse or hospitalization in the interim,” she said.

Dr. Shah added that in her experience patients who require multiple transitions are either started on lower-efficacy medications at treatment initiation or have highly refractory disease.

The study’s findings underscore that “identifying additional risk factors and underlying reasons for these findings will be imperative in the future,” Dr. Shah said.

The study was supported by Revert Health, a corporation founded by Dr. Okuda. Dr. Okuda reports receiving personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, TG Therapeutics, Viela Bio, and research support from Biogen, EMD Serono/Merck, and Novartis. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

A version of this article first appeared on Medscape.com.

Aurora, Colo. – The access to and quality of multiple sclerosis (MS) care varies substantially depending on a patient’s race, ethnicity, gender, and geography, according to research on patient-reported health inequities presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

”Equal access to and quality of care are critical for managing a progressive disease such as multiple sclerosis,” said Chris Hardy, of Publicis Health Media, and her associates. “Despite increased awareness of health outcome disparities in the U.S., certain patients still experience inequities in care.”

The researchers sent emails to members of MyMSTeam, an online support network of more than 197,000 members, to request completion of a 34-question online survey. Questions addressed respondents’ ability to access care, resources in their neighborhood, and their interactions with their health care providers. Questions also addressed the burden of MS on individuals’ quality of life, which was considerable across all demographics. The 1,935 patients with MS who responded were overwhelmingly White, though the demographics varied by question.
 

A ‘widespread and significant problem’

“This study is important in pointing out the unfortunate, obvious [fact] that lack of access and lack of availability to treatment is still a widespread and significant problem in this country,” commented Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates who was not involved in the study. “Improving effective treatment of disease requires a more granular understanding of disease impact on a quantitative, multidimensional, objective patient-centric approach,” he added. “Racial and ethnic barriers to effective treatment cannot be allowed nor tolerated. We need to be more acutely aware that outreach, digital health, and remote assessments are tools that we need to incorporate to improve access and do better.”

The pervasive impact of MS

Overall, 85% of respondents reported that MS made it harder to do everyday chores, and 84% said their MS made it harder to exercise and interfered with their everyday life. Similarly high proportions of respondents reported that their MS causes them a lot of stress (80%), makes them feel anxious or depressed (77%), disrupts their work/employment (75%), and interferes with their social life (75%). In addition, more than half said their diagnosis negatively affects their family (59%) and makes them feel judged (53%).

Deanne Power, RN, MSCN, the lead nurse care partner at Octave Bioscience, who spoke as a representative of the study authors, said it’s critical that clinicians be aware of the health inequities that exist among their patient population.

“Some patients have lower income or language issues where English is not their primary language, and they don’t have access and are even afraid to call doctor or reach out [for help],” Ms. Power said. “If providers aren’t actively aware of these situations and talk to their patients, they can’t just say, ‘Oh, well, I just want you to go fill this prescription,’ when they don’t have money to put food on their table. Providers have got to know their patients as [more than] just an MS patient. This is a human being in front of you, and you better know what their life is like, because it’s impacting their MS.”
 

Access to care varied by race

Among the 1,906 respondents who answered questions about access to care, 9% were Black, 5% were Hispanic, and the rest were White. In these questions, differences between demographics arose when it came to individuals’ ability to conveniently see an MS specialist and their subsequent use of emergency services. For example, only 64% of Hispanic respondents reported convenient access to a health care provider specializing in MS, compared with 76% of White and 78% of Black respondents.

A significantly higher proportion of Hispanics also reported that they could not take time off from work when they were sick (25%) or to attend a doctor appointment (20%), compared with White (15% and 9%, respectively) and Black (18% and 12%) respondents. Meanwhile, a significantly higher proportion of Hispanics (35%) reported visiting the emergency department in the past year for MS-related issues, compared with White (19%) or Black (25%) respondents.

White respondents consistently had greater convenient access to dental offices, healthy foods, outpatient care, gyms, and parks and trails, compared with Black and Hispanic patients’ access. For example, 85% of White patients had convenient access to dental offices and 72% had access to outpatient care, compared with Black (74% and 65%) and Hispanic (78% and 52%) patients. Two-thirds of Hispanic respondents (67%) reported access to healthy foods and to gyms, parks, or trails, compared with more than three-quarters of both White and Black patients.
 

Other barriers to MS care

Both racial/ethnic and gender disparities emerged in how patients felt treated by their health care providers. Men were significantly more likely (70%) than women (65%) to say their health care provider listens to and understands them. A statistically significant higher proportion of men (71%) also said their clinician explained their MS test results to them, compared with women (62%), and only 28% of women, versus 37% of men, said their provider developed a long-term plan for them.

Anne Foelsch, the vice president of strategic partnerships at MyHealthTeam, who works with the authors, noted the large discrepancy that was seen particularly for Hispanic patients in terms of how they felt treated by their health care provider.

“Doctors might perceive that the relationship is the same with all of their patients when their patients have a very different perception of what that relationship is and whether they’re not being heard,” Ms. Foelsch said. “It’s important that clinicians take a little bit of time and learn a little bit more about a patient’s perspective and what it’s like when they have a chronic condition like MS and how it impacts their life, looking for those nuances that are different based on your ethnicity.”

Just over half of Hispanic patients (54%) said their provider explained their MS test results, compared with nearly two-thirds of White patients (65%) and 61% of Black patients. Hispanic patients were also less likely (55%) to say they felt their provider listens to and understands them than White (67%) or Black (65%) patients. Two-thirds of White respondents (67%) said their doctor recommended regular check-ups, compared with just over half of Black and Hispanic respondents (55%).

Other statistically significant disparities by race/ethnicity, where a higher proportion of White patients responded affirmatively than Black or Hispanic patients, included feeling treated with respect by their health care provider, feeling their provider is nonjudgmental, and saying their provider spends enough time with them, addresses their MS symptoms, and encourages shared decision-making.

“This study nicely documents and points out that despite our best intentions, we need to do much better as a community to help those with chronic and potentially disabling diseases like MS,” Dr. Gudesblatt said. “The racial, ethnic, and gender disparities only result in greater disability and societal costs by those who can least afford it. All therapies fail due to nonadherence, limited access, lack of insurance coverage, limited insurance coverage, high copays, long waits, cultural biases, and more.”

The researchers acknowledged that their survey respondents may not be representative of all patients with MS because the survey relied on those who chose to respond to the online survey.

The study authors were all employees of Publicis Health Media or MyHealthTeam. Dr. Gudesblatt reported no disclosures.
 

Aurora, Colo. – The access to and quality of multiple sclerosis (MS) care varies substantially depending on a patient’s race, ethnicity, gender, and geography, according to research on patient-reported health inequities presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

”Equal access to and quality of care are critical for managing a progressive disease such as multiple sclerosis,” said Chris Hardy, of Publicis Health Media, and her associates. “Despite increased awareness of health outcome disparities in the U.S., certain patients still experience inequities in care.”

The researchers sent emails to members of MyMSTeam, an online support network of more than 197,000 members, to request completion of a 34-question online survey. Questions addressed respondents’ ability to access care, resources in their neighborhood, and their interactions with their health care providers. Questions also addressed the burden of MS on individuals’ quality of life, which was considerable across all demographics. The 1,935 patients with MS who responded were overwhelmingly White, though the demographics varied by question.
 

A ‘widespread and significant problem’

“This study is important in pointing out the unfortunate, obvious [fact] that lack of access and lack of availability to treatment is still a widespread and significant problem in this country,” commented Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates who was not involved in the study. “Improving effective treatment of disease requires a more granular understanding of disease impact on a quantitative, multidimensional, objective patient-centric approach,” he added. “Racial and ethnic barriers to effective treatment cannot be allowed nor tolerated. We need to be more acutely aware that outreach, digital health, and remote assessments are tools that we need to incorporate to improve access and do better.”

The pervasive impact of MS

Overall, 85% of respondents reported that MS made it harder to do everyday chores, and 84% said their MS made it harder to exercise and interfered with their everyday life. Similarly high proportions of respondents reported that their MS causes them a lot of stress (80%), makes them feel anxious or depressed (77%), disrupts their work/employment (75%), and interferes with their social life (75%). In addition, more than half said their diagnosis negatively affects their family (59%) and makes them feel judged (53%).

Deanne Power, RN, MSCN, the lead nurse care partner at Octave Bioscience, who spoke as a representative of the study authors, said it’s critical that clinicians be aware of the health inequities that exist among their patient population.

“Some patients have lower income or language issues where English is not their primary language, and they don’t have access and are even afraid to call doctor or reach out [for help],” Ms. Power said. “If providers aren’t actively aware of these situations and talk to their patients, they can’t just say, ‘Oh, well, I just want you to go fill this prescription,’ when they don’t have money to put food on their table. Providers have got to know their patients as [more than] just an MS patient. This is a human being in front of you, and you better know what their life is like, because it’s impacting their MS.”
 

Access to care varied by race

Among the 1,906 respondents who answered questions about access to care, 9% were Black, 5% were Hispanic, and the rest were White. In these questions, differences between demographics arose when it came to individuals’ ability to conveniently see an MS specialist and their subsequent use of emergency services. For example, only 64% of Hispanic respondents reported convenient access to a health care provider specializing in MS, compared with 76% of White and 78% of Black respondents.

A significantly higher proportion of Hispanics also reported that they could not take time off from work when they were sick (25%) or to attend a doctor appointment (20%), compared with White (15% and 9%, respectively) and Black (18% and 12%) respondents. Meanwhile, a significantly higher proportion of Hispanics (35%) reported visiting the emergency department in the past year for MS-related issues, compared with White (19%) or Black (25%) respondents.

White respondents consistently had greater convenient access to dental offices, healthy foods, outpatient care, gyms, and parks and trails, compared with Black and Hispanic patients’ access. For example, 85% of White patients had convenient access to dental offices and 72% had access to outpatient care, compared with Black (74% and 65%) and Hispanic (78% and 52%) patients. Two-thirds of Hispanic respondents (67%) reported access to healthy foods and to gyms, parks, or trails, compared with more than three-quarters of both White and Black patients.
 

Other barriers to MS care

Both racial/ethnic and gender disparities emerged in how patients felt treated by their health care providers. Men were significantly more likely (70%) than women (65%) to say their health care provider listens to and understands them. A statistically significant higher proportion of men (71%) also said their clinician explained their MS test results to them, compared with women (62%), and only 28% of women, versus 37% of men, said their provider developed a long-term plan for them.

Anne Foelsch, the vice president of strategic partnerships at MyHealthTeam, who works with the authors, noted the large discrepancy that was seen particularly for Hispanic patients in terms of how they felt treated by their health care provider.

“Doctors might perceive that the relationship is the same with all of their patients when their patients have a very different perception of what that relationship is and whether they’re not being heard,” Ms. Foelsch said. “It’s important that clinicians take a little bit of time and learn a little bit more about a patient’s perspective and what it’s like when they have a chronic condition like MS and how it impacts their life, looking for those nuances that are different based on your ethnicity.”

Just over half of Hispanic patients (54%) said their provider explained their MS test results, compared with nearly two-thirds of White patients (65%) and 61% of Black patients. Hispanic patients were also less likely (55%) to say they felt their provider listens to and understands them than White (67%) or Black (65%) patients. Two-thirds of White respondents (67%) said their doctor recommended regular check-ups, compared with just over half of Black and Hispanic respondents (55%).

Other statistically significant disparities by race/ethnicity, where a higher proportion of White patients responded affirmatively than Black or Hispanic patients, included feeling treated with respect by their health care provider, feeling their provider is nonjudgmental, and saying their provider spends enough time with them, addresses their MS symptoms, and encourages shared decision-making.

“This study nicely documents and points out that despite our best intentions, we need to do much better as a community to help those with chronic and potentially disabling diseases like MS,” Dr. Gudesblatt said. “The racial, ethnic, and gender disparities only result in greater disability and societal costs by those who can least afford it. All therapies fail due to nonadherence, limited access, lack of insurance coverage, limited insurance coverage, high copays, long waits, cultural biases, and more.”

The researchers acknowledged that their survey respondents may not be representative of all patients with MS because the survey relied on those who chose to respond to the online survey.

The study authors were all employees of Publicis Health Media or MyHealthTeam. Dr. Gudesblatt reported no disclosures.
 

Aurora, Colo. – The access to and quality of multiple sclerosis (MS) care varies substantially depending on a patient’s race, ethnicity, gender, and geography, according to research on patient-reported health inequities presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.

”Equal access to and quality of care are critical for managing a progressive disease such as multiple sclerosis,” said Chris Hardy, of Publicis Health Media, and her associates. “Despite increased awareness of health outcome disparities in the U.S., certain patients still experience inequities in care.”

The researchers sent emails to members of MyMSTeam, an online support network of more than 197,000 members, to request completion of a 34-question online survey. Questions addressed respondents’ ability to access care, resources in their neighborhood, and their interactions with their health care providers. Questions also addressed the burden of MS on individuals’ quality of life, which was considerable across all demographics. The 1,935 patients with MS who responded were overwhelmingly White, though the demographics varied by question.
 

A ‘widespread and significant problem’

“This study is important in pointing out the unfortunate, obvious [fact] that lack of access and lack of availability to treatment is still a widespread and significant problem in this country,” commented Mark Gudesblatt, MD, a neurologist at South Shore Neurologic Associates who was not involved in the study. “Improving effective treatment of disease requires a more granular understanding of disease impact on a quantitative, multidimensional, objective patient-centric approach,” he added. “Racial and ethnic barriers to effective treatment cannot be allowed nor tolerated. We need to be more acutely aware that outreach, digital health, and remote assessments are tools that we need to incorporate to improve access and do better.”

The pervasive impact of MS

Overall, 85% of respondents reported that MS made it harder to do everyday chores, and 84% said their MS made it harder to exercise and interfered with their everyday life. Similarly high proportions of respondents reported that their MS causes them a lot of stress (80%), makes them feel anxious or depressed (77%), disrupts their work/employment (75%), and interferes with their social life (75%). In addition, more than half said their diagnosis negatively affects their family (59%) and makes them feel judged (53%).

Deanne Power, RN, MSCN, the lead nurse care partner at Octave Bioscience, who spoke as a representative of the study authors, said it’s critical that clinicians be aware of the health inequities that exist among their patient population.

“Some patients have lower income or language issues where English is not their primary language, and they don’t have access and are even afraid to call doctor or reach out [for help],” Ms. Power said. “If providers aren’t actively aware of these situations and talk to their patients, they can’t just say, ‘Oh, well, I just want you to go fill this prescription,’ when they don’t have money to put food on their table. Providers have got to know their patients as [more than] just an MS patient. This is a human being in front of you, and you better know what their life is like, because it’s impacting their MS.”
 

Access to care varied by race

Among the 1,906 respondents who answered questions about access to care, 9% were Black, 5% were Hispanic, and the rest were White. In these questions, differences between demographics arose when it came to individuals’ ability to conveniently see an MS specialist and their subsequent use of emergency services. For example, only 64% of Hispanic respondents reported convenient access to a health care provider specializing in MS, compared with 76% of White and 78% of Black respondents.

A significantly higher proportion of Hispanics also reported that they could not take time off from work when they were sick (25%) or to attend a doctor appointment (20%), compared with White (15% and 9%, respectively) and Black (18% and 12%) respondents. Meanwhile, a significantly higher proportion of Hispanics (35%) reported visiting the emergency department in the past year for MS-related issues, compared with White (19%) or Black (25%) respondents.

White respondents consistently had greater convenient access to dental offices, healthy foods, outpatient care, gyms, and parks and trails, compared with Black and Hispanic patients’ access. For example, 85% of White patients had convenient access to dental offices and 72% had access to outpatient care, compared with Black (74% and 65%) and Hispanic (78% and 52%) patients. Two-thirds of Hispanic respondents (67%) reported access to healthy foods and to gyms, parks, or trails, compared with more than three-quarters of both White and Black patients.
 

Other barriers to MS care

Both racial/ethnic and gender disparities emerged in how patients felt treated by their health care providers. Men were significantly more likely (70%) than women (65%) to say their health care provider listens to and understands them. A statistically significant higher proportion of men (71%) also said their clinician explained their MS test results to them, compared with women (62%), and only 28% of women, versus 37% of men, said their provider developed a long-term plan for them.

Anne Foelsch, the vice president of strategic partnerships at MyHealthTeam, who works with the authors, noted the large discrepancy that was seen particularly for Hispanic patients in terms of how they felt treated by their health care provider.

“Doctors might perceive that the relationship is the same with all of their patients when their patients have a very different perception of what that relationship is and whether they’re not being heard,” Ms. Foelsch said. “It’s important that clinicians take a little bit of time and learn a little bit more about a patient’s perspective and what it’s like when they have a chronic condition like MS and how it impacts their life, looking for those nuances that are different based on your ethnicity.”

Just over half of Hispanic patients (54%) said their provider explained their MS test results, compared with nearly two-thirds of White patients (65%) and 61% of Black patients. Hispanic patients were also less likely (55%) to say they felt their provider listens to and understands them than White (67%) or Black (65%) patients. Two-thirds of White respondents (67%) said their doctor recommended regular check-ups, compared with just over half of Black and Hispanic respondents (55%).

Other statistically significant disparities by race/ethnicity, where a higher proportion of White patients responded affirmatively than Black or Hispanic patients, included feeling treated with respect by their health care provider, feeling their provider is nonjudgmental, and saying their provider spends enough time with them, addresses their MS symptoms, and encourages shared decision-making.

“This study nicely documents and points out that despite our best intentions, we need to do much better as a community to help those with chronic and potentially disabling diseases like MS,” Dr. Gudesblatt said. “The racial, ethnic, and gender disparities only result in greater disability and societal costs by those who can least afford it. All therapies fail due to nonadherence, limited access, lack of insurance coverage, limited insurance coverage, high copays, long waits, cultural biases, and more.”

The researchers acknowledged that their survey respondents may not be representative of all patients with MS because the survey relied on those who chose to respond to the online survey.

The study authors were all employees of Publicis Health Media or MyHealthTeam. Dr. Gudesblatt reported no disclosures.
 

DENVER – The use of the monoclonal antibody satralizumab (Enspryng) for the long-term treatment of anti–aquaporin-4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) provides sustained freedom from relapse with no new safety concerns over 5 years, new research shows.  

“In long-term observations, we are seeing a nice, sustained suppression of relapses early, as well as late, in treatment,” said study investigator Anthony Traboulsee, MD, University of British Columbia, Vancouver, in presenting the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“It remains very tolerable with no participants discontinuing because of side effects,” he said. “And importantly, [there are] no signs of a delayed risk of infections for both monotherapy and combination therapy.”

Satralizumab, a monoclonal recycling antibody, targets the interleukin (IL)–6 receptor, which is elevated in the serum and cerebrospinal fluid of patients in NMOSD.

The drug was approved by the Food and Drug Administration in 2020 for the treatment of AQP4 antibody–positive NMOSD after favorable results from two key trials: SAkuraSky and SAkuraStar.

The FDA approval marked satralizumab as the third therapy for NMOSD, following eculizumab (Soliris) and inebilizumab (Uplizna).

Satralizumab is administered in subcutaneous injections every 4 weeks after a run-in period of injections at weeks 0, 2, and 4.

Longest trial to date

To evaluate the drug’s long-term efficacy in the treatment of AQP4 IgG–positive NMOSD, patients from the two previous phase 3 trials were entered into the single arm, open-label SAkuraMoon study and continued treatment with the satralizumab 120 mg injections once monthly, with or without immunosuppressive therapy.

The study included 106 patients (mean age 44 years, 89.6% women), all of whom had received one or more doses of satralizumab by the data cutoff of January 2022.

With a median duration of satralizumab exposure of 5 years, the overall adjusted annualized rate of investigator protocol-defined relapse (ARR) was 0.09.

Longitudinal assessment further showed no significant increase in the relapse rate over the course of the study, with an ARR rate of 0.16 at year 1; 0.10 at year 2; 0.05 at year 3; and 0.07 at year 4.

At week 240 (4.6 years), 72% of satralizumab-treated patients were relapse-free, with 91% free from severe relapse.

In addition, 85% of patients had no sustained disability, as measured by Expanded Disability Status Scale (EDSS) worsening, over the study period.  

Asked if there are potential subgroups of patients who may be more susceptible to the worsening of disability, Dr. Traboulsee responded “not that we can tell as of yet.”

“I would like to explore this further as this is a relatively new observation, and, as far as I know, this is the longest follow-up for an NMO treatment trial cohort,” he said.

Favorable safety profile

The safety profile was also favorable, consistent with results in the earlier trials. The longer exposure to satralizumab was not associated with a higher risk of severe (grade 3 or higher) laboratory changes versus the double-blind studies. “Rates of adverse events and serious adverse events with overall satralizumab treatment were comparable with the double-blind periods,” said Dr. Traboulsee.

“With satralizumab combined with immunosuppressant therapy, we’re not seeing an increased rate of infections, because it’s not an immune suppressant – it doesn’t suppress lymphocytes or lower immunoglobulin,” he added.

While the use of combination therapy has been an important clinical concern, Dr. Traboulsee noted that “this does not appear to be the case with satralizumab when combined with daily prednisone or daily azathioprine.”

“There is no increased risk of infections, compared with placebo, and it interestingly appears lower than patients on prednisone or azathioprine alone,” he said.

While the median follow-up was 5 years, some in the clinical trial population have been on treatment for up to 7.9 years.

“Based on the current safety and efficacy data, they could stay on this therapy indefinitely, in my opinion,” Dr. Traboulsee said.

In addition to its long-term safety and efficacy, satralizumab “is easy for patients to take and does not require access to an infusion center. It’s easy for physicians to monitor safety, especially since no additional vaccinations or precautions are required beyond what is done in routine care.”

“What I conclude from that clinically is that this is a highly effective and safe therapy by itself or in combination with another agent,” Dr. Traboulsee said.

He noted that the lack of a bump in infections is “really encouraging and very important with a chronic disease that affects elderly patients. So far, so good,” he added.

‘A good first-line therapy’

Commenting on the study, Shailee Shah, MD, an assistant professor in the neuroimmunology division at Vanderbilt University Medical Center, Nashville, Tenn., agreed that the findings bode well for satralizumab’s long-term benefits.

“These are promising results and suggest that satralizumab is very effective in the long term, and even when patients relapse, those relapses are less severe than they would likely be if the patient were off therapy,” she said.

She noted that, while the ability to self-administer injections with satralizumab is convenient, preferences vary.

“This is patient dependent,” Dr. Shah said. “For some patients an injectable medication is ideal but for others an infusion medication [such as eculizumab] is preferred.”

Overall, however, Dr. Shah described satralizumab as “a good first-line therapy for patients with NMOSD in addition to eculizumab/ravulizumab and inebilizumab.”

“It is reasonable to consider this medication in isolation or with concomitant immunosuppressive therapy,” she said.

Dr. Traboulsee’s disclosures include relationships with Novartis, Roche, Sanofi (Genzyme), Ingo Kleiter, Alexion, Almirall, Bayer, Biogen, Celgene, Genentech, Hexal, Horizon, Merck, and Sanofi. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

DENVER – The use of the monoclonal antibody satralizumab (Enspryng) for the long-term treatment of anti–aquaporin-4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) provides sustained freedom from relapse with no new safety concerns over 5 years, new research shows.  

“In long-term observations, we are seeing a nice, sustained suppression of relapses early, as well as late, in treatment,” said study investigator Anthony Traboulsee, MD, University of British Columbia, Vancouver, in presenting the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“It remains very tolerable with no participants discontinuing because of side effects,” he said. “And importantly, [there are] no signs of a delayed risk of infections for both monotherapy and combination therapy.”

Satralizumab, a monoclonal recycling antibody, targets the interleukin (IL)–6 receptor, which is elevated in the serum and cerebrospinal fluid of patients in NMOSD.

The drug was approved by the Food and Drug Administration in 2020 for the treatment of AQP4 antibody–positive NMOSD after favorable results from two key trials: SAkuraSky and SAkuraStar.

The FDA approval marked satralizumab as the third therapy for NMOSD, following eculizumab (Soliris) and inebilizumab (Uplizna).

Satralizumab is administered in subcutaneous injections every 4 weeks after a run-in period of injections at weeks 0, 2, and 4.

Longest trial to date

To evaluate the drug’s long-term efficacy in the treatment of AQP4 IgG–positive NMOSD, patients from the two previous phase 3 trials were entered into the single arm, open-label SAkuraMoon study and continued treatment with the satralizumab 120 mg injections once monthly, with or without immunosuppressive therapy.

The study included 106 patients (mean age 44 years, 89.6% women), all of whom had received one or more doses of satralizumab by the data cutoff of January 2022.

With a median duration of satralizumab exposure of 5 years, the overall adjusted annualized rate of investigator protocol-defined relapse (ARR) was 0.09.

Longitudinal assessment further showed no significant increase in the relapse rate over the course of the study, with an ARR rate of 0.16 at year 1; 0.10 at year 2; 0.05 at year 3; and 0.07 at year 4.

At week 240 (4.6 years), 72% of satralizumab-treated patients were relapse-free, with 91% free from severe relapse.

In addition, 85% of patients had no sustained disability, as measured by Expanded Disability Status Scale (EDSS) worsening, over the study period.  

Asked if there are potential subgroups of patients who may be more susceptible to the worsening of disability, Dr. Traboulsee responded “not that we can tell as of yet.”

“I would like to explore this further as this is a relatively new observation, and, as far as I know, this is the longest follow-up for an NMO treatment trial cohort,” he said.

Favorable safety profile

The safety profile was also favorable, consistent with results in the earlier trials. The longer exposure to satralizumab was not associated with a higher risk of severe (grade 3 or higher) laboratory changes versus the double-blind studies. “Rates of adverse events and serious adverse events with overall satralizumab treatment were comparable with the double-blind periods,” said Dr. Traboulsee.

“With satralizumab combined with immunosuppressant therapy, we’re not seeing an increased rate of infections, because it’s not an immune suppressant – it doesn’t suppress lymphocytes or lower immunoglobulin,” he added.

While the use of combination therapy has been an important clinical concern, Dr. Traboulsee noted that “this does not appear to be the case with satralizumab when combined with daily prednisone or daily azathioprine.”

“There is no increased risk of infections, compared with placebo, and it interestingly appears lower than patients on prednisone or azathioprine alone,” he said.

While the median follow-up was 5 years, some in the clinical trial population have been on treatment for up to 7.9 years.

“Based on the current safety and efficacy data, they could stay on this therapy indefinitely, in my opinion,” Dr. Traboulsee said.

In addition to its long-term safety and efficacy, satralizumab “is easy for patients to take and does not require access to an infusion center. It’s easy for physicians to monitor safety, especially since no additional vaccinations or precautions are required beyond what is done in routine care.”

“What I conclude from that clinically is that this is a highly effective and safe therapy by itself or in combination with another agent,” Dr. Traboulsee said.

He noted that the lack of a bump in infections is “really encouraging and very important with a chronic disease that affects elderly patients. So far, so good,” he added.

‘A good first-line therapy’

Commenting on the study, Shailee Shah, MD, an assistant professor in the neuroimmunology division at Vanderbilt University Medical Center, Nashville, Tenn., agreed that the findings bode well for satralizumab’s long-term benefits.

“These are promising results and suggest that satralizumab is very effective in the long term, and even when patients relapse, those relapses are less severe than they would likely be if the patient were off therapy,” she said.

She noted that, while the ability to self-administer injections with satralizumab is convenient, preferences vary.

“This is patient dependent,” Dr. Shah said. “For some patients an injectable medication is ideal but for others an infusion medication [such as eculizumab] is preferred.”

Overall, however, Dr. Shah described satralizumab as “a good first-line therapy for patients with NMOSD in addition to eculizumab/ravulizumab and inebilizumab.”

“It is reasonable to consider this medication in isolation or with concomitant immunosuppressive therapy,” she said.

Dr. Traboulsee’s disclosures include relationships with Novartis, Roche, Sanofi (Genzyme), Ingo Kleiter, Alexion, Almirall, Bayer, Biogen, Celgene, Genentech, Hexal, Horizon, Merck, and Sanofi. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.

DENVER – The use of the monoclonal antibody satralizumab (Enspryng) for the long-term treatment of anti–aquaporin-4 (AQP4) antibody–positive neuromyelitis optica spectrum disorder (NMOSD) provides sustained freedom from relapse with no new safety concerns over 5 years, new research shows.  

“In long-term observations, we are seeing a nice, sustained suppression of relapses early, as well as late, in treatment,” said study investigator Anthony Traboulsee, MD, University of British Columbia, Vancouver, in presenting the findings at the annual meeting of the Consortium of Multiple Sclerosis Centers.

“It remains very tolerable with no participants discontinuing because of side effects,” he said. “And importantly, [there are] no signs of a delayed risk of infections for both monotherapy and combination therapy.”

Satralizumab, a monoclonal recycling antibody, targets the interleukin (IL)–6 receptor, which is elevated in the serum and cerebrospinal fluid of patients in NMOSD.

The drug was approved by the Food and Drug Administration in 2020 for the treatment of AQP4 antibody–positive NMOSD after favorable results from two key trials: SAkuraSky and SAkuraStar.

The FDA approval marked satralizumab as the third therapy for NMOSD, following eculizumab (Soliris) and inebilizumab (Uplizna).

Satralizumab is administered in subcutaneous injections every 4 weeks after a run-in period of injections at weeks 0, 2, and 4.

Longest trial to date

To evaluate the drug’s long-term efficacy in the treatment of AQP4 IgG–positive NMOSD, patients from the two previous phase 3 trials were entered into the single arm, open-label SAkuraMoon study and continued treatment with the satralizumab 120 mg injections once monthly, with or without immunosuppressive therapy.

The study included 106 patients (mean age 44 years, 89.6% women), all of whom had received one or more doses of satralizumab by the data cutoff of January 2022.

With a median duration of satralizumab exposure of 5 years, the overall adjusted annualized rate of investigator protocol-defined relapse (ARR) was 0.09.

Longitudinal assessment further showed no significant increase in the relapse rate over the course of the study, with an ARR rate of 0.16 at year 1; 0.10 at year 2; 0.05 at year 3; and 0.07 at year 4.

At week 240 (4.6 years), 72% of satralizumab-treated patients were relapse-free, with 91% free from severe relapse.

In addition, 85% of patients had no sustained disability, as measured by Expanded Disability Status Scale (EDSS) worsening, over the study period.  

Asked if there are potential subgroups of patients who may be more susceptible to the worsening of disability, Dr. Traboulsee responded “not that we can tell as of yet.”

“I would like to explore this further as this is a relatively new observation, and, as far as I know, this is the longest follow-up for an NMO treatment trial cohort,” he said.

Favorable safety profile

The safety profile was also favorable, consistent with results in the earlier trials. The longer exposure to satralizumab was not associated with a higher risk of severe (grade 3 or higher) laboratory changes versus the double-blind studies. “Rates of adverse events and serious adverse events with overall satralizumab treatment were comparable with the double-blind periods,” said Dr. Traboulsee.

“With satralizumab combined with immunosuppressant therapy, we’re not seeing an increased rate of infections, because it’s not an immune suppressant – it doesn’t suppress lymphocytes or lower immunoglobulin,” he added.

While the use of combination therapy has been an important clinical concern, Dr. Traboulsee noted that “this does not appear to be the case with satralizumab when combined with daily prednisone or daily azathioprine.”

“There is no increased risk of infections, compared with placebo, and it interestingly appears lower than patients on prednisone or azathioprine alone,” he said.

While the median follow-up was 5 years, some in the clinical trial population have been on treatment for up to 7.9 years.

“Based on the current safety and efficacy data, they could stay on this therapy indefinitely, in my opinion,” Dr. Traboulsee said.

In addition to its long-term safety and efficacy, satralizumab “is easy for patients to take and does not require access to an infusion center. It’s easy for physicians to monitor safety, especially since no additional vaccinations or precautions are required beyond what is done in routine care.”

“What I conclude from that clinically is that this is a highly effective and safe therapy by itself or in combination with another agent,” Dr. Traboulsee said.

He noted that the lack of a bump in infections is “really encouraging and very important with a chronic disease that affects elderly patients. So far, so good,” he added.

‘A good first-line therapy’

Commenting on the study, Shailee Shah, MD, an assistant professor in the neuroimmunology division at Vanderbilt University Medical Center, Nashville, Tenn., agreed that the findings bode well for satralizumab’s long-term benefits.

“These are promising results and suggest that satralizumab is very effective in the long term, and even when patients relapse, those relapses are less severe than they would likely be if the patient were off therapy,” she said.

She noted that, while the ability to self-administer injections with satralizumab is convenient, preferences vary.

“This is patient dependent,” Dr. Shah said. “For some patients an injectable medication is ideal but for others an infusion medication [such as eculizumab] is preferred.”

Overall, however, Dr. Shah described satralizumab as “a good first-line therapy for patients with NMOSD in addition to eculizumab/ravulizumab and inebilizumab.”

“It is reasonable to consider this medication in isolation or with concomitant immunosuppressive therapy,” she said.

Dr. Traboulsee’s disclosures include relationships with Novartis, Roche, Sanofi (Genzyme), Ingo Kleiter, Alexion, Almirall, Bayer, Biogen, Celgene, Genentech, Hexal, Horizon, Merck, and Sanofi. Dr. Shah reports that she has served on advisory boards for Horizon, Alexion, and Genentech.