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Complement Inhibitor Scores Impressive Data in CIDP
DENVER — , with good results in treatment-refractory and treatment-naive patients, according to results from a phase 2 clinical trial.
‘Impressive’ Results
The results were impressive, especially given that riliprubart outperformed IVIG, according to Frank Tennigkeit, PhD, senior director of pediatric development rare diseases at UCB Biosciences, who attended the session at the 2024 annual meeting of the American Academy of Neurology, where the study was presented. “There are few trials on CIDP, and the standard data are IVIG data.
“This is really amazing, especially in refractory patients. I turned to my neighbor [during the presentation] and said, ‘I’ve never seen CIDP data that good in my life. It works in all kinds of different patient populations, and also on the refractory ones. That’s what you want. That’s where the need is. And you saw a consistent effect and a strong effect on top of standard of care,” said Dr. Tennigkeit.
“It’s impressive. The only problem with CIDP is that it’s very difficult to compare treatments, because everyone has a different outcome. This was an open-label study, so there’s always a confounding bias. The proof of the pudding is going to be in a phase 3 blinded, randomized trial, but what I really admire about them, and I thought was very gutsy, is that they’re going head-to-head versus IVIG. I haven’t seen anyone who’s done that yet [in CIDP],” said Shalom Patole, MD, an internist and telehealth consultant in India, who also attended the session.
An Open-Label Phase 2 Study
The study had a somewhat unique design, according to Richard Lewis, MD, who presented the results. It was an open-label design that examined three subpopulations: 25 who had objective response to treatments (standard of care [SOC]–treated, mean age, 58.2 years; 80% male), 18 refractory patients who had been off treatment for up to 12 weeks (SOC-refractory, mean age, 63.9 years; 61% male), and 12 patients who had not been treated at all for at least 6 months or were treatment-naive (SOC-naive, mean age, 59.1 years; 67% male).
At 24 weeks, “if you looked at the treated group, 88% of those patients improved to remain stable, and only 12% relapsed. Most significantly, these patients who had responded to their IVIG, who were supposedly doing pretty well, 44% of those actually got better, so they improved from what would have been a pretty good baseline. The refractory patients, despite flunking the other treatments, 50% actually passed or improved with the treatment, so a significant response rate in a group that was not responding so well,” said Dr. Lewis, who is a neurologist at Cedars Sinai Medical Center.
The researchers also found that treatment with riliprubart led to inhibition of complement activity and a trend in reduction in neurofilament light chain levels by week 24 in all three groups.
Treatment-emergent adverse events occurred in 60% of the SOC-treated group, 72% of the SOC-refractory group, and 75% of the SOC-naive group, though grade 3 or higher events were rare (4%, 17%, and 8%, respectively). There was one death in the SOC-treated group and one in the SOC-refractory group. Both patients were elderly and had comorbid conditions.
Challenging the Current Standard of Care
The data have led to two additional phase 3 trials, one in refractory patients (Mobilize), and another for patients treated with IVIG who have residual disability (Vitalize). Sanofi is also planning a phase 3, placebo-controlled trial with one arm that will compare the antibody to IVIG, “which is a pretty ambitious trial design,” admitted Dr. Lewis.
Such a strategy is risky, but it could represent a big payoff for Sanofi if the phase 3 studies replicate the phase 2 studies. “No one would be using IVIG anymore if you beat IVIG by 50%. That will be the standard. If you do the trial [versus IVIG], you have a higher risk, but if you win it, you will win big,” said Dr. Tennigkeit.
The study was funded by Sanofi. Dr. Lewis has financial relationships with CSL Behring, Grifols, Pfizer, Sanofi, Argenx, Pharnext, Roche, Johnson & Johnson, Takeda, Boehringer Ingelheim, Nuvig, Dianthus, Janssen, Medscape, Alexion, Alnylam, and Novartis. Dr. Tennigkeit is an employee of UCB Biosciences. Dr. Patole has no relevant financial disclosures.
DENVER — , with good results in treatment-refractory and treatment-naive patients, according to results from a phase 2 clinical trial.
‘Impressive’ Results
The results were impressive, especially given that riliprubart outperformed IVIG, according to Frank Tennigkeit, PhD, senior director of pediatric development rare diseases at UCB Biosciences, who attended the session at the 2024 annual meeting of the American Academy of Neurology, where the study was presented. “There are few trials on CIDP, and the standard data are IVIG data.
“This is really amazing, especially in refractory patients. I turned to my neighbor [during the presentation] and said, ‘I’ve never seen CIDP data that good in my life. It works in all kinds of different patient populations, and also on the refractory ones. That’s what you want. That’s where the need is. And you saw a consistent effect and a strong effect on top of standard of care,” said Dr. Tennigkeit.
“It’s impressive. The only problem with CIDP is that it’s very difficult to compare treatments, because everyone has a different outcome. This was an open-label study, so there’s always a confounding bias. The proof of the pudding is going to be in a phase 3 blinded, randomized trial, but what I really admire about them, and I thought was very gutsy, is that they’re going head-to-head versus IVIG. I haven’t seen anyone who’s done that yet [in CIDP],” said Shalom Patole, MD, an internist and telehealth consultant in India, who also attended the session.
An Open-Label Phase 2 Study
The study had a somewhat unique design, according to Richard Lewis, MD, who presented the results. It was an open-label design that examined three subpopulations: 25 who had objective response to treatments (standard of care [SOC]–treated, mean age, 58.2 years; 80% male), 18 refractory patients who had been off treatment for up to 12 weeks (SOC-refractory, mean age, 63.9 years; 61% male), and 12 patients who had not been treated at all for at least 6 months or were treatment-naive (SOC-naive, mean age, 59.1 years; 67% male).
At 24 weeks, “if you looked at the treated group, 88% of those patients improved to remain stable, and only 12% relapsed. Most significantly, these patients who had responded to their IVIG, who were supposedly doing pretty well, 44% of those actually got better, so they improved from what would have been a pretty good baseline. The refractory patients, despite flunking the other treatments, 50% actually passed or improved with the treatment, so a significant response rate in a group that was not responding so well,” said Dr. Lewis, who is a neurologist at Cedars Sinai Medical Center.
The researchers also found that treatment with riliprubart led to inhibition of complement activity and a trend in reduction in neurofilament light chain levels by week 24 in all three groups.
Treatment-emergent adverse events occurred in 60% of the SOC-treated group, 72% of the SOC-refractory group, and 75% of the SOC-naive group, though grade 3 or higher events were rare (4%, 17%, and 8%, respectively). There was one death in the SOC-treated group and one in the SOC-refractory group. Both patients were elderly and had comorbid conditions.
Challenging the Current Standard of Care
The data have led to two additional phase 3 trials, one in refractory patients (Mobilize), and another for patients treated with IVIG who have residual disability (Vitalize). Sanofi is also planning a phase 3, placebo-controlled trial with one arm that will compare the antibody to IVIG, “which is a pretty ambitious trial design,” admitted Dr. Lewis.
Such a strategy is risky, but it could represent a big payoff for Sanofi if the phase 3 studies replicate the phase 2 studies. “No one would be using IVIG anymore if you beat IVIG by 50%. That will be the standard. If you do the trial [versus IVIG], you have a higher risk, but if you win it, you will win big,” said Dr. Tennigkeit.
The study was funded by Sanofi. Dr. Lewis has financial relationships with CSL Behring, Grifols, Pfizer, Sanofi, Argenx, Pharnext, Roche, Johnson & Johnson, Takeda, Boehringer Ingelheim, Nuvig, Dianthus, Janssen, Medscape, Alexion, Alnylam, and Novartis. Dr. Tennigkeit is an employee of UCB Biosciences. Dr. Patole has no relevant financial disclosures.
DENVER — , with good results in treatment-refractory and treatment-naive patients, according to results from a phase 2 clinical trial.
‘Impressive’ Results
The results were impressive, especially given that riliprubart outperformed IVIG, according to Frank Tennigkeit, PhD, senior director of pediatric development rare diseases at UCB Biosciences, who attended the session at the 2024 annual meeting of the American Academy of Neurology, where the study was presented. “There are few trials on CIDP, and the standard data are IVIG data.
“This is really amazing, especially in refractory patients. I turned to my neighbor [during the presentation] and said, ‘I’ve never seen CIDP data that good in my life. It works in all kinds of different patient populations, and also on the refractory ones. That’s what you want. That’s where the need is. And you saw a consistent effect and a strong effect on top of standard of care,” said Dr. Tennigkeit.
“It’s impressive. The only problem with CIDP is that it’s very difficult to compare treatments, because everyone has a different outcome. This was an open-label study, so there’s always a confounding bias. The proof of the pudding is going to be in a phase 3 blinded, randomized trial, but what I really admire about them, and I thought was very gutsy, is that they’re going head-to-head versus IVIG. I haven’t seen anyone who’s done that yet [in CIDP],” said Shalom Patole, MD, an internist and telehealth consultant in India, who also attended the session.
An Open-Label Phase 2 Study
The study had a somewhat unique design, according to Richard Lewis, MD, who presented the results. It was an open-label design that examined three subpopulations: 25 who had objective response to treatments (standard of care [SOC]–treated, mean age, 58.2 years; 80% male), 18 refractory patients who had been off treatment for up to 12 weeks (SOC-refractory, mean age, 63.9 years; 61% male), and 12 patients who had not been treated at all for at least 6 months or were treatment-naive (SOC-naive, mean age, 59.1 years; 67% male).
At 24 weeks, “if you looked at the treated group, 88% of those patients improved to remain stable, and only 12% relapsed. Most significantly, these patients who had responded to their IVIG, who were supposedly doing pretty well, 44% of those actually got better, so they improved from what would have been a pretty good baseline. The refractory patients, despite flunking the other treatments, 50% actually passed or improved with the treatment, so a significant response rate in a group that was not responding so well,” said Dr. Lewis, who is a neurologist at Cedars Sinai Medical Center.
The researchers also found that treatment with riliprubart led to inhibition of complement activity and a trend in reduction in neurofilament light chain levels by week 24 in all three groups.
Treatment-emergent adverse events occurred in 60% of the SOC-treated group, 72% of the SOC-refractory group, and 75% of the SOC-naive group, though grade 3 or higher events were rare (4%, 17%, and 8%, respectively). There was one death in the SOC-treated group and one in the SOC-refractory group. Both patients were elderly and had comorbid conditions.
Challenging the Current Standard of Care
The data have led to two additional phase 3 trials, one in refractory patients (Mobilize), and another for patients treated with IVIG who have residual disability (Vitalize). Sanofi is also planning a phase 3, placebo-controlled trial with one arm that will compare the antibody to IVIG, “which is a pretty ambitious trial design,” admitted Dr. Lewis.
Such a strategy is risky, but it could represent a big payoff for Sanofi if the phase 3 studies replicate the phase 2 studies. “No one would be using IVIG anymore if you beat IVIG by 50%. That will be the standard. If you do the trial [versus IVIG], you have a higher risk, but if you win it, you will win big,” said Dr. Tennigkeit.
The study was funded by Sanofi. Dr. Lewis has financial relationships with CSL Behring, Grifols, Pfizer, Sanofi, Argenx, Pharnext, Roche, Johnson & Johnson, Takeda, Boehringer Ingelheim, Nuvig, Dianthus, Janssen, Medscape, Alexion, Alnylam, and Novartis. Dr. Tennigkeit is an employee of UCB Biosciences. Dr. Patole has no relevant financial disclosures.
FROM AAN 2024
Approved Therapy for ALS Is Withdrawn When New Study Shows No Benefit
DENVER —
As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.
Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.
PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
ALSFRS-R Served as Primary Endpoint in Both Trials
In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).
The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.
In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.
For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.
Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.
As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
Differences Between Two Trials Were Evaluated
The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.
When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.
An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.
Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
‘Unfortunate’ Results
Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.
Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.
In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.
“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.
However, he believes that the study will still have value for better understanding ALS.
“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”
Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.
DENVER —
As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.
Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.
PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
ALSFRS-R Served as Primary Endpoint in Both Trials
In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).
The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.
In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.
For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.
Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.
As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
Differences Between Two Trials Were Evaluated
The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.
When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.
An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.
Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
‘Unfortunate’ Results
Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.
Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.
In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.
“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.
However, he believes that the study will still have value for better understanding ALS.
“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”
Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.
DENVER —
As a result, “PB&TURSO is no longer available for new patients in the United States of Canada,” reported Leonard H. van den Berg, MD, PhD, Direction of the Netherlands ALS Center, UMC Utrecht Brain Center, Utrecht, the Netherlands.
Although the drug is now being withdrawn, patients on therapy as of April 4 who wish to stay on treatment “can be transitioned to a free drug program,” added Dr. van den Berg, who presented the results of this new trial, called PHOENIX, at the 2024 annual meeting of the American Academy of Neurology.
PB&TURSO, marketed as Relyvrio (Amylyx), is a combination of sodium phenylbutyrate (PB) and taurursodiol (TAURO). Having shown promise for preventing neuronal death in experimental and early human studies, it was approved on the basis of the of the double-blind multicenter CENTAUR trial published in The New England Journal of Medicine in 2022.
ALSFRS-R Served as Primary Endpoint in Both Trials
In CENTAUR, like the newly completed PHOENIX, the primary outcome was rate of decline in the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) over 24 weeks. On this endpoint, the rate of change for those randomized to PB&TAURO was –1.24 points per month versus –1.66 points per month on placebo, a difference of 0.42 points that met statistical significance (P = .02).
The CENTAUR trial, which enrolled 177 patients, also showed no differences between those in the experimental and placebo arms for any of the secondary endpoints, including time to tracheostomy, permanent ventilation, or death.
In the much larger and longer PHOENIX trial, 664 ALS patients were randomized in a 3:2 ratio to PB&TURSO or placebo. Fifty-seven percent in each group completed 48 weeks of follow-up. The proportions of patients who withdrew from the study were similar across the reasons, such as adverse events and disease progression.
For the ALSFRS-R primary endpoint at 48 weeks, the decline in both groups was essentially linear and almost completely overlapped with a final change from baseline of –14.98 points in the PB&TURSO group that was statistically indistinguishable from the –15.32 point-change (P = .667) in the placebo group, Dr. van den Berg reported.
Similarly, there were no clinically meaningful or statistically significant differences in the secondary endpoints of mean change in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) scores or mean change in slow vital capacity (SVC) when compared to baseline or between arms.
As in CENTAUR, the most common side effects associated with PB&TURSO were gastrointestinal, particularly diarrhea (31% vs 10%), but serious adverse events were slightly less common on PT&TURSO (26% vs 28%), and Dr. van der Berg characterized the drug as “generally well tolerated.”
Differences Between Two Trials Were Evaluated
The entry criteria for PHOENIX trial differed modestly from those of the CENTAUR trial. Clinically definite or probable ALS was required in only two or more body regions versus three or more in the earlier trial. Patients were also allowed entry with SVC greater than 60% versus greater than 55% for CENTAUR and have had a longer period since symptom onset (< 24 vs < 18 months). Both studies permitted use of edaravone.
When stratified, patients who entered PHOENIX with CENTAUR-like entry criteria had a similar response to PB&TURSO relative to those who did not. Similarly, there were no meaningful differences between those enrolled in European study sites versus elsewhere. Background edaravone versus no edaravone also had no apparent effect on outcomes.
An ongoing open-label extension of the PHOENIX trial is still collecting data on survival, which was a prespecified endpoint. This endpoint, which requires 70% or more of patients to have died or have been followed for 3 or more years since the last patient was randomized, is not expected until February 2026.
Although “there are further biomarker and subgroup analyses planned,” Dr. van den Berg said that the neutral results of the PHOENIX trial, which he characterized as the largest controlled trial in ALS ever conducted, do not encourage further studies with this agent.
‘Unfortunate’ Results
Robert Bowser, PhD, chief scientific officer and chair of the department of translational neuroscience, Barrow Neurological Institute, Phoenix, called the results “unfortunate.” Just last year, Dr. Bowser published a study showing a reduction in the concentration of biomarkers associated with ALS among patients in the CENTAUR study who were treated with PB&TURSO.
Moreover, the reduction in the serum concentrations of the biomarkers he studied, which included C-reactive protein and YKL-40, correlated with ALSFRS-R total score.
In that paper, he speculated that CRP and YKL-40 might emerge as treatment-sensitive biomarkers in ALS “pending further confirmatory studies, but Dr. Bowser indicated that the PHOENIX study has prompted the correct response from the manufacturers.
“Credit should be given to the leaders at Amylyx for following through with their promise to remove the drug from the market if the PHOENIX study did not confirm the results from the CENTAUR study,” he said.
However, he believes that the study will still have value for better understanding ALS.
“As we move forward, it will be interesting to see biomarker data generated from the biosamples collected during the PHOENIX trial to learn more about treatment impact on biomarkers within those that received the drug,” he said. “I am sure we will continue to learn more from the PHOENIX trial.”
Dr. van den Berg has financial relationships with approximately 10 pharmaceutical companies, including Amylyx, which provided funding for the PHOENIX trial. Dr. Bowser reported no potential conflicts of interest.
FROM AAN 2024
Positive Results From Phase 2 Trial Support Potential New Option for Control of CIDP
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
FROM AAN 2024
Prominent Researcher Describes Pivot From ALS Treatment to Prevention
DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.
According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.
“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.
In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.
“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,
This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
The New Focus on Prevention
The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.
There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.
A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.
Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.
Dr. Feldman reported no potential conflicts of interest.
DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.
According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.
“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.
In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.
“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,
This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
The New Focus on Prevention
The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.
There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.
A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.
Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.
Dr. Feldman reported no potential conflicts of interest.
DENVER — After working for decades in a field littered with promising but failed clinical trials, a prominent researcher in amyotrophic lateral sclerosis (ALS) has decided to turn her attention to prevention, a direction of research that she thinks has more promise.
According to the gene-time hypothesis, duration of exposure to noxious chemicals and genetic susceptibility are key drivers of ALS risk, explained Eva Feldman, MD, PhD, director of the ALS Center of Excellence at the University of Michigan, Ann Arbor. She believes that existing research in risk modification is already promising.
“I think ALS prevention is real and attainable,” she said as this year’s recipient of the Sheila Essey Award for significant contributions in ALS research.
In describing her “pivot” to prevention from treatment at the 2024 annual meeting of the American Academy of Neurology, Dr. Feldman described her growing pessimism about treating a disease that has so consistently resisted even stabilization, let alone cure.
“I spent 10 years trying to repurpose IGF-1 as an ALS therapy. We took it from preclinical work all the way to a phase 3 multicenter trial, but in the end no effect was seen,” Dr. Feldman said,
This was followed by another 10 years spent on the promise of stem cells. In this case, she was eventually involved in two multicenter trials. In fact, trials are still ongoing in Europe, but Dr. Feldman said this strategy is “no longer going forward in the United States,” and she no longer anticipates favorable results.
The New Focus on Prevention
The basic concept in the prevention studies she is now working on with Stephen Goutman, MD, a frequent coauthor, and other colleagues at her center, is that the duration of exposure to persistent organic pollutants (POPs), along with some degree of genetic predisposition, determines risk for ALS. The simple idea is the reducing exposure will reduce ALS risk.
There is already substantial support for the underlying time-gene hypothesis, according to Dr. Feldman. Among several examples, she described work with 122 POPS that appear individually and in many cases collectively to correlate with ALS risk. Recent work with an environmental risk score (ERS) that permits studies of risk when accounting for exposure to families of pollutants, has supported these as potentially modifiable risks.
A high ERS “correlates with an ALS risk that is 3 to 4 times higher than a low score,” she said. In addition, those ALS patients with a high relative to a low ERS have a significant 0.6-year reduction in median survival.
Some specific POPs, such as pesticides, correlate with increased risk by themselves, but Dr. Feldman has begun focusing on occupational exposures, particularly in industries that are most likely to increase exposure POPs. Several of the POPs most implicated in ALS, such as polychlorinated biphenyls used in coolants and lubricants, organochlorine pesticides, and polybrominated diphenyl esters, are already banned or mostly banned in the United States, but they persist in the environment and remain legal elsewhere.
Dr. Feldman reported no potential conflicts of interest.
FROM AAN 2024
Chronic Pain Linked to Accelerated Brain Aging
, new research showed.
Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual’s brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.
The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.
“We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention,” said co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing.
“We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk,” Dr. Liu said.
The study was published online in Nature Mental Health.
Common Condition
CMP affects more than 40% of the world’s population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.
To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.
Using their brain age model, investigators observed significantly increased brain aging, or “predicted age difference,” only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.
This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.
These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.
“We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk,” corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, said in a news release.
A Future Treatment Target?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, noted that in this study, people with KOA showed signs of “faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years,” Dr. Lakhan said.
“Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments,” he added.
“Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own,” Dr. Lakhan noted.
The “good news,” he said, is that there are many “well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox.”
Support for the study was provided by the STI-2030 Major Project, the National Natural Science Foundation of China, the Scientific Foundation of the Institute of Psychology, Chinese Academy of Sciences, and the Young Elite Scientist Sponsorship Program by the China Association for Science and Technology. Dr. Liu and Dr. Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual’s brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.
The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.
“We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention,” said co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing.
“We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk,” Dr. Liu said.
The study was published online in Nature Mental Health.
Common Condition
CMP affects more than 40% of the world’s population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.
To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.
Using their brain age model, investigators observed significantly increased brain aging, or “predicted age difference,” only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.
This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.
These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.
“We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk,” corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, said in a news release.
A Future Treatment Target?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, noted that in this study, people with KOA showed signs of “faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years,” Dr. Lakhan said.
“Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments,” he added.
“Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own,” Dr. Lakhan noted.
The “good news,” he said, is that there are many “well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox.”
Support for the study was provided by the STI-2030 Major Project, the National Natural Science Foundation of China, the Scientific Foundation of the Institute of Psychology, Chinese Academy of Sciences, and the Young Elite Scientist Sponsorship Program by the China Association for Science and Technology. Dr. Liu and Dr. Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
Using structural MRI data from more than 9000 adults with knee osteoarthritis (KOA) from the UK Biobank, investigators developed a brain age model to compare an individual’s brain age with their chronological age. Those with KOA showed a much faster rate of brain aging than healthy individuals.
The acceleration in brain aging was largely driven by the hippocampus and predicted memory decline and incident dementia during follow-up. Researchers identified a gene highly expressed in glial cells as a possible genetic factor for accelerated brain aging.
“We demonstrate the accelerated brain aging and cognitive decline in chronic musculoskeletal pain, in particular knee osteoarthritis, and provide a neural marker for early detection and intervention,” said co-first author Jiao Liu, PhD candidate, Chinese Academy of Sciences, Beijing.
“We are interested to know how to slow down the aging brain in chronic musculoskeletal pain patients. Proper exercise and lifestyle may reduce the risk,” Dr. Liu said.
The study was published online in Nature Mental Health.
Common Condition
CMP affects more than 40% of the world’s population and has been shown to have a harmful impact on cognitive function, although the exact mechanisms remain unclear. Prior research suggests that inflammatory markers associated with brain aging are higher in patients with CMP, suggesting a link between brain aging and CMP.
To investigate further, researchers explored patterns of brain aging in healthy cohorts and cohorts with four common types of CMP — chronic knee pain, chronic back pain, chronic neck pain, and chronic hip pain.
Using their brain age model, investigators observed significantly increased brain aging, or “predicted age difference,” only in individuals with KOA (P < .001). The observation was validated in an independent dataset (P = .020), suggesting a pattern of brain aging acceleration specific to KOA.
This acceleration was primarily driven by key brain regions involved in cognitive processing, including hippocampus and orbitofrontal cortex, and was correlated with longitudinal memory decline and dementia risk.
These data also suggest that the SLC39A8 gene, which is highly expressed in glial cells, might be a key genetic factor underpinning this acceleration.
“We not only revealed the specificity of accelerated brain aging in knee osteoarthritis patients, but importantly, we also provided longitudinal evidence suggesting the ability of our brain aging marker to predict future memory decline and increased dementia risk,” corresponding author Yiheng Tu, PhD, also with Chinese Academy of Sciences, Beijing, said in a news release.
A Future Treatment Target?
Commenting on this research, Shaheen Lakhan, MD, PhD, a neurologist and researcher based in Miami, noted that in this study, people with KOA showed signs of “faster brain aging on scans. Think of it as your brain wearing a disguise, appearing older than its actual years,” Dr. Lakhan said.
“Inflammation, a key player in osteoarthritis, might be playing a double agent, wreaking havoc not just on your joints but potentially on your memory too. Researchers even identified a specific gene linked to both knee pain and faster brain aging, hinting at a potential target for future treatments,” he added.
“Importantly, the increased risk of cognitive decline and dementia associated with chronic pain is likely one of many factors, and probably not a very high one on its own,” Dr. Lakhan noted.
The “good news,” he said, is that there are many “well-established ways to keep your brain sharp. Regular exercise, a healthy diet, and staying mentally stimulated are all proven strategies to reduce dementia risk. Think of chronic pain management as another tool you can add to your brain health toolbox.”
Support for the study was provided by the STI-2030 Major Project, the National Natural Science Foundation of China, the Scientific Foundation of the Institute of Psychology, Chinese Academy of Sciences, and the Young Elite Scientist Sponsorship Program by the China Association for Science and Technology. Dr. Liu and Dr. Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM NATURE MENTAL HEALTH
Billions Spent on DMD Meds Despite Scant Proof of Efficacy
Three genetically targeted drugs for Duchenne muscular dystrophy (DMD) — eteplirsen, golodirsen, and casimersen — cost the US health care system more than $3 billion between 2016 and 2022, despite a lack of confirmatory efficacy data, a new analysis showed.
“We were certainly surprised to see how much was spent on these drugs during the period when we were still waiting for evidence to confirm whether or not they were effective,” study investigator Benjamin Rome, MD, MPH, with the Program on Regulation, Therapeutics, and Law, Harvard Medical School and Brigham and Women’s Hospital, Boston, told this news organization.
“With these drugs often costing over $1 million a year, these results show how spending can add up even for drugs that treat a rare disease,” Dr. Rome added.
The study was published online March 11, 2024, in JAMA.
No Confirmatory Research
Investigators estimated public and private spending on eteplirsen, golodirsen, and casimersen for DMD during 2016 and 2022 — years in which these drugs were marketed without the required confirmatory studies completed.
Annual net sales, which include rebates and statutory discounts to Medicaid or 340B entities, for the three drugs totaled $3.1 billion during the study period. Estimated Medicaid and Medicare spending accounted for $1.2 billion of that total. Of this total, Medicaid programs spent $1.1 billion (34% of US net sales) and Medicare spent $104 million (3% of US net sales).
Overall sales for the drugs increased from $7 million in 2016 to $879 million in 2022, while Medicaid and Medicare spending rose from $25 million in 2017 to $327 million in 2022.
Most of the spending on these therapies was for eteplirsen ($2.6 billion [82%]), “the efficacy of which has yet to be determined in a confirmatory trial more than 7 years after the drug’s accelerated approval,” the authors noted.
Of the total amount spent on the three drugs, US payers spent an estimated $301 million (10%) on casimersen and $263 million (8%) on golodirsen.
The findings point to the importance of follow up on drugs that are approved with preliminary evidence, Rome said.
“Congress and the US Food and Drug Administration have already made some important changes to the accelerated approval pathway, so hopefully we won’t see cases of multi-year delays in the future,” he said.
“Payers, including public payers like Medicare and Medicaid, need tools to financially encourage companies to complete the follow-up trials, such as paying less for drugs with accelerated approval or engaging in outcomes-based contracts to ensure they don’t pay billions of dollars for drugs that ultimately turn out not to be effective,” Dr. Rome added.
Reached for comment, Adam C. Powell, PhD, president, Payer+Provider Syndicate, noted that when a condition impacts a small population, as is the case with muscular dystrophy, there are fewer people over which to spread the cost of treatment development.
Dr. Powell pointed to a recent report that showed the average cost of developing a new drug exceeds $2 billion. The finding in the current study, that three DMD treatments had combined net sales of $3.1 billion over a 7-year period, “suggests that their developers may not have yet recouped their development costs,” Dr. Powell told this news organization.
“Unless the cost of drug development can be lessened through innovations in artificial intelligence or other means, high spending per patient for drugs addressing uncommon conditions is to be expected,” noted Dr. Powell, who was not part of the study.
“That said, it is concerning when substantial funds are being spent by public payers on treatments that do not work,” he added. “As the authors suggest, one option is to tie reimbursement to efficacy. While patients living with deadly conditions cannot indefinitely wait for treatments to be validated, clawing back payments in the event of inefficacy is always an option.”
The study was funded by Arnold Ventures. Dr. Rome reported receiving grants from the Elevance Health Public Policy Institute, the National Academy for State Health Policy, and several state prescription drug affordability boards outside the submitted work. Powell had no relevant disclosures.
A version of this article appeared on Medscape.com .
Three genetically targeted drugs for Duchenne muscular dystrophy (DMD) — eteplirsen, golodirsen, and casimersen — cost the US health care system more than $3 billion between 2016 and 2022, despite a lack of confirmatory efficacy data, a new analysis showed.
“We were certainly surprised to see how much was spent on these drugs during the period when we were still waiting for evidence to confirm whether or not they were effective,” study investigator Benjamin Rome, MD, MPH, with the Program on Regulation, Therapeutics, and Law, Harvard Medical School and Brigham and Women’s Hospital, Boston, told this news organization.
“With these drugs often costing over $1 million a year, these results show how spending can add up even for drugs that treat a rare disease,” Dr. Rome added.
The study was published online March 11, 2024, in JAMA.
No Confirmatory Research
Investigators estimated public and private spending on eteplirsen, golodirsen, and casimersen for DMD during 2016 and 2022 — years in which these drugs were marketed without the required confirmatory studies completed.
Annual net sales, which include rebates and statutory discounts to Medicaid or 340B entities, for the three drugs totaled $3.1 billion during the study period. Estimated Medicaid and Medicare spending accounted for $1.2 billion of that total. Of this total, Medicaid programs spent $1.1 billion (34% of US net sales) and Medicare spent $104 million (3% of US net sales).
Overall sales for the drugs increased from $7 million in 2016 to $879 million in 2022, while Medicaid and Medicare spending rose from $25 million in 2017 to $327 million in 2022.
Most of the spending on these therapies was for eteplirsen ($2.6 billion [82%]), “the efficacy of which has yet to be determined in a confirmatory trial more than 7 years after the drug’s accelerated approval,” the authors noted.
Of the total amount spent on the three drugs, US payers spent an estimated $301 million (10%) on casimersen and $263 million (8%) on golodirsen.
The findings point to the importance of follow up on drugs that are approved with preliminary evidence, Rome said.
“Congress and the US Food and Drug Administration have already made some important changes to the accelerated approval pathway, so hopefully we won’t see cases of multi-year delays in the future,” he said.
“Payers, including public payers like Medicare and Medicaid, need tools to financially encourage companies to complete the follow-up trials, such as paying less for drugs with accelerated approval or engaging in outcomes-based contracts to ensure they don’t pay billions of dollars for drugs that ultimately turn out not to be effective,” Dr. Rome added.
Reached for comment, Adam C. Powell, PhD, president, Payer+Provider Syndicate, noted that when a condition impacts a small population, as is the case with muscular dystrophy, there are fewer people over which to spread the cost of treatment development.
Dr. Powell pointed to a recent report that showed the average cost of developing a new drug exceeds $2 billion. The finding in the current study, that three DMD treatments had combined net sales of $3.1 billion over a 7-year period, “suggests that their developers may not have yet recouped their development costs,” Dr. Powell told this news organization.
“Unless the cost of drug development can be lessened through innovations in artificial intelligence or other means, high spending per patient for drugs addressing uncommon conditions is to be expected,” noted Dr. Powell, who was not part of the study.
“That said, it is concerning when substantial funds are being spent by public payers on treatments that do not work,” he added. “As the authors suggest, one option is to tie reimbursement to efficacy. While patients living with deadly conditions cannot indefinitely wait for treatments to be validated, clawing back payments in the event of inefficacy is always an option.”
The study was funded by Arnold Ventures. Dr. Rome reported receiving grants from the Elevance Health Public Policy Institute, the National Academy for State Health Policy, and several state prescription drug affordability boards outside the submitted work. Powell had no relevant disclosures.
A version of this article appeared on Medscape.com .
Three genetically targeted drugs for Duchenne muscular dystrophy (DMD) — eteplirsen, golodirsen, and casimersen — cost the US health care system more than $3 billion between 2016 and 2022, despite a lack of confirmatory efficacy data, a new analysis showed.
“We were certainly surprised to see how much was spent on these drugs during the period when we were still waiting for evidence to confirm whether or not they were effective,” study investigator Benjamin Rome, MD, MPH, with the Program on Regulation, Therapeutics, and Law, Harvard Medical School and Brigham and Women’s Hospital, Boston, told this news organization.
“With these drugs often costing over $1 million a year, these results show how spending can add up even for drugs that treat a rare disease,” Dr. Rome added.
The study was published online March 11, 2024, in JAMA.
No Confirmatory Research
Investigators estimated public and private spending on eteplirsen, golodirsen, and casimersen for DMD during 2016 and 2022 — years in which these drugs were marketed without the required confirmatory studies completed.
Annual net sales, which include rebates and statutory discounts to Medicaid or 340B entities, for the three drugs totaled $3.1 billion during the study period. Estimated Medicaid and Medicare spending accounted for $1.2 billion of that total. Of this total, Medicaid programs spent $1.1 billion (34% of US net sales) and Medicare spent $104 million (3% of US net sales).
Overall sales for the drugs increased from $7 million in 2016 to $879 million in 2022, while Medicaid and Medicare spending rose from $25 million in 2017 to $327 million in 2022.
Most of the spending on these therapies was for eteplirsen ($2.6 billion [82%]), “the efficacy of which has yet to be determined in a confirmatory trial more than 7 years after the drug’s accelerated approval,” the authors noted.
Of the total amount spent on the three drugs, US payers spent an estimated $301 million (10%) on casimersen and $263 million (8%) on golodirsen.
The findings point to the importance of follow up on drugs that are approved with preliminary evidence, Rome said.
“Congress and the US Food and Drug Administration have already made some important changes to the accelerated approval pathway, so hopefully we won’t see cases of multi-year delays in the future,” he said.
“Payers, including public payers like Medicare and Medicaid, need tools to financially encourage companies to complete the follow-up trials, such as paying less for drugs with accelerated approval or engaging in outcomes-based contracts to ensure they don’t pay billions of dollars for drugs that ultimately turn out not to be effective,” Dr. Rome added.
Reached for comment, Adam C. Powell, PhD, president, Payer+Provider Syndicate, noted that when a condition impacts a small population, as is the case with muscular dystrophy, there are fewer people over which to spread the cost of treatment development.
Dr. Powell pointed to a recent report that showed the average cost of developing a new drug exceeds $2 billion. The finding in the current study, that three DMD treatments had combined net sales of $3.1 billion over a 7-year period, “suggests that their developers may not have yet recouped their development costs,” Dr. Powell told this news organization.
“Unless the cost of drug development can be lessened through innovations in artificial intelligence or other means, high spending per patient for drugs addressing uncommon conditions is to be expected,” noted Dr. Powell, who was not part of the study.
“That said, it is concerning when substantial funds are being spent by public payers on treatments that do not work,” he added. “As the authors suggest, one option is to tie reimbursement to efficacy. While patients living with deadly conditions cannot indefinitely wait for treatments to be validated, clawing back payments in the event of inefficacy is always an option.”
The study was funded by Arnold Ventures. Dr. Rome reported receiving grants from the Elevance Health Public Policy Institute, the National Academy for State Health Policy, and several state prescription drug affordability boards outside the submitted work. Powell had no relevant disclosures.
A version of this article appeared on Medscape.com .
Neurologists Read Signs to Diagnose Functional Neurological Disorders
They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.
Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.
“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.
“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.
However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
Varying Definitions
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”
Dr. Hallett offers his own definition of FND, which includes the following characteristics:
- A neurological disorder, characterized by almost any type of neurological symptom
- Not voluntarily produced
- Caused by a brain network dysfunction that does not exclude the possibility of normal function
- Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
- Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.
The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.
Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.
Women comprise between 60% and 75% of the population with FNDs.
Diagnosis
FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.
She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.
For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.
Clinicians may also make unwarranted assumptions about a given patient, excluding an FND diagnosis in, say, a young woman with symptoms of anxiety. Alternatively, clinicians may either include or exclude a diagnosis based on personality factors or on a prior stressor, neither of which alone are sufficiently diagnostic.
Additionally, a clinician may be tempted to make the diagnosis of an FND based on the absence of findings on standard exams rather than on rule-in signs and symptoms, she emphasized.
Functional seizures
A definitive diagnosis can depend on the type of disorder.
“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.
There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.
Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.
Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
Functional movement disorders
Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.
For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.
One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.
When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.
“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
Treatment
In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.
“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.
Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.
“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.
This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.
They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.
Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.
“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.
“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.
However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
Varying Definitions
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”
Dr. Hallett offers his own definition of FND, which includes the following characteristics:
- A neurological disorder, characterized by almost any type of neurological symptom
- Not voluntarily produced
- Caused by a brain network dysfunction that does not exclude the possibility of normal function
- Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
- Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.
The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.
Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.
Women comprise between 60% and 75% of the population with FNDs.
Diagnosis
FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.
She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.
For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.
Clinicians may also make unwarranted assumptions about a given patient, excluding an FND diagnosis in, say, a young woman with symptoms of anxiety. Alternatively, clinicians may either include or exclude a diagnosis based on personality factors or on a prior stressor, neither of which alone are sufficiently diagnostic.
Additionally, a clinician may be tempted to make the diagnosis of an FND based on the absence of findings on standard exams rather than on rule-in signs and symptoms, she emphasized.
Functional seizures
A definitive diagnosis can depend on the type of disorder.
“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.
There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.
Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.
Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
Functional movement disorders
Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.
For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.
One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.
When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.
“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
Treatment
In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.
“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.
Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.
“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.
This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.
They have gone by many different names over the centuries: hysteria, psychosomatic illnesses, psychogenic neurological disorders, conversion disorders, dissociative neurological symptom disorders. The terminology may change, but functional neurological disorders by any other name are still real and serious yet treatable phenomena.
Functional neurological disorders, or FNDs, live at the crossroads of neurology and psychiatry, and they are as much a product of the body as they are of the brain, say neurologists who specialize in treating these complex and clinically challenging conditions.
“Whether they’re easily recognized or not depends on someone’s training and experience in this regard,” said Mark Hallett, MD, of the Human Motor Control Section of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.
“The difficulty has been that there hasn’t been very good education about functional disorders over the last 50 years or so,” he said in an interview.
However, with training and experience, clinicians can learn to identify these common and disabling conditions, Dr. Hallett said.
Varying Definitions
The Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) labels FND as “conversion disorder,” and lists diagnostic criteria that include “one or more symptoms of altered voluntary motor or sensory function; clinical findings provide evidence of incompatibility between the symptom and recognized neurological or medical conditions; the symptom or deficit is not better explained by another medical or mental disorder;” and “the symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.”
Dr. Hallett offers his own definition of FND, which includes the following characteristics:
- A neurological disorder, characterized by almost any type of neurological symptom
- Not voluntarily produced
- Caused by a brain network dysfunction that does not exclude the possibility of normal function
- Sometimes due in part to a psychological cause, and not explained by other neurological pathology that may or may not be present
- Symptoms may be inconsistent (variable) or incompatible (incongruent) with other known neurological disorders or human anatomy and physiology.
The two most common types of FND are psychogenic nonepileptic seizures and functional movement disorders, but patients may also have functional sensory, visual, auditory, speech, and urologic disorders, and even functional coma.
Dr. Hallett cited studies showing that an estimated 9% of neurology hospital admission are for FNDS, and that among patients in neurology clinics 5.4% had a diagnosis of FND, and 30% had an FND as part of the diagnosis.
Women comprise between 60% and 75% of the population with FNDs.
Diagnosis
FND is not, as once thought, a diagnosis of exclusion, but is based on signs and symptoms, which may be either inconsistent or irreversible and may occur in the absence of a stressor, said Sara Finkelstein, MD, MSc, of the Functional Neurological Disorder Unit in the Department of Neurology at Massachusetts General Hospital in Boston.
She emphasized that there are several diagnostic pitfalls that clinicians need to be aware of.
For example, “just because a patient has a psychiatric history does not mean that they have a functional neurological disorder,” she said in an interview.
Clinicians may also make unwarranted assumptions about a given patient, excluding an FND diagnosis in, say, a young woman with symptoms of anxiety. Alternatively, clinicians may either include or exclude a diagnosis based on personality factors or on a prior stressor, neither of which alone are sufficiently diagnostic.
Additionally, a clinician may be tempted to make the diagnosis of an FND based on the absence of findings on standard exams rather than on rule-in signs and symptoms, she emphasized.
Functional seizures
A definitive diagnosis can depend on the type of disorder.
“Many functional seizures have some clinical manifestations that are apparent, but as seizures are intermittent the doctor may not see one, and it may depend upon someone taking a video of the person with the seizure perhaps, or bringing them into a hospital and watching them until they do have the seizure,” Dr. Hallett said.
There are some manifestations that indicate the likelihood that a seizure has a functional origin, and when there is uncertainty EEG can help to nail down a diagnosis, he added.
Dr. Finkelstein noted that exam signs with good reliability for functional seizures include eye closure or resistance to opening; duration longer than 2 minutes; stopping and starting; asynchronous limb movements; patient maintenance of awareness during a generalized event; and ictal weeping.
Differential diagnoses included migraine with complex aura, dissociation related to posttraumatic stress disorder, or anxiety.
Functional movement disorders
Dr. Finkelstein cautioned that when evaluating patients for potential functional movement disorders, it’s important to not jump to conclusions.
For example, the amplitude of tremor can vary in Parkinson’s disease and essential tremor as well as in functional tremor. The clinician should not read too much into the observation that a patient’s tremor gets worse with increasing stress as stress can exacerbate most tremor types, she said.
One sign that tremor could be functional (dystonic tremor) is irregularity of amplitude and frequency, she noted.
When assessing patients with gait disorder, it’s important to understand that there is no single sign that is specially characteristic for a given disorder, and just because a patient has a “bizarre” gait, it doesn’t necessarily signal a functional disorder.
“A dystonic gait may improve with an alternate motor pattern or be inconsistent over time,” Dr. Finkelstein said.
Treatment
In a comprehensive review published in The Lancet: Neurology in 2022, Dr. Hallett and colleagues said that good doctor-patient communications and understanding of each patient’s needs and goals are essential for effective treatment of all FNDs.
“Neurologists have traditionally avoided taking responsibility for people with FND, although are often most appropriate to engage patients in treatment. Explaining the diagnosis with clarity, confidence, using the principles of a ‘rule in’ process, is a key step in treatment,” they wrote.
Treatment can take several forms, depending on the FND, and may include physiotherapy for patients with functional movement disorders and psychological therapy for patients with functional seizures.
“With increasing evidence-based treatment, the diagnosis of FND should be seen as a process of looking for potentially reversible cause of disability and distress whether or not an individual has abnormalities on conventional laboratory or radiological testing,” Dr. Hallett and colleagues concluded.
This article was based on interviews and from presentations by Dr. Hallett and Dr. Finkelstein at a 2023 meeting of the Indiana Neurological Society. Dr. Hallett and Dr. Finkelstein declared no conflicts of interest.
FROM THE INDIANA NEUROLOGICAL SOCIETY’S FUNCTIONAL NEUROLOGICAL DISORDERS CONFERENCE
Essential Tremor Tied to a Threefold Increased Risk for Dementia
, new research showed.
In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.
The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Mild Cognitive Impairment Prevalence Nearly Double
For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.
At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.
During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.
The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.
“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
Far From Trivial
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”
“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.
“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.
The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.
The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Mild Cognitive Impairment Prevalence Nearly Double
For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.
At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.
During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.
The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.
“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
Far From Trivial
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”
“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.
“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.
The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
, new research showed.
In a prospective, longitudinal study, incidence of dementia was nearly 20% among older adults with ET. However, the rates were lower than those in adults with Parkinson’s disease.
The study is “the most complete exposition of the longitudinal trajectory of cognitive impairment in an ET cohort,” said the authors, led by Elan D. Louis, MD, MSc, from University of Texas Southwestern Medical Center in Dallas, Texas.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
Mild Cognitive Impairment Prevalence Nearly Double
For the study, 222 adults with ET with an average age of 79 years at baseline underwent detailed cognitive assessments and were followed for an average of 5 years.
At baseline, 168 people had normal cognitive skills, 35 had mild cognitive impairment (MCI), and 19 had dementia. During the follow-up, 59 individuals developed MCI and 41 developed dementia.
During the follow-up, the cumulative prevalence of dementia was 18.5%, and the average annual conversion rate of MCI to dementia was 12.2% — nearly threefold higher than rates in the general population and roughly one-half the magnitude of those reported for adults with Parkinson’s disease.
The cumulative prevalence of MCI (26.6%) was nearly double that of the general population but less than that in patients with Parkinson’s disease.
“Our data indicate that the prevalence of and conversion rates to dementia in ET fall between those associated with the natural course of aging and the more pronounced rates observed in individuals with Parkinson’s disease,” the researchers wrote in their conference abstract.
Far From Trivial
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, Florida, said, “The days of viewing ET as just a ‘nuisance tremor’ are over. This study shatters the notion that essential tremor is a trivial condition.”
“Moving forward, the research agenda must further elucidate the link between ET and dementia and develop neuroprotective strategies. But this study represents a seismic shift in how we understand essential tremor,” Dr. Lakhan said.
“The benign label no longer applies given the cognitive risks ET patients face. Our clinical practice and communication with patients must adapt accordingly,” he added.
The study was supported by the National Institutes of Health. Drs. Louis and Lakhan had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
Promising Results for Investigational Myasthenia Gravis Drug
, data from a new phase 3 study showed.
After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.
The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.
“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.
The findings were published online in JAMA Neurology.
Unmet Need
A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.
The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.
Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.
“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.
Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.
The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.
The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.
All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
Bests Placebo
Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.
Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.
Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).
While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.
In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.
In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).
Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).
Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.
Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
Well Tolerated
On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.
The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).
“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.
Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.
High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.
The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.
In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.
The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.
The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
Questions Remain
Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.
It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.
The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.
“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.
The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.
A version of this article first appeared on Medscape.com.
, data from a new phase 3 study showed.
After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.
The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.
“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.
The findings were published online in JAMA Neurology.
Unmet Need
A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.
The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.
Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.
“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.
Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.
The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.
The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.
All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
Bests Placebo
Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.
Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.
Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).
While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.
In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.
In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).
Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).
Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.
Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
Well Tolerated
On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.
The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).
“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.
Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.
High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.
The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.
In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.
The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.
The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
Questions Remain
Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.
It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.
The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.
“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.
The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.
A version of this article first appeared on Medscape.com.
, data from a new phase 3 study showed.
After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.
The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.
“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.
The findings were published online in JAMA Neurology.
Unmet Need
A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.
The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.
Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.
“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.
Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.
The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.
The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.
All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
Bests Placebo
Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.
Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.
Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).
While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.
In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.
In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).
Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).
Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.
Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
Well Tolerated
On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.
The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).
“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.
Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.
High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.
The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.
In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.
The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.
The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
Questions Remain
Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.
It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.
The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.
“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.
The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
Chronic Fatigue Syndrome and Fibromyalgia: A Single Disease Entity?
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.
A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.
Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.
“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.
“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”
The study was published in the December 2023 issue of Annals of Medicine.
Cutting-Edge Technology
“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”
But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.
“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”
Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”
Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”
Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.
The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”
The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.
This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.
In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
Shared Pathophysiology?
Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.
The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.
Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.
the authors stated.
They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.
They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.
But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
‘Noncontributory’ Findings
Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.
“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”
He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.
In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”
Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.
Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”
He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.
Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.
The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.
A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.
Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.
“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.
“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”
The study was published in the December 2023 issue of Annals of Medicine.
Cutting-Edge Technology
“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”
But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.
“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”
Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”
Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”
Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.
The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”
The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.
This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.
In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
Shared Pathophysiology?
Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.
The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.
Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.
the authors stated.
They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.
They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.
But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
‘Noncontributory’ Findings
Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.
“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”
He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.
In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”
Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.
Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”
He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.
Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.
The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) have overlapping neurologic symptoms — particularly profound fatigue. The similarity between these two conditions has led to the question of whether they are indeed distinct central nervous system (CNS) entities, or whether they exist along a spectrum and are actually two different manifestations of the same disease process.
A new study utilized a novel methodology — unbiased quantitative mass spectrometry-based proteomics — to investigate this question by analyzing cerebrospinal fluid (CSF) in a group of patients with ME/CFS and another group of patients diagnosed with both ME/CFS and FM.
Close to 2,100 proteins were identified, of which nearly 1,800 were common to both conditions.
“ME/CFS and fibromyalgia do not appear to be distinct entities, with respect to their cerebrospinal fluid proteins,” lead author Steven Schutzer, MD, professor of medicine, Rutgers New Jersey School of Medicine, told this news organization.
“Work is underway to solve the multiple mysteries of ME/CFS, fibromyalgia, and other neurologic-associated diseases,” he continued. “We have further affirmed that we have a precise objective discovery tool in our hands. Collectively studying multiple diseases brings clarity to each individual disease.”
The study was published in the December 2023 issue of Annals of Medicine.
Cutting-Edge Technology
“ME/CFS is characterized by disabling fatigue, and FM is an illness characterized by body-wide pain,” Dr. Schutzer said. These “medically unexplained” illnesses often coexist by current definitions, and the overlap between them has suggested that they may be part of the “same illness spectrum.”
But co-investigator Benjamin Natelson, MD, professor of neurology and director of the Pain and Fatigue Study Center, Mount Sinai, New York, and others found in previous research that there are distinct differences between the conditions, raising the possibility that there may be different pathophysiological processes.
“The physicians and scientists on our team have had longstanding interest in studying neurologic diseases with cutting-edge tools such as mass spectrometry applied to CSF,” Dr. Schutzer said. “We have had success using this message to distinguish diseases such as ME/CFS from post-treatment Lyme disease, multiple sclerosis, and healthy normal people.”
Dr. Schutzer explained that Dr. Natelson had acquired CSF samples from “well-characterized [ME/CFS] patients and controls.”
Since the cause of ME/CFS is “unknown,” it seemed “ripe to investigate it further with the discovery tool of mass spectrometry” by harnessing the “most advanced equipment in the country at the pacific Northwest National Laboratory, which is part of the US Department of Energy.”
Dr. Schutzer noted that it was the “merger of different clinical and laboratory expertise” that enabled them to address whether ME/CFS and FM are two distinct disease processes.
The choice of analyzing CSF is that it’s the fluid closest to the brain, he added. “A lot of people have studied ME/CFS peripherally because they don’t have access to spinal fluid or it’s easier to look peripherally in the blood, but that doesn’t mean that the blood is where the real ‘action’ is occurring.”
The researchers compared the CSF of 15 patients with ME/CFS only to 15 patients with ME/CFS+FM using mass spectrometry-based proteomics, which they had employed in previous research to see whether ME/CFS was distinct from persistent neurologic Lyme disease syndrome.
This technology has become the “method of choice and discovery tool to rapidly uncover protein biomarkers that can distinguish one disease from another,” the authors stated.
In particular, in unbiased quantitative mass spectrometry-based proteomics, the researchers do not have to know in advance what’s in a sample before studying it, Dr. Schutzer explained.
Shared Pathophysiology?
Both groups of patients were of similar age (41.3 ± 9.4 years and 40.1 ± 11.0 years, respectively), with no differences in gender or rates of current comorbid psychiatric diagnoses between the groups.
The researchers quantified a total of 2,083 proteins, including 1,789 that were specifically quantified in all of the CSF samples, regardless of the presence or absence of FM.
Several analyses (including an ANOVA analysis with adjusted P values, a Random Forest machine learning approach that looked at relative protein abundance changes between those with ME/CFS and ME/CFS+FM, and unsupervised hierarchical clustering analyses) did not find distinguishing differences between the groups.
the authors stated.
They noted that both conditions are “medically unexplained,” with core symptoms of pain, fatigue, sleep problems, and cognitive difficulty. The fact that these two syndromes coexist so often has led to the assumption that the “similarities between them outweigh the differences,” they wrote.
They pointed to some differences between the conditions, including an increase in substance P in the CSF of FM patients, but not in ME/CFS patients reported by others. There are also some immunological, physiological and genetic differences.
But if the conclusion that the two illnesses may share a similar pathophysiological basis is supported by other research that includes FM-only patients as comparators to those with ME/CFS, “this would support the notion that the two illnesses fall along a common illness spectrum and may be approached as a single entity — with implications for both diagnosis and the development of new treatment approaches,” they concluded.
‘Noncontributory’ Findings
Commenting on the research, Robert G. Lahita, MD, PhD, director of the Institute for Autoimmune and Rheumatic Diseases, St. Joseph Health, Wayne, New Jersey, stated that he does not regard these diseases as neurologic but rather as rheumatologic.
“Most neurologists don’t see these diseases, but as a rheumatologist, I see them every day,” said Dr. Lahita, professor of medicine at Hackensack (New Jersey) Meridian School of Medicine and a clinical professor of medicine at Rutgers New Jersey Medical School, New Brunswick. “ME/CFS isn’t as common in my practice, but we do deal with many post-COVID patients who are afflicted mostly with ME/CFS.”
He noted that an important reason for fatigue in FM is that patients generally don’t sleep, or their sleep is disrupted. This is different from the cause of fatigue in ME/CFS.
In addition, the small sample size and the lack of difference between males and females were both limitations of the current study, said Dr. Lahita, who was not involved in this research. “We know that FM disproportionately affects women — in my practice, for example, over 95% of the patients with FM are female — while ME/CFS affects both genders similarly.”
Using proteomics as a biomarker was also problematic, according to Dr. Lahita. “It would have been more valuable to investigate differences in cytokines, for example,” he suggested.
Ultimately, Dr. Lahita thinks that the study is “non-contributory to the field and, as complex as the analysis was, it does nothing to shed differentiate the two conditions or explain the syndromes themselves.”
He added that it would have been more valuable to compare ME/CFS not only to ME/CFS plus FM but also with FM without ME/CFS and to healthy controls, and perhaps to a group with an autoimmune condition, such as lupus or Hashimoto’s thyroiditis.
Dr. Schutzer acknowledged that a limitation of the current study is that his team was unable analyze the CSF of patients with only FM. He and his colleagues “combed the world’s labs” for existing CSF samples of patients with FM alone but were unable to obtain any. “We see this study as a ‘stepping stone’ and hope that future studies will include patients with FM who are willing to donate CSF samples that we can use for comparison,” he said.
The authors received support from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and National Institute of Neurological Disorders and Stroke. Dr. Schutzer, coauthors, and Dr. Lahita reported no relevant financial relationships.