Jeff Evans

VANCOUVER – Women with epilepsy have fertility rates comparable with healthy women in the general population, according to results from the first prospective observational cohort study to make the comparison.

During the year-long Women With Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD) study, 70% of women with epilepsy and 67% of healthy control women became pregnant, and there was no significant difference in the mean time to pregnancy between those with and without epilepsy (6 months vs. 9 months, respectively), Dr. Page Pennell reported at the annual meeting of the American Academy of Neurology.

Live births occurred in 82% of pregnancies of women with epilepsy and 80% of controls, while miscarriages occurred in 13% and 20%, respectively. Both of those rates are very similar to the general population. Another 5% of pregnancies in women with epilepsy were ectopic, terminated due to chromosomal abnormality, or lost to follow-up.

“These findings should reassure women with epilepsy and clinicians when counseling women with epilepsy who are planning pregnancy,” said Dr. Pennell, director of research for the division of epilepsy in the department of neurology at Brigham and Women’s Hospital in Boston. She is a primary investigator of the study along with Dr. Jacqueline French, professor of neurology at NYU Langone Medical Center and Dr. Cynthia Harden, system director of epilepsy services at Mount Sinai Beth Israel, both in New York.

“I think overall the findings are more in the light of myth busting. ... We don’t necessarily see a lot of problems with fertility, yet the literature suggests that the birth rates are much lower,” Dr. Harden said in an interview.

“It’s really the first solid evidence, and it’s nice because in a sea of bad news for women when it comes to family planning and achieving pregnancy and pregnancy outcomes, I think this was very positive to say that their ability to achieve pregnancy was no different than what was reported by a control population without epilepsy,” Dr. Katherine Noe, an epilepsy specialist at the Mayo Clinic in Scottsdale, Ariz., said when asked to comment on the study.

“There was certainly reason to be concerned,” said Dr. Noe, who was not involved in the study. “We have a lot of data saying that babies exposed to antiepileptic drugs are more likely to have malformations, and so you could have a baby that already early in pregnancy has severe malformations that would be more likely to end in spontaneous abortion.”

Dr. Noe said that pregnancy registry data indicate that women with epilepsy may be more likely to have a pregnancy that ends in a miscarriage. Investigators for several studies published in 2015 reported that women with epilepsy face greater risk for morbidity and adverse outcomes at the time of delivery and during pregnancy than women without epilepsy (JAMA Neurol. 2015;72[9]:981-8 and Lancet. 2016;386[10006]:1845–52). Women with epilepsy also have been thought to be more prone to infertility for various reasons, including menstrual irregularities, polycystic ovarian syndrome related to antiepileptic medications, and early menopause, she said.

Three previous studies had reported that women with epilepsy had birth rates as low as only one-quarter to one-third that of women without epilepsy. There have been many reasons reported for why that might be the case, including lower marriage rates, sexual dysfunction, lower libido (in both men and women with epilepsy), and increased number of anovulatory cycles, or greater choice to not become pregnant, Dr. Pennell said.

The WEPOD study enrolled 89 women with epilepsy and 109 healthy controls who were seeking to become pregnant and had stopped using contraception within 6 months of enrollment or were about to stop using it. The investigators excluded women with infertility, polycystic ovarian syndrome, endometriosis, endocrine disorder, and heavy smoking, or who were not in an exclusive heterosexual relationship with a significant other or spouse.

Participants received iPod touch devices with an app with which they tracked menses and intercourse, as well as antiepileptic drug use and seizures in women with epilepsy. “This was a particularly novel part of the study,” Dr. Harden said. It allowed the investigators to track adherence very well. Participants logged about 87% of their days in the app, and the investigators could see when the entries were made.

Women in both groups had a mean age of about 31 years and mean body mass index of about 25 kg/m². Overall, 52%-58% had undergone a prior pregnancy. Women with epilepsy, compared with controls, were less often Asian (17% vs. 6%) or African American (16% vs. 1%). The education level of participants was “fairly similar” between the groups, and slightly more women with epilepsy were unemployed (21% vs. 10%). Women with epilepsy also were more often married than were controls (89% vs. 75%).

During the study, 36% of women with epilepsy were still having seizures. At enrollment, most of the women’s seizure types were generalized (30%) or focal only (63%). Dr. Pennell noted that the antiseizure medications that the women were taking were typical for women of reproductive age: lamotrigine monotherapy (44%), levetiracetam monotherapy (28%), monotherapy with a strong enzyme-inducing drug (12%), other polytherapy (10%), polytherapy with a strong enzyme-inducing drug (6%), other monotherapy (3%), or no antiseizure medication (2%). A few women either added or stopped drugs during the study. A total of 18 women with epilepsy and 15 healthy controls dropped out.

As expected, age affected the likelihood of becoming pregnant, as well as number of prior pregnancies. Body mass index did not affect the likelihood of becoming pregnant, while white race and being married increased the likelihood.

In future analyses, the investigators are planning on checking whether ovulatory rates, frequency of intercourse, and time of intercourse had any impact on pregnancy, and in women with epilepsy, they will check the effect of the type of antiseizure medication and seizure-related factors.

“I think our findings will stand with future analyses.” Dr. Harden said. “The most interesting future findings may come from within the epilepsy group,” she said, noting that older antiepileptic medications have been previously associated with difficulty conceiving.

The WEPOD study was funded by the Milken Family Foundation, the Epilepsy Therapy Project, and the Epilepsy Foundation.

[email protected]

VANCOUVER – Women with epilepsy have fertility rates comparable with healthy women in the general population, according to results from the first prospective observational cohort study to make the comparison.

During the year-long Women With Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD) study, 70% of women with epilepsy and 67% of healthy control women became pregnant, and there was no significant difference in the mean time to pregnancy between those with and without epilepsy (6 months vs. 9 months, respectively), Dr. Page Pennell reported at the annual meeting of the American Academy of Neurology.

Live births occurred in 82% of pregnancies of women with epilepsy and 80% of controls, while miscarriages occurred in 13% and 20%, respectively. Both of those rates are very similar to the general population. Another 5% of pregnancies in women with epilepsy were ectopic, terminated due to chromosomal abnormality, or lost to follow-up.

“These findings should reassure women with epilepsy and clinicians when counseling women with epilepsy who are planning pregnancy,” said Dr. Pennell, director of research for the division of epilepsy in the department of neurology at Brigham and Women’s Hospital in Boston. She is a primary investigator of the study along with Dr. Jacqueline French, professor of neurology at NYU Langone Medical Center and Dr. Cynthia Harden, system director of epilepsy services at Mount Sinai Beth Israel, both in New York.

“I think overall the findings are more in the light of myth busting. ... We don’t necessarily see a lot of problems with fertility, yet the literature suggests that the birth rates are much lower,” Dr. Harden said in an interview.

“It’s really the first solid evidence, and it’s nice because in a sea of bad news for women when it comes to family planning and achieving pregnancy and pregnancy outcomes, I think this was very positive to say that their ability to achieve pregnancy was no different than what was reported by a control population without epilepsy,” Dr. Katherine Noe, an epilepsy specialist at the Mayo Clinic in Scottsdale, Ariz., said when asked to comment on the study.

“There was certainly reason to be concerned,” said Dr. Noe, who was not involved in the study. “We have a lot of data saying that babies exposed to antiepileptic drugs are more likely to have malformations, and so you could have a baby that already early in pregnancy has severe malformations that would be more likely to end in spontaneous abortion.”

Dr. Noe said that pregnancy registry data indicate that women with epilepsy may be more likely to have a pregnancy that ends in a miscarriage. Investigators for several studies published in 2015 reported that women with epilepsy face greater risk for morbidity and adverse outcomes at the time of delivery and during pregnancy than women without epilepsy (JAMA Neurol. 2015;72[9]:981-8 and Lancet. 2016;386[10006]:1845–52). Women with epilepsy also have been thought to be more prone to infertility for various reasons, including menstrual irregularities, polycystic ovarian syndrome related to antiepileptic medications, and early menopause, she said.

Three previous studies had reported that women with epilepsy had birth rates as low as only one-quarter to one-third that of women without epilepsy. There have been many reasons reported for why that might be the case, including lower marriage rates, sexual dysfunction, lower libido (in both men and women with epilepsy), and increased number of anovulatory cycles, or greater choice to not become pregnant, Dr. Pennell said.

The WEPOD study enrolled 89 women with epilepsy and 109 healthy controls who were seeking to become pregnant and had stopped using contraception within 6 months of enrollment or were about to stop using it. The investigators excluded women with infertility, polycystic ovarian syndrome, endometriosis, endocrine disorder, and heavy smoking, or who were not in an exclusive heterosexual relationship with a significant other or spouse.

Participants received iPod touch devices with an app with which they tracked menses and intercourse, as well as antiepileptic drug use and seizures in women with epilepsy. “This was a particularly novel part of the study,” Dr. Harden said. It allowed the investigators to track adherence very well. Participants logged about 87% of their days in the app, and the investigators could see when the entries were made.

Women in both groups had a mean age of about 31 years and mean body mass index of about 25 kg/m². Overall, 52%-58% had undergone a prior pregnancy. Women with epilepsy, compared with controls, were less often Asian (17% vs. 6%) or African American (16% vs. 1%). The education level of participants was “fairly similar” between the groups, and slightly more women with epilepsy were unemployed (21% vs. 10%). Women with epilepsy also were more often married than were controls (89% vs. 75%).

During the study, 36% of women with epilepsy were still having seizures. At enrollment, most of the women’s seizure types were generalized (30%) or focal only (63%). Dr. Pennell noted that the antiseizure medications that the women were taking were typical for women of reproductive age: lamotrigine monotherapy (44%), levetiracetam monotherapy (28%), monotherapy with a strong enzyme-inducing drug (12%), other polytherapy (10%), polytherapy with a strong enzyme-inducing drug (6%), other monotherapy (3%), or no antiseizure medication (2%). A few women either added or stopped drugs during the study. A total of 18 women with epilepsy and 15 healthy controls dropped out.

As expected, age affected the likelihood of becoming pregnant, as well as number of prior pregnancies. Body mass index did not affect the likelihood of becoming pregnant, while white race and being married increased the likelihood.

In future analyses, the investigators are planning on checking whether ovulatory rates, frequency of intercourse, and time of intercourse had any impact on pregnancy, and in women with epilepsy, they will check the effect of the type of antiseizure medication and seizure-related factors.

“I think our findings will stand with future analyses.” Dr. Harden said. “The most interesting future findings may come from within the epilepsy group,” she said, noting that older antiepileptic medications have been previously associated with difficulty conceiving.

The WEPOD study was funded by the Milken Family Foundation, the Epilepsy Therapy Project, and the Epilepsy Foundation.

[email protected]

VANCOUVER – Women with epilepsy have fertility rates comparable with healthy women in the general population, according to results from the first prospective observational cohort study to make the comparison.

During the year-long Women With Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD) study, 70% of women with epilepsy and 67% of healthy control women became pregnant, and there was no significant difference in the mean time to pregnancy between those with and without epilepsy (6 months vs. 9 months, respectively), Dr. Page Pennell reported at the annual meeting of the American Academy of Neurology.

Live births occurred in 82% of pregnancies of women with epilepsy and 80% of controls, while miscarriages occurred in 13% and 20%, respectively. Both of those rates are very similar to the general population. Another 5% of pregnancies in women with epilepsy were ectopic, terminated due to chromosomal abnormality, or lost to follow-up.

“These findings should reassure women with epilepsy and clinicians when counseling women with epilepsy who are planning pregnancy,” said Dr. Pennell, director of research for the division of epilepsy in the department of neurology at Brigham and Women’s Hospital in Boston. She is a primary investigator of the study along with Dr. Jacqueline French, professor of neurology at NYU Langone Medical Center and Dr. Cynthia Harden, system director of epilepsy services at Mount Sinai Beth Israel, both in New York.

“I think overall the findings are more in the light of myth busting. ... We don’t necessarily see a lot of problems with fertility, yet the literature suggests that the birth rates are much lower,” Dr. Harden said in an interview.

“It’s really the first solid evidence, and it’s nice because in a sea of bad news for women when it comes to family planning and achieving pregnancy and pregnancy outcomes, I think this was very positive to say that their ability to achieve pregnancy was no different than what was reported by a control population without epilepsy,” Dr. Katherine Noe, an epilepsy specialist at the Mayo Clinic in Scottsdale, Ariz., said when asked to comment on the study.

“There was certainly reason to be concerned,” said Dr. Noe, who was not involved in the study. “We have a lot of data saying that babies exposed to antiepileptic drugs are more likely to have malformations, and so you could have a baby that already early in pregnancy has severe malformations that would be more likely to end in spontaneous abortion.”

Dr. Noe said that pregnancy registry data indicate that women with epilepsy may be more likely to have a pregnancy that ends in a miscarriage. Investigators for several studies published in 2015 reported that women with epilepsy face greater risk for morbidity and adverse outcomes at the time of delivery and during pregnancy than women without epilepsy (JAMA Neurol. 2015;72[9]:981-8 and Lancet. 2016;386[10006]:1845–52). Women with epilepsy also have been thought to be more prone to infertility for various reasons, including menstrual irregularities, polycystic ovarian syndrome related to antiepileptic medications, and early menopause, she said.

Three previous studies had reported that women with epilepsy had birth rates as low as only one-quarter to one-third that of women without epilepsy. There have been many reasons reported for why that might be the case, including lower marriage rates, sexual dysfunction, lower libido (in both men and women with epilepsy), and increased number of anovulatory cycles, or greater choice to not become pregnant, Dr. Pennell said.

The WEPOD study enrolled 89 women with epilepsy and 109 healthy controls who were seeking to become pregnant and had stopped using contraception within 6 months of enrollment or were about to stop using it. The investigators excluded women with infertility, polycystic ovarian syndrome, endometriosis, endocrine disorder, and heavy smoking, or who were not in an exclusive heterosexual relationship with a significant other or spouse.

Participants received iPod touch devices with an app with which they tracked menses and intercourse, as well as antiepileptic drug use and seizures in women with epilepsy. “This was a particularly novel part of the study,” Dr. Harden said. It allowed the investigators to track adherence very well. Participants logged about 87% of their days in the app, and the investigators could see when the entries were made.

Women in both groups had a mean age of about 31 years and mean body mass index of about 25 kg/m². Overall, 52%-58% had undergone a prior pregnancy. Women with epilepsy, compared with controls, were less often Asian (17% vs. 6%) or African American (16% vs. 1%). The education level of participants was “fairly similar” between the groups, and slightly more women with epilepsy were unemployed (21% vs. 10%). Women with epilepsy also were more often married than were controls (89% vs. 75%).

During the study, 36% of women with epilepsy were still having seizures. At enrollment, most of the women’s seizure types were generalized (30%) or focal only (63%). Dr. Pennell noted that the antiseizure medications that the women were taking were typical for women of reproductive age: lamotrigine monotherapy (44%), levetiracetam monotherapy (28%), monotherapy with a strong enzyme-inducing drug (12%), other polytherapy (10%), polytherapy with a strong enzyme-inducing drug (6%), other monotherapy (3%), or no antiseizure medication (2%). A few women either added or stopped drugs during the study. A total of 18 women with epilepsy and 15 healthy controls dropped out.

As expected, age affected the likelihood of becoming pregnant, as well as number of prior pregnancies. Body mass index did not affect the likelihood of becoming pregnant, while white race and being married increased the likelihood.

In future analyses, the investigators are planning on checking whether ovulatory rates, frequency of intercourse, and time of intercourse had any impact on pregnancy, and in women with epilepsy, they will check the effect of the type of antiseizure medication and seizure-related factors.

“I think our findings will stand with future analyses.” Dr. Harden said. “The most interesting future findings may come from within the epilepsy group,” she said, noting that older antiepileptic medications have been previously associated with difficulty conceiving.

The WEPOD study was funded by the Milken Family Foundation, the Epilepsy Therapy Project, and the Epilepsy Foundation.

[email protected]

VANCOUVER – A new American Academy of Neurology practice guideline on the efficacy and safety evidence for botulinum toxin treatment of blepharospasm, cervical dystonia, spasticity, and headache has updated the last recommendations published in 2008, but leaves some relevant clinical concerns and off-label uses unaddressed.

The 2016 update, published April 18 in Neurology, adds new individual evidence for the use of the four branded formulations of the two commercially available botulinum toxin serotypes, A and B, for the aforementioned indications rather than lumping all recommendations for botulinum toxin together as in the 2008 guidelines. However, questions remain on the differences between the different products in clinical practice, especially since the formulations show little clinical difference in head-to-head comparisons for some of the indications, especially for the serotype A formulations.

Jeff Evans/Frontline Medical News

In a press briefing on the new guidelines at the annual meeting of the American Academy of Neurology, guidelines coauthor Dr. Mark Hallett noted that nothing really surprised the experienced 14-member committee that put the guidelines together. “The reason that we chose these four different diseases is because we already had the sense that they were going to change in the particular ways that they did. We didn’t know exactly, of course, what was going to happen, but we had a sense that there were sufficient data that it was worth looking at them.”

For blepharospasm, the totality of evidence suggests that onabotulinumtoxinA (onaBoNT-A; Botox) and incobotulinumtoxinA (incoBoNT-A; Xeomin) injections should be considered and are probably safe and effective (level B recommendation), while abobotulinumtoxinA (aboBoNT-A; Dysport) may be considered (level C) and is possibly effective. The evidence shows that incoBoNT-A and onaBoNT-A have equivalent efficacy and aboBoNT-A and onaBoNT-A are possibly equivalent. There was not enough evidence to determine the efficacy of rimabotulinumtoxinB for blepharospasm (rimaBoNT-B; Myobloc).

The rigorousness of clinical trials in evaluating the efficacy and safety of botulinum toxin has evolved since the Food and Drug Administration approved onaBoNT-A and incoBoNT-A to treat blepharospasm, but no new trials have been conducted to give it a higher level of recommendation despite their well-known magnitude of benefit, said Dr. Hallett, chief of the National Institute of Neurological Disorders and Stroke medical neurology branch and its human motor control section.

New evidence added to the already well-established data on the effectiveness of botulinum toxin for cervical dystonia suggest that onaBoNT-A and incoBoNT-A are probably safe and effective and should be considered. In addition, aboBoNT-A and rimaBoNT-B have already proven effectiveness and safety and should be offered. The lack of class I studies for onaBoNT-A and incoBoNT-A led to the lower level of recommendation for them despite an extensive clinical history of their use in cervical dystonia, the guideline committee wrote (Neurology. 2016 Apr 18. doi: 10.1212/WNL.0000000000002560).

In adults with upper-limb spasticity, all three serotype A formulations – onaBoNT-A, aboBoNT-A, and incoBoNT-A – are effective and safe in reducing symptoms and improving passive limb function. All three achieved level A evidence to recommend that they should be offered. One comparative trial showed enough evidence to say that onaBoNT-A is probably superior to tizanidine for reducing upper-extremity tone and should be considered before it. RimaBoNT-B has level B evidence to advise that it should be considered and is probably safe and effective. None of the formulations have enough data to determine their efficacy on active limb function.

Fewer trials have examined the safety and effectiveness of botulinum toxin formulations for reducing lower leg spasticity in adults. The guidelines panel found enough evidence to recommend that aboBoNT-A and onaBoNT-A are safe and effective and should be offered (level A). There were no trials with high enough level of quality to determine whether incoBoNT-A or rimaBoNT-B were effective for lower-leg spasticity. None of the four agents had enough evidence to support their ability to improve active function associated with lower-limb spasticity.

At the press briefing, guidelines first author Dr. David M. Simpson expressed hope that a more refined methodology for evaluating spasticity might be achieved in future trials of botulinum toxin to detect the potentially subtle effects the agents may have on certain patients who are more likely to achieve benefits in active limb function. Currently, trials use a standardized set of outcomes to try to detect differences in patients with wide-ranging severity of symptoms and types of injury that led to spasticity. Dr. Simpson is professor of neurology at Mount Sinai in New York, as well as director of the neuromuscular diseases division and director of the clinical neurophysiology laboratories.

Positive results for onaBoNT-A in two pivotal trials in chronic migraine that were published since the last guidelines give the formulation the only FDA-approved indication for a botulinum toxin in chronic migraine and earned it a level A recommendation from the guidelines committee. However, in the trials it had a relatively small magnitude of efficacy in reducing the number of headache days by 15% versus placebo. The guidelines also advise not using onaBoNT-A in episodic migraine based on three negative trials. No high-quality trials have evaluated any formulation to change the overall 2008 guidelines’ advice that botulinum toxin is probably ineffective for treating chronic tension-type headaches.

Familiarity with appropriate dosing and side effects may allow clinicians to use the products off-label for indications in the guidelines for which clinical trials were not available, Dr. Richard L. Barbano of the movement disorders division at the University of Rochester noted in an editorial about the guidelines (Neurol Clin Pract. 2016 Apr 18. doi: 10.1212/CPJ.0000000000000244). “Off-label use is common in clinical practice. Little data exist to indicate that any of the different formulations, with attention to appropriate dosing and side effects, would not be effective in treating these other conditions. There are also a number of other neurologic conditions not discussed in the guideline in which botulinum toxin has shown efficacy, such as hemifacial spasm and other focal dystonias. Lack of sufficient high-level evidence to support a level A or B guideline recommendation does not negate their potential utility and likewise, there is little evidence to recommend one formulation over another.”

“In some circumstances where the drugs are relatively equivalent, some people prefer to stick with one so they get used to it more, and they can have more of a sense of what the dosing is, given that the doses may be different with the compounds and have different side effects,” Dr. Hallett said in an interview, noting that availability and price also might enter into a clinician’s decision on what to do.

Dr. Barbano also said that cost and value are becoming more important, and neurologists should consider when botulinum toxin therapy should be chosen among existing alternative treatment options, particularly for chronic migraine.

The guidelines are endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine and the American Society of Plastic Surgeons.

Dr. Hallett reported serving as chair of the Neurotoxin Institute Advisory Council and has received research grants from Allergan and Merz Pharmaceuticals. Dr. Simpson reported receiving research grants from and served as a consultant for Allergan, Ipsen, Merz Pharmaceuticals, and Acorda Therapeutics. Five other coauthors of the guidelines disclosed relationships with manufacturers of botulinum toxin formulations. Dr. Barbano reported serving on a scientific advisory board for Allergan and receiving research support from Allergan, Vaccinex, and Biotie.

[email protected]

VANCOUVER – A new American Academy of Neurology practice guideline on the efficacy and safety evidence for botulinum toxin treatment of blepharospasm, cervical dystonia, spasticity, and headache has updated the last recommendations published in 2008, but leaves some relevant clinical concerns and off-label uses unaddressed.

The 2016 update, published April 18 in Neurology, adds new individual evidence for the use of the four branded formulations of the two commercially available botulinum toxin serotypes, A and B, for the aforementioned indications rather than lumping all recommendations for botulinum toxin together as in the 2008 guidelines. However, questions remain on the differences between the different products in clinical practice, especially since the formulations show little clinical difference in head-to-head comparisons for some of the indications, especially for the serotype A formulations.

Jeff Evans/Frontline Medical News

In a press briefing on the new guidelines at the annual meeting of the American Academy of Neurology, guidelines coauthor Dr. Mark Hallett noted that nothing really surprised the experienced 14-member committee that put the guidelines together. “The reason that we chose these four different diseases is because we already had the sense that they were going to change in the particular ways that they did. We didn’t know exactly, of course, what was going to happen, but we had a sense that there were sufficient data that it was worth looking at them.”

For blepharospasm, the totality of evidence suggests that onabotulinumtoxinA (onaBoNT-A; Botox) and incobotulinumtoxinA (incoBoNT-A; Xeomin) injections should be considered and are probably safe and effective (level B recommendation), while abobotulinumtoxinA (aboBoNT-A; Dysport) may be considered (level C) and is possibly effective. The evidence shows that incoBoNT-A and onaBoNT-A have equivalent efficacy and aboBoNT-A and onaBoNT-A are possibly equivalent. There was not enough evidence to determine the efficacy of rimabotulinumtoxinB for blepharospasm (rimaBoNT-B; Myobloc).

The rigorousness of clinical trials in evaluating the efficacy and safety of botulinum toxin has evolved since the Food and Drug Administration approved onaBoNT-A and incoBoNT-A to treat blepharospasm, but no new trials have been conducted to give it a higher level of recommendation despite their well-known magnitude of benefit, said Dr. Hallett, chief of the National Institute of Neurological Disorders and Stroke medical neurology branch and its human motor control section.

New evidence added to the already well-established data on the effectiveness of botulinum toxin for cervical dystonia suggest that onaBoNT-A and incoBoNT-A are probably safe and effective and should be considered. In addition, aboBoNT-A and rimaBoNT-B have already proven effectiveness and safety and should be offered. The lack of class I studies for onaBoNT-A and incoBoNT-A led to the lower level of recommendation for them despite an extensive clinical history of their use in cervical dystonia, the guideline committee wrote (Neurology. 2016 Apr 18. doi: 10.1212/WNL.0000000000002560).

In adults with upper-limb spasticity, all three serotype A formulations – onaBoNT-A, aboBoNT-A, and incoBoNT-A – are effective and safe in reducing symptoms and improving passive limb function. All three achieved level A evidence to recommend that they should be offered. One comparative trial showed enough evidence to say that onaBoNT-A is probably superior to tizanidine for reducing upper-extremity tone and should be considered before it. RimaBoNT-B has level B evidence to advise that it should be considered and is probably safe and effective. None of the formulations have enough data to determine their efficacy on active limb function.

Fewer trials have examined the safety and effectiveness of botulinum toxin formulations for reducing lower leg spasticity in adults. The guidelines panel found enough evidence to recommend that aboBoNT-A and onaBoNT-A are safe and effective and should be offered (level A). There were no trials with high enough level of quality to determine whether incoBoNT-A or rimaBoNT-B were effective for lower-leg spasticity. None of the four agents had enough evidence to support their ability to improve active function associated with lower-limb spasticity.

At the press briefing, guidelines first author Dr. David M. Simpson expressed hope that a more refined methodology for evaluating spasticity might be achieved in future trials of botulinum toxin to detect the potentially subtle effects the agents may have on certain patients who are more likely to achieve benefits in active limb function. Currently, trials use a standardized set of outcomes to try to detect differences in patients with wide-ranging severity of symptoms and types of injury that led to spasticity. Dr. Simpson is professor of neurology at Mount Sinai in New York, as well as director of the neuromuscular diseases division and director of the clinical neurophysiology laboratories.

Positive results for onaBoNT-A in two pivotal trials in chronic migraine that were published since the last guidelines give the formulation the only FDA-approved indication for a botulinum toxin in chronic migraine and earned it a level A recommendation from the guidelines committee. However, in the trials it had a relatively small magnitude of efficacy in reducing the number of headache days by 15% versus placebo. The guidelines also advise not using onaBoNT-A in episodic migraine based on three negative trials. No high-quality trials have evaluated any formulation to change the overall 2008 guidelines’ advice that botulinum toxin is probably ineffective for treating chronic tension-type headaches.

Familiarity with appropriate dosing and side effects may allow clinicians to use the products off-label for indications in the guidelines for which clinical trials were not available, Dr. Richard L. Barbano of the movement disorders division at the University of Rochester noted in an editorial about the guidelines (Neurol Clin Pract. 2016 Apr 18. doi: 10.1212/CPJ.0000000000000244). “Off-label use is common in clinical practice. Little data exist to indicate that any of the different formulations, with attention to appropriate dosing and side effects, would not be effective in treating these other conditions. There are also a number of other neurologic conditions not discussed in the guideline in which botulinum toxin has shown efficacy, such as hemifacial spasm and other focal dystonias. Lack of sufficient high-level evidence to support a level A or B guideline recommendation does not negate their potential utility and likewise, there is little evidence to recommend one formulation over another.”

“In some circumstances where the drugs are relatively equivalent, some people prefer to stick with one so they get used to it more, and they can have more of a sense of what the dosing is, given that the doses may be different with the compounds and have different side effects,” Dr. Hallett said in an interview, noting that availability and price also might enter into a clinician’s decision on what to do.

Dr. Barbano also said that cost and value are becoming more important, and neurologists should consider when botulinum toxin therapy should be chosen among existing alternative treatment options, particularly for chronic migraine.

The guidelines are endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine and the American Society of Plastic Surgeons.

Dr. Hallett reported serving as chair of the Neurotoxin Institute Advisory Council and has received research grants from Allergan and Merz Pharmaceuticals. Dr. Simpson reported receiving research grants from and served as a consultant for Allergan, Ipsen, Merz Pharmaceuticals, and Acorda Therapeutics. Five other coauthors of the guidelines disclosed relationships with manufacturers of botulinum toxin formulations. Dr. Barbano reported serving on a scientific advisory board for Allergan and receiving research support from Allergan, Vaccinex, and Biotie.

[email protected]

VANCOUVER – A new American Academy of Neurology practice guideline on the efficacy and safety evidence for botulinum toxin treatment of blepharospasm, cervical dystonia, spasticity, and headache has updated the last recommendations published in 2008, but leaves some relevant clinical concerns and off-label uses unaddressed.

The 2016 update, published April 18 in Neurology, adds new individual evidence for the use of the four branded formulations of the two commercially available botulinum toxin serotypes, A and B, for the aforementioned indications rather than lumping all recommendations for botulinum toxin together as in the 2008 guidelines. However, questions remain on the differences between the different products in clinical practice, especially since the formulations show little clinical difference in head-to-head comparisons for some of the indications, especially for the serotype A formulations.

Jeff Evans/Frontline Medical News

In a press briefing on the new guidelines at the annual meeting of the American Academy of Neurology, guidelines coauthor Dr. Mark Hallett noted that nothing really surprised the experienced 14-member committee that put the guidelines together. “The reason that we chose these four different diseases is because we already had the sense that they were going to change in the particular ways that they did. We didn’t know exactly, of course, what was going to happen, but we had a sense that there were sufficient data that it was worth looking at them.”

For blepharospasm, the totality of evidence suggests that onabotulinumtoxinA (onaBoNT-A; Botox) and incobotulinumtoxinA (incoBoNT-A; Xeomin) injections should be considered and are probably safe and effective (level B recommendation), while abobotulinumtoxinA (aboBoNT-A; Dysport) may be considered (level C) and is possibly effective. The evidence shows that incoBoNT-A and onaBoNT-A have equivalent efficacy and aboBoNT-A and onaBoNT-A are possibly equivalent. There was not enough evidence to determine the efficacy of rimabotulinumtoxinB for blepharospasm (rimaBoNT-B; Myobloc).

The rigorousness of clinical trials in evaluating the efficacy and safety of botulinum toxin has evolved since the Food and Drug Administration approved onaBoNT-A and incoBoNT-A to treat blepharospasm, but no new trials have been conducted to give it a higher level of recommendation despite their well-known magnitude of benefit, said Dr. Hallett, chief of the National Institute of Neurological Disorders and Stroke medical neurology branch and its human motor control section.

New evidence added to the already well-established data on the effectiveness of botulinum toxin for cervical dystonia suggest that onaBoNT-A and incoBoNT-A are probably safe and effective and should be considered. In addition, aboBoNT-A and rimaBoNT-B have already proven effectiveness and safety and should be offered. The lack of class I studies for onaBoNT-A and incoBoNT-A led to the lower level of recommendation for them despite an extensive clinical history of their use in cervical dystonia, the guideline committee wrote (Neurology. 2016 Apr 18. doi: 10.1212/WNL.0000000000002560).

In adults with upper-limb spasticity, all three serotype A formulations – onaBoNT-A, aboBoNT-A, and incoBoNT-A – are effective and safe in reducing symptoms and improving passive limb function. All three achieved level A evidence to recommend that they should be offered. One comparative trial showed enough evidence to say that onaBoNT-A is probably superior to tizanidine for reducing upper-extremity tone and should be considered before it. RimaBoNT-B has level B evidence to advise that it should be considered and is probably safe and effective. None of the formulations have enough data to determine their efficacy on active limb function.

Fewer trials have examined the safety and effectiveness of botulinum toxin formulations for reducing lower leg spasticity in adults. The guidelines panel found enough evidence to recommend that aboBoNT-A and onaBoNT-A are safe and effective and should be offered (level A). There were no trials with high enough level of quality to determine whether incoBoNT-A or rimaBoNT-B were effective for lower-leg spasticity. None of the four agents had enough evidence to support their ability to improve active function associated with lower-limb spasticity.

At the press briefing, guidelines first author Dr. David M. Simpson expressed hope that a more refined methodology for evaluating spasticity might be achieved in future trials of botulinum toxin to detect the potentially subtle effects the agents may have on certain patients who are more likely to achieve benefits in active limb function. Currently, trials use a standardized set of outcomes to try to detect differences in patients with wide-ranging severity of symptoms and types of injury that led to spasticity. Dr. Simpson is professor of neurology at Mount Sinai in New York, as well as director of the neuromuscular diseases division and director of the clinical neurophysiology laboratories.

Positive results for onaBoNT-A in two pivotal trials in chronic migraine that were published since the last guidelines give the formulation the only FDA-approved indication for a botulinum toxin in chronic migraine and earned it a level A recommendation from the guidelines committee. However, in the trials it had a relatively small magnitude of efficacy in reducing the number of headache days by 15% versus placebo. The guidelines also advise not using onaBoNT-A in episodic migraine based on three negative trials. No high-quality trials have evaluated any formulation to change the overall 2008 guidelines’ advice that botulinum toxin is probably ineffective for treating chronic tension-type headaches.

Familiarity with appropriate dosing and side effects may allow clinicians to use the products off-label for indications in the guidelines for which clinical trials were not available, Dr. Richard L. Barbano of the movement disorders division at the University of Rochester noted in an editorial about the guidelines (Neurol Clin Pract. 2016 Apr 18. doi: 10.1212/CPJ.0000000000000244). “Off-label use is common in clinical practice. Little data exist to indicate that any of the different formulations, with attention to appropriate dosing and side effects, would not be effective in treating these other conditions. There are also a number of other neurologic conditions not discussed in the guideline in which botulinum toxin has shown efficacy, such as hemifacial spasm and other focal dystonias. Lack of sufficient high-level evidence to support a level A or B guideline recommendation does not negate their potential utility and likewise, there is little evidence to recommend one formulation over another.”

“In some circumstances where the drugs are relatively equivalent, some people prefer to stick with one so they get used to it more, and they can have more of a sense of what the dosing is, given that the doses may be different with the compounds and have different side effects,” Dr. Hallett said in an interview, noting that availability and price also might enter into a clinician’s decision on what to do.

Dr. Barbano also said that cost and value are becoming more important, and neurologists should consider when botulinum toxin therapy should be chosen among existing alternative treatment options, particularly for chronic migraine.

The guidelines are endorsed by the American Association of Neuromuscular & Electrodiagnostic Medicine and the American Society of Plastic Surgeons.

Dr. Hallett reported serving as chair of the Neurotoxin Institute Advisory Council and has received research grants from Allergan and Merz Pharmaceuticals. Dr. Simpson reported receiving research grants from and served as a consultant for Allergan, Ipsen, Merz Pharmaceuticals, and Acorda Therapeutics. Five other coauthors of the guidelines disclosed relationships with manufacturers of botulinum toxin formulations. Dr. Barbano reported serving on a scientific advisory board for Allergan and receiving research support from Allergan, Vaccinex, and Biotie.

[email protected]

A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.

The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.

Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.

[email protected]

A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.

The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.

Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.

[email protected]

A biosimilar version of the anti–tumor necrosis factor–alpha agent Remicade has been approved by the Food and Drug Administration, making it the first biosimilar drug approved by the agency for inflammatory diseases and just the second biosimilar it has approved.

The agency said in its April 5 announcement that the biosimilar drug, to be marketed as Inflectra, will have the same indications as Remicade: moderately to severely active Crohn’s disease in patients aged 6 years and older who have had an inadequate response to conventional therapy; moderately to severely active ulcerative colitis that has inadequately responded to conventional therapy; moderately to severely active rheumatoid arthritis in combination with methotrexate; active ankylosing spondylitis; active psoriatic arthritis; and chronic, severe plaque psoriasis.

Courtesy Wikimedia Commons/ FitzColinGerald/Creative Commons License

The drug, given the generic name of infliximab-dyyb under the agency’s nomenclature for biosimilar products, earned its approval as a biosimilar by showing it has no clinically meaningful differences in terms of safety and effectiveness from Remicade. According to FDA regulations, biosimilar products can have only minor differences in clinically inactive components and must have the same mechanism(s) of action (to the extent that it is known) and route(s) of administration, dosage form(s), and strength(s) as the reference product; and can be approved only for the indication(s) and condition(s) of use that have been approved for the reference product.

Inflectra’s approval is only as a biosimilar, not as an interchangeable product. The agency has yet to define the regulatory requirements for interchangeability that are necessary to meet the requirements of the Biologics Price Competition and Innovation Act of 2009. That Act states that an approved biosimilar “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” A statement about implementation of the Act on the FDA website explains that for interchangeability, “a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product.”

Like Remicade, Inflectra will come with a boxed warning and a Medication Guide that describes important information about its uses and risks, which include serious infections (tuberculosis, bacterial sepsis, invasive fungal infections, and others), lymphoma and other malignancies, liver injury, blood problems, lupuslike syndrome, psoriasis, and in rare cases, nervous system disorders.

Inflectra is manufactured by Celltrion, based in South Korea, for Illinois-based Hospira. Inflectra’s label can be found here.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

[email protected]

The lack of available treatments that adequately treat Parkinson’s disease psychosis proved to be a big motivating factor for a majority of members of the Food and Drug Administration’s Psychopharmacologic Drugs Advisory Committee, who voted at a meeting March 29 that the benefits of the novel drug pimavanserin outweigh its risks.

The panel voted 12-2 in support of the benefit-to-risk ratio for pimavanserin, a selective 5-hydroxytryptamine_2A (5-HT_2A) inverse agonist that does not affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems, according to its developer, Acadia Pharmaceuticals.

Although Acadia submitted just one positive phase III trial out of a total of four 6-week, randomized, placebo-controlled trials of pimavanserin, committee members voted 12-2 that the company “provided substantial evidence of the effectiveness” of the drug for the treatment of psychosis associated with Parkinsons’s disease (PDP). Another 11-3 vote supported the question of whether pimavanersin’s safety profile was “adequately characterized.”

Results from the single phase III trial conducted in 199 patients with Parkinsons’s disease psychosis (PDP) unequivocally showed that 34 mg/day pimavanserin improved scores on an abbreviated, 9-item version of the 20-item Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions score, called the SAPS-PD. After 6 weeks, SAPS-PD scores declined by a statistically significant 3.1 points or 23.1% on active treatment versus placebo, which was an absolute decrease of about 6 points from baseline. One of the questions brought up by FDA reviewers and panelists was whether the 3.1-point difference (on the SAPS-PD’s 45-point scale) seen between active treatment and placebo was of great enough clinical benefit to outweigh the higher rate of serious adverse events observed with pimavanserin versus placebo across all of the 6-week trials.

Across all four 6-week studies, serious adverse events occurred in 16 (7.9%) of 202 patients who took 34 mg pimavanserin and in 8 (3.5%) of 231 placebo-treated patients. Three deaths occurred in the patients who received pimavanserin, and one in the placebo arms. However, none of the deaths were considered to be a drug-related event, and the deaths were not pathologically unique relative to what is expected in the disease course of patients with PDP. The death of another patient who had received 10 mg pimavanserin in an earlier uncontrolled trial also was reported.

Meanwhile, the drug did not worsen motor symptoms of Parkinson’s disease.

FDA analyses showed that 11 patients would need to be treated in order for 1 patient to have a 50% reduction in the SAPS-PD, which corresponds to “much improvement,” whereas 22 patients would need to be treated for 1 to be harmed with a serious adverse event (SAE). This means that for every two patients who have a 50% reduction in the SAPS-PD, one will have a serious adverse event attributable to pimavanserin. Overall, 37.2% of patients in the pimavanserin arm of the phase III trial had a 50% decline in the SAPS-PD after 6 weeks, compared with 27.8% in the placebo arm.

However, the number needed to harm/number needed to treat ratio for SAEs had wide confidence intervals, and there was a high degree of uncertainty about its magnitude such that the inclusion of just one or two more SAEs would substantially change the ratio, many panelists agreed.

Some panelists voiced concern about pimavanserin being called an antipsychotic, even though it has demonstrated no proof of efficacy in conditions with classical symptoms of psychosis, such as schizophrenia, and worried about its off-label use in patients with other conditions who have psychotic symptoms. They also called for a postmarketing observational study to track the safety of the drug if it is approved.

Pimavanserin’s application received breakthrough drug status from the FDA and was fast tracked, and a decision is expected from the agency by May 1. If approved, pimavanserin would be marketed under the trade name Nuplazid.

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Patients with childhood-onset systemic lupus erythematosus (SLE) who transitioned to adult care without a formal transitioning process had long periods without care despite having moderate disease activity and also frequently reported anxiety and depression in a retrospective study of 50 patients during a 3-year period at Brigham and Women’s Hospital Lupus Center in Boston.

Dr. Mary Beth Son of Boston Children’s Hospital and her colleagues found that the patients went a mean of nearly 9 months from their last pediatric rheumatology visit to their first adult rheumatology visit, and 72% had at least one gap in care, defined as no appointments in a recommended time frame. A total of 32% had more than one missed appointment, although there was an average of only 9% of appointments missed per patient. The investigators determined that missed appointments were significantly associated with white race, education below the high school level, and medication nonadherence (Lupus. 2016 Mar 23. doi: 10.1177/0961203316640913).

©Stuart Jenner/Thinkstock

“The finding of lower educational level leading to a suboptimal transition outcome may help to delineate an at-risk population that requires further support during the process of transition. ... Although missed appointments weren’t prominent, the majority of our patients experienced gaps in care whereby they didn’t schedule appointments within the recommended time frame per the treating physician. The lack of appropriate scheduling with its concomitant potentially serious consequences demonstrates the need to educate transition patients regarding the importance of scheduling their own appointments,” the investigators wrote.

Scores of the SLE Disease Activity Index remained stable from a mean of 5.7 at baseline to 4.7 at year 3, but Systemic Lupus International Collaborating Clinics/ACR Damage Index for Systemic Lupus Erythematosus scores rose significantly from 0.46 to 0.78. Depression and anxiety diagnoses or symptoms increased significantly from 10% to 26%, and the investigators noted that “more than one-quarter of them required support from social work for a variety of serious circumstances including homelessness, substance abuse, and incarceration.”

The patients were diagnosed at a mean age of 14.5 years, and most were white (42%), African American (22%), Hispanic (22%), or Asian (10%). They had a mean age of 19.5 years at their first Lupus Center visit and 21.9 years at their last.

The investigators noted that the patients’ relatively high socioeconomic status (zip code–based annual household income of $50,000-$100,000 in 60% and $100,000 or more in 32%) may limit the generalizability of the study.

The authors reported having no relevant conflicts of interest. Dr. Son was supported by a Boston Children’s Hospital Career Development Fellowship and another author’s grant from the National Institutes of Health helped to support the study.

[email protected]

Patients with childhood-onset systemic lupus erythematosus (SLE) who transitioned to adult care without a formal transitioning process had long periods without care despite having moderate disease activity and also frequently reported anxiety and depression in a retrospective study of 50 patients during a 3-year period at Brigham and Women’s Hospital Lupus Center in Boston.

Dr. Mary Beth Son of Boston Children’s Hospital and her colleagues found that the patients went a mean of nearly 9 months from their last pediatric rheumatology visit to their first adult rheumatology visit, and 72% had at least one gap in care, defined as no appointments in a recommended time frame. A total of 32% had more than one missed appointment, although there was an average of only 9% of appointments missed per patient. The investigators determined that missed appointments were significantly associated with white race, education below the high school level, and medication nonadherence (Lupus. 2016 Mar 23. doi: 10.1177/0961203316640913).

©Stuart Jenner/Thinkstock

“The finding of lower educational level leading to a suboptimal transition outcome may help to delineate an at-risk population that requires further support during the process of transition. ... Although missed appointments weren’t prominent, the majority of our patients experienced gaps in care whereby they didn’t schedule appointments within the recommended time frame per the treating physician. The lack of appropriate scheduling with its concomitant potentially serious consequences demonstrates the need to educate transition patients regarding the importance of scheduling their own appointments,” the investigators wrote.

Scores of the SLE Disease Activity Index remained stable from a mean of 5.7 at baseline to 4.7 at year 3, but Systemic Lupus International Collaborating Clinics/ACR Damage Index for Systemic Lupus Erythematosus scores rose significantly from 0.46 to 0.78. Depression and anxiety diagnoses or symptoms increased significantly from 10% to 26%, and the investigators noted that “more than one-quarter of them required support from social work for a variety of serious circumstances including homelessness, substance abuse, and incarceration.”

The patients were diagnosed at a mean age of 14.5 years, and most were white (42%), African American (22%), Hispanic (22%), or Asian (10%). They had a mean age of 19.5 years at their first Lupus Center visit and 21.9 years at their last.

The investigators noted that the patients’ relatively high socioeconomic status (zip code–based annual household income of $50,000-$100,000 in 60% and $100,000 or more in 32%) may limit the generalizability of the study.

The authors reported having no relevant conflicts of interest. Dr. Son was supported by a Boston Children’s Hospital Career Development Fellowship and another author’s grant from the National Institutes of Health helped to support the study.

[email protected]

Patients with childhood-onset systemic lupus erythematosus (SLE) who transitioned to adult care without a formal transitioning process had long periods without care despite having moderate disease activity and also frequently reported anxiety and depression in a retrospective study of 50 patients during a 3-year period at Brigham and Women’s Hospital Lupus Center in Boston.

Dr. Mary Beth Son of Boston Children’s Hospital and her colleagues found that the patients went a mean of nearly 9 months from their last pediatric rheumatology visit to their first adult rheumatology visit, and 72% had at least one gap in care, defined as no appointments in a recommended time frame. A total of 32% had more than one missed appointment, although there was an average of only 9% of appointments missed per patient. The investigators determined that missed appointments were significantly associated with white race, education below the high school level, and medication nonadherence (Lupus. 2016 Mar 23. doi: 10.1177/0961203316640913).

©Stuart Jenner/Thinkstock

“The finding of lower educational level leading to a suboptimal transition outcome may help to delineate an at-risk population that requires further support during the process of transition. ... Although missed appointments weren’t prominent, the majority of our patients experienced gaps in care whereby they didn’t schedule appointments within the recommended time frame per the treating physician. The lack of appropriate scheduling with its concomitant potentially serious consequences demonstrates the need to educate transition patients regarding the importance of scheduling their own appointments,” the investigators wrote.

Scores of the SLE Disease Activity Index remained stable from a mean of 5.7 at baseline to 4.7 at year 3, but Systemic Lupus International Collaborating Clinics/ACR Damage Index for Systemic Lupus Erythematosus scores rose significantly from 0.46 to 0.78. Depression and anxiety diagnoses or symptoms increased significantly from 10% to 26%, and the investigators noted that “more than one-quarter of them required support from social work for a variety of serious circumstances including homelessness, substance abuse, and incarceration.”

The patients were diagnosed at a mean age of 14.5 years, and most were white (42%), African American (22%), Hispanic (22%), or Asian (10%). They had a mean age of 19.5 years at their first Lupus Center visit and 21.9 years at their last.

The investigators noted that the patients’ relatively high socioeconomic status (zip code–based annual household income of $50,000-$100,000 in 60% and $100,000 or more in 32%) may limit the generalizability of the study.

The authors reported having no relevant conflicts of interest. Dr. Son was supported by a Boston Children’s Hospital Career Development Fellowship and another author’s grant from the National Institutes of Health helped to support the study.

[email protected]