The 69th American Academy of Neurology Annual Meeting (AAN 2017)
New Data on Teriflunomide, Alemtuzumab Announced
SANOFI GENZYME ANNOUNCED additional investigational data on 2 multiple sclerosis (MS) drugs stemming from follow-ups in phase 3 trials.
Teriflunomide (Aubagio) has been FDA-approved since 2012 and is an oral treatment for relapsing MS. Data announced at the AAN meeting came from the TOPIC trial, designed to assess whether early initiation of the drug following a first clinical episode of MS might delay or prevent progression to clinically definite multiple sclerosis (CDMS). In the trial, patients on both 7-mg and 14-mg regimens were “significantly less likely than placebo (P < .05) to develop CDMS, the primary endpoint.”
The crux of the terflunomide announcement, however, had to do with cortical gray matter atrophy. The drug was shown to have a “consistent and significant effect on reducing cortical gray matter atrophy across all time points evaluated over 2 years,” accord- ing to a news release from the company.
Cortical gray matter volume (CGMV) was measured using SIENAX multi-time point analysis at baseline and every 6 months for 2 years. Roughly 200 patients were in the placebo, 7-mg, and 14-mg groups.
Comparative retention versus placebo was higher through- out the study, but varied: 58.2% in the 7-mg group (P = .071) and 119.2% in the 14-mg group at 6 months (P = .017); 79.8% (P = .054) and 61.4% (P = .036), respectively, at 12 months; 69.5% (P = .004) and 66.8% (P = .003) at 18 months; and 46.0% and 40.2% (P = .042) at 24 months.
“The reduced risk of conversion to CDMS indicates that teriflunomide may favorably impact the early neurodegenerative com- ponent of MS,” that study concluded.
The company’s other announcement regarded alemtuzumab (Lemtrada), and included 6 years of extension data from the CARE-MS II study. The twice-annually infused drug was studied in
patients with relapsing-remitting multiple sclerosis (RRMS) judged to have highly active disease (HAD), defined as ≥2 relapses in the year prior to randomization and ≥1 gadolinium-enhancing lesion at baseline. The extension period followed the 2-year core study, focused on disease progression, and allowed patients to receive as-needed alemtuzumab or other disease-modifying treatment.
Patients received either the alemtuzumab infusions twice per year or 44 g of interferon beta-1a 3 times per week. The study assessed patients on multiple metrics, including Functional Assessment of MS; a short-form, 36-item survey (SF-36) that had both physical and mental component summaries; and an EuroQol-5 dimensions visual analog scale.
In each case, the drug seemed to provide what the study called “durable efficacy in the absence of continuous treatment.”
Perhaps most significantly to the company, the results indicated that a disease relapse did not necessarily spell a lack of response to the drug. “The 24% of Lemtrada-treated patients in CARE-MS II who relapsed between their first and second courses experienced a marked improvement in clinical and MRI disease activity at year 2, which was maintained through 6 years,” the press release quoted Barry Singer, MD, the director of the MS Center for Innovations in Care at Missouri Baptist Medical Center in St. Louis.
In patients who had relapsed between treatment courses, the annual relapse rate declined continuously from year 1 through year 6, and in those who had not relapsed, the rate maintained a low of 0.2 until dropping to 0.1 in year 6. In those who had relapsed, 80% were also free of confirmed disease worsening be- tween years 1 and 2, dipping to 60% by year 6, with even higher number in the nonrelapsing group.
Both studies were presented in poster sessions at the conference and featured research sponsored by Sanofi Genzyme. ■
Brivaracetam Safe With Other Epilepsy Drugs
IN A POSTER, RESEARCHERS from the University of Cincinnati studied brivaracetam (Briviact/UCB Pharma) for drug–drug interactions (DDIs) using data from a wealth of previous phase 2 and phase 3 studies. Brivaracetam is an antiepileptic drug that was approved for use by the Food and Drug Administration (FDA) in 2016.
The drug was approved because it was shown to be effective in reducing seizure frequency when combined with other agents. Upon approval, Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research, said he was “pleased that patients with epilepsy have a new treatment option,” citing the wide range of responses people with epilepsy have to various drugs designed for it.
The drug is approved as an add-on treatment for those 16 years or older who have partial, or focal, seizures. Given its status as an add-on, any DDIs it may have are important to know. Although its exact working mechanism is unknown, it has a selective affinity for protein 2A in the brain, potentially contributing to its anticonvulsant effect. It’s typically taken twice daily in doses ranging between 50 mg and 200 mg.
In the study, the drug’s impact on enzyme-inducing antiepileptic drugs (AEDs) including carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PBI) was assessed in 5 different phase 2 and 3 trials, and its impact on CYP3A was investigated in healthy controls using midazolam as a probe.
“In patients with epilepsy, brivaracetam did not alter the concentrations of AEDs lamotrigine, levetiracetam, oxcarbazepine, topiramate, valproate, carbamazepine, lacosamide, PBI, pregabalin, phenytoin, or zonisamide, in a clinically relevant manner,” the team, led by Brian Moseley, MD, concluded. A “modest increase” in PHT exposure was, however, observed when combined with a “supra-therapeutic” 400-mg daily dose of brivaracetam.
The drug did significantly increase CBZ epoxide concentration in a dose-related manner, but that increase was not observed to indicate symptoms of toxicity. It did not significantly inhibit nor induce CYP3A. The authors also found it had no clinically significant effects on oral contraceptives.
The only notable exception in terms of DDIs was rifampin, which the study calls a “potent, enzyme-inducing antibiotic.” Brivaracetam exposure was nearly halved by the product, requiring an increased dose “of up to 100% in patients on concomitant rifampin.” It was the only counteraction that brought a recommendation of dose adjustment.
The findings of the meta-analysis led the authors to conclude that brivaracetam “is unlikely to have clinically relevant interactions with any commonly prescribed AEDs,” and that dosage adjustments would not be required when co-administered with CBZ, PBI, PHT, or contraceptives, but monitoring of PHT levels was recommended. ■
Early Findings Suggest Potential New Treatment for MS
PRELIMINARY STUDY results hint at the possibility for a new type of progressive multiple sclerosis (MS) treatment. Data from the first 6 patients enrolled in the phase 1 study, designed to include 10 patients, were presented at the AAN meeting.
Researchers from The University of Queensland, Brisbane, Australia, led by Michael Pender, MD, PhD, sought to investigate the relationship between MS and the common herpes virus Epstein-Barr virus (EBV), a virus that causes no symptoms in most people, but often leads to mononucleosis if contracted as a teenager or adult.
The study focused on the initial 6 individuals with progressive MS who also had moderate to severe disability. The researchers found that some patients with MS experience altered immune response, leading T cells to be unable to control EBV-infected B cells. The cells, when accumulated, would produce antibodies that destroy myelin.
For the study, the team removed the patients’ own T cells and stimulated them to recognize and kill all cells infected with EBV. Patients were injected with infusions of escalating T-cell doses every 2 to 8 weeks and were followed through 26 weeks specifically to assess side effects and potential signs of improvement.
The hope was that eliminating EBV-infected B cells could suppress myelin eradication in patients with MS, curbing the incidence of neurologic dysfunction. According to Pender, even though the initial goal of the study wasn’t to measure the treatment’s efficacy, 3 of the 6 study participants reportedly had improved symptoms following the first infusion:
- One person with secondary progressive MS had a significant increase in ambulation from 100 yards with a walker at the start of the study, and over the previous 5 years, to three-quarters of a mile and was later able to walk shorter distances with only 1-sided assistance.
- Another participant exhibited improved color vision and visual acuity.
- All 3 responding patients showed improvements in fatigue and the ability to complete daily activities.
Despite these positive results, the researchers acknowledged the need for a larger patient cohort to further evaluate the findings. “While these results are very preliminary and much more research is needed, we are excited there were no serious side effects,” Pender said. ■
AAN Releases Guidelines for Sudden Unexpected Death in Epilepsy
AT A PRESS conference during the AAN meeting, Cynthia L. Harden, MD, clinical epilepsy services at Mount Sinai Health System, and Elizabeth Donner, MD, of the University of Toronto, announced a new set of guidelines from the American Academy of Neurology (AAN) regarding sudden unexpected death in epilepsy, or SUDEP.
“There is an uncommon risk of death that people with epilepsy, and their loved ones, may not know about,” Harden opened in her introduction. “SUDEP is when someone with epilepsy, but other- wise healthy, dies suddenly with no known cause.”
The guideline is a collaboration between the AAN and the American Epilepsy Society and is endorsed by the International Child Neurology Association. Harden says it is intended to “bring clarity to the discussion, giving healthcare providers practical in- formation they can use.”
After extensive reviews, the team found that the condition was rare in children, only impacting 1 in 4500 children with epilepsy per year, although the number is higher for adults, at 1 in 1000. The most major risk factor that the team identified was generalized tonic-clonic seizure, “the kind of seizure that most people think about when they think about seizures,” Donner said.
Those who suffer 3 or more seizures per year are 15 times
more likely to die suddenly than those who did not have such seizures, according to the team’s research. “In total, this translates to up to 18 in 1000 deaths per year in people with epilepsy who have generalized tonic-clonic seizures.”
Donner, reinforcing the importance of putting together these guidelines, said, “I would hope that this can be a motivator to pursue treatments beyond medication when medication isn’t successful at treating seizures...we need people to feel safe and motivated to work with their healthcare team to find other treatments, like surgery and other approaches to managing seizures.”
“Using the AAN guideline methodology, we were able to pro- vide nuance to those risk factors,” Harden said, adding that the importance was being able to separate out risk factors based on the strength of evidence supporting them. Delivering the information to patients is important, says Harden, who “couches” SUDEP as “the most severe risk of epilepsy.”
Donner emphasized the difficulty of discussing epilepsy and death, and the importance of not only addressing the topic in practice but also creating the guidelines. “Parents who have witnessed their child have a particularly convulsive, full-body-shaking seizure are terrified...it’s almost the elephant in the room.”
The research was published in the AAN’s journal Neurology. ■
Cannabidiol May Cut Number of Seizures in Half
THE RESULTS OF a randomized, double-blind, placebo-controlled study presented at the AAN meeting suggests that cannabidiol may cut the number of seizures in half for some children and adults who have Lennox-Gastaut syndrome (LGS).
Beginning in childhood, those with the severe epilepsy syndrome can experience different types of seizures, including atonic drop seizures, in which there is a sudden loss of muscle tone, causing the in- dividual to go limp or collapse. They can also experience tonic-clonic seizures, in which they lose consciousness, their muscles stiffen, and they go into full-body convulsions.
Cannabidiol is a cannabis compound that does not possess the psychoactive properties of THC and does not create a “high” or a feel- ing of being “stoned.”
In the study, nearly 40% of the patients with LGS had at least a 50% reduction in drop seizures when they took a liquid form of cannabidiol, compared with 15% of patients who took a placebo.
“Our study found that cannabidiol shows great promise in that it may reduce seizures that are otherwise difficult to control,” said study author Anup Patel, MD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine in Columbus.
The study followed 225 patients with LGS for 14 weeks; their average age was 16 years. The patients had an average of 85 drop seizures per month, had already tried an average of 6 epilepsy drugs that did not work, and were taking an average of 3 epilepsy drugs during the study.
Patients were given either a higher dose of 20-mg/kg daily cannabidiol, a lower dose of 10-mg/kg daily cannabidiol, or a placebo as an add-on to their current medications. Patients taking the 20-mg dose had a 42% reduction in drop seizures, those taking the 10-mg dose had a 37% reduction, and the placebo group had a 17% reduction in drop seizures.
Up to 66% of the patients who received cannabidiol reported improvement compared with 44% of the patients who received the placebo. A New Drug Application will be submitted to the FDA later this year. The study was supported by GW Pharmaceuticals, the developer of cannabidiol. In the United States, GW operates as Greenwich Biosciences Inc. ■