Next-Generation Headache Treatment Race Heats Up as Competing Companies Release Phase 3 Monoclonal Antibody Data
Eli Lilly and Teva Pharmaceuticals have each unveiled Phase 3 data for their respective monoclonal antibodies in development for the treatment of migraine. Both agents are biologic entities that bind and inhibit the activity of calcitonin gene related peptide (CGRP).
In the EVOLVE-1 study, patients with episodic migraine treated with Lilly’s galcanezumab 120mg over a six-month period experienced an average reduction of 4.7 monthly migraine days. Patients receiving 240mg experienced an average reduction of 4.6 days, compared to 2.8 days for placebo. In the similarly designed EVOLVE-2 study, patients receiving the 120mg dose of galcanezumab experienced an average reduction of 4.3 monthly migraine days, compared to 4.2 days in the 240mg group and 2.3 days for the placebo group.
Additionally, patients treated with galcanezumab experienced statistically significant improvement compared to placebo on several pre-specified secondary endpoints, including response rates and measures of daily activities. Findings from the three-month REGAIN study were similar, with an average reduction of 4.8 days for 120mg and 4.6 days for 240mg as compared to 2.7 days for placebo.
In these three studies, the most common adverse events were injection site reactions, including pain, according to the company. The observed safety and tolerability profile was consistent with findings from previous studies of galcanezumab.
While galcanezumab was investigated for the treatment of episodic migraine, Teva’s fremanezumab was evaluated in patients with chronic migraine. Results from the Phase 3 HALO study showed that patients treated with fremanezumab experienced a statistically significant average reduction of 2.5 days in the number of monthly headache days of at least moderate severity vs. placebo during the 12-week period after first dose, and an average reduction of 4.6 and 4.3 days for monthly and quarterly dosing regimens, respectively. The trial included patients that were on monotherapy as well as those on stable doses of prophylactic medications.
Patients treated with fremanezumab also experienced significant improvement compared to placebo for both monthly and quarterly dosing regimens in response rate, onset of efficacy, efficacy as monotherapy, and disability, according to the findings. The most common adverse event was injection site pain.
Teva plans to submit a Biologics License Application (BLA) to the FDA later this year. The company is also evaluating fremanezumab in a Phase 3 trial in patients with episodic migraine. Lilly also plans to submit a BLA in the second half of 2017 and is evaluating galcanezumab for the treatment of cluster headache, with Phase 3 trial results expected in 2018.
For more insight on fremanezumab, galcanezumab, and other monoclonal antibodies in development for the treatment of headache and migraine, read Dr. Peter McAllister’s article in the May edition of Practical Neurology®, entitled “Monoclonal Antibodies and Migraine: What the Neurologist Needs to Know”.
NEJM Publishes Phase 3 Data for Epidiolex in Dravet Syndrome; Mid-2017 NDA Submission Anticipated
Migraine Prevalence Higher in Collegiate Athletes, New Study Finds
New findings suggest that collegiate athletes have an increased prevalence of migraines, with female athletes being particularly affected. In a retrospective cross-sectional survey, researchers evaluated 834 student athletes from NCAA Division-I institutions (Headache, May 7, 2017). The sample included athletes in a variety of sports with differing degrees of contact exposure. The survey consisted of 20 questions pertaining to personal and family history of headache, as well as a concussion history. Findings revealed that 23.7 percent of participants reported having a personal history of migraine, while 25.2 percent had a history of sinus headache, and 12.3 percent had a history of tension type headache. Moreover, among athletes with a prior history of concussion, 46.3 percent of females reported a history of migraine, while only 32.2 percent of males reported history of migraine. The authors noted that further inquiry is needed to eludicate the etiology of increases in migraine prevalence.
Stay tuned for more coverage of this study and other developments in concussion research and assessment in the July/August edition of Practical Neurology®.
The New England Journal of Medicine has published results from a Phase 3 study showing that Epidiolex (cannabidiol, GW Pharmaceuticals) reduces monthly convulsive seizure frequency in children with Dravet syndrome, compared to placebo. The study randomized 120 children ages two to 18 years with Dravet syndrome whose seizures were not controlled by their current anti-epileptic regimen, to receive either Epidiolex (20 mg/kg/day) or placebo in addition to standard treatment. Patients in the study had tried a median of four prior anti-epileptic drugs and were taking a median of three during the study. Over the 14-week treatment period, patients taking Epidiolex had a 39 percent median reduction in convulsive seizures compared to placebo (13 percent), with a 23 percent estimated median treatment difference between the two groups. In addition, the proportion of patients who had a 50 percent or greater reduction in convulsive seizure frequency was 43 percent with Epidiolex versus 27 percent with placebo. Treatment with Epidiolex was generally well tolerated as well, with a safety profile consistent with prior open label experience.
Epidiolex is a liquid formulation of purified, plant-derived cannabidiol (CBD), a non-psychoactive cannabinoid. It is being studied for the treatment of a number of rare, severe pediatric-onset epilepsy disorders. GW Pharmaceuticals has noted that it remains on target to submit a New Drug Application for Epidiolex by the middle of 2017. Currently there are no drugs approved for Dravet syndrome in the US.
In a recent interview with Practical Neurology®, GW Pharmaceuticals CEO Justin Gover noted that the company has taken the right steps to develop and investigate cannabidiol as a novel agent that can potentially offer a meaningful therapy to patients. “Our job now as a company is to do the right thing by the product, make sure that we present a compelling case to the FDA, and have a team that can launch this and manufacture it appropriately,” said Mr. Gover.
Epidiolex is also being studied for the treatment of Lennox-Gastaut Syndrome (LGS). See the May edition of Practical Neurology® for coverage of data presented at the recent American Academy of Neurology meeting, as well as for more observations from Mr. Gover.
Elevated B2M Levels Tied to Ischemic Stroke Risk in Women
Beta 2-microglobulin (B2M) levels may be an indicator of ischemic stroke risk in women, according to new findings published in Neurology (May 10). Investigators performed a nested case-control study among women enrolled in the Nurses’ Health Study who provided blood samples between 1989 and 1990 and were free of prior stroke and cancer. They analyzed the association between B2M and ischemic stroke using multivariable conditional logistic regression to adjust for traditional stroke risk factors in 473 ischemic stroke cases.
World Conference on Neurology and Brain Disorders 2017
Congress of the International Headache Society
World Congress of Neurology 2017
American Academy of Neurology Fall Conference
Las Vegas, Nevada
American Epilepsy Society Annual Meeting
The analysis showed that median levels of B2M were higher among cases than among controls. Additionally, women in the highest B2M quartile had a multivariable-adjusted increased risk of ischemic stroke compared to those in the lowest quartile. Results were similar when restricted to those without evidence of chronic kidney disease (estimated glomerular filtration rate ≥60 mL·min−1·1.73 m−2).
In an exploratory analysis, the association between B2M and thrombotic stroke was similar to the overall ischemic stroke results, but no association was observed for embolic stroke risk.
Celgene’s MS Agent Reduces Annual Relapse Rate; Falls Short of Disability Endpoint in Phase 3 Studies
New Phase 3 findings suggest that Celgene’s investigational ozanimod for relapsing multiple sclerosis (MS) reduces annualized relapse rate in a clinically meaningful way but does not significantly impact disease disability. In the RADIANCE trial, 1,313 patients with relapsing MS were randomized to receive either 0.5mg or 1mg of ozanimod, a sphingosine 1-phosphate 1 (S1PR1) and 5 (S1PR5) receptor modulator, or weekly interferon beta-1a (Avonex), over a two-year period. Both doses of ozanimod demonstrated significant and clinically meaningful reductions in the annualized relapse rate versus Avonex, while the oral selective S1P 1 and 5 receptor modulator also achieved significance for the two key secondary endpoints.
However, ozanimod was not associated with a significant difference in the rate of disease progression versus Avonex, based on a pre-specified pooled analysis of data from the RADIANCE trial and the late-stage SUNBEAM study reported earlier this year.
Celgene is expected to submit a New Drug Application to the FDA later this year.
Endovascular Intervention Found Effective for “Late Window” Stroke Patients: DAWN Trial Analysis
Though the window for endovascular treatment may be open longer than previously thought, timely treatment remains critical, according to the trial’s co-lead investigator.
The window for reducing disability and improving functional independence in stroke patients receiving endovascular therapy could extend as far as 24 hours, according to preliminary results from the DAWN trial presented at the European Stroke Organization Conference (ESOC). Assessing late-window and wake-up stroke patients, investigators found that treatment with the Trevo Retriever (Stryker) significantly decreased post-stroke and improved functional independence at 90 days when compared to medical management alone (48.6 percent versus 13.1 percent), a relative reduction in disability of 73 percent. The findings also revealed that one in 2.8 patients treated with the Trevo Retriever within 24 hours of a stroke is saved from severe disability.
According to co-principal investigator Tudor G. Jovin, MD, Associate Professor of Neurology and Neurosurgery at the University of Pittsburgh, these findings suggest the potential for broadening the current guideline of delivering thrombectomy treatment in a less-than-six-hour time window. “We have been using rigid time windows for the selection of patients ever since we started using reperfusion therapy,” said Dr. Jovin in an interview with Practical Neurology®. “This is the first randomized trial that dispels the notion that treatment beyond this window would not be beneficial.”
Despite the investigators’ conservative estimates when setting out to perform the study, the results suggest a notable magnitude of benefit, according to Dr. Jovin. “The difference between outcome rates in the control group versus the treatment group is the largest of any stroke trials performed to date,” said Dr. Jovin. While the results indicate that patients with large vessel occlusion may benefit from treatment beyond the recommended six-hour window, Dr. Jovin emphasized that the need for timely intervention remains paramount. “The message of this trial is not that we can take our time with these patients,” he said. The sooner the patient is treated, higher is the likelihood that they will have what Dr. Jovin calls mismatch, which is the difference between a brain that is irreversibly damaged and a brain that is threatened to undergo infarction. “The basic pathophysiological principle of reperfusion therapy is that we are trying to treat a patient with as much mismatch as possible.” In most patients, mismatch decreases as time moves on, underscoring the need for timely intervention. However, the DAWN results show that there are patients who still have mismatch beyond the six-hour window who would benefit from intervention, according to Dr. Jovin. “Patients who come to the hospital beyond six hours should not be treated any different than patients who come within six hours and should screened and evaluated appropriately.”
In terms of next steps, Dr. Jovin believes that the DAWN results pose several important questions for future inquiries, particularly concerning inclusion criteria. Under the study’s strict inclusion criteria, the powerful treatment benefits may suggest that a wider pool of patients may also benefit from this approach. “An important question we’re facing is up to what point on the scale of age and volume of baseline infarct is there benefit? Should we loosen up inclusion criteria and allow larger baseline infarct so we can treat more patients?”
Beyond the research spectrum, systems of care are gradually evolving to ensure that all patients presenting beyond six-hour window will get screened appropriately and transferred for endovascular treatment if appropriate. This process, however, will not unfold as rapidly as the data, according to Dr. Jovin. “The whole stroke community was relatively unprepared when five large positive trials were all published,” he said. “Right now the infrastructure lags behind the data, nevertheless the creation of adequate infrastructure has been identified as a top priority for the field of endovascular treatment of stroke.”