Ryan Black

Major changes may be coming for the prevention of persistent migraines, according to Amaal Starling, MD, of the Mayo Clinic.  

At the 69th Annual Meeting of the American Academy of Neurology, Starling gave a plenary address about the difficulties of treating those with chronic migraine, and how monoclonal antibody drugs may soon be an effective preventative treatment.  

“There’s an overwhelming number of patients that should be on preventive therapy but are not. In fact, 33% are recommended prevention medications, but only 3% to 13% are using prevention medications,” she said.  

Setting up the discussion with a hypothetical patient case, she spoke of typical issues of skepticism and expectations. Epilepsy, blood pressure, and depression drugs like topiramate, propranolol, amitriptyline, and venlafaxine are currently often prescribed for migraine prevention, leading patients to question why a drug with another primary use is being given to them. Such medications also often take some time for their effects to be felt, leading to patient treatment abandonment when they are still having migraines not long after initiation. At one year, such drugs only have a 13 to 16% continuation rate one year after baseline.  

Today, Starling says neurology is “several steps closer” to effective migraine prevention medications thanks to developments in monoclonal antibodies (mAbs) that inhibit calcitonin gene-related peptide (CGRP). CGRP is a 37-amino acid neuropeptide believed to be released during migraine that localizes in the trigeminal ganglia and spinal trigeminal nuclei, consistent with a migraine’s central and peripheral manifestations.  

“It is found that infusion of CGRP can trigger spontaneous migraine attacks,” said Starling, “and during spontaneous migraine attacks, there is an elevation of CGRP levels.” In addition, there are findings that those with chronic migraines have consistently elevated levels of CGRP compared to healthy controls.  

“The hypothesis is that CGRP antagonists can be an effective treatment for migraine,” she said. Earlier forms of CGRP receptor agonists, gepants, were found effective in inhibiting migraines, but in some trials had an unfortunate predisposition to liver toxicity. Starling notes that “the gepant story is not over” and different formulations of such agents are still being explored with different compositions.  

Monoclonal antibodies are seen as a potentially better option for CGRP inhibition, as they are large, highly target-specific molecules with long half-lives that allow for monthly administration and thus better potential adherence. Major pharmaceutical companies are currently piloting a host of mAbs for the purpose of inhibiting migraines, including galcanazumab, fremanezumab, eptinezumab, and erenumab.  

Starling compared various trials of the mAbs at hand, noting that every one so far had met its primary endpoints, and that “Three of the monoclonal antibodies have undergone not only episodic migraine trials but also chronic migraine trials and still met primary endpoints,” she said.

Across the trials, there were consistent improvements in monthly migraine days, with high rates of patients seeing 50% or 75% reductions in days plagued by them. Unlike with other treatments, as well, many mAbs have shown separation from placebo in less than a week, including one trial of their use on chronic migraine that showed improvements in 3 days.  

“In addition, there have been no drug-related serious adverse events that have been reported thus far,” Starling continued, “It has a much better profile, and it makes sense. This is disease-specific, mechanism-based treatment which will have less off-target effects.”  

There are still many questions about mAbs for migraine prevention, including where exactly they are working, whether or not they can identify and study super-responders in trials, and what the long-term effects of CGRP modulation are. Still, Starling is exceedingly optimistic about the treatments.  

“Welcome to this new era,” she said.  

Phase 3 results of a double-blind, placebo controlled trial of one of the drugs, erenumab, will be presented in a highly-anticipated session later in the conference.

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Major changes may be coming for the prevention of persistent migraines.

New Treatments for Migraines on the Horizon

In a poster presented at the 69th Annual Meeting of the American Academy of Neurology, researchers from the University of Cincinnati studied brivaracetam (Briviact) for drug-drug interactions (DDI) 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 FDA in 2016.

The drug was approved because it was shown 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 a racetam, and it’s approved as an add-on treatment for those aged 16 or older who have partial, or focal, seizures. Given its status as an add-on, any DDIs it may have are important to know. Though its exact working mechanism is unknown, it has a selective affinity for protein 2A (SV2A) in the brain, potentially contributing to its anticonvulsant effect. It’s typically taken twice daily in doses ranging between 50 and 200mg.

In the study, the drugs 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, phenobarbital, pregabalin, phenytoin or zonisamide, in a clinically-relevant manner,” in any manner, the team led by Brian Moseley, MD, concluded. A “modest increase” in PHT exposure was, however, observed when combined with a “supra-therapeutic” 400mg 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, PB, PHT or contraceptives, though monitoring of PHT levels was recommended.

The study was sponsored by UCB Pharma, who make Briviact.

Brivaracetam was approved because it was effective reducing seizure frequency when combined with other agents. 

Brivaracetam Found Safe in Combination with Other Epilepsy Drugs

	Even more resources pertaining to headaches and migraines can be found on 

Monoclonal antibody drugs may soon be an effective preventative treatment for chronic migraines.

Monoclonal Antibodies Herald New Era in Migraine Treatment

At the annual meeting of the American Academy of Neurology, held this year in Boston, Massachusetts, David Dodick, MD, presented the findings of a phase 3, double-blind, placebo-controlled study of the use of erenumab in the prevention of migraines.

Erenumab is a monoclonal antibody that inhibits calcitonin gene-related peptide (CGRP), a neuropeptide strongly believed to play a role in the pathology of migraines. It is being developed by Amgen, who sponsored the study, and is one of a slew of such drugs currently in development by different companies.

The ARISE trial featured 577 adult patients, primarily Caucasian and female, who suffer episodic migraine (EM), equally randomized into either a placebo group or a group that received subcutaneous erenumab monthly at dose of 70mg. The primary endpoint was change in monthly migraine days (MMD) from baseline to 9-12 weeks, with secondary endpoints of responder rate of reduction in MMDs by 50% or more, change in other migraine medication use, and improvements in impairment and function. The trial featured a double-blind treatment phase of 12 weeks followed by an open-label phase of 28 weeks.

Patients had a baseline MMD of 8.3. Those treated with the drug experienced an average decrease of 2.9 MMD, compared to 1.8 in placebo. For the secondary endpoint of 50% or greater reduction in MDD, 10% more patients in the erenumab group met the goal than in the placebo group (40% to 30%). No major treatment-related adverse side effects were reported, with erenumab presenting a similar safety profile to placebo.

The ARISE trial’s “sister trial”, STRIVE, produced consistent results, though that study went further to also include testing of an alternate 140mg dose.

Natalia Sana Rost, MD, addressed the findings in a press conference earlier in the day. The Acting Chair of the AAN Science Committee, Rost’s devoted her press conference to some of the most compelling clinical trials of new treatments for neurological conditions, and she was not short on praise for the potential of CGRP inhibitors. “For many years we actually lacked any disease-targeted and disease specific medications for migraines,” she said, before championing the unique specificity of erenumab in migraine deterrence.

Still, Rost emphasized that “There is no holy grail,” keeping her optimism closer to the chest than did Amaal Starling, MD, in a session on monoclonal antibodies yesterday, who actually referred to the search for a disease-specific migraine treatment with minimal side effects as a quest for the Holy Grail. Such treatments project to be quite expensive, and the deviation from the erenumab group to the placebo group was significant without being a colossal blowout.

“It’s key that we stay focused on balancing out the cost versus effectiveness. I think this is the elephant in the room,” Rost said, “I can tell you that among the patient population there are sufferers who would pretty much pay any money to be free of their disease, even though they should realize that it’s not free.” 

Erenumab is a monoclonal antibody that inhibits a neuropeptide strongly believed to play a role in the pathology of migraines. 

Erenumab Shows Promise Treating Migraines in Phase 3 Trial

During a plenary speech at the American Academy of Neurology’s Annual Meeting in Boston, Massachusetts, Louise D. McCullough, MD, PhD, spoke of potential explanations for the elevated stroke risk that women face as compared to men.

McCullough is a professor and the Chair of Department of Neurology at the McGovern Medical School at the University of Texas. She cited the statistics, mentioning that 63% of stroke deaths currently occur in women, and women typically have worse survival rates and outcomes, and the CHA2DS2-VASC risk assessment assigns a point simply for female gender. Women are more likely to be disabled or die from a stroke, and 35% more likely than age-matched men to end up in a nursing home as a result of a stroke.

Atrial fibrillation is also more commonly the etiology behind stroke in women than in men.

“These strokes are big, so it’s not surprising which person is going to do better,” she said, “With our population aging this is just going to become more and more of an issue.”

Despite the chasm, according to McCullough’s review of studies, men are more likely to receive anticoagulants than women, and clinical trials of novel oral anticoagulants (NOACs) have under-represented females. A lot of earlier trials, as well, were conducted with the Veterans Affairs population, she said, contributing to further underrepresentation.

“You need to screen your older patients, your older women, for AFib, and have a pretty low threshold to treat them,” McCullough stressed, mentioning that 30% of men with the condition are anticoagulated compared to only 17% of women.

Within the studies, there exist some gender differences in outcomes from NOAC treatments. Men, it seems, receive better stroke protection from the drugs, whereas women are less prone to major bleeding events, the most concerning and common side effects. This could be the result of yet-to-be-explained differences in how men and women coagulate.

“We have to insist on doing sex-specific analysis. We have to do it,” she said, though she indicated that there may be a social factor, as women are often less likely to participate in clinical trials to start with.

“The most important indicator of outcomes we have found is pre-stroke function,” said McCullough, calling for more sophistication in the appraisal of outcomes-taking into account decreased function prior to the event. She believes it may be found that women may well fare about the same as men, but had lower function prior to the event that makes the outcomes seeming drastically worse.

A potentially surprising risk factor she discussed was loneliness, or social isolation. After the age of 80, more than half of women (52%) end up living alone, compared to less than a third of men at that age (29%), a difference achieved by outliving their spouses, friends, and sometimes even their children. Psychosocial stress can raise stroke risk by 25-45%, and contribute to worsened outcomes.

The presenter pointed to novel studies in stroke-induced mice that found those that were isolated prior to a stroke had massively worse outcomes than those who lived with other mice prior. All of the mice were administered the same scale of stroke, but the previously isolated mice, genetically identical, declined and died far more frequently over the following weeks.

Gender Gap in Stroke Risk Attributed to Atrial Fibrillation, Loneliness

Not even a full month since first being approved by the FDA for treatment of atopic dermatitis (AD), Sanofi and Regeneron’s burgeoning blockbuster dupilumab (Dupixent) is already being dragged to court again.

Sanofi and Regeneron pre-emptively sued Amgen back in March in an attempt to protect the drug, hoping a court decision would be a bulwark against a potential claim from Amgen that the mechanisms behind dupilumab were a violation of their intellectual property rights.

In previous efforts to develop an asthma medication, Amgen’s Immunex subsidiary received a ‘487 patent protecting the development of anti-interleukin-4 receptor antibodies. Dupilumab is a fully human monoclonal antibody directed against the body’s interleukin (IL)-4 and IL-13 receptors. Both are cytokines believed to play a major role in the manifestation of allergic diseases, and dupilumab is also undergoing trials in an ongoing effort to see it approved for the treatment of asthma as well.

The newest suit comes from Amgen, claiming patent infringement against Sanofi and Regeneron based on those biological mechanisms.

There is little argument against dupilumab's efficacy, with countless trials showing it to be a potent drug for those with moderate to severe AD. In the SOLO 1 and 2 trials, which tested more than 1300 patients whose AD was rated 3 (moderate) or 4 (severe) on the Investigator’s Global Assessment (IGA; 0-4 scale), scores dropped to 0 or 1 after 16 weeks in over 35% of all patients compared to 10% or less in placebo groups. Three-fourths of those studied saw reductions on the Eczema Area and Severity Index, with minimal side effects reported.

The drug was released with high expectations, projecting annual sales in the billions of dollars and believed to have the potential to “revolutionize” the treatment of AD. Dupilumab carries a hefty price tag of about $37,000 per year for treatment.

“There will be cheaper options to treat atopic dermatitis systemically,” the lead author of the SOLO studies told MD Magazine in a previous interview, “but they do not show the same level of effectiveness and are limited by significant side effects.”

“Not only has it shown efficacy in atopic dermatitis, but dupilumab also has shown efficacy in related atopic conditions such as asthma and nasal polyps," Regeneron’s Executive Director Bola Akinlade, MD, MBA, told 

Sanofi and Regeneron already find themselves in another patent battle with the complainant, Amgen, over PCSK9 inhibitors. In early January, a federal judge ruled that their alirocumab (Praluent) violated Amgen’s patents on evolocumab (Repatha). The decision is currently under review by a federal appeals court, but if upheld it would effectively leave Repatha as the only PCSK9 inhibitor legally authorized for domestic sale. Both drugs are cholesterol-lowering agents administered by injection.

That PCSK9 fight extends beyond the 3 companies involved: fellow pharma giants Pfizer, Ipsen, and Eli Lilly all filed amicus briefs siding with Sanofi and Regeneron, while AbbVie weighed in with one that vouched for strong patent protection, seemingly aligned with Amgen’s position. The squabble has been ongoing since 2014.

There is little indication that the fight will be over any time soon. Given that Sanofi and Regeneron are also pursuing the drug as a potential asthma treatment (and it has performed well already for that condition in trials), and Amgen initially received the IL-4 inhibitor patent in respect to asthma medications, the litigious tale of dupilumab seems to be at the very beginning.

It remains to be seen how it will intertwine with the fight over PCSK9 inhibitors, and to what end it may deprive patients access to effective new treatments.

Amgen is claiming patent infringement against Sanofi and Regeneron based on the biological mechanisms of dupilumab (Dupixent).