Ryan Black

There may finally be a slew of new antibody-based medications coming to market that will help improve these patients’ quality of life by decreasing their monthly migraine days (MMDs). Few of the millions of people who suffer from the disabling neuro- logical condition are currently on any preventative treatment. In April, during a plenary address at the 69th Annual Meeting of the American Academy of Neurology in Boston, Amaal Starling, MD, a neurologist in Scottsdale, Arizona, who is affiliated with Mayo Clinic, said the simple reason for this is because “there really haven’t been any good, specific medications to treat it.”â€¨

Anti-epileptic, hypertension, and antidepressant drugs—such as topiramate, propranolol, amitriptyline, and venlafaxine&mdash;are often pre- scribed for migraine prevention, leading patients to question why a drug with another primary use is being given to them. Such medications also often take a longer time for their effects to be felt, leading patients to abandon treatment when they are still having migraines not long after initiation. At 1 year, these drugs only have a 13% to 16% continuation rate, Starling explained.

The ravaging impact of migraines nationwide is hard to understate. As the third most prevalent and sixth most disabling disease in the world, according to the Migraine Research Foundation,1 these painful neurological attacks cost employers in the United States more than 113 million employee work days per year, with a financial bite of more than $13 billion. The foundation has other hefty numbers, too: $1 billion is spent every year in the United States on diagnostic scans, such as magnetic resonance imaging and computed tomography, due to headaches and migraines. Altogether, the bundled cost assessment of lost productivity and healthcare treatment expenditures puts the total price tag of migraines at $36 billion annually.

A truly effective preventative treatment would satiate a health care community desperate for one. Now, Starling says neurology is “several steps closer” to effective migraine prevention medications coming to market.

Monoclonal antibodies (mAbs) inhibit calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide believed to be released during a migraine that localizes in the trigeminal ganglia and spinal trigeminal nuclei, consistent with central and peripheral manifestations. Earlier forms of CGRP receptor agonists, gepants, were found to be effective in inhibiting migraines, but, in some trials, they were found to have an unfortunate predisposition to liver toxicity, Starling explained.

“...(I)nfusion of CGRP can trigger spontaneous migraine attacks and during spontaneous migraine attacks, there is an elevation of CGRP levels,” she said, adding that there are findings that patients with chronic migraines (CM) have consistently elevated levels of CGRP compared with healthy controls.

“The hypothesis is that CGRP antagonists can be an effective treatment for migraine,” Starling continued, noting that “the gepant story is not over” and different formulations of such agents are still being explored with different compositions. However, mAbs are seen as a significantly better option for CGRP inhibition.

The mAbs in development are large, highly target-specific molecules with long half-lives that allow for monthly injection and, thus, potentially better adherence. Across all trials, there have been consistent improvements in MMDs. Unlike with other treatments, many mAbs have shown separation from placebo in less than a week, including 1 trial of their use on CM that showed improvements in 3 days.

Options may soon be knocking at the market’s door as pharmaceutical giants begin reporting their phase 3 results to the US Food and Drug Administration (FDA): erenumab (Amgen), galcanezumab (Eli Lilly), fremanezumab (Teva Pharmaceuticals), and eptinezumab (Alder BioPharmaceuticals) among them.2-5â€¨Jumping out front in the race, Amgen came to the AAN meeting with phase 3 results on erenumab already in hand.2 The ARISE trial featured 577 adult patients with episodic migraine (EM), primarily Caucasian and female, who were equally randomized into either a placebo group or a group that received erenumab 70 mg as a monthly subcutaneous dose. The primary endpoint was changed in MMDs from baseline to 9 to 12 weeks. Secondary endpoints were responder rate of reduction in MMDs by >50%, 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.

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

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

Natalia Sana Rost, MD, addressed the findings in a press conference at the AAN meeting. Rost, who is the acting chair of the AAN’s Science Committee, called the results among the most compelling clinical findings brought to the meeting, 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.â€¨ In May 2017, Eli Lilly reported its phase 3 results for the EVOLVE-1, EVOLVE-2, and REGAIN, in which its investigational treatment, galcanezumab, met primary endpoints in all 3 trials.3 The patients in both EVOLVE-1 and EVOLVE-2 had an average of 9.1 MMDs at baseline. The primary endpoint in both of these studies was the mean change from baseline in MMDs over the 6-month, double-blind treatment phase.â€¨In EVOLVE-1, patients with EM who were treated over a 6-month period with galcanezumab experienced significant reductions in the number of MMDs. The 120-mg dose yielded an average 4.7-day reduction and the 240-mg dose yielded an average 4.6-day reduction, compared with an average 2.8-day reduction on placebo (

<.001 for both dose groups). Reporting similar results, EVOLVE-2 showed that the 120-mg dose yielded an average reduction of 4.3 MMDs and the 240-mg dose yielded an average 4.2-day reduction, compared with the average 2.3-day reduction for placebo (

Over a 3-month period, REGAIN showed that patients with CM experienced an average reduction of 4.8 MMDs on the 120-mg dose and 4.6 days on the 240-mg dose compared with patients on placebo, who experienced a 2.7-day reduction (

<.001 for both dose groups). The patients in this trial had experienced an average of 19.4 MMDs at baseline. The primary endpoint in REGAIN was the mean change from baseline in MMDs over the 3-month, double-blind treatment phase.

On the heels of those announcements came news from Teva that fremanezumab also showed positive results from its phase 3 HALO CM study.4 Patients treated with either of the dosing regimens of the investigational drug experienced a statistically significant 2.5-day reduction in the number of MMDs during the 12-week period after the first dose; a 4.6-day reduction (

< .0001) for the monthly dose, and a 4.3-day reduction (

< .0001) for the quarterly dose, compared with placebo. The 3 groups (N = 1130) were evenly distributed after randomization.

The patients in HALO CM also experienced significant improvement on all secondary endpoints compared with placebo, including response rate, onset of efficacy, efficacy as monotherapy, and dis- ability. Teva plans to submit a Biologics License Application to the FDA later this year, and its phase 3 HALO study in EM will report topline results soon.

Just prior to going to press at the end of June, Alder rang in with its phase 3 results on eptinezumab, which met both primary and secondary endpoints in the PROMISE 1 pivotal clinical trial on the drug’s effects on EM.5 From an average of 8.6 MMDs at baseline, the primary endpoint of statistically significant reductions in MMDs was met over week 1 through week 12, with a 4.3-day reduction for the 300-mg dose (

= .0001) and a 3.9-day reduction for the 100-mg dose (

= .0179) compared with an average 3.2-day reduction for placebo.

Among the secondary endpoints met in PROMISE 1 were a ≥75% reduction in MMDs over week 1 through week 4 of 31.5% for the 300-mg dose (

= .0112), compared with 20.3% for placebo. Also met was a ≥50% reduction in MMDs that was achieved by 56.3% of the patients over week 1 through week 12 for the 300-mg dose (

= .0085, unadjusted), compared with 37.4% for placebo.

Alder is now turning its sights on enrollment for PROMISE 2, a second pivotal phase 3 study that will investigate eptinezumab’s effects on CM, as well as tracking for its Biologics License Application submission with the FDA in the second half of 2018.

Still, even with this flurry of positive phase 3 reporting, Rost emphasized that there was no “holy grail,” and was more cautious in her optimism than Starling, who used the phrase in reference to the search for a disease-specific migraine treatment with minimal side effects. There are still many questions about CGRP antibodies for migraine prevention, including where exactly they are working, whether or not they can identify and study super-responders in trials, what percentage of patients actually respond to the drugs, and what the long-term effects of CGRP modulation are. However, the safety profiles look promising at the moment.

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

1. Migraine Research Foundation. Migraine facts. migraineresearchfoundation.org/ about-migraine/migraine-facts/. Accessed June 26, 2017.â€¨

2. Black R. Phase 3 ARISE trial showserenumab’s migraine-blocking potential. 

April 25, 2017. mdmag.com/conference-coverage/aan-2017/phase-3- arise-trial-shows-erenumabs-migraine-blocking-potential. Accessed June 26, 2017.

3. Lilly announces positive results for three phase 3 studies ofgalcanezumab for the prevention of episodic and chronic migraine [news release]. Indianapolis, IN: Eli Lilly; May 12, 2017. investor.lilly.com/releasedetail.cfm?ReleaseID=1026201. Accessed June 26, 2017.â€¨

4. Teva announces positive results for phase III study offremanezumab for the prevention of chronic migraine [news release]. Jerusalem, Israel: Teva Pharmaceu- tical Industries; May 31, 2017. tevapharm.com/news/teva_announces_positive_re- sults_for_phase_iii_study_of_fremanezumab_for_the_prevention_of_chronic_mi- graine_05_17.aspx. Accessed June 26, 2017.â€¨

5. Alder BioPharmaceuticals announces positiveeptinezumab phase 3 results for prevention of frequent episodic migraine [news release]. Bothell, WA: Alder Bio- Pharmaceuticals; June 27, 2017. investor.alderbio.com/releasedetail.cfm?Release- ID=1031418. Accessed June 27, 2017.

Articles

Studies offer hope that CGRP antibodies will lead to better treatment for disabling headaches.

Migraine Prevention Moves Into Focus With New Clinical Trials

Ashok Balasubramanyam, MD, was biting off a broad topic at the Pri-Med West conference in Anaheim, California. Balasubramanyam’s talk revolved around type 2 diabetes, specifically asking whether or not improving glycemic control can prevent complications like cardiac disease and stroke, in addition to detailing what major trials have shown for different drugs’ ability to lower h1bA1c.

“The goal of diabetes management is not simply to achieve good glucose level, it’s to prevent complications,” he began. He then lauded two studies that were both approaching their 20

 anniversaries but both still yielding important follow-up data. For type 2 diabetes, he evoked the United Kingdom Prospective Diabetes Study (UKPDS), and for type 1 he mentioned the Diabetes Complications and Control Trials (DCCT).

“Both of these large cohorts have shown us that if you manage to get the hemoglobin A1c down to 7% or less, you can certainly reduce microvascular complications long term,” he said. The benefit of those risk reductions, he said, were shown to be immediate. As far as macrovascular complications went, differences did emerge, but they took much longer.

Using data from the EDIC study, which was the long-term follow-up to the DCCT, he showed a graph of a1c levels in which the lines representing the tightly-controlled group and the regular treatment group eventually converged, as the formerly tightly-controlled group reverted back to normal care and corresponding a1c levels. But in a second graph, there was a large divergence over time, starting around 8 to 10 years, in which members of the once-intensely-controlled group maintained lower rates of cardiovascular events as the rate among those who had received normal treatment throughout began to rocket up.

“The vascular organs somehow retain the memory of having previously been in excellent control,” he said. “Attaining excellent glycemic control, even if just for a relatively short period of time, 4, 5, or 6 years, seems to have excellent benefits. This alone, if nothing else, should make us not lapse into a sort of inertia, saying ‘oh well, it’ll take a long time to get benefit,’ getting good glycemic control for as long as you can is certainly beneficial.”

In the UKPDS for type 2 diabetes, sustained benefit was seen to emerge in the once again even after a1c levels flattened to a mean, according to Balasubramanyam. That trial followed patients on monotherapies, namely sulfonylurea and metformin, rather than combinations. The sustained reduction in diabetes-related endpoints at 10 years in the metformin group was 21%, compared to 9% in the sulfonylurea group, according to a study published in 

Under the pretense that these trends spell reduced longterm complications in both diabetes types, Balasubramanyam followed with a rundown of the available therapies and how recommendations prioritize them. Metformin as a monotherapy is considered the first step, with an expected capability of lowering a1c by 1.0-2.0%, and other drugs added one by one if response is insufficient. Somewhere between 6 and 10% of patients, however, may not be able to tolerate it due to complications with renal function. For such patients, he says to simply start them on the next step, which would by sulfonylurea.

From there, it is recommended to tack on thiazolidinedione (TZD) treatments, the glitazones, which can have a strong 1-1.5% lowering effect on a1c, but complications that may “dampen our enthusiasm,” as Balasubramanyam put it. Alpha glucosidase inhibitors can follow, though their impact on a1c is much more modest. “Not terribly popular drug, but in certain patients it might be just enough to get them to the threshold that you want,” he said.

The glucagon-like peptide-1 (GLP-1) receptor agonists were portrayed in the presentation as the new hot commodity, thanks to their “fantastic marketing.” “The oral ingestion of glucose gives a much more profound effect of insulin secretion than does intravenous,” he explained, noting a potential anticipatory neurological effect related to eating, and the drugs go to work when those neurological signals come down, which make them “a very beautiful way to smooth out metabolism.” They include exenatide, liraglutide, and dulaglutide and have the potential to drop a1c by about 1% on average and may cause some beneficial weight loss, but their cost may be prohibitive.

Dipeptidyl peptidase-4 (DPP-4) inhibitors, which Balasubramanyam called the “coudins” of the GLP-1 receptor agonists, fall next in the recommendations, followed by the new SGLT2 inhibitors and insulin.

“This is not rocket science by any means,” says Balasubramanyam on the tiers of treatment, “it really is a matter of practical application of drugs based on their mode of action and cost and so forth,” he said. Lifestyle interventions, regarding exercise and diet, should always be among the first “prescriptions” in attempting to control a1c, before stacking a series of drugs on top.

Dr. Balasubramanyam detailed the ongoing GRADE trial, currently enrolling and being run by the National Institutes of Health, which takes patients already on metformin but not responding enough, and randomizes them along that roadmap in a time-to-failure trial. Enrollment ends next month, and the full cohort will be 5,000.

The importance of determining the best, safest, and most cost-effective combinations of therapies to lower a1c is important, he says, for mitigating potential long-term complications of diabetes, given that the vast majority of type 2 diabetes patients die from cardiovascular causes.

"It's not rocket science," says Ashok Balasubramanyam, MD.

A Roadmap to Lower a1c Control May Have CV Benefits

For the third installment of an insightful interview with Paul Kaufman, MD, the tenured expert dove in on his hopes for the future of glaucoma research and treatment.

Kaufman also spoke of the importance of having a physical meeting like ARVO every year in maintaining advances and facilitating real collaboration. And he would know the significance: on top of being the Chair-Emeritus of the Department of Ophthalmology & Visual Sciences at the University of Wisconsin School of Medicine and Public Health, he formerly was President and Executive Vice President of the Association for Research in Vision and Ophthalmology (ARVO).

At ARVO 2017, he delivered a keynote lecture on glaucoma and presbyopia and was awarded Friedenwald Award for his work.

Videos

The esteemed ophthalmologist spoke of novel therapies, importance of collaboration.

Paul Kaufman Hopeful, Inspired for Future of Glaucoma Research

	In this second installment of our conversation, the esteemed Paul Kaufman, MD spoke of unmet needs for the glaucoma patients, including a lack of ophthalmologists that ranges from tens of thousands to one patient in wealthy nations all the way up to millions to one in other places. He also spoke of ways to innovate in the clinical treatment of the disease, including harnessing viruses as ophthalmologic tools.

	Kaufman is the Chair-Emeritus of the Department of Ophthalmology & Visual Sciences at the University of Wisconsin School of Medicine and Public Health, in addition to being the former President and Executive Vice President of the Association for Research in Vision and Ophthalmology (ARVO). At ARVO 2017, he delivered a keynote lecture on glaucoma and presbyopia and was awarded Friedenwald Award for his work.

	Despite decades in the business, countless accolades and titles, and over 350 published studies, one would be hard-pressed to find someone as thoughtful, focused, and humble about their work. In advance of his lecture and award presentation, Kaufman sat down with 

 for an expansive interview about his motivations, career, and how he sees ophthalmology evolving over time.

In the second leg of a weighty interview, Kaufman ruminates on what more is needed.