CGRP Monoclonals: Safe, Effective for Migraine in Phase 3 Trials

Daniel M. Keller, PhD

September 22, 2017

VANCOUVER, Canada — Phase 3 results of four monoclonal antibodies in development for the treatment or prevention of migraine, all of which inhibit signaling by calcitonin gene-related peptide (CGRP), suggest that in general, all performed similarly — both in efficacy, depending on the specific endpoints, and in safety and tolerability.

The main differences between the drugs, galcanezumab (Eli Lilly), fremanezumab (Teva Pharmaceuticals), eptinezumab (Alder Biopharmaceuticals), and erenumab (Amgen), were in doses, routes of administration, and the target of the antibodies.

The results of studies looking at these drugs were presented here at the 18th Congress of the International Headache Society (IHC) 2017.

CGRP has been studied extensively and has been implicated in the pathophysiology of migraine. This 37–amino acid neuropeptide is widely distributed throughout the body and is involved in several physiologic processes. Small molecule antagonists of its receptors have shown that the pathway is a valid mechanism to target for the treatment of migraine, but toxicity and other issues have limited their development.

Now, several companies are developing monoclonal antibodies to target the CGRP pathway.

REGAIN Trial for Chronic Migraine

In an evening session featuring presentations on all four monoclonals, Sheena Aurora, MD, Eli Lilly, discussed the results of the double-blind treatment phase of the REGAIN trial, which assessed galcanezumab in patients with chronic migraine.

The drug, which is a fully humanized monoclonal that selectively binds to CGRP, is injected subcutaneously once a month. At doses of 120 mg per month (n = 278) or 240 mg per month (n = 277), the active drug proved superior to placebo (n = 558).

The treatment groups were well matched by sex (85% female), with a mean age of around 40 years, a 20-year history of migraine, and a mean of 15 monthly migraine headache days (MHDs) with medication use. In about 25% to 35% of the participants, two or more past preventive treatments had failed, and medication overuse occurred in about 64%. The 120-mg group received a 240-mg loading dose on the first injection.

At months 1 to 3, the overall mean change from baseline in MHDs was –2.74 for placebo, –4.83 for the 120-mg dose, and –4.62 for the 240-mg dose (P < .001 for both doses vs placebo). A drop in the number of monthly headaches was apparent at 1 month.

Almost twice as many participants in the drug groups (approximately 27%) experienced a 50% reduction in monthly MHDs compared with the placebo group (15.4%, P < .001).

Active drug therapy was associated with statistically significant improvement on the Migraine-Specific Quality of Life questionnaire and on monthly days with acute medication use.

About 50% of each of the three groups reported treatment-associated adverse effects, but serious adverse effects were rare. Participants tolerated the active treatment well, with few dropouts. Most of the dropouts were in the placebo group (49 of 558).

In summary, either dose of the active drug "provided clinical benefit and improved function in patients with chronic migraine," Dr Aurora reported. Lilly plans to file for approval of the drug this year.

EVOLVE-1, EVOLVE-2 Trials

In addition to chronic migraine, galcanezumab also offered benefit in episodic migraine.

In the phase 3, double-blind, placebo-controlled EVOLVE-1 (NCT02614183) and EVOLVE-2 (NCT02614196) trials, participants were 18 to 65 years old and had migraine with or without aura 4 to 14 days per month — -- with at least 2 attacks per month. Patient characteristics were very similar to those in the REGAIN trial except that in the EVOLVE trials, the participants had about 9 mean MHDs per month. Patient retention was better than 80% for all groups.

EVOLVE-1 was performed only in the United States and Canada, whereas EVOLVE-2 was more multinational. The drug was given subcutaneously each month in both trials.

In EVOLVE-1, the mean changes in MHDs from baseline over months 1 to 6 for placebo, the 120-mg dose of galcanezumab, and the 240-mg dose were –2.81, –4.73, and –4.57, respectively (both P < .001 vs placebo). Results for EVOLVE-2 were similar.

In EVOLVE-1, the proportion of patients having a 50% improvement in MHDs was around 60% on either dose vs about 40% with placebo. Again, EVOLVE-2 results were similar.

During his presentation, Vladimir Skljarevski, MD, senior medical director at Eli Lilly, said the effect on migraine headache reduction was apparent in the first month, and even within the first week.

Migraine-specific quality-of-life measures also improved, and the number of serious adverse events (SAEs) was low in all groups.

HALO EM for Episodic Migraine

Ernesto Aycardi, MD, Teva Pharmaceuticals, presented results of another CGRP-binding monoclonal antibody, fremanezumab (formerly TEV-48125), for the prevention of episodic migraine. Patients receiving monthly subcutaneous dosing at 225 mg (n = 290) and quarterly dosing at 675 mg (n = 291) were tested against a group receiving placebo (n = 294).

The phase 3 HALO EM study (NCT02629861) included adults aged 18 to 70 years. All had migraine 6 to 14 days per month for 12 months or more and had unsuccessfully tried typical migraine preventive treatments for 3 or more months.

The mean age for the study population was about 41 years, and patients had a 20-year history of migraine. Ninety percent of the participants in each treatment group completed the study.

Both drug doses reduced the mean number of headache days by 3.0 to 3.6 days per month compared with baseline; and the effect was apparent by week 1. In addition, results for the active treatment groups were superior to those for placebo at all time points out to 3 months (all P < .002).

More patients receiving quarterly (44.4%) or monthly (47.7%) regimens achieved a 50% or greater reduction in monthly headache days compared with those receiving placebo (27.9%). The fremanezumab groups also had fewer days requiring any acute headache medication and had improved disability scores. Besides local injection reactions, adverse events, including SAEs, were quite rare.

Dr Aycardi recommended that future studies focus on the long-term efficacy of fremanezumab and its potential to reduce the progression from episodic to chronic migraine.

HALO CM, PROMISE-1

Stephen Silberstein, MD, Thomas Jefferson University, Philadelphia, Pennsylvania, presented results of HALO CM, a similar study of the drug in chronic migraine. The dosing regimens were the same as in HALO EM except that in the monthly regimen, a loading dose of 675 mg was used for the first injection.

At baseline, all three groups had about 16 days with migraine, of which about 13 were of at least moderate severity. Fremanezumab significantly reduced the monthly average number of days of at least moderate severity compared with baseline and with placebo out to 3 months (–4 to –5 days; all P < .001). Again, the effect was apparent at 1 week.

The treatment also reduced the overall monthly mean number of migraine days by 4.9 days with quarterly dosing and by 5.0 days with monthly dosing; but, as in most of these sorts of studies, placebo had a sizeable effect as well (–3.2 days). Still, the active treatment was significantly superior.

As in the study of episodic migraine, productivity loss was improved with fremanezumab, and SAEs were very rare, with three in each monoclonal arm and six in the placebo arm.

Dr Silberstein noted that the drug's safety, tolerability, early onset of efficacy, and flexible dosing "may increase adherence and improve clinical outcomes for migraine patients."

Another CGRP-binding monoclonal antibody, eptinezumab, showed significant efficacy vs placebo for prophylaxis of frequent episodic migraine in the Prevention of Migraine via Intravenous Eptinezumab Safety and Efficacy (PROMISE-1) trial, Jeffrey Smith, MD, Alder BioPharmaceuticals, reported.

The drug was administered subcutaneously at 30, 100, or 300 mg monthly for 4 months, as was placebo (n = approximately 222 in each group). Participants were about 40 years old; about 82% of each group was female; and all had approximately a 17-year history of migraines, averaging 8.4 to 8.7 migraines per month.

The mean reduction of monthly migraine days from baseline with the active drug ranged from 3.9 to 4.3 days vs 3.1 days with placebo for weeks 1 to 12 (all P < .02 vs placebo).

Also at weeks 1 to 12, 49.8% to 56.3% of participants receiving the active drug had a response of 50% or greater vs 37.4% of those receiving placebo (all P < .01 vs placebo).

On day 1, there was about a 50% reduction in the number of patients receiving the drug who experienced a migraine vs a 21.7% reduction with placebo. As with the other monoclonals, safety and tolerability were very good and equivalent to those seen with placebo.

Safety-Specific Study

Because CGRP is a neuropeptide widely distributed in the body with various physiologic functions, including acting as a potent vasodilator, a randomized, double-blind, placebo-controlled trial of erenumab was conducted to assess its effects on exercise time during a treadmill test of patients with stable angina.

Unlike monoclonal antibodies that target CGRP, erenumab is a monoclonal that blocks the CGRP receptor.

Presenter Daniel Mikol, MD, PhD, Amgen, explained that during myocardial ischemia  cardiac sensory nerves release vasodilatory mediators, including CGRP. Therefore, it was advisable to see whether blocking the action of CGRP might worsen stress-induced myocardial ischemia in patients with stable angina.

Patients were screened with two qualifying exercise treadmill tests (exercise lasting 3 to 12 minutes, angina symptoms, and/or ST-segment depression) over a period of up to 6 weeks. They were then randomly assigned to placebo (n = 44) or a single intravenous 140-mg dose of erenumab (n = 45), with repeat exercise testing on day 1. Safety data were collected out to 12 weeks.

The participants had a median age of about 65 years; about 90% were men. The patients had a history of cardiovascular disease, with some having coronary interventions.

The difference in total exercise time was –11 seconds (95% confidence interval [CI], –44.9 to 22.9 seconds) for the erenumab vs placebo group. This figure was greater than the –90-second lower limit of the 90% CI and is thus consistent with the hypothesis that erenumab did not decrease exercise capacity compared with placebo when measured by total exercise time.

There was also no apparent difference between erenumab and placebo in the time to exercise-induced angina (P = .69) or the time to onset of 1-mm or greater ST-segment depression.

At the 12-week follow-up, no patients had died and there was only one SAE, which was in the placebo group.

Perspective on Monoclonals in Migraine

All of the monoclonal antibodies have long half-lives in the blood and a corresponding long duration of action. Thus, they can be administered monthly, or even quarterly, and maintain efficacy.

Patricia Pozo-Rosich, MD, PhD, Vall d'Hebron University Hospital, Barcelona, Spain, told Medscape Medical News she thinks all of the monoclonal antibodies in development for acute migraine treatment or prophylaxis are similar in efficacy and safety. However, "maybe we will see differences once we try them."

She noted that if a patient is refractory to one monoclonal, others may need to be tried. "But if I would have to bet on it, I don't think there will be changes," said Dr Pozo-Rosich. "People either respond or not. If you are a responder, you probably are a responder to all four monoclonal antibodies."

She said route of administration may affect the onset of efficacy, with intravenous being faster than subcutaneous methods, although administration must take place in the hospital. But, as shown in these studies, efficacy was seen quite early for each of the monoclonals.

Concerning a list of pros and cons, each drug "differentiates themselves in small, little things," she said, adding that the bigger issue is which one gets approval and to market first. "So I think it's really a race."

Dr Pozo-Rosich noted that she looks forward to seeing how these drugs work in the longer term. Currently, migraine preventive therapy has to be given for 9 to 12 months before there is a chance of reducing therapy without patients going back to their old patterns of headache frequency. But with longer therapy, and especially if the patients have changed their lifestyle, the frequency of attacks may stay stable even if the drug is tapered down.

Effective Over Time?

Monoclonals were developed as an acute treatment to lower CGRP levels during headache, said Dr Pozo-Rosich. But from different published studies, it looks like CGRP stays elevated more or less permanently in chronic migraine.

"I'm not too sure how much CGRP monoclonal antibodies will change the biology or the functioning of the whole brain in order for us to be able to not have very prolonged treatments, or how long these preventive treatments will have to be," she said.

Another clinical issue will be how these new treatments may be used in relation to other drugs, possibly in combination, and how each treatment may affect the efficacy of others.

The presented studies "just demonstrated good enough efficacy to go to market," she said. "But the brain is very intelligent; and if you block one way, maybe it goes to another way." So one cannot be sure at this point whether the monoclonal drugs may lose efficacy over time, said Dr Pozo-Rosich.

She noted that CGRP is a mediator but not the origin of migraine, so her research group is studying the interictal period to assess what is going on. "It might even give us a way of phenotyping patients" to subcategorize migraine and use different medications for different types, such as in triptan responders or anti-CGRP responders.

She cautioned that access to the new drugs will depend on each healthcare system, which will determine whether a drug is available at all and for how long a patient may receive it.

"Huge Advance" — If Not Too Costly

Werner Becker, MD, University of Calgary, Alberta, Canada, agrees about the effectiveness of these drugs but also cautions that price will determine, to a large extent, how widely they may be used. "Given their side effect profile, they could be a huge advance if they aren't too costly," he told Medscape Medical News.

"They could be very useful, I think, because they seem as effective as anything else. At this point they're not super drugs," said Dr Becker. "Their effectiveness in chronic migraine, for example, seems pretty similar to Botox [botulinum toxin]. Having said that, it's a lot fewer injections."

In clinical trials that he participated in, "patients said these drugs changed their lives, and over the open-label 1-year period, the drugs seemed to retain their efficacy," he said. "So, if they work for a year, they may well work much longer."

Dr Becker noted that one patient wanted to stay on the particular monoclonal after the end of the trial, but she could not get it and slowly got worse again over several months. "So I think they do have a long-term potential, and they will help a lot of people."

He described these drugs as "a game changer in the sense that we think we know their mode of action." Although it is not known exactly where they work, researchers have a better idea of their mode of action (against CGRP signaling) than they do for other prophylactics, "where we really have no clue how [they] work," he said.

For many years, researchers have debated whether migraines originate in the central nervous system (CNS) or in the periphery. Monoclonal antibodies are big molecules, so they probably do not cross the blood-brain barrier to any large extent and therefore seem to be acting on mechanisms in the periphery. 

Thus, the three monoclonals that bind CGRP must be binding it in the periphery, said Dr Becker. This reasons that erenumab, which blocks the CGRP receptor, acts in the trigeminal vascular system outside the CNS.

"So the periphery must be initiating the attack and also maintaining it," he said. "The periphery is obviously very important; it's not the whole story, but [it is] very important."

Studies on galcanezumab were sponsored/funded by Eli Lilly or one of its subsidiaries. Dr Aurora and Dr Skljarevski are employees/stockholders of Eli Lilly. Dr Aycardi is an employee of Teva Pharmaceuticals. Dr Silberstein is a consultant to Alder, Allergan, Autonomic Technologies, Avanir, Curelater Inc, Depomed, Dr. Reddy's Laboratories, Ensured, ElectroCore Medical, eNeura Therapeutics, INSYS Therapeutics, Lilly USA, Supernus Pharmaceuticals, Teva Pharmaceuticals, Theranica, and Trigemina. Teva funded the studies on fremanezumab. Dr Smith is employed by Alder BioPharmaceuticals, which funded the study on eptinezumab. Dr Mikol is an employee of Amgen. Amgen and Novartis funded the study on erenumab. Dr Pozo-Rosich participated in clinical trials of eptinezumab but did not personally receive any compensation. Dr Becker has participated in clinical trials on the monoclonal antibodies for Lilly, Amgen, and Teva.

18th Congress of the International Headache Society (HIS) 2017. Presented September 8, 2017. All of the oral presentations were based on poster presentations PO-01-194, PO-01-195, PO-01-196, PO-01-197, PO-01-198, and PO-01-201.

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