Botox is one of the most well-known branded prescription drugs on the market, filtering through to TV and pop culture references due to its success as a wrinkle-erasing injection.
But the drug also earns hundreds of millions annually as a therapeutic for obscure uses like excessive sweating, and is one of the few approved preventative treatments for chronic migraine, a particularly crippling condition that affects millions of Americans.
For many migraine sufferers, though, Botox remains insufficient to fully alleviate symptoms and has shown no benefit in treating episodic migraine, a less frequent but still debilitating type of migraine. Outside of Botox, the remaining choices are repurposed medicines like anticonvulsant topiramate or the generic triptan family of drugs, both of which have unwelcome side effects.
Inadequate treatment options coupled with a high prevalence makes for a particularly underserved patient population, both in the U.S. and globally. That market opportunity has propelled interest in a new class of preventative therapies known as calcitonin gene-related peptide (CGRP) inhibitors.
Headlined by four late-stage antibodies, the drugs could represent a step-change in the treatment of migraine — and potentially rake in billions of dollars in future sales for the drugmakers developing them. Competition is fierce and no one drug has yet emerged as clearly superior. Payers, already cost averse, may balk at the prospect of four new pricey biologics indicated for a patient population that’s larger than that of rheumatoid arthritis.
A new class
CGRP is a protein that acts as a neurotransmitter and is involved in the initiation of migraine symptoms. Blocking the CGRP pathway, either by targeting the receptor itself or a related ligand, appears to shut down the transmission of migraine triggers inside the central nervous system.
Over the last 10 months, CGRP inhibitors from Eli Lilly & Co., Amgen, Teva Pharmaceuticals and Alder BioPharmaceuticals have all advanced out of Phase 3 testing. Results from those and previous studies have shown the drugs’ relatively similar ability to reduce the frequency of both chronic and episodic migraines — boding well for patients.
With some variation, the four treatments appear to shave off an average of about three to four migraine days a month for people with episodic migraine. For chronic migraine, which is defined as 15 or more headache days per month, that figure looks to be more like four to six days (although not all Phase 3 data has come in for each drug in chronic migraine).
For people suffering from the frequent disruption of migraine symptoms, that kind of reduction can be significant.
"More and more we think about migraine as a spectrum. What we are learning is that there is a tipping point where if someone starts having more than four attacks a month, they seem to get very disabled," said Sheena Aurora, launch leader for Eli Lilly’s drug galcanezumab, in an interview.
Where CGRP drugs stand out even more, though, is in the number of patients who experience dramatic reductions in the number of monthly migraine days.
"What we have seen in these trials, for the very first time in migraine therapy, we have seen 100% responders, 75% responders. That has never been seen. That would probably be where it is more clinically meaningful," Aurora said.
In two Phase 3 trials of galcanezumab in episodic migraine, for instance, Lilly reported between 33% and 38% of patients experienced at least a 75% reduction in monthly migraine days. Between 11% and 16% saw their migraines disappear over the six-month study period.
Alder’s eptinezumab performed similarly, cutting the monthly migraine days by 75% in about 30% of patients at the highest dose. An average of one in five had a 100% response in any given month over the course of Alder’s study.
Running in a four-way race
If all goes well with regulators, one or more of the four drugs could be on the market in the U.S. as early as next year.
Amgen, which is partnered with Novartis, filed its antibody erenumab with the Food and Drug Administration first after positive clinical results in September and November of last year.
Lilly and Teva plan to file for approval for their respective compounds with the agency later this year, while Alder anticipates a submission in the second half of next year after completing a second Phase 3 study in chronic migraine.
Naturally, with four similar drugs hitting regulator’s desks in a year or two span, markets and investors are wondering how each will stack up against the others. A broad, relatively untapped market could mean there is room for all four. Or weaker results from one or more could mean another steals a commanding market share.
This past week that yardstick was applied to Alder, who reported its Phase 3 study in episodic migraine met both primary and secondary goals. Normally, for a clinical-stage biotech with no marketed products, such positive results would buoy shares to new heights.
Instead, Alder stock lost a quarter of its value. The loss of market confidence looked to be related to the relatively lower benefit Alder’s drug, eptinezumab, delivered over placebo. Neurological studies tend to have higher placebo effects, meaning placebo-adjusted responses are seen as more meaningful. In the trial testing eptinezumab, the placebo response was noticeably higher than placebo responses seen in studies of the other CGRP drugs.
Trial results of CGRP inhibitors in episodic migraine
|Study||Dose||Treatment reduction from baseline||Placebo reduction from baseline||Placebo-adjusted reduction from baseline|
|Galcanezumab (Eli Lilly)||Evolve-1||120 mg/mo.||-4.7||-2.8||-1.9|
|Erenumab (Amgen, Novartis)||Arise||70 mg/mo.||-2.9||-1.8||-1.1|
|Fremanezumab (Teva)||Halo EM||225 mg/mo.||-3.7||-2.2||-1.5|
Measured in mean monthly migraine days
SOURCE: Company Press Releases
That said, the treatment effect seen for the higher dose of eptinezumab came in toward the top end of the range of monthly migraine day reductions seen across CGRP studies. Some, including Alder, suggest the high placebo effect seen could be due to the intravenous administration of eptinezumab.
Eptinezumab also showed a rapid onset of action, delivering relief to more than half of patients one day following administration of the 300 mg high dose. Such a benefit could help Alder compete, even if it arrives to market late.
Still, the other three drugs are all administered subcutaneously — a more convenient option for patients that could wash out any edge eptinezumab might have with its longer, quarterly dosing schedule.
Alder CEO Randy Schatzman sees it differently, though. "What we hear from patients, their preference is to take fewer injections on an annual basis. So they will lean towards any one who has less frequent dosing," he said in a May interview.
"We want a well-differentiated profile that despite the fact that there are agents already out there, that physicians would be motivated to encourage their patients to try the Alder drug."
Spending on specialty medicines, which tend to be more expensive, has risen steadily over the past decade and now represents nearly 40% of overall medicine spend, according to data from QuintilesIMS. Pricier biologics have stretched healthcare budgets, leading payers to begin pushing back on drug prices.
If all four CGRP inhibitors win FDA approval, payers will be looking at four new biologic drugs indicated for a wide swath of patients entering the market. High launch prices could prompt payers to enact strict utilization management criteria or otherwise limit uptake — a dynamic that has hurt the new cholesterol-lowering PCSK9 inhibitors.
"I think a lot of the payers got scared off by the PCSK9 class just out of sheer size and concern there," said Bill Ratner, senior director of global headache and pain marketing at Eli Lilly, in a May interview with BioPharma Dive. "The goal would be to partner with them effectively so they understand who it is going for and who it is not.”
Company releases frequently cite the 38 million people in the U.S. currently suffering from some type of migraine, chronic or episodic. Of that number, though, only about 40% would be eligible for preventive therapy.
But within that smaller subset of the patient population, it’s not clear how to determine who will be a "super-responder," i.e. who will see the 75% or 100% reductions in migraine frequency that represents the greater promise of the CGRP class. Faced with high costs, payers may seek to limit use to patients who benefit the most.
Eli Lilly believes payers will require patients to fail other treatments before covering CGRP inhibitors, at least at first.
"I would not say that we necessarily would have to step through Botox to get a CGRP agent, but definitely the generics," said Christi Shaw, president of Lilly Bio-Medicines on a June 19 call.
Lilly also anticipates payers will need to be educated on the need for better options for patients with episodic migraine. Much of the current familiarity with migraine treatment is tied to the chronic form of the condition, Ratner said, likely due to the approval of Botox for those patients.