Multiple therapeutic candidates directly targeting migraine are preparing to rush to market. For patients and prescribers, they couldn't come soon enough.

"The biggest limitation we've had for the treatment of both episodic and chronic migraine has been the absence of good prevention," said Stewart Tepper, professor of neurology in the Geisel School of Medicine at Dartmouth. Existing migraine drugs "all were invented for something else and all have side effects, and patients don't like them."

Stephen Silberstein, director of the headache center in the department of neurology at Jefferson University Hospital, agreed.

"Most of the drugs we have only work about half the time," Silberstein told BioWorld Insight. "Many have side effects that are very troubling to patients," not to mention contraindications for those who take beta blockers, tricyclic antidepressants and other medications for co-existing conditions, he added.

Although new formulations of sumatriptan have continued to filter to market, the tight race among late-stage migraine candidates has focused mainly on oral calcitonin gene-related peptide (CGRP) receptor antagonists. The first two agents in that category, erenumab from partners Amgen Inc. and Novartis AG and fremanezumab from Otsuka Pharmaceutical Co. Ltd. and Teva Pharmaceutical Industries Ltd., are expected to win FDA approval by midyear. Their emergence will represent something of a revolution in the space, Tepper said, since "they're designed for migraine. They're not something else jerry-rigged to have modest effects in prevention."

The convenience of once-monthly to once-quarterly dosing associated with anti-CGRP monoclonal antibodies (MAbs) likely will improve patient adherence, he added. And, since anti-CGRPs were designed precisely to target migraine, they've shown a benign tolerability profile.

"As far as we can tell, they don't seem to take any ancillary prisoners," Tepper told BioWorld Insight. "Other than some pain at the site of injection for the subcutaneous versions, there doesn't seem to be a significant side effect issue."

The anti-CGRPs also solve another perennial shortcoming of migraine treatment: response time. With current drugs, "it usually takes two to four weeks to get people up to the proper dose," Tepper said, "then another two to four months to see whether the drugs work. The monoclonal antibodies kick in within a week and show meaningful clinical effect within a month."

Despite a high placebo effect across many studies in the class, "the overall effectiveness is probably higher, if you look at the 75 percent responder rates," he added.

'This is a hopeful time'

Migraine – from the Greek hemicrania, "half of the head" – is characterized by a severe, seriously debilitating and usually unilateral form of episodic headache that may be preceded by aura and is frequently associated with neurological and gastrointestinal symptoms such as nausea, vomiting, diarrhea, photophobia, phonophobia and osmophobia, according to Cortellis Disease Briefings. An untreated migraine headache attack may last up to 72 hours.

Migraine that occurs fewer than 15 days per month is considered episodic, with more frequent occurrence defined as chronic. Although the precise etiology and pathophysiology remain unknown, the disorder is ranked as the world's third most prevalent, according to The international classification of headache disorders, 3rd edition, released earlier this year.

In fact, migraine is more common in the U.S. than asthma and diabetes combined, said Kathleen Digre, professor of neurology and ophthalmology, director of headache and neuro-ophthalmology and vice chair for clinical strategy in neurology at the University of Utah. Although it's not always recognized as a primary care disorder, many patients present first to their family physicians, "who should be taking care of this, although many feel uncomfortable doing so," Digre said.

"We may have 36 million to 39 million people in America with migraine, and about half of them are not always diagnosed," she added, even though migraine is among the top 10 disabling conditions in the world, according to the World Health Organization.

Findings reported last month from a quantitative opinion survey sponsored by Eli Lilly and Co. – another CGRP contender – revealed that the worst migraine pain ranked higher than that of childbirth among those surveyed who had experienced both (n=244, an average score of 8.6 compared to 7.3, on a scale of one to 10) and higher than the pain associated with kidney stones and broken bones (8.3 and 7, respectively).

Survey respondents included 1,018 U.S. adults, including 518 people diagnosed with migraine by a health care provider, 200 people who know someone with migraine and 300 community members who do not know someone with migraine.

Even when correctly diagnosed, many patients – especially those with chronic migraine – don't receive preventive and sometimes even proper acute treatment, Digre said. But "this is a hopeful time," she added. "Not only can we diagnosis migraine more easily, but we also now are going to have new tools in our toolbox to treat it."

Three CGRP MAbs likely to market by year-end

Erenumab, a fully human MAb with a May 17 PDUFA date, likely will be the first CGRP out of the gate. Late in 2016, Basel, Switzerland-based Novartis and Amgen, of Thousand Oaks, Calif., unveiled results that showed a high dose of erenumab, previously AMG-334 and branded Aimovig, trimmed about two more migraine days than placebo from an average 8.3 monthly migraine days suffered by patients during the last three months of a confirmatory phase III experiment. A low dose of the antibody bested placebo by 1.4 days. Safety was deemed comparable to placebo, according to Amgen. (See BioWorld Today, Nov. 18, 2016.)

At the 2017 annual meeting of the American Academy of Neurology, investigators reporting data from the STRIVE migraine prevention trial of erenumab hailed the arrival of the CGRP receptor blockade as the first mechanism-specific, migraine targeted preventive treatment approach. (See BioWorld Today, April 26, 2017.)

Fremanezumab is expected to see FDA action by June. Teva, of Jerusalem, submitted a BLA in October 2017 for the humanized MAb and has filed a patent infringement lawsuit against Lilly, saying the latter was aware of Teva's intellectual property but "nonetheless is seeking to launch its own competing biologic product, which will undermine the value of Teva's substantial investment."

The Lilly candidate, galcanezumab, is expected to complete its FDA review by October. In May of last year, the Indianapolis-based pharma reported that the antibody met its primary endpoint in three phase III trials – EVOLVE-1, EVOLVE-2 and REGAIN – showing statistically significant reductions in the number of monthly migraine headache days compared to placebo at two studied doses. (See BioWorld Today, May 15, 2017.)

The late-stage migraine development pipeline also is stocked with CGRP prospects. Farthest down the pike is eptinezumab from Alder Biopharmaceuticals Inc., which in January inked a European patent settlement and global license agreement with Teva covering anti-CGRP therapy, giving the company "freedom to operate worldwide and sufficient funding to launch and commercialize eptinezumab" through 2020, Leerink Partners LLC's Paul Matteis wrote last month in an earnings note on Alder's year-end financials. By midyear, the company is expected to report 12-month data on episodic migraine from the phase III PROMISE 1 (Prevention Of Migraine via Intravenous eptinezumab Safety and Efficacy) study and six-month data on chronic migraine from PROMISE 2.

No surprises are expected; top-line data in chronic migraine patients from the PROMISE program showed that eptinezumab met the primary endpoint with statistical significance vs. placebo (p<0.0001) for both dose levels tested following the first quarterly infusion and met the key secondary endpoints with statistical significance vs. placebo, including prevention beginning day one (p<0.0001) and 50 percent (p<0.0001) and 75 percent (p<0.0001) responder rates month one through month three. (See BioWorld, June 28, 2017.)

The key differentiator for eptinezumab is that the humanized MAb is dosed intravenously every three months, compared to monthly subcutaneous dosing for its rivals.

Orals could offer useful alternative to biologics

Then, there are the orals. This month, Biohaven Pharmaceutical Holding Co. Ltd. enrolled the first patient in a phase III trial of the Zydis, its orally dissolving tablet (ODT) formulation of rimegepant, which the New Haven, Conn.-based company is advancing in episodic and high-frequency episodic migraine. Two ongoing pivotal phase III trials examining the efficacy of rimegepant 75 mg vs. placebo are expected to report data this month, with top-line results from the phase III rimegepant Zydis ODT trial due in the fourth quarter.

Not to be outdone, Allergan plc has a pair of CGRP receptor antagonists: ubrogepant, which is in phase III testing, and atogepant, in phase II development. Last month, the Dublin-based company reported that ubrogepant hit the co-primary efficacy endpoints in ACHIEVE I, the first of two pivotal phase III trials, with both 50-mg and 100-mg doses showing a statistically significant difference in the percentage of individuals who achieved pain freedom two hours after the initial dose compared to placebo (50 mg vs. placebo, p=0.0023, 100 mg vs. placebo, p=0.0003) – response rates of about 19 percent and 21 percent, respectively, for the treatment arms compared to 12 percent for placebo.

Allergan also saw a statistically significant difference in the percentage of individuals who achieved absence of their most bothersome migraine-associated symptom – photophobia, phonophobia or nausea – two hours after initial dose of the study drug compared to placebo. (See BioWorld, Feb. 7, 2018.)

Top-line data from the second phase III study, ACHIEVE II, which is testing 25-mg and 50-mg doses of ubrogepant compared to placebo, are expected by midyear. Predicated on a successful outcome, the company plans to file a new drug application next year.

Experts in the field are watching the oral CGRP studies not only for effectiveness but also for signs of liver toxicity. The ubrogepant ACHIEVE I study reported six cases with aminotransferase (ALT or AST) elevations greater than three times the upper limit of normal (ULN), including five on the ubrogepant arms. Allergan cited alternative explanations of concomitant illness or medication in every case, adding that none was noted by the liver safety adjudication board to have a probable relationship to the study drug. Additionally, no cases of Hy's law occurred.

Although the jury on the orals is out until all of the data are in, they would serve as a useful alternative to biologics in the toolbox of migraine therapies, according to Tepper, especially to treat women of childbearing age who might become pregnant. Too, the CGRP small-molecule receptor antagonists would address the biggest issue with standard-of-care triptans, which are contraindicated in patients with vascular disease, he said.

Broad range of mechanisms in preclinical efforts

With its CGRP candidates, Allergan is seeking to supplement rather than supplant its Botox (onabotulinumtoxinA) franchise for chronic migraine treatment.

"The agent with the fewest side effects that we have now is Botox," Silberstein said.

He also voiced interest in earlier-stage pituitary adenylate cyclase-activating polypeptides, or PACAPs. The Amgen-Novartis-partnered AMG-301 is the first PACAP type 1 receptor antagonist to move into the clinic, according to Cortellis Clinical Trials Intelligence. Two additional assets in that class – a PAC1 antagonist monoclonal antibody from Amgen and ALD-1910, a PACAP-38 ligand inhibitor from Alder – remain in discovery, along with a broad range of mechanisms for the 28 preclinical migraine-targeting drug candidates cited by Cortellis. (See chart, below.)

Among early stage companies targeting the space, Impel Neuropharma Inc., of Seattle, closed a series C round of up to $36 million at the end of 2016 to propel its drug-device pipeline in migraine, pain and Alzheimer's. Last month, the company reported results from a phase I proof-of-concept trial testing INP-104, an intranasal version of dihydroergotamine dosed via the firm's Precision Olfactory Deliver, or POD, device, in acute migraine, showing a statistically significant improvement in bioavailability (Cmax and AUC) over a currently approved dihydroergotamine mesylate nasal spray. The company expects to begin a pivotal safety study this year.

Achelios Therapeutics Inc., of Chapel Hill, N.C., is advancing Topofen (ELS-M11), a gel formulation of the nonsteroidal anti-inflammatory drug ketoprofen designed to treat acute and chronic migraine by regulating neuronal CGRP release and preventing the generation of prostaglandins to suppress the neurogenic inflammatory response. The company reported last year that it completed a type C meeting with the FDA to discuss phase IIa data and an approval pathway for the candidate.

Another, Satsuma Pharmaceuticals Inc., of San Francisco, a spinout of Shin Nippon Biomedical Laboratories, is advancing lead candidate STS-101, which combines the migraine drug dihydroergotamine with the firm's dry-powder nasal formulation and delivery technologies. The program is still preclinical.

Just last month, Xoc Pharmaceuticals Inc., closed a tranched $30 million series A financing led by New Enterprise Associates to complete preclinical testing and take its two lead compounds, including migraine-targeting XC-101, into the clinic. The Los Gatos, Calif.-based company was founded by a team of Map Pharmaceuticals Inc. alumni. (See BioWorld, Feb. 7, 2018.)

Efforts to modify triptans, by companies such as Zosano Pharma Corp., also benefit the space. Last year, Zosano got a pivotal phase III win when its fast-acting zolmitriptan-coated microneedle patch, M-207, met both co-primary endpoints of the Zotrip trial, delivering freedom from pain at two hours for 41.5 percent of treated patients and relieving the most bothersome symptom for a majority of those treated at the same time point. (See BioWorld Today, Feb. 14, 2017.)

And Tepper cited lasmiditan, a 5-HT1F agonist from Lilly, gained in last year's $960 million acquisition of Colucid Pharmaceuticals Inc. In September, Lilly reported results from the phase III SPARTAN study at the Congress of the International Headache Society in Vancouver, British Columbia, showing statistically significant improvements vs. placebo in treating acute migraine with the oral small molecule. (See BioWorld Today, Jan. 19, 2017.)

Other areas that show promise in migraine treatment include non-invasive neuromodulation devices – at least four are expected to gain approval by this time next year, with several others in the pipeline, Tepper said – and reformulations of other drug classes, such as nonsteroidal anti-inflammatories.

Usefulness will depend 'entirely on cost and access'

For now, all eyes are on the anti-CGRP MAbs. With negligible differences in their efficacy, safety and tolerability, at least in the view of clinicians, the ability to integrate the new class into clinical practice will depend "entirely on cost and access," Tepper said.

"If the cost is low enough and access is high, they will be absolutely revolutionary and completely change the way we practice," he said. "If cost and access are acceptable, why would you treat a patient with nine disabling headache days a month with the very poor oral preventions that we currently have, all of them with a plethora of side effects that patients hate? When you look at people that we currently put on oral prevention, 80 percent of them are off those drugs within a year."

Treating physicians could easily argue that patients should start with the anti-CGRP MAbs for episodic and chronic migraine patients, Tepper said, but he worries that the new class could become the PCSK9s of the neurology field – "potentially paradigm-shifting drugs that nobody can get ahold of because the cost is too high and the payers won't agree to allow anybody to take them."

Some analysts have suggested that competition among anti-CGRP developers will lower prices. In December, Jefferies LLC analyst Biren Amin posted findings from a payer discussion suggesting that "clear differences" among agents in the class may drive adoption despite similarities such as self-administered injectables and a competitive arena. "Given symptomatic disease with migraines, it may be more difficult to deny reimbursement," he added, and "given there's more than one CGRP, [the payer] could enter into an exclusive contract, similar to what they've done with Repatha."

Tepper is skeptical.

"These are astonishingly effective drugs for my patients, and it will be a shame if cost and access are the key barriers," he said. "But that's what I think it's going to be about."

No matter what happens with pricing, experts agree anti-CGRPs will certainly be introduced as drugs of last resort following the failure of anti-epileptics, antidepressants, antihypertensives and Botox.

"We will not be able to use them first," Silberstein maintained. "Basically, patients will have to fail two or three other drugs before they can even get them."

Once the CGRPs are in use for about six months, however, Silberstein is optimistic that their effectiveness over other migraine drugs will be proven.

And despite the inevitable pricing pressures, at least at the outset, for the migraine space as a whole, "we're in a new revolution," Digre said. "It's not just the CGRP inhibitors and peptides and antibodies coming to market. We've got other classes of drugs that are looking at the actual pathophysiology of migraine and trying to target that pathophysiology, just like we've done in other conditions, such as multiple sclerosis. For the first time, we're finally trying to directly target the process of the disease."