Allergan's Ubrogepant Succeeds In Second Acute Migraine Phase III Study

The company intends to seek US FDA approval in the first half of 2019 for its CGRP inhibitor and believes that liver toxicity previously associated with oral drugs in this class are not a problem for its candidate ubrogepant.

Allergan PLC had its confidence in the oral CGRP inhibitor ubrogepant confirmed when the drug succeeded in a second Phase III clinical trial in the treatment of acute migraine headaches, justifying a submission to the US FDA in the first half of 2019.

The calcitonin gene-related peptide (CGRP) inhibitors in late stages of development are chasing a market that hasn't had a new therapy approved in more than a decade, but will compete with generic triptans for payers' attention. Allergan believes that its drug addresses an unmet need for patients who don't respond to or can't tolerate triptans or other migraine therapies, but it's also facing multiple competitors – including at least one other novel mechanism of action, a type of serotonin receptor agonist that acts in a similar way as triptans.

Amgen Inc. and its partner Novartis AG are likely to be the first to market with a CGRP inhibitor and Amgen believes that its candidate Aimovig (erenumab), which specifically targets the CGRP receptor, is differentiated enough from its competitors to grab significant market share. (Also see "As Amgen Looks To Aimovig's Launch, It May Learn From Repatha's Past" - Scrip, 25 Apr, 2018.)

However, Allergan's ubrogepant could be the first oral CGRP-targeting drug and the first to offer patients a treatment for when a headache strikes, since Aimovig and other monoclonal antibodies from Eli Lilly & Co., Teva Pharmaceutical Industries Ltd. and Alder Biopharmaceuticals Inc. are being developed as preventative therapies.

Allergan reported positive results for ubrogepant 50 mg and 100 mg doses in the Phase III ACHIEVE I clinical trial in February, but the company also has a second oral CGRP inhibitor known as atogepant, which is being studied as a prophylactic in a Phase IIb clinical trial with data expected later this year. Both were licensed in 2015 from Merck & Co. Inc., which previously ended development of the CGRP inhibitor telcagepant after it and prior CGRP inhibitors ran up against liver toxicity problems. (Also see "Allergan migraine portfolio grows with Merck CGRP antagonists" - Scrip, 8 Jul, 2015.)

Safety And Efficacy Confirmed?

Allergan's Chief Research and Development Officer David Nicholson said the Phase III ACHIEVE II study confirmed ubrogepant's efficacy by providing freedom from pain and freedom from most bothersome symptoms (MBS) at two hours – the co-primary endpoints of the study – similar to the efficacy seen in ACHIEVE I. The second set of Phase III results also showed "that the safety, like the monoclonal antibodies, is clean in terms of the side effect profile," Nicholson said.

ACHIEVE II enrolled 1,686 adults who were treated with placebo, ubrogepant 25 mg or ubrogepant 50 mg when a moderate-to-severe migraine headache occurred. The modified ITT (mITT) population included 1,355 patients.

Allergan reported that in the mITT population, 20.7% of patients treated with ubrogepant 25 mg, 21.8% of patients treated with ubrogepant 50 mg and 14.3% who received a placebo achieved pain freedom at two hours after the initial dose (p=0.0285 for 25 mg versus placebo; p=0.0129 for 50 mg versus placebo).

Also in the mITT group, 34.1% of patients treated with ubrogepant 25 mg, 38.9% treated with ubrogepant 50 mg and 27.4% in the placebo arm achieved freedom from MBS two hours after the initial dose (p=0.0711 for 25 mg versus placebo; p=0.0129 for 50 mg versus placebo). The result for the 25 mg dose was not statistically significant.

The 50 mg dose of ubrogepant, but not the 25 mg dose, also had statistically significant results compared with placebo in terms of the percentage of patients with sustained pain relief from two to 24 hours and sustained pain freedom from two to 24 hours compared with placebo (p=0.0129 for both). Ubrogepant 50 mg also had a statistically significant effect on photophobia (p= 0.0167) and phonophobia (p= 0.0440) two hours after the initial dose versus placebo.

Allergan described ubrogepant as well tolerated and similar to placebo with no signal of hepatotoxicity. Nausea and dizziness were the most common adverse events, but both were experienced by fewer than 2.5% of ubrogepant-treated patients.

Liver Toxicity Appears Unrelated

There were four cases of aminotransferase (ALT or AST) elevations greater than three times, but not higher than five times, the upper limit of normal (ULN), within 30 days of treatment, including one patient treated with placebo. None of the four cases were believed by the study's liver safety adjudication board to be related to ubrogepant. One of the ALT elevations was observed within seven days of dosing in a patient treated with ubrogepant 50 mg, but it was attributed to exercise-induced rhabdomyolysis. There were no cases of Hy's Law.

"We're convinced that we have not seen a liver signal in these two Phase III acute studies," Nicholson said. "In ACHIEVE I, there were clear alternative explanations [for the six ALT elevations, including one on placebo.]"

But with safety often a sticking point when drugs come under FDA review for approval, Biomedtracker noted in an April 27 report that despite the ACHIEVE I and II liver safety panels' determinations, "regulators will likely scrutinize the [ALT elevation] cases … and it will be important to see data from the extension trial."

Stock analysts appeared more comfortable with the liver safety panel's findings in ACHIEVE II, declaring that the ALT elevations are not a major concern going forward. Evercore ISI's Umer Raffat said in an April 27 note that one of the study's most important findings was that there were no ALT elevations at five times or greater than the ULN.

Raffat noted that "when I aggregate the liver tox data from both Allergan Phase III trials, and zoom in specifically on ALT>3x cases that happen within seven days of dosing, there's no signal. This may be the single most important point in favor of the oral CGRP class (and I acknowledge that Biohaven saw zero imbalance in their study)."

Allergan's closest competitor in the oral CGRP space is Biohaven Pharmaceuticals Holding Co. Ltd., which also has its candidate rimegepant in Phase III studies for acute treatment of migraine. Biohaven reported positive data from two Phase III trials in March and indicated that it would seek FDA approval in 2019.

'Commercialization Gets Complicated'

Credit Suisse analyst Vamil Divan said in an April 27 note that approval of ubrogepant, particularly at the 50 mg dose, is likely, but "commercialization gets complicated" because of competition in the migraine space, including both oral and injectable CGRP inhibitors and another new mechanism of action.

"Based on the solid efficacy and safety data to date, we think the 50 mg dose will be easily approved by the FDA. The 25 mg and 100 mg doses will be trickier given they were only included in one trial and the 25 mg dose missed one of the co-primary endpoints in [ACHIEVE II]," Divan wrote. "However, there is a competing product, Lilly's lasmiditan, which has a different mechanism of action and slightly better efficacy profile, although also [there are] some questions around dizziness and tolerability of the drug. Allergan also faces competition from a competing oral CGRP in rimegepant."

In addition to its two completed Phase III studies, Biohaven is developing an orally disintegrating tablet (ODT) version of rimegepant under an agreement with Catalent Swindon Zydis, which quickly dissolves to reach maximum plasma concentration in the blood about 30 minutes faster than the original formulation, and Phase III results for the ODT drug are expected later this year.

Biohaven's other oral CGRP inhibitor BHV-3500 is a preclinical candidate that's expected to enter Phase I this year and will be developed for both acute and prophylactic treatment of migraines. Both rimegepant and BHV-3500 are licensed from Bristol-Myers Squibb Co. (Also see "Deal Watch: Ionis Turns To Affiliate Akcea In Amyloidosis" - Scrip, 15 Mar, 2018.)

However, both Allergan's and Biohaven's candidates have yet another late-stage oral migraine drug competitor. Lilly reacquired lasmiditan via the $960m purchase of CoLucid Pharmaceuticals Inc. in January 2017. (Also see "Lilly Pays Nearly $1bn To Regain Migraine Candidate It Once Sold For $1m" - Scrip, 18 Jan, 2017.) Final data from Phase III SPARTAN study for lasmiditan and a new drug application (NDA) submission to the FDA expected are expected later this year.

Lasmiditan is a serotonin receptor agonist that is a selective inhibitor of 5-HT1F receptors in the trigeminal pathway. Some of the triptans act on that subtype, although their affinity for the 5-HT1B and 5-HT1D receptors is thought to be the source of their anti-migraine activity.

Both the CGRP inhibitor and drugs like lasmiditan are expected to be acceptable alternatives to triptans, which are contraindicated for many migraine patients due to cardiovascular risks.

Divan said that during a recent "Therapeutics Day" hosted by Credit Suisse that two doctors said ubrogepant, rimegepant and lasmiditan all have a place in the migraine market, but they were most interested in prescribing lasmiditan.

"This choice was not just due to the efficacy profile, but the fact that by the time these drugs are approved, many patients will likely be transitioning to long-term anti-CGRP antibodies [from available generics] for migraine prophylaxis," Divan wrote. "The doctors wonder how effective an anti-CGRP oral can be in patients that are already treated with an anti-CGRP biologic."

Lilly has said that it sees having both two options to offer physicians who treat migraines – the CGRP-targeting biologic galcanezumab for prophylaxis and lasmiditan for acute symptom relief – as a competitive advantage. (Also see "Lilly Breathing Down Amgen/Novartis's Necks With Three Phase III Migraine Wins" - Scrip, 12 May, 2017.)

Allergan essentially has a three-pronged migraine approach. In addition to ubrogepant and atogepant, the company's top-selling product Botox (onabotulinumtoxinA) is approved as a migraine prophylaxis, which is its biggest therapeutic indication. (Also see "Allergan’s Oral Drugs Overlooked In CGRP Inhibitor Development Race" - Scrip, 30 Sep, 2016.)