DUBLIN—In early June, Allergan plc announced positive results from CGP-MD-01, a Phase 2b/3 clinical trial evaluating the efficacy, safety and tolerability of orally administered atogepant. All active treatment arms of atogepant met the primary endpoint across all doses and dose regimens, with a statistically significant reduction from baseline in monthly migraine/probable migraine (MPM) headache days in patients with episodic migraine treated with atogepant compared with placebo for 12 weeks.
Atogepant is Allergan’s second orally-administered investigational calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. Atogepant follows ubrogepant, Allergan’s first oral investigational CGRP antagonist for the acute treatment of migraine, which reported two positive Phase 3 pivotal trial results earlier this year. Allergan will continue with its Phase 3 program for atogepant, following discussions with regulatory authorities.
“We are extremely pleased to share these positive results for atogepant—our first phase 2b/3 study in episodic migraine—which represent a tremendous opportunity in the prevention of migraine, with a convenient oral dosage form that is currently unavailable,” says David Nicholson, chief research and development officer at Allergan. “Atogepant is a novel, highly potent, orally-administered CGRP receptor antagonist in development for the prevention of migraine. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology.
“Antagonism of these receptors reduces pain and the other symptoms of migraine. Atogepant is chemically distinct from ubrogepant, our orally-administered CGRP receptor antagonist for the acute treatment of migraine, with a higher potency and longer half-life, making it suitable for preventive treatment.”
In study CGP-MD-01 834 U.S. adult patients were randomized to placebo, 10-mg once per day (QD), 30-mg QD, 30-mg BID, 60-mg QD or 60-mg twice per day (BID) and treated under double-blind conditions for 12 weeks, for the prevention of episodic migraine. Efficacy analyses were based on the modified intent-to-treat population of 795 patients.
The primary efficacy endpoint was the change from baseline in mean MPM headache days across the 12-week treatment period.
All active treatment groups demonstrated a statistically significant reduction from baseline in the primary efficacy parameter (10 mg QD vs. placebo, p=0.0236; 30 mg QD vs. placebo, p=0.0390; 60 mg QD vs. placebo, p=0.0390; 30 mg BID vs. placebo; p=0.0034, 60 mg BID vs. placebo, p=0.0031).
The reported p-values are adjusted for multiple comparisons by controlling the overall type I error rate of the study at 5 percent, two-sided. Additional details and results from other endpoints are anticipated to be presented at upcoming scientific meetings.
“Atogepant is an oral CGRP antagonist that will allow us to address the preventive treatment of episodic migraine and subsequently, chronic migraine. Given its safety and heritage in chronic migraine as well as its unique mechanism of action and HCP administration, we expect Botox to continue to the be the foundation of chronic migraine therapy,” notes Nicholson.
“Atogepant will provide an oral CGRP antagonistic option; this is important given the preference of many patients for an oral formulation,” he continues. “While atogepant will allow us to address the preventive treatment of episodic migraine and chronic migraine, many migraine sufferers will still experience breakthrough headaches on preventive medications, and therefore, will need an acute treatment option such as ubrogepant. Allergan recognizes that many migraine sufferers may require multiple treatment options to help prevent migraines/headaches and also address moments when they have a breakthrough headache/migraine.”
In the CGP-MD-01 trial, atogepant was well tolerated. The most common adverse events were nausea, fatigue, constipation, nasopharyngitis and urinary tract infection, which were reported with a frequency of more than 5 percent in at least one atogepant treatment arm and greater than placebo. There was no signal of hepatotoxicity with atogepant in this study with daily administration over 12 weeks. The liver safety profile for atogepant was similar when compared to placebo.
“The positive results from this study show that oral atogepant has a compelling profile relative to other treatment options on the market and in development for the prevention of migraine. We are excited about the prospects for this product and rapidly moving to the next stage of development,” said Bill Meury, chief commercial officer at Allergan. “Allergan has one of the most innovative and deepest product lines for migraine in the industry, with Botox approved for the prevention of chronic migraine and oral atogepant and ubrogepant in development for the prevention and acute treatment of migraine.”
“These exciting results demonstrate the potential for atogepant for a broad spectrum of migraine patients. The efficacy and safety across doses and dose regimens show promise in a patient population with high unmet treatment needs,” said Dr. Peter Goadsby, a neurologist and professor at Kings College London and the University of California, San Francisco. “Results from this atogepant trial provide continued evidence for the clinical potential of oral CGRP antagonists and the substantial value of progressing research and developing new treatments for migraine patients.”
“We are excited about advancing our migraine program with two investigational small molecule oral CGRP receptor antagonists ... These are expected to be the first oral CGRP receptor antagonists to market,” Nicholson concludes.
Ubrogepant enters Phase 3
DUBLIN—In April, Allergan announced positive results from ACHIEVE II (UBR-MD-02), the second of two pivotal Phase 3 clinical trials evaluating the efficacy, safety and tolerability of orally administered ubrogepant 25 mg and 50 mg compared to placebo in a single migraine attack in adults. The ACHIEVE II study included 1,686 U.S. adult patients randomized to placebo, ubrogepant 25 mg and 50 mg, to treat a single migraine attack of moderate-to-severe headache intensity.
“We are pleased to share these positive results from ACHIEVE II, our second Phase 3 study supporting the efficacy, safety, and tolerability of 50 mg ubrogepant. The consistency in response between both ACHIEVE I and ACHIEVE II provides further evidence that ubrogepant, an oral calcitonin gene-related peptide (CGRP) receptor antagonist, offers a promising opportunity for the acute treatment of migraine,” said David Nicholson, chief research and development officer of Allergan.
Both dosages showed a statistically significant greater percentage of ubrogepant patients achieving pain freedom at two hours after the initial dose as compared to placebo patients, and the 50 mg dose demonstrated a statistically significant greater percentage of ubrogepant patients achieving absence of the most bothersome migraine-associated symptom at two hours after the initial dose.
The 25 mg dose demonstrated improvement, but failed to demonstrate statistical significance.
The 50 mg dose of ubrogepant also showed a statistically significant greater percentage of patients achieving pain relief at two hours, sustained pain relief from two to 24 hours, and sustained pain freedom from two to 24 hours after the initial dose as compared to placebo. In addition, ubrogepant 50 mg also showed a statistically significant greater percentage of patients achieving absence of photophobia and phonophobia at two hours after the initial dose as compared to placebo. Ubrogepant 25 mg failed to demonstrate statistical significance in these endpoints.
In ACHIEVE II, ubrogepant was well tolerated and demonstrated a safety profile similar to placebo. There was no signal of hepatotoxicity for ubrogepant.
The most common adverse events were nausea and dizziness, neither of which was reported with a frequency more than 2.5 percent. Additional results from this study are anticipated to be released at upcoming scientific meetings throughout 2018, and Allergan anticipates filing of a New Drug Application to the FDA in 2019.