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Replacing a needle with a pill
DUBLIN—Aimed at relieving and preventing the debilitating effects of migraine without the adverse effects of opioids, global pharmaceutical Allergan plc has come up with its first oral calcitonin gene-related peptide (CGRP) receptor agent in the form of a pill, as opposed to an injection.
On Feb. 6, Allergan announced positive results from ACHIEVE I (UBR-MD-01), the first of two pivotal Phase 3 clinical trials evaluating the efficacy, safety and tolerability of orally administered ubrogepant 50 mg and 100 mg compared to placebo in a single migraine attack in adults. The study met co-primary endpoints in the first of two Phase 3 studies.
Considered potential game-changers, Allergan’s CGRP receptor antagonists—ubrogepant in Phase 3 for the acute treatment of migraine and atogepant in Phase 2B for the prevention of migraine—are expected to be the first oral CGRP receptor antagonists to market, possibly as soon as 2020.
“We are pleased with the favorable results of our ACHIEVE I study, which support the efficacy, safety and tolerability profile of ubrogepant,” states David Nicholson, chief research and development officer for Allergan. “We are confident that ubrogepant, an oral calcitonin gene-related peptide receptor antagonist, will be an option for the treatment of migraines in adults. Allergan remains committed to identifying, developing and bringing to market therapies that address unmet need for patients suffering from this debilitating disease.”
Allergan believes oral therapy, as opposed to injection, will likely appeal to individuals with migraine. Migraine is defined as a chronic disease with episodic attacks characterized by neurological symptoms—such as headache pain, nausea and sensitivity to light and sound—that are often incapacitating.
The current standards of care in the acute treatment of migraine are not optimal for many patients due to partial effectiveness, poor tolerability or contraindications, Nicholson says. As a consequence, patients may experience repeated, uncontrolled attacks leading to medication overuse, possible opioid addiction and increased risk of migraine disease progression.
Chronic migraine is a distinct neurological condition affecting 3.2 million Americans, defined as having 15 or more headache days per month, with headaches lasting four hours a day or longer and at least eight of those headache days being associated with migraine, Nicholson explains. One of seven adults suffer from migraine episodes globally.
Ubrogepant is a novel, highly potent, orally administered CGRP receptor antagonist in development for the acute treatment of migraine, Nicholson says. CGRP and its receptors are expressed in regions of the nervous system associated with migraine pathophysiology. CGRP receptor antagonism is a novel mechanism of action for the acute treatment of migraine that clearly differs from the mechanisms of currently available triptans (serotonin 1B/1D agonists) and opioids.
Allergan has marketed Botox, an injection therapy, but believes more people would take advantage of a new migraine therapy in pill form, Nicholson notes. Botox is the first and only FDA-approved (in 2010) preventive treatment for chronic migraine. According to Allergan, unlike acute treatments, which are taken to treat a headache or migraine once it’s already begun, Botox prevents headaches and migraines before they even start. Botox prevents on average eight to nine headache days and migraine/probable migraine days a month (vs. six to seven for placebo).
The ACHIEVE I study included 1,327 U.S. adult patients randomized to placebo, ubrogepant 50 mg or ubrogepant 100 mg, who were treated for a single migraine attack of moderate to severe headache intensity.
Both doses showed a statistically significant greater percentage of ubrogepant patients achieving pain freedom at two hours after the initial dose as compared to placebo patients. The study also found that ubrogepant was well tolerated, with an adverse event profile similar to placebo. The most common adverse events were nausea, somnolence and dry mouth—none of which were reported with a frequency of more than 5 percent.
In terms of hepatic safety, across all treatment arms including placebo, there were six cases with aminotransferase (ALT or AST) elevations greater than three times the upper limit of normal. There were alternative explanations in all cases (concomitant illness or medication), and none were noted by the liver safety adjudication board to have a probable relationship to ubrogepant. Also, there were no cases of Hy’s Law, which states that hepatocellular drug-induced liver injury with jaundice indicates a serious reaction and is used widely to determine risk for acute liver failure.
“Despite the prevalence of migraine and availability of several treatment options, the disease remains underdiagnosed and undertreated,” states lead investigator Dr. Richard B. Lipton, vice chair of neurology, professor of epidemiology and population health and director of the Montefiore Headache Center at the Albert Einstein College of Medicine. “There is also low persistence and adherence to the current standard-of-care treatments. There remains a need for new treatments with improved benefit-risk profiles. Results from this ubrogepant Phase 3 trial are important in progressing the research and developing therapies to help migraine patients.”
Additional results from this Phase 3 study are anticipated to be released at upcoming scientific meetings throughout 2018.
Results of the second Phase 3 trial, ACHIEVE II (UBR-MD-02), are expected in the first half of 2018. Allergan anticipates filing of a New Drug Application to the FDA in 2019.