Top-line data from three pivotal studies of Allergan plc's NMDA receptor modulator, rapastinel, in major depressive disorder (MDD) found adjunctive therapy with the candidate no better than a placebo in improving symptoms of the condition. An interim analysis of a fourth trial, in preventing relapses, appeared unlikely to meet its endpoints, either, the company said.
The setback, a marked contrast to Janssen Pharmaceuticals Inc.'s success in winning FDA approval of another NMDA receptor modulator Tuesday, calls into question the value of Allergan's acquisition of the drug's inventor, Naurex Inc., for $560 million up front and $75 million in milestone payments to date. It also served as "a vivid reminder that drug development is extremely challenging, especially in mental health," said David Nicholson, Allergan's chief research and development officer. (See BioWorld Today, July 28, 2015.)
Three separate studies, RAP-MD-01, -02 and -03, evaluated adding rapastinel or placebo to treatment for people with MDD who were only partially responsive to the antidepressants they were already taking. Rapastinel, tested in two different doses, was given once weekly as a bolus I.V. injection in addition to an oral antidepressant.
The rapastinel treatment arms of all three studies failed to differentiate from placebo on both the primary and key secondary endpoints, each of which measured changes from baseline in patients' scores on the Montgomery-Asberg Depression Rating Scale, a clinician-rated scale to assess depressive symptomatology.
A global phase III monotherapy program comparing rapastinel to placebo and a phase II study of the drug in patients with MDD at imminent risk of committing suicide is still actively recruiting.
"We will evaluate the impact of these data on the ongoing monotherapy MDD program and suicidality in MDD study," said Nicholson, adding that his team expects to make a decision on the programs later this year. A company representative did not answer a question about whether the outcome of the adjunctive therapy studies would necessitate a future write-down of the asset.
About 16 million Americans are living with MDD, with 6.7 percent of U.S. adults reporting at least one MDD episode in the past year, according to Allergan. Nicholson expressed deep disappointment in the rapastinel trials' outcomes, restating Allergan's commitment to the space, in which it already sells Viibryd (vilazodone). But even as a full release of data was put off until presentation at a future scientific meeting, Allergan investors seemed mostly unfazed by the news, lifting company shares (NYSE:AGN) 4 percent to close at $143 on Thursday.
To put rapastinel's importance in the company's portfolio in context, Allergan's total neuroscience and urology segment brought in about $1.72 billion in 2018 revenue for the company. Botox (onabotulinumtoxinA)-based therapies accounted for about $1.64 billion of that amount. Accordingly, FDA acceptance of two supplemental BLAs seeking to expand approved uses of the blockbuster medicine, announced a day after the rapastinel results, carried greater weight.
The rapastinel data "shouldn't be surprising to anyone," said Mizuho Securities analyst Irina Koffler. "And while we saw some encouraging signals in the earlier trials, we gave this event 50/50 odds in the end," she said. She expects the outcome may lead to "additional restructuring and potential leadership changes within the organization, which would all be welcomed by an increasingly hostile group of shareholders."
In addition to rapastinel, Allergan is also working on AGN-241751, another NMDA partial agonist for the potential oral treatment of MDD. Sourced from Naurex spin-off Aptinyx Inc., the molecule is now being tested in phase II proof-of-concept studies exploring different dosing regimens. Top-line data from the studies are expected in the second half this year. Koffler said her team believes the program will be dropped. (See BioWorld, Jan. 17, 2019.)