Missed efficacy endpoints in two phase III trials of Alkermes plc's lead candidate, the once-daily depression medicine ALKS 5461, dragged company shares (NASDAQ:ALKS) down by 44.2 percent, or $26.71, to close at $33.71 on Thursday, as analysts deeply discounted the drug's chances of success, cutting millions of dollars of projected revenue from the company's future earnings.
Alkermes, which is pushing ahead with the program, said that in response it will increase trial enrollment and update its statistical analysis plan for a third late-stage study, called FORWARD-5.
Though there is precedent in Otsuka Pharmaceutical Co Ltd.'s Rexulti (brexpiprazole) for a depression drug to gain FDA approval based on just one positive phase III study, "at this point, (we) think the likelihood of success for the product making it to the market is very low," Credit Suisse analyst Vamil Divan wrote. In step with analysts at Jefferies and JP Morgan, Credit Suisse removed all potential sales for ALKS 5461 from its models.
ALKS 5461 comprises a combination of samidorphan an oral opioid modulator formerly known as ALKS 33 and the opioid buprenorphine. Alkermes is developing it for the treatment of major depressive disorder (MDD) in patients who have an inadequate response to standard antidepressant therapies, an indication for which it gained FDA fast track status in October 2013. MDD is the most common type of depression, with a global point prevalence of 4.7 percent and a pooled annual incidence of 3 percent, both based on a systematic review of published epidemiological studies, according to Thomson Reuters Cortellis.
Top-line results from FORWARD-1, an earlier phase III study, confirmed the safety and tolerability of ALKS 5461 in one-week and two-week dose-escalation schedules, also demonstrating in exploratory analyses that patients who received it on either schedule experienced a statistically significant reduction in depressive symptoms from baseline. But that positive picture is muddied by the two new trials, both of which compared ALKS 5461 to placebo on the change from baseline on the MontgomeryÅsberg Depression Rating Scale (MADRS). (See BioWorld Today, March 7, 2014.)
One study, FORWARD-3, tested a formulation of ALKS 5461 containing 2 mg of buprenorphine and 2 mg of samidorphan vs. placebo in 429 patients. It found no treatment effect for the drug and a placebo response that was greater than that observed in FORWARD-4, a trial that tested the same dose vs. placebo in addition to a lower dose 0.5 mg/0.5 mg version of the pill in 385 patients. Although the drug missed its endpoint in FORWARD-4, too, Alkermes said there was "a clear trend toward efficacy" with the 2 mg/2 mg dose in that study, providing enough supportive evidence to move ahead with FORWARD-5, the third pivotal efficacy study.
Ongoing now, FORWARD-5 is testing two dose levels of ALKS 5461 (2 mg/2 mg and 1 mg/1 mg). Though it shares common design and analysis features with FORWARD-4, its enrollment will now be increased and the statistical analysis plan will be updated, Alkermes noted, though a representative of the company said no further details of that change are being publicly disclosed now. The company plans to provide an update later this quarter on the projected timing of completion for the study.
"In the case of a clear positive outcome for FORWARD-5, Alkermes believes that the evidence provided by it and the previously completed successful, randomized, placebo-controlled phase II study, together with supportive evidence from FORWARD-4, collectively could provide substantial evidence of efficacy for ALKS 5461 for the adjunctive treatment of MDD," it said in a statement.
Alkermes' experience with the placebo response in FORWARD-3 is not wholly surprising. Studies testing antidepressants against placebo suggest that 40 percent of response is due to the placebo effect. (That's part of the reason there are so many trials in the FORWARD program.) However, an additional element is at play in the study with the inclusion of samidorphan, a mu-opioid antagonist intended to control side effects associated with the opioid component: Marta Pecina, a research assistant professor in the University of Michigan department of psychiatry and the author of a recent article proving the role of opioid mediated neurotransmission in the formation of placebo effects in depression, told BioWorld Today that "a potential limitation of samidorphan could be that, in addition to reducing side effects it is also reducing placebo effects in the drug arm, because of its mu-opioid antagonist properties, and therefore it's going to be harder to show a drug-placebo difference."
The failure of antidepressant responses to separate from placebo has contributed to the reduction or discontinuation of research on new treatments for depression, she wrote in her recent study, published in the November 2015 issue of JAMA Psychiatry. In parallel with efforts to develop new drugs, "we need to put further efforts into developing ways to control for placebo responses and effective ways to assess drug-placebo interactions," she said.
While standing by Alkermes' prospects in the long term, JP Morgan analyst Cory Kasimov wrote that the company's 2016 catalysts "aren't convincing us to hang on in near-term."
Over the course of the year ahead, he said his team expects quarterly updates to provide insight into the launch of Aristada (aripiprazole lauroxil), Alkermes' extended-release injection to treat adults with schizophrenia and on commercial progress for Vivitrol (naltrexone), approved in the U.S. and Russia for the treatment of alcohol dependence and for the prevention of relapse to opioid dependence. (See BioWorld Today, April 17, 2006.)
Early data on two new candidates, ALKS 7119, a potential treatment of agitation in patients with Alzheimer's disease, MDD and other central nervous system diseases and for the immuno-oncology candidate RDB 1450 could also arrive this year.
"One wildcard out there, in our view, is M&A, where ALKS could conceivably be a player on either the buying or possibly even the selling side," Kasimov wrote.