Alkermes third time lucky with ALKS 5461, but doubts linger

Alkermes ($ALKS) is hoping to become a phoenix from the flames with new data showing that its twice-failed depression drug ALKS-5461 finally produced some positive results.

Let’s go back to the start of the year when the Dublin, Ireland-based biotech saw its candidate ALKS-5461 fail to hit the primary endpoints in the first two of three Phase III studies, delivering a gut punch to the co and the field.

Alkermes cited a higher placebo response and other reasons for its flops, but some suggested its trial designs were not up to scratch. Few believed it was a glitch in the Matrix, and Alkermes saw a 44% shares drop on the news, wiping $4 billion from its market cap.

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Last night, however, the company produced the much-anticipated third Phase III study, which in January it had noted could deliver the goods.

In the 400-patient test, known as FORWARD-5, the med met its primary endpoint: namely, a statistically significant improvement for ALKS 5461 compared with placebo on the change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS), a measure of antidepressive effect used in depression studies. The drug is designed as an adjunct for those who are resistant to other meds. 

Based on these results, Alkermes said it now plans to speak with FDA staffers about the next steps toward seeking approval. Cue its shares bouncing nearly 45% afterhours when the news broke.

Elliot Ehrich, CMO of Alkermes, said: “With the successful completion of the FORWARD-5 study and data from more than 1,500 patients to date, we have established a strong foundation of evidence of ALKS 5461’s clinical utility in the adjunctive treatment of major depressive disorder.

“With these data now in hand, we will move forward rapidly to meet with the FDA to determine the appropriate next steps toward a regulatory submission for ALKS 5461, with a goal of bringing this important new medication to patients with MDD.”

In a call last night, Richard Pops, chairman of the company, said he will look to “request a meeting within a matter of a few days or a couple weeks” with the FDA about these data. He added that they are not planning to conduct any additional studies.

The drug works as a once-daily pill combining samidorphan and buprenorphine, a centrally acting opioid modulator. ALKS 5461 is also in tests for other areas, such as autism, OCD and anxiety.

But doubts still remain about its viability, not only because it missed its target on two out of three tests, but also because while the drug showed superiority over placebo on two different depression scales at the higher of two tested doses, the lower missed significance compared with a dummy treatment.

It also appears that the company tweaked the study, prompted by the failures seen back in January.

In a call with investors last night, Ehrich said: “In September, we went with a division of psychiatric products at the FDA and reviewed the data from the FORWARD-3 and FORWARD-4 studies. FORWARD-4 was a negative study based primarily on the selection of a single time point for the primary analysis. Overall the data provided strong evidence, a supportive evidence of ALKS 5461 at the 2mg/2mg dose. FORWARD-3 was less informative despite a relatively consistent effect of ALKS 5461 and this was due to the high placebo response observed in the study.

“Taken together the datasets from the two studies provided us with a wealth of knowledge we could apply to FORWARD-5 particularly related to the statistical analysis plan. In order to avoid the risk of determining success or failure based on a single time point in an inherently variable disease, we pre-specified the primary endpoint for FORWARD-5 is the change in depression scores from baseline to an average over the final weeks in the two stages.”

He said that this continuous measurement of efficacy across multiple time points “is a more powerful and precise depiction of the drug's efficacy profile.”

He added that, in addition to that change, the biotech also chose to use the six-item MADRS-6 as its primary efficacy assessment. MADRS-6 focuses on the core symptoms of mood and excludes symptoms that are commonly observed in other disease states where that may be attributable to background therapy.

“As a result MADRS-6 may provide a more specific measurement of antidepressant activity,” he said. “The study also achieved significance on the MADRS-10 as well as MADRS-6.”

But he explained that while the co submitted its statistical analysis plan for FORWARD-5 to the FDA, “The agency did not provide feedback on a stat plan prior to unbinding of the data this week. However, they acknowledge receipt of the plan and are aware of our approach. And we will discuss the results of the entire FORWARD program at our next meeting.”

He concluded: “Each of the studies in the FORWARD program contributes data useful in assessing the safety and efficacy of ALKS 5461 on a standalone basis and taken collectively. For this reason, we also pre-specified a statistical plan for pooling data from FORWARD-5 and FORWARD-4 which shared a similar design.

“We've just started this work but the initial results are powerful, the sample sizes increased P-values drop. This underscores the informative power of a large dataset as well as ALKS 5461’s consistent anti-depressive effect which we will be presenting these data to the FDA in the future and to you.”