FDA Blasts Data, Trial Design For Alkermes Depression Drug

Xconomy Boston — 

The FDA this morning has issued a scathing review of an experimental drug that could be, if the agency ends up approving it next year, a new option for the millions of Americans who struggle with depression and don’t respond to typical treatment.

The drug is known as ALKS-5461, from Dublin and Waltham, MA-based Alkermes (NYSE: ALKS), and on Thursday, a panel of outside experts will debate whether the FDA should give it the green light in 2019.

Ahead of that meeting, FDA scientists have issued a review of ALKS-5461. The document is critical of the data Alkermes has accrued, the trial design it used, and whether the drug—which contains an opioid—will be safe for patients to take.

It should be noted that FDA drug review documents often take a strikingly negative tone, and the agency has approved psychiatric drugs off of mixed clinical results before. Nonetheless, shares of Alkermes fell roughly 6.5 percent in pre-market trading as investors began to digest the information.

The review of ALKS-5461 is being closely watched for a few reasons. Depression—specifically, major depressive disorder (MDD), the most common form of the disease and what ALKS-5461 is aimed at—is an epidemic in the U.S. MDD affects 18.1 million Americans, or 6.7 percent of the U.S. population 18 or older in a given year, and is the leading cause of disability in the country for people between 18 and 44.3 years old, according to the nonprofit Anxiety and Depression Association of America.

People diagnosed with MDD get antidepressants known in shorthand as SSRIs or SNRIs, which are meant to boost levels of a brain chemical called serotonin and thus lift peoples’ mood. But those drugs don’t work for everyone. And a variety of meta-analyses done over the years have only further fueled a debate about how effective antidepressants actually are. What’s more, there’s no effective way to predict who will respond best. And the options for people who fail SSRIs/SNRIs are more invasive, including deep brain stimulation.

These factors make any new depression drug a very big deal for public health, and a potentially huge selling drug for its developer. That’s why shares of Alkermes, a company best known for its roots as a drug delivery specialist, have had such huge swings on updates to the ALKS-5461 program. And those swings should continue this week. Stifel analyst Paul Matteis estimated Alkermes’ shares could surge 15 to 20 percent on good news this week. He predicts more than $500 million in peak sales for ALKS-5461 if the drug was approved.

Yet ALKS-5461 isn’t a slam dunk for an FDA approval. The drug has had a mixed track record in clinical testing, which consists of four placebo-controlled trials—one Phase 2 test, and a troika of Phase 3 studies dubbed Forward 3, 4, and 5. Those data were accrued from studies that used a novel design, a two-stage trial known as a sequential parallel comparison design (SPCD), that the FDA hasn’t seen before.

Only one of the three Forward studies hit its main goal. And the one that did, Forward 5, succeeded because Alkermes measured patients’ depression symptoms over multiple weeks and averaged them. In the two that failed, Alkermes picked results from a single week to measure against a baseline established at the start of the trial. Alkermes executives have previously said, for instance, that Forward 4 would have succeeded too had the company used a time-averaged measure.

The mixed results for ALKS-5461 aren’t surprising: Placebo-controlled studies of depression drugs (and other treatments for psychiatric disorders) are notoriously challenging and often fail due to placebo effects that can confound the results. Alkermes used the SPCD protocol to try to wash out the placebo effect, but still saw it crop up.

The FDA, cognizant of these issues, does have a track record of approving psychiatric drugs off of a mixed bag of clinical data. That’s why Alkermes, in its rebuttal, is pointing to the “totality of the data” it has accrued as proof the drug works.

“Efficacy has been demonstrated across multiple studies and across multiple randomizations,” Alkermes wrote.

Nonetheless, FDA scientists blasted many aspects of Alkermes’ approach. They disagreed with Alkermes’ decision to switch its statistical analysis plan. They didn’t like using an averaged result, which, they say, “carr[ies] less weight” than a comparison to a baseline number. The FDA also advised against Alkermes using a shorter version of a standard depression test in clinical testing. And the agency was critical of using SPCD, which it hasn’t yet endorsed as a way to prove a depression drug works and for which it has a “number of unresolved questions regarding clinical interpretability.”

The Alkermes drug also works differently from other approved antidepressants. But that difference is controversial. The drug balances opioid receptors in the brain by combining an opioid drug for pain relief (buprenorphine, which is also used to treat opioid addiction) with a chemical (samidorphan) meant to counteract its addictive properties. Alkermes has argued that the drug has done just that in clinical testing, but it’s a hot button issue given the opioid epidemic gripping the nation.

Indeed, FDA scientists argued that it hasn’t been “conclusively proven” that samidorphan can totally ward off the negative effects of opioids, and that there has been evidence of a “mild opiate effect” in testing. One of the questions set for Thursday’s panel is whether experts have any concerns about the “use, misuse, and abuse” of the drug.

Alkermes also got a “refuse to file” letter from the FDA in March after filing for approval of ALKS-5461, indicating the FDA needed more information—including possibly another clinical trial—before reviewing the application. Surprisingly, the agency changed its mind within weeks after Alkermes “clarified certain aspects” of the application, but Alkermes never disclosed what those clarifications were. FDA documents show the agency made “some factual errors” and rescinded its letter after correcting them.

Taken together—the huge need for a new type of depression drug versus the issues in Alkermes’ program—the case for ALKS-5461 is complicated. The application “tests the leniency of one of the more flexible divisions within the FDA,” Matteis wrote in August. He believes the drug only has a 30 percent chance of approval. But “even in light of this flexibility we worry that the ALKS-5461 package simply asks for too much.”

ALKS-5461 isn’t the only depression drug, meanwhile, that will be in the FDA’s crosshairs this week. On Friday, a panel of experts is set to review brexanolone, from Sage Therapeutics (NASDAQ: SAGE), which could be the first-ever drug specifically approved for postpartum depression.