Alkermes is a believer in the classic idiom, the third time’s the charm. The pharma company recently announced success on its third-late stage clinical for ALKS 5461, which it hopes will become a new antidepressant blockbuster. In January of 2016 two previous phase III trials failed to achieve their primary endpoints and the company’s stock price took a nosedive. After the positive results of the FORWARD-5 study, shares were up over 30%. Alkermes plans to meet with the FDA in order to argue that despite failing in its two previous phase III clinical trials, the FDA should approve ALKS 5461 and “bring this new medication to patients with MDD [major depressive disorder].”  FDA regulations require a total of two successful phase III trials with statistical significance over placebo. What’s going on here?

The FORWARD-4 clinical trial tested two dose levels of ALKS 5461, 2mg and .5 mg and it failed to meet its initial primary endpoint, “change from baseline in the Montgomery Asberg Depression Rating Scale (MADRS) total score.” Post-hoc statistical analysis done on the FORWARD-4 data indicated the group receiving the higher 2mg dose of ALKS 5461 had a statistically significant difference on the MADRS. Alkermes then decided to “update” their methodology and analysis for FORWARD-5. In other words, Alkermes used statistical analysis of the failed FORWARD-4 trial to uncover a significant result within a subpopulation of the study that was not targeted in their initial study design. They then modified their methodology and analysis of the FORWARD-5 trial to match the post-hoc analysis.

In a previous article on the FORWARD-3 and FORWARD-4 failed clinical trials, “Nearsighted Drug Development,” I expressed the opinion that this seemed a bit like cheating. Nevertheless, it seems that changing the methodology from what was initially proposed for an ongoing trial is permitted. But would it be appropriate for the FDA to reconsider the post-hoc analysis of the FORWARD-4 trial as a “successful” clinical trial? It seems a bit like trying to argue that the FDA should give Alkermes credit for positive results in FORWARD-4 even though those positive results only became apparent after the fact—when they began to fiddle around with the data to see if they could find something positive.

Another disturbing claim by Alkermes is with how they describe ALKS 5461. It is “designed to rebalance brain function that is dysregulated in the state of depression.” As I pointed out in “Nearsighted Drug Development,” the chemical imbalance theory of depression is now said to be an urban myth even by pro drug psychiatrists like Ronald Pies.

If approved, ALKS 5461 is proposed as an add-on, adjunctive medication in the treatment of major depression for patients “with an inadequate response to standard antidepressant therapies.” However, there is a hint that if approved ALKS 5461 could be put forward by the company as a standalone treatment for depression. Elliot Ehrich, the CMO of Alkermes, said the studies in the FORWARD program contributed data useful in assessing the safety and efficacy of ALKS 5461 on a standalone basis and if taken as an adjunct medication.

It also appears that if the FDA does not agree to approve ALKS 5461 as a treatment for MDD based upon the above discussed rationale, Alkermes will drop it. Richard Pops, the chairman of Alkermes, said they are not planning to conduct any additional studies on ALKS 5461. Is this just a cut your losses decision to forego the additional cost of another clinical trial for the company? Or is it a veiled threat to the FDA that Alkermes will shelve any future work on a product that was once approved by the agency for a fast track drug development status? In other words will the FDA permit post hoc analysis of a phase III clinical trial turn a failed trial into a successful one?

What is at stake here is that the active ingredient in ALKS 5461 is a known opioid, with an acknowledged addictive potential—buprenorphine. Buprenorphine is a Schedule III controlled substance.  Combining it with an opioid antagonist (samidorphan) does not lessen its addictive potential. In higher doses buprenorphine is used as a maintenance drug therapy for opioid dependence (Suboxone; Subutex; Zubsolv). Regularly, opioid dependent individuals have told me that getting off of buprenorphine was harder than heroin or methadone.

Higher doses and longer term use of buprenorphine influence the length of time for withdrawal or discontinuation. And guess what, depression is one of the commonly experienced withdrawal symptoms. The Addiction Blog posted some helpful information on “How long does buprenorphine withdrawal last?” Note that the website is not taking an anti-buprenorphine position. It begins by saying “Buprenorphine can be a useful drug prescribed to treat opiate addiction.”

Within the first 24 to 72 hours, physical withdrawal symptoms peak in severity and intensity with common symptoms such as: diarrhea, sweating, nausea, dilated pupils, watery eyes and restlessness. As the first week progresses, aches, stomach cramps, and joint pain will probably continue. General feelings of discomfort and problems sleeping can occur. “Mood swings are also common, with bouts of anxiety or depression.”  After two weeks, the pain and discomfort of acute physical withdrawal should be less severe, but depression and an extreme loss of motivation can set in.

After [the] three to four week mark, most of the physical withdrawal symptoms will be gone, however … intense drug cravings may be present for those addicted to buprenorphine. Depression is also common. This time is very important, as you will be very vulnerable to relapse. . . . However, psychological withdrawal symptoms can last for months after cessation.

Now “relapse” here refers to resuming active opioid use or abuse. But in reviewing the withdrawal symptoms described above, the relapse experienced could just as easily be interpreted as a depression relapse by individuals attempting to taper off of long term ALKS 5461 use.

So someone could add ALKS 5461 to their antidepressant of choice, take it for an extended period of time and see a clear remission of their depressive symptoms. If they were to then attempt a taper off of ALKS 5461, they would likely experience the above described buprenorphine withdrawal symptoms, interpret them as a return of depressive symptoms, and resume using ALKS 5461. If ALKS 5461 is used as a stand-alone treatment for depression, a misinterpretation of withdrawal symptoms as a relapse of depression is also likely occur. Similar to long-term antidepressant users, there could be a “Hotel California” effect—you can taper down any time you want, but you can never leave.

With continued use of buprenorphine, there comes a point where the brain produces an inadequate amount of neurotransmitters in the body. People going through buprenorphine PAWS [post acute withdrawal syndrome] manifest long lasting changes in the brain as a result of long term use. These changes are slower to reverse and can persist for many months, depending on the frequency and amount of past dosing.

I don’t know whether the above concerns will be considered in an FDA review of the Alkermes request to approve ALKS 5461. I hope they are. But if Alkermes is successful in bringing its drug to market, “where new therapeutic options are highly sought after as millions of patients in the U.S. do not respond to standard courses of antidepressant therapy,” be prepared for what seems to be an unavoidable cycle of depression treatment perpetuating depression and further treatment. While the rhetoric appears overblown to some, I do believe there is a “Coming Depression Apocalypse” if ALKS 5461 is approved by the FDA.