There has been a major trend in recent years for biopharmaceutical companies to develop treatments for diseases suffered by relatively small patient populations. While 2015 saw the FDA approve drugs for major diseases like diabetes, psoriasis and heart disease, more striking were the approvals for drugs that are “targeted therapies” to treat specific forms of cancer or drugs for rare diseases. There are good reasons for the industry to move in this direction: Usually, the R&D costs for bringing forward such “niche medicines” are lower because clinical trials can be much smaller in scope; there are few, if any, drugs on the market for these patients and, given the high medical need, regulatory agencies will give priority reviews; and, most notably, such drugs can command extremely favorable pricing.
This is certainly great news for patients with rare diseases whose needs had not been focused on in the past. However, this trend has had the consequence of R&D being shifted away from diseases which, despite the existence of marketed drugs to treat them, are still underserved as existing medicines are far from optimal. One such area is depression. There is already a variety of drugs for this disease: selective serotonin reuptake inhibitors (SSRIs) like
Given the drawbacks to existing anti-depressants, one would think that this is a ripe area for innovation. Yet, for the most part, most big pharmaceutical companies have stopped their R&D efforts in depression. One reason is a lack of new, compelling science into new ways to approach this disease. But the bigger issue is the challenge of achieving commercial success with a new drug given the hurdles that the existing, generic medicines present. While not perfect, these drugs are effective and payers will insist that physicians try every available drug if necessary, before turning to any new, more expensive medicine.
However, not everyone is deterred by these challenges. Alkermes is one company that is betting a lot on finding a breakthrough treatment for depression. They believe that ALKS 5461 might represent such a breakthrough. It is actually a combination of drugs: Buprenorphine, a kappa-opioid receptor (KOR) antagonist and samidorphan, a mu-opioid (MOR) antagonist. This combination is designed to maximize the antidepressant KOR effects of buprenorphine while counteracting its addictive potential with samidorphan’s MOR activity. Alkermes CEO Richard Pops recently shared his enthusiasm about ALKS 5461 with me. “We are doing real science here. This is the most important depression medicine in 20 years.” He also talked about the potential impact that ALKS 5461 might have. “What we are doing is important for millions of patients as depression is not a rare disease.”
Indeed, early clinical studies with ALKS 5461 looked very promising. An early phase 1 study showed that the drug was superior to placebo in patients with depression who had failed conventional therapy. Furthermore, this effect was manifest in seven days and the drug appeared to be well tolerated. A subsequent phase 2 study supported this early optimism and Alkermes launched an aggressive phase 3 program consisting of the FORWARD-3, 4 and 5 trials.
Then reality set in. On January 21, Alkermes announced that ALKS 5461 did NOT meet the prespecified goals in FORWARD-3 and 4. The problem was not that the drugs didn’t work. Rather, the patients in the placebo arm of the study had a significant positive response.
Wall Street’s response was swift. Alkermes stock dropped from about $60/share to $33/share almost immediately.
Pops was surprised by the market reaction, referring to it as “shoot first and ask questions later” attitude. He went on to say that “the Street’s reaction didn’t really reflect the facts in the ALKS 5461 story.” Pops makes a fair point. While any drug trial can be impacted by the dreaded placebo effect, trials for drugs to treat depression are especially prone to do this. It would be surprising for most to learn that companies needed to run as many as seven phase 3 trials with the SSRIs in order to meet the FDA requirement of two positive trials for approval. When people who suffer from depression are entered into a clinical trial, weekly meetings with their healthcare provider, talking out their personal issues and getting a pill, all can contribute to a sense of well-being that effectively makes a depressed patient feel better--despite only taking a sugar pill.
So, where does this leave Alkermes and their breakthrough drug program? Pops is optimistic. First of all, FORWARD-4 showed a clear trend toward efficacy on the primary endpoint in the high dose group, and post hoc analyses achieved statistical significance for this same dose group on one endpoint (MADRS). Then, there is the ongoing FORWARD-5 trial. As Pops said, “There’s no guarantee that FORWARD-5 will be positive.” But, if it is, he believes that the combination of this study, the data from FORWARD-4, which he described as a “near miss," and the earlier clinical data could prove sufficient to convince the FDA to approve ALKS 5461. As he said, “This drug has a great risk-benefit profile--it’s a benign agent.”
All of drug R&D is risky, and there’s a natural tendency for companies to try to mitigate the risk in their portfolio as much as possible. Despite the need for new antidepressants, the challenges in being successful in this arena are higher than most, causing many to shy away. Pops and his colleagues at Alkermes, however, have taken it on. Wall Street thinks that this might have been a mistake. But there are millions of depressed patients who are hoping that they win. FORWARD-5 will tell.
