Alkermes PLC (NASDAQ: ALKS) just announced positive Phase 3 results for its novel antidepressant ALKS 5461, and it’s serving as a rising tide — a storm surge even — for many biotech companies in the depression space. Despite this, perhaps paradoxically, the area of suicide and suicidal ideation remains chronically underserved.

In 2014 there were 43,000 suicides. There is no drug to treat suicidal ideation in depressive disorders. This is not for incidental reasons but inherent in the condition itself. How so? The very symptom of suicidal thought is an exclusionary criterion for virtually all clinical trials in psychiatry. Compounding the difficulty is that endpoints in psychiatry are difficult to measure and often self-reported. Firms tend to shy away from this kind of structurally difficult pathway.

Suicidality is not to be confused with major depressive disorder (MDD), which is Alkermes’s target indication for ALKS 5461. The two are linked, but not the same. Despite the obvious link between depression and suicidality, it is important to conceptually separate the two. Since October 2004, antidepressants including GlaxoSmithKline PLC’s (NYSE: GSK) Paxil, Zoloft from Pfizer Inc. (NYSE: PFE), and even pioneer Prozac from Eli Lilly & Co (NYSE: LLY) all have black box warnings for increased risk of suicide. ALKS 5461 will probably require the same label if approved.

How can this be? The theory is that while depression and suicidality often come together, depression sufferers do not have the energy to actually commit suicide. Once depression lifts due to treatment, the suicidal thoughts do not go away. At that point the sufferer may actually go through with the act. Antidepressants can also cause akathisia, a feeling of inner restlessness, and this phenomenon is also associated with suicidal ideation.

Ever since the very recent discovery that low dose ketamine is effective in relieving suicidal thoughts specifically, select Big Pharma and small startups have been working on the problem, with limited success. The problems with ketamine are extensive. It is rife for abuse, especially with repeated dosing. It is only short-acting, lasting for about a week until the anti-suicidal effects wear off. The danger limits it from a marketing perspective and it can’t be prescribed outpatient.

But the promise is still there for ketamine. It does work. It’s just that companies need to figure out how to blunt its danger and extend its effects. Allergan PLC (NYSE: AGN) is the biggest name pursuing a class of drugs that have a similar but slightly different mechanism of action to ketamine. Ketamine is an NMDA receptor blocker, while Allergan’s Rapastinel (acquired from Naurex) is a receptor modulator. This slightly different mechanism of action is thought to blunt the dissociative side effects of ketamine, and we will see if this works as trials progress.

Cerecor Inc. (NASDAQ: CERC), which jumped even higher than Alkermes on the recent news, is at the tail end of a Phase 2 trial for CERC-301, which should report results by the end of the year. A previous Phase 2 trial in 2014 showed safety but failed to duplicate the results of a previous pilot study. The company decided to go ahead with CERC-301 anyway and results are imminent.

While none of these are targeting suicidal ideation directly, there is potential to pursue that target directly in the future due to similarity to ketamine with these drugs. Turing Pharmaceuticals was pursuing a suicide indication with esketamine but has since expunged it from its pipeline. Johnson & Johnson (NYSE: JNJ) is pursuing an intranasal formulation of esketamine, but the abuse potential is still there and intranasal drugs are unlikely to be administered outpatient. AstraZeneca PLC (NYSE: AZN) was also pursuing a version of ketamine up to February 2014, but a failed Phase 2 trial led to its burial.

A possible answer to the suicidal ideation problem may be in a private company called NeuroRx, which unlike the others listed above is not trying to modify ketamine’s mechanism of action but rather extend its efficacy. The indication is specifically for suicidal ideation in bipolar patients rather than strictly MDD patients, and the idea is to first administer low dose IV ketamine, and then add their proprietary fixed dose combination of two already-approved oral outpatient drugs (D-cycloserine and lurasidone) in order to extend the effect.

Initial clinical results show that the combination can extend ketamine’s effects for up to eight weeks. The study was small on 12 patients, but it’s a start and would be the first drug specifically designed to treat suicidal ideation in bipolar patients. The incidence of suicide in bipolar disorder is higher than in any other depressive disorder.  It is estimated that over a period of five years, one out five patients will have suicidal ideation or attempt suicide. An IND filing for a Phase 2/3 study is imminent, and patent issues have recently been settled on the matter.

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