Cerecor Inc. shares (NASDAQ:CERC) lost more than half their value Wednesday after the company reported that its fast-acting antidepressant candidate, CERC-301, failed to help patients with moderate to severe depression see significant improvement, as measured by a scale sensitive to rapid-acting drugs for the condition. Further analysis may better explain the top-line data, the company said, but for now it's turning its attention to CERC-501, another antidepressant with a different mechanism of action.

The phase II study failed to demonstrate efficacy on the primary endpoint for mean improvement in Bech-6, a subset of the Hamilton Depression Scale (HDRS-17), averaged over days two and four post-dosing. CERC-301 was licensed from Merck & Co. Inc. for $750,000 plus potential milestone payments.

Looking for a bright spot, Baltimore-based Cerecor said that some signals of efficacy for a 20-mg dose of CERC-301 at day two appeared for prespecified secondary endpoints. But the finding didn't reach statistical significance on either the Bech-6 scale used to measure the study's primary endpoint or the Hamilton Depression Scale, a superset of Bech-6.

Cerecor President and CEO Uli Hacksell said he was disappointed, but did draw some lessons from the study's outcome: "One is that more frequent dosing may be something that one should do in a potential additional study with CERC-301. Another one would be to look at higher doses," he said during a conference call held to discuss the outcome.

Data from the trial of the selective NMDA receptor subunit 2B antagonist will now get a full analysis, but plans for announcing CERC-301's future were calendared for "a later date."

With a three-week, randomized, double-blind, placebo-controlled, sequential parallel comparison design, the study looked at intermittent doses of adjunctive CERC-301 (12 mg or 20 mg) or placebo in the treatment of subjects with major depressive disorder (MDD) who had not adequately responded to earlier antidepressant therapy, either with a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine uptake inhibitor. The study also included a one-week follow-up. (See BioWorld Today, Oct. 24, 2016.)

The study randomized 115 subjects in two sequential one-week periods. Those patients that didn't respond to placebo in the first week-long period were re-randomized in the second week-long run to either CERC-301 or another round with placebo. Participants received treatment at the beginning of each period. The results of both one-week periods were then averaged.

Mean improvement from baseline on the Bech-6 scale, averaged over days two and four post-treatment for the first one-week period was 3.82 for placebo vs. 2.5 for the 12-mg dose of CERC-301 and 4.11 for the 20-mg dose. During the second one-week period, improvement from baseline hit 2.86 for placebo, 1.64 for the 12-mg dose and 3.38 for the 20-mg dose.

Consistent with previous trials, Cerecor said the drug was generally well-tolerated with no significant adverse events reported and no discontinuations due to adverse events. The most commonly reported issues seen were increased blood pressure, dizziness, sleepiness and paresthesia.

For the nine months ended Sept. 30, Cerecor reported spending about $2.5 million on its CERC-301 R&D. At the end of the same period, the company had cash and cash equivalents of $8.8 million. Company shares closed 56 percent lower on Wednesday at $2.08, losing $2.64.

Closer on the event horizon is a readout of a phase II study of CERC-501 for smoking cessation, due later this month. Though interesting, CERC-501's potential application as an adjunctive treatment of MDD is the higher-stakes trial, especially in light of the setback with '301. A phase II study of '501 in MDD is expected to start in 2017.

Cerecor acquired exclusive global rights to CERC-501 from Eli Lilly and Co. in 2015 for $750,000 plus potential milestones and future royalties. The kappa-selective opioid receptor antagonist has been tested in investigator-led phase II proof-of-concept trial to assess its value in the augmentation of antidepressant therapy in patients with treatment-resistant depression study, but the trial was later terminated.

Cerecor was founded in May 2011, in large part as a vehicle for going after very specific subgroups of patients as a path to hopefully avoid the high failure rates seen in big pharma's neuroscience development landscape. At the time it first began to seriously pursue CERC-301, Evotec AG's EVT-100 program was also gearing up. Evotec now lists development of that program of NMDA NR2B subtype specific antagonists as "under review." (See BioWorld Today, July 22, 2014.)