Minerva Neurosciences Inc. CEO Rémy Luthringer said his firm knew about the cyberattack on a contractor helping with the roluperidone phase III trial in schizophrenia "toward the end of the summer," when "the provider was trying to solve the problem" and ultimately did. But the attack still meant an enrollment delay, and Wall Street reacted accordingly. Despite imminent, possibly transforming data in major depressive disorder (MDD), investors pushed Minerva shares (NASDAQ:NERV) down $2.04, or 26.3%, Tuesday to close at $5.71.

Specifically, Minerva said the finish of recruitment will now happen at about year-end, and top-line data from the 12-week, double-blind part of the study are due in the first half of 2020 with roluperidone, designed to block the serotonin receptor subtype 5-HT2A. Minerva previously forecasted top-line data in the fourth quarter of this year. So far, 384 patients of the targeted 501 have been signed up, with 33 in screening. "Probably, I mean, things were going on much before" Minerva learned of the cyberattack, Luthringer said during a conference call update. In any case, he said, "the problem is under control [and] we are back on track."

The trial is a multicenter, randomized, parallel group, placebo-controlled experiment to evaluate the efficacy and safety of 32-mg and 64-mg doses of roluperidone as measured by the Positive and Negative Syndrome Scale Marder negative symptoms factor score. The core 12-week portion is followed by a 40-week, open-label extension period during which patients on the drug continue receiving their original dose and patients on placebo receive one of the two doses of roluperidone.

Luthringer said the number of trial sites has not changed. "With all the studies I have done in my life, I learned something, [and that is] that you should really stick to what you have decided at the beginning. [We] have not too [many] sites because this [could increase] variability" and thereby introduce more noise than necessary into the results. With enrollment not yet complete, he could not provide exact figures but said the number of patients between the U.S. and Europe is "splitting up quite nicely. The U.S. started before Europe [but] things are already going in the right direction" in terms of the division, he said.

Outside of schizophrenia, Minerva provided an update on MIN-117's phase IIb trial in moderate to severe MDD, where top-line results are expected in the fourth quarter of this year. MIN-117 targets the adrenergic alpha 1a, alpha 1b, 5-HT1A, 5-HT2A receptors, along with serotonin and the dopamine transporter. Jefferies analyst Biren Amin finds the compound intriguing, and said in a Sept. 16 report that "anything larger than a 3-point difference from placebo on the Montgomery Asberg Depression Rating Scale [MADRS] would be meaningful (if p < 0.05). Current standard of care has shown MADRS change of 2 to 4 points," he noted. "MIN-117 is not in our model, but shares could be up more than 70% [if data are positive] given up to 6 million co-morbid depression patients with anxiety in the U.S. On the anxiety Hamilton Anxiety Rating scale, we think a Sage-like effect (around 4 points) would be meaningful." Amin refers to Cambridge, Mass.-based Sage Therapeutics Inc.'s SAGE-217, a next-generation positive allosteric modulator that has been optimized for selectivity to synaptic and extrasynaptic GABAA receptors and a pharmacokinetic profile intended for daily oral dosing. SAGE-217 has received breakthrough therapy designation from the FDA for MDD.

In a report Tuesday, Amin reiterated his hopes for MIN-117, which he pointed out is not only absent from his official considerations but "not in anyone's models. We think MIN-117 is receiving very little value, and could provide a significant upside surprise for investors." As for roluperidone, no data from the phase III study itself was compromised by the cyberattack and the stock price drop reflects a buying opportunity, in his view.

Too many options, CEO says

Minerva also has a phase II study testing seltorexant, a selective orexin-2 receptor antagonist partnered with New Brunswick, N.J.-based Johnson & Johnson (J&J) in MDD, where long-term (24-week/six-month), flexibly dosed drug (20 mg or 40 mg) was compared to flexibly dosed quetiapine XR (Seroquel, Astrazeneca plc) 150 mg or 300 mg as adjunctive treatment. A total of 102 patients not responding adequately to selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors were enrolled. The primary endpoint was discontinuation of therapy, due to all causes, over six months. Mood improvement, measured using MADRS, and safety and tolerability were also evaluated. The exploratory effort was meant mainly to generate data for planning phase III studies and was not powered to detect statistical significance. Quetiapine XR was used as a comparator because it is the only medication approved for the adjunctive treatment of MDD in both the U.S. and Europe. Seltorexant showed a quantitative advantage in the number of discontinuations due to all causes, with 41% discontinuation in the seltorexant arm vs. 47% in the quetiapine XR arm. As expected, there was not a statistical separation between the two treatment arms, the company said. Mood improvement as measured by MADRS total score showed patients treated with seltorexant 20-mg dose experienced a greater improvement at week 24 (-22.7 points), compared to those treated with seltorexant 40-mg dose (-7.9 points), quetiapine 150-mg dose (-17 points) and quetiapine 300-mg dose (-14.8 points).

As proved out in previous trials of seltorexant in MDD, a greater improvement in MADRS total score was observed in patients with sleep disturbance (Insomnia Severity Index ≥15) who received the 20-mg seltorexant dose. In those patients with insomnia, the improvements observed were -26.5 for the 20-mg seltorexant dose, -7 for the 40-mg seltorexant dose, -18.2 for the 150-mg quetiapine dose and -13.8 for the 300-mg quetiapine dose. The overall safety profile of the seltorexant groups was favorable compared to quetiapine, consistent with prior seltorexant studies, and extended to longer-term exposure over six months. Patients given seltorexant also experienced fewer potentially treatment-related discontinuations than did patients receiving quetiapine (29.4% vs. 47.1%). The results of the study, taken with those of the two previous studies in MDD patients and in insomnia, will guide Minerva in designing a phase III program for the drug that could encompass insomnia as well as MDD.

"This molecule is so interesting that we have a problem, which is [that] we have too many options," Luthringer said. "Most of these patients are completely, I would say, relieved from any depression disorders," a response related to the drug's ability to control hyperarousal. "At the end of the day, this is translated in the symptoms of insomnia. So, technically, insomnia and mood are linked together. We are currently working very closely with our colleagues from J&J in order to come up with the optimal plan for the two indications. And we are in the preparation mode to go to the FDA for advice."

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