Investors in Minerva Neurosciences Inc. on Dec. 1 gave a chilly reception to reported FDA feedback on the company's experimental treatment for the negative symptoms in schizophrenia, roluperidone. Though the drug failed to deliver statistically significant differences vs. placebo in a phase III study this year, CEO Remy Luthringer outlined a potential path to NDA filing for the candidate using a modified intent-to-treat analysis of the trial and evidence from other ongoing evaluations.
If the company's strategy works, it will have overcome substantial objections voiced by the regulator in a Nov. 10 meeting. But, as reflected in a 25.7% decline in company shares (NASDAQ:NERV) to $2.89 on Dec. 1, some investors aren't sticking around to find out.
The meeting, initiated by Minerva, sought to address two main topics: its readiness for an NDA filing and the FDA's take on the company's desire to exclude some data it sees as having undercut the phase III outcome. The regulator's responses were relayed via a company press release, not an official copy of the meeting minutes.
On the readiness front, Minerva said it sought the FDA's confirmation that, "based on the totality of evidence," data from its phase IIb and phase III studies of roluperidone constitute substantial evidence of the effectiveness of the 64-mg dose of the drug and would warrant review of an NDA. Instead, the FDA called the phase IIb study "problematic because it did not use the commercial formulation of roluperidone" which was used in the phase III trial "and was conducted solely outside the United States," the company said.
Minerva said it has comparable pharmacokinetic data for the formulations used in the trials and intends to perform a pivotal bioequivalence study to bridge the two formulations.
Could one trial be enough?
In addition, the company said the FDA pointed to a failure of either dose of roluperidone tested in the studies to show a statistically significant separation from placebo in the 12-week intent-to-treat analysis set. Without that, "there would be substantial review issues due to the lack of two adequate and well-controlled trials to support efficacy claims for this indication," the regulator cautioned.
But maybe one adequate and well-controlled study and confirmatory evidence would be enough? The company suggested that given the unmet need for treating the negative symptoms in schizophrenia, the regulator's own guidance might make it so.
To get there, Minerva suggested its phase III trial could serve as that study if it excluded "patients with implausible behavioral and physiological data" from one site for the trial. Subtracting data on those 17 patients from the study's total 513 patients would "address the lack of separation at week 12," it said. Were that move to gain acceptance, roluperidone would have achieved a "nominal statistically significant result (p ≤ 0.044) on the primary endpoint, the Marder Negative Symptoms Factor Score of the Positive and Negative Syndrome Scale," the company concluded. An open-label study of roluperidone remains underway.
"As a priority, we plan to communicate with FDA regarding their comments about the phase IIb study, and continue to move forward with the clinical pharmacology, non-clinical and CMC work needed to support an NDA submission," Luthringer said. "Following completion of the open-label extension of the phase III study, we expect to request a pre-NDA meeting with FDA to discuss the NDA submission plans based on the clinical efficacy and safety data," he added.
Looking ahead to the possibilities, Jefferies analyst Biren Amin said that "we think NERV faces an uphill battle unless it conducts a new phase III trial to prove roluperidone's clinical relevance."
In early November, H.C. Wainwright analyst Douglas Tsao saw the same possibility. "A potential study would likely be smaller and shorter than the current trial, test only a 64-mg dose, and not include an open-label extension (OLE), though similar endpoints to the previous phase III are likely," he wrote, estimating such a study could cost between $15 million and $20 million to run.
"If initiated in early 2021, the trial may be completed by mid-2022, resulting in a potential filing in 2H22 and possible approval towards late 2023, just 18 months after the initial timeline, a modest delay in our view," he said.
Minerva did not respond to a request for further information on Dec. 1.