Minerva Neurosciences, Inc. (NASDAQ: NERV), a clinical-stage
biopharmaceutical company focused on the development of therapies
to treat central nervous system (CNS) disorders, today announced
that it has received official meeting minutes from the November 10,
2020 Type C meeting with the U.S. Food and Drug Administration
(FDA) regarding development of roluperidone for treatment of
negative symptoms in schizophrenia.
The objective of this meeting was to obtain FDA input regarding
the roluperidone data package and its readiness to support a New
Drug Application (NDA) submission. The two main topics addressed
during the meeting were:
1. Readiness for
submission of NDA
Minerva requested confirmation from FDA that, based on the
totality of evidence, the data from the MIN-101C03 (Phase 2b) and
MIN-101C07 (Phase 3) studies constitute substantial evidence of the
effectiveness of the 64 milligrams (mg) dose of roluperidone
for the treatment of negative symptoms in schizophrenia and would
warrant review of an NDA submission.
FDA advised that the Phase 2b study is problematic because it
did not use the commercial formulation of roluperidone and was
conducted solely outside of the United States. In addition, FDA
commented that the Phase 3 study does not appear to be capable of
supporting substantial evidence of effectiveness, because neither
dose of roluperidone showed a statistically significant separation
from placebo at Week 12 in the intent-to-treat (ITT) analysis set.
FDA cautioned that an NDA submission based on the current data from
the Phase 2b and Phase 3 studies would be highly unlikely to be
filed and that, at a minimum, there would be substantial review
issues due to the lack of two adequate and well-controlled trials
to support efficacy claims for this indication.
FDA acknowledged that the data from the Phase 2b and Phase 3
studies appear to show promising signals and encouraged Minerva to
continue the development of roluperidone for treatment of negative
symptoms in schizophrenia, which FDA confirmed is an unmet
need.
Minerva recognizes FDA’s comments but believes they can be
addressed based on published regulatory guidance and precedents.
The company has comparable pharmacokinetic data for the
formulations used in Phase 2b and Phase 3 (the commercial
formulation) and intends to perform a pivotal bioequivalence study
to bridge the two formulations. In addition, Minerva believes the
Phase 3 study has shown that US data and ex-US data are comparable,
and that many precedents exist where drugs were approved by FDA
based solely on ex-US data. Minerva believes that, in the Phase 3
study, results from the modified ITT (mITT) analysis set that
excludes patients with implausible behavioral and physiological
data from one site (17 of a total of 513 patients) address the lack
of separation at Week 12.
2. FDA’s
consideration of both ITT and mITT data
analyses from Phase 3 study
In the briefing book for the Type C meeting, Minerva highlighted
that the exclusion of implausible behavioral and physiological data
from 17 patients at one site forms the basis of the mITT analysis
set as outlined in the Statistical Analysis Plan submitted to FDA
before unblinding the study.
For the mITT analysis set, the 64 mg dose of roluperidone
achieved a nominal statistically significant result (p-value ≤
0.044) on the primary endpoint, the Marder Negative Symptoms Factor
Score (NSFS) of the Positive and Negative Syndrome Scale (PANSS).
The details of both the ITT and mITT results for the primary (NSFS)
and key secondary endpoint, the Personal and Social Performance
(PSP) total score, can be found at the end of this press
release.
FDA advised that their consideration of both the mITT and ITT
results would be a matter of review and that in principle all sites
should be included in the primary analysis set, and FDA cannot
determine at this time whether data from the referenced site should
be removed without a thorough evaluation. FDA indicated that
Minerva should include justification for exclusion of these data in
the future NDA package and provide primary results both with and
without these data.
Other matters
In addition to the two main agenda items described above, the
use of the PSP total score in the label and the adequacy of the
PANSS and PSP instruments and related constructs to assess the
efficacy of roluperidone were also discussed. Minerva expects to
provide requested literature to support the instruments’
psychometric properties to FDA.
Future development of roluperidone
Minerva intends to continue development and NDA activities
consistent with FDA’s December 2019 draft guidance titled
“Demonstrating Substantial Evidence of Effectiveness for Human Drug
and Biological Products.” Where the target indication is an unmet
need such as negative symptoms in schizophrenia, the guidance
allows the FDA to consider one adequate and well-controlled study
and confirmatory evidence as an alternative to two adequate and
well-controlled studies to establish effectiveness.
“We thank FDA for their constructive approach and comments
related to the development of roluperidone and their recognition of
the significant unmet medical need which exists for patients and
their families,” said Dr. Remy Luthringer, Executive Chairman and
Chief Executive Officer. “As a priority, we plan to communicate
with FDA regarding their comments about the Phase 2b study, and
continue to move forward with the clinical pharmacology,
non-clinical, and CMC work needed to support an NDA submission.
Following completion of the open label extension of the Phase 3
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. Minerva plans to share additional information as it becomes
available.”
Roluperidone Phase 3: ITT and mITT NSFS & PSP total
score change from baseline scores and p-values |
Timepoint |
Intent-to-Treat |
Modified Intent-to-Treat
(Excluding patients from
1 site) |
Placebo(N=172) |
64 mg Roluperidone(N=171) |
p-value |
Placebo(N=167) |
64 mg Roluperidone(N=162) |
p-value |
Primary Endpoint: Marder Negative Symptoms Factor
Score |
Week 2 |
-1.6 (0.22) |
-1.9 (0.22) |
NS |
-1.6 (0.22) |
-1.9 (0.22) |
0.311 |
Week 4 |
-2.0 (0.26) |
-2.9 (0.26) |
0.007 |
-2.0 (0.26) |
-3.0 (0.27) |
0.005 |
Week 8 |
-2.9 (0.30) |
-3.8 (0.32) |
0.027 |
-2.9 (0.31) |
-3.9 (0.32) |
0.021 |
Week 12 |
-3.5 (0.34) |
-4.3 (0.38) |
0.064 |
-3.5 (0.35) |
-4.5 (0.35) |
0.044 |
Key Secondary Endpoint: Personal and Social Performance
Total Score |
Week 4 |
1.3 (0.56) |
3.2 (0.56) |
0.005 |
1.2 (0.58) |
3.3 (0.59) |
0.004 |
Week 8 |
2.8 (0.66) |
4.8 (0.66) |
0.019 |
2.8 (0.68) |
4.9 (0.68) |
0.014 |
Week 12 |
3.9 (0.73) |
6.1 (0.73) |
0.021 |
3.8 (0.75) |
6.2 (0.77) |
0.017 |
About Minerva Neurosciences:
Minerva’s portfolio of compounds includes: roluperidone
(MIN-101), in clinical development for schizophrenia; a potential
royalty stream from seltorexant (MIN-202 or JNJ-42847922), in
clinical development for insomnia and MDD; and MIN-301, in
pre-clinical development for Parkinson’s disease. Minerva’s common
stock is listed on the NASDAQ Global Market under the symbol
“NERV.” For more information, please visit
www.minervaneurosciences.com.
Forward-Looking Safe Harbor Statement
This press release contains forward-looking statements.
Forward-looking statements are statements that are not historical
facts, reflect management’s expectations as of the date of this
press release, and involve certain risks and uncertainties.
Forward-looking statements include, without limitation, statements
herein with respect to Minerva’s ability to successfully address
FDA’s concerns regarding the data package of roluperidone (MIN-101)
and its suitability to support NDA filing or approval; Minerva’s
interpretations of FDA regulatory guidance documents and precedents
the likelihood of establishing bioequivalence between the
formulations of roluperidone used in the Phase 2 and Phase 3
studies or the comparability of roluperidone’s US data and ex-US
data; Minerva’s ability to justify exclusion of data from the Phase
3 study’s primary analysis set; whether the mITT analysis set
addresses the lack of statistical separation at Week 12 in the ITT
set; Minerva’s ability to address FDA’s comments regarding the
adequacy of the PANSS and PSP instruments; the conduct of clinical
pharmacology, non-clinical, CMC and other work needed to support
NDA submission; the completion of the open label extension of the
Phase 3 study; Minerva’s plan to request a pre-NDA meeting with
FDA; the clinical and therapeutic potential of roluperidone; the
likelihood of future sales and a royalty stream from seltorexant;
the timing and outcomes of future interactions with U.S. and
foreign regulatory bodies; our ability to successfully develop and
commercialize our therapeutic products; the sufficiency of our
current cash position to fund our operations; and management’s
ability to successfully achieve its goals. These forward-looking
statements are based on our current expectations and may differ
materially from actual results due to a variety of factors
including, without limitation, whether roluperidone will advance
further in the clinical trials process and whether and when, if at
all, it will receive final approval from the U.S. Food and Drug
Administration or equivalent foreign regulatory agencies and for
which indications; failure to obtain regulatory approval in
additional international jurisdictions preventing us from marketing
our product candidates in such jurisdictions; whether any of our
therapeutic products will be successfully marketed if approved;
whether any of our therapeutic product discovery and development
efforts will be successful; management’s ability to successfully
achieve its goals; our ability to raise additional capital to fund
our operations on terms acceptable to us; risks and uncertainties
arising as a result of the ongoing COVID-19 pandemic; and general
economic conditions. These and other potential risks and
uncertainties that could cause actual results to differ from the
results predicted are more fully detailed under the caption “Risk
Factors” in our filings with the Securities and Exchange
Commission, including our Quarterly Report on Form 10-Q for the
quarter ended September 30, 2020, filed with
the Securities and Exchange Commission on November 2, 2020.
Copies of reports filed with the SEC are posted on our
website at www.minervaneurosciences.com. The forward-looking
statements in this press release are based on information available
to us as of the date hereof, and we disclaim any obligation to
update any forward-looking statements, except as required by
law.
Contact:William B. BoniVP, Investor
Relations/Corp. CommunicationsMinerva Neurosciences, Inc.(617)
600-7376
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