Minerva Neurosciences Announces Results of Dose Escalation Study Evaluating Roluperidone (MIN-101) Administered at Supra-Therapeutic Doses in Healthy Volunteers
- Findings suggest expanded therapeutic window and significantly improved cardiovascular safety margin compared to formulation used in Phase 2b trial
- All doses tested up to 256 milligrams appear safe and well tolerated with no significant changes in cardiac repolarization and QTc intervals
- Tested formulation is used in ongoing Phase 3 trial
- Data to be reviewed at Minerva’s roluperidone update and key opinion leader event on
Tuesday, November 20, 2018beginning at 8:00 a.m. Eastern Timein New York
The primary objectives of the study included the evaluation of the pharmacokinetics, dose-proportionality and the effect of plasma concentrations of roluperidone and its main metabolites on pharmacodynamic parameters using electrocardiogram (ECG) Fridericia-corrected QT interval (QTcF), a measurement of cardiac function. Secondary objectives included evaluation of safety and tolerability. A third objective was to provide an estimate of the supra-therapeutic dose to be used in the thorough QT study planned as part of the New Drug Application (NDA).
The trial included a total of 90 subjects. 72 received 7 different doses of roluperidone, and 18 received placebo. All subjects who were dosed completed the study as planned except for one male subject who received placebo and subsequently withdrew his consent.
Data from this trial demonstrated the following:
- The pharmacokinetics of roluperidone and its metabolites were dose proportional.
- No QTcF duration > 480 milliseconds (msec) or increases > 60 msec compared to baseline values were observed in any subject.
- 160 mg was the only roluperidone dose to show an adjusted QTcF mean increase from baseline of 10.7 msec. All other doses showed means -1.3 to 5 msec.
- No significant change in repolarization was observed.
- Two subjects (11%) in the placebo group and nine subjects (13%) in the roluperidone group reported adverse events that were mild to moderate in severity and resolved without sequelae.
- Doses up to 160 mg or 2.5 multiples of the highest dose being tested in the ongoing Phase 3 trial had no effect on any cardiac safety parameters.
- Slight but not clinically relevant increases in heart rate were observed in the placebo group and some of the roluperidone doses.
- No serious adverse events were reported.
Additional details will be presented at the Company’s roluperidone update and key opinion leader event on
“We believe these findings suggest an expanded therapeutic window and a significantly improved safety margin for roluperidone,” said Dr.
“Furthermore, we believe these data suggest the potential for future testing of roluperidone in schizophrenic patients with an exacerbation of psychosis at higher doses than those being used in the Phase 3 trial,” said Dr. Saoud.
The Company had previously established the following in a study comparing the Phase 3 formulation and the Phase 2b formulation:
- Bioequivalent exposures of roluperidone as measured by area under the curve (AUC) for both the Phase 3 and Phase 2b trials (AUC is the main efficacy driver for the drug);
- Reduction of the Cmax of BFB-520 by approximately 30% in the Phase 3 formulation compared to that used in Phase 2b, thus explaining the increased safety margin reported above;
- No observations of QTcF prolongations throughout the study;
- No observable food effect, thus allowing administration of the drug with or without food without changing its pharmacokinetic properties;
- Confirmation of the overall safety and tolerability profile of roluperidone.
The ongoing Phase 3 trial with roluperidone is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study to evaluate the efficacy and safety of 32 mg and 64 mg of roluperidone as monotherapy in adult patients with negative symptoms of schizophrenia. The 12-week study will be followed by a 40-week, open-label extension period during which patients on drug will continue receiving their original dose and patients on placebo will receive either 32 mg or 64 mg of roluperidone. Approximately 500 patients are expected to be enrolled at approximately 60 clinical sites in the U.S. and Europe. Top-line results from the 12-week double-blind phase of this trial are expected in mid-2019.
The previously announced Phase 2b trial with roluperidone achieved its primary endpoint, demonstrating a statistically significant benefit of the compound over placebo in improving negative symptoms1,,. Roluperidone was reported to be well tolerated, and the incidence and types of side effects did not differ significantly between the roluperidone group and the placebo group. Unlike many currently marketed antipsychotic drugs, no metabolic adverse effects, no weight gain and no extra-pyramidal symptoms were observed.
Roluperidone is a drug candidate with equipotent affinities for 5‑hydroxytryptamine-2A (5-HT2A) and sigma2 and at lower affinity levels, α1-adrenergic receptors. Roluperidone exhibits no affinity for dopaminergic, muscarinic, cholinergic and histaminergic receptors. Roluperidone has no direct dopaminergic post-synaptic blocking effects, known to be involved in some side effects like extrapyramidal symptoms, sedation, prolactin increases and weight gain.
Forward-Looking Safe Harbor Statement
This press release contains forward-looking statements which are subject to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. 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 statements herein with respect to the timing and scope of current clinical trials and results of clinical trials with roluperidone (MIN-101); the timing and scope of future clinical trials and results of clinical trials with roluperidone; the clinical and therapeutic potential of roluperidone; 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
VP, Investor Relations/
1 Davidson, M. et al., Efficacy and Safety of MIN-101: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial of a New Drug in Development for the Treatment of Negative Symptoms in Schizophrenia,
2 Kirkpatrick, B. et al., The brief negative symptom scale (BNSS): Sensitivity to treatment effects, Schizophr. Res. (2017), https://www.ncbi.nlm.nih.gov/pubmed/29275856
3 Keefe, Richard et al., Cognitive effects of MIN-101 in patients with schizophrenia and negative symptoms: results from a randomized controlled trial: https://doi.org/10.4088/JCP.17m11753
Source: Minerva Neurosciences, Inc