In the second half of the year, Minerva Neurosciences Inc. plans to initiate a single phase III trial of lead candidate MIN-101 that will enroll about 500 individuals with schizophrenia to evaluate improvement in negative symptoms. If the trial succeeds, the FDA agreed the data could form the basis – in conjunction with findings from the company's phase IIb trial – for a new drug application (NDA) submission.

Data from the phase IIb study included observations of a direct effect on negative symptoms, rather than an indirect or pseudo effect linked to improvements in other symptoms. The findings, reported last year by Waltham, Mass.-based Minerva, also supported a durable effect through 36 weeks of treatment, including a 12-week double-blind, placebo-controlled core phase and a 24-week, open-label extension phase. (See BioWorld Today, May 27, 2016.)

At the conclusion of the extension period of the phase III trial, the overall number of patients exposed to MIN-101 since the initiation of clinical development is expected to provide sufficient long-term safety data to support an NDA filing, according to Minerva.

MIN-101, an equally potent antagonist of the sigma-2 and 5-hydroxytryptamine-2A (5-HT2A) receptors, also has lower affinity at alpha 1-adrenergic receptors – thus, no direct dopaminergic post-synaptic blocking effects, known to be involved in certain side effects of conventional schizophrenia medications, such as extrapyramidal symptoms, sedation, prolactin increases and weight gain.

Buy-in from FDA officials on the single phase III followed the company's end-of-phase II meeting, during which Minerva shared preclinical and clinical efficacy, safety and tolerability data, although the discussion focused mainly on how to calculate the primary endpoint in the pivotal study.

"They did not push back on any points we proposed," Remy Luthringer, Minerva's president and CEO, told BioWorld Today, noting that the phase IIb study, which enrolled 244 patients, was powered similar to a pivotal study and the statistical analysis was conducted in much the same way. "There was a real consensus here," he said.

MIN-101 met its primary endpoint by showing statistically significant benefit in improving negative symptoms as measured by the pentagonal structure model of the Positive and Negative Syndrome Scale (PANSS). The effect was shown for both doses tested: 32 mg (p

The specificity of MIN-101's therapeutic effects was validated by the stability of positive symptoms observed over the duration of treatment and a side effect profile comparable to placebo, particularly with respect to extrapyramidal symptoms, which can include dystonia, Parkinsonism, bradykinesia, tremor and tardive dyskinesia.

The double-blind, randomized, placebo-controlled, 12-week phase III study will test two doses of MIN-101 in individuals with schizophrenia whose negative and positive symptoms have been stable for several months prior to enrollment. The study is targeting patients with moderate to severe negative symptoms, as indicated by a specified minimum threshold baseline score on the PANSS negative subscale. No atypical antipsychotics will be co-administered at any stage in the study. The primary endpoint will be improvement in negative symptoms at 12 weeks as measured by the PANSS Marder negative factor score.

The Marder negative subscore is similar to the White negative subscore used in the phase IIb trial but eliminates four items and adds one on active social avoidance – an item highly correlated with functional outcomes, according to Minerva.

Secondary efficacy endpoints will include the Clinical Global Impression of Severity, or CGI-S, scale and Personal and Social Performance total score.

Similar to the phase IIb, following the double-blind phase patients will be permitted to enter a 36-week open-label extension phase in which all patients will receive active treatment. The trial is expected to encompass approximately 60 sites across the U.S. and Europe.

Also like the phase IIb study, patients enrolled in the phase III will have cardiac function assessed via electrocardiograms. Discontinuation criteria based on PANSS and cardiac electrophysiological criteria are incorporated into the study protocol.

'NEGATIVE SYMPTOMS NOT SPECIFIC TO SCHIZOPHRENIA'

The phase III design is intended to replicate the experience of real-world clinical practice in schizophrenia, in which patients report dissatisfaction with continuous antipsychotic treatment and often discontinue treatment. The input of key opinion leaders (KOLs) – especially an understanding of how MIN-101 could be used in practice – has been vital throughout the development program, Luthringer said. With experience in clinical psychiatry and previous positions as chief medical officer for Index Ventures and head of France's FORENAP, Institute for Research in Neuroscience and Neuropsychiatry, Luthringer counted himself as one of those first KOLs. The differentiated profile of MIN-101 also allowed Minerva to recruit Michael Davidson, whom Luthringer cited as one the top five experts in the field of schizophrenia, as chief medical officer.

Luthringer also named Philip Harvey, professor of psychiatry and director of the division of psychology at the University of Miami Miller School of Medicine, and Brian Kirkpatrick, chairman of the department of psychiatry and behavioral sciences at the University of Nevada School of Medicine, as global leaders in the field who signed on as consultants to Minerva and participated with the company at the end-of-phase II meeting, based on their faith in the asset. Both plan to join the company's scheduled conference call Tuesday morning to discuss the phase III development plan.

"Without this [KOL] network, it would not have been possible to start to think about changing the way you can treat these patients," Luthringer said. Over six decades, big pharma has been loath to abandon conventional efforts to treat schizophrenia by blocking the dopamine D2 receptor, he added – indeed, "there are still people who think you cannot treat these patients without dopamine blocking," Luthringer said.

By targeting 5-HT2A, MIN-101 is designed to have an effect on schizophrenia symptoms such as hallucinations, delusions, agitation and thought and movement disorders as well as side effects associated with antipsychotic treatments. Blocking 5-HT2A also promotes slow wave sleep, which is often disrupted in patients with schizophrenia.

Simultaneously blocking sigma-2, involved in movement control and psychotic symptom control, also modulates dopamine and increases calcium levels in neurons in the brain, which can improve memory. The phase III trial will seek to confirm the clinically meaningful effects on negative symptoms seen in the phase IIb study and determine whether patients remain stable in terms of positive symptoms, without experiencing adverse effects.

"Our development strategy for MIN-101 is driven by the recognition that, while positive symptoms are present intermittently and are a hallmark of early schizophrenia, negative symptoms persist and worsen over the lifetimes of the majority of schizophrenic patients, severely limiting their social and vocational reintegration over the longer term," Luthringer said.

Minerva has committed to seek initial approval for a label that broadly targets schizophrenia patients between the ages of 18 and 55, although the drug's greatest effect has been seen in the youngest quartile, from 18 to 33. Such a finding makes sense intuitively, he observed.

"If you can change the course of negative symptoms, you might influence the overall course of the disease," Luthringer said.

Following a potential approval in schizophrenia, Minerva is eyeing trials that would expand the treated population to adolescents as young as 14 at high risk for schizophrenia who show negative symptoms during the prodromal phase of the disorder.

And, while "people should understand that negative symptoms are really key and problematic in schizophrenia, negative symptoms are not specific to schizophrenia," affecting the ability of patients to work, care for their families and even perform activities of daily living, Luthringer pointed out. Thus, the company will continue to assess MIN-101 across neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, mood disorders, schizophrenia spectrum disorders and autism spectrum disorders.

But first things first.

"What we have here is a drug for negative symptoms in schizophrenia," Luthringer emphasized. "We want to keep [the trial] as clean as possible, even though there are a lot of other patients who might benefit."

With $85 million in the bank, Minerva is prepared to run the phase III program on its own, with money to spare. Advancing three earlier-stage molecules – MIN-202 in insomnia and mood disorders, MIN-117 in major depressive disorder and MIN-301 in Parkinson's disease – beyond proof of concept would, however, require additional funds.

Although investor reaction to the phase III plan was more muted than the response to the phase IIb data, when shares more than doubled, the company's stock (NASDAQ:NERV) nevertheless gained 80 cents, or 10.7 percent, Monday to close at $8.30.

In a company update, Lifesci Capital's David Sherman wrote that disclosure of the phase III design and timetable "should provide investors with greater clarity and comfort on the regulatory path forward for MIN-101."

Jefferies LLC analyst Biren Amin, who had "expected FDA may require two phase III studies," also pointed out in a flash note that Minerva's management "was conservative in their dropout rate assumptions when determining the necessary number of patients" for the phase III study, assuming a 40 percent dropout rate vs. 31 percent rate in the phase IIb trial.

Final data from the phase III trial of MIN-101 are expected in the first half of 2019, with Minerva expected to submit a rolling NDA.

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