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Roluperidone (MIN-101)

For the treatment of Schizophrenia

We are developing Roluperidone, our lead product candidate, as a treatment for the negative symptoms of schizophrenia that can persist chronically throughout patients’ lifetimes and contribute to poor quality of life and functional outcomes. Roluperidone has been shown to block serotonin receptors and sigma receptors, two receptors in the brain that are involved in the regulation of mood, cognition, sleep and anxiety.

Roluperidone is meant to block a specific subtype of serotonin receptor called 5-HT2A. When 5-HT2A is blocked, certain symptoms of schizophrenia, such as hallucinations, delusions, agitation and thought and movement disorders, as well as the side effects associated with antipsychotic treatments, can be minimized. Additionally, blocking 5-HT2A promotes slow wave sleep, a sleep stage often disrupted in patients with schizophrenia.

Importantly, Roluperidone is also meant to block a specific subtype of sigma receptor called sigma2, which is involved in movement control, psychotic symptom control and learning and memory. Blocking sigma2 also modulates other neurotransmitters in the brain, in particular dopamine, which is important as individuals with schizophrenia often have elevated levels of dopamine in their brains. Blocking sigma2 also increases calcium levels in neurons in the brain, which can improve memory. Recent literature has also indicated that a sub-type of progesterone protein complex might also be a putative binding site for sigma2 receptors and might explain the effects on cognition of Roluperidone.

Most currently approved therapies for schizophrenia are primarily directed toward positive symptoms. As a result, patients with predominantly negative symptoms are often underserved. Negative symptoms constitute the main burden of illness and represent an important unmet need as no treatment is currently approved for these symptoms. These symptoms are responsible for the poor psychosocial functioning and vocational and social capabilities of patients. Side effects of current pharmaceutical treatment options include sedation, uncontrollable muscle movements, weight gain, cognitive impairment, and sleep disorders.

Recent Developments and Next Steps

In December 2017, we announced the screening of the first patient in the pivotal Phase 3 clinical trial of Roluperidone (Study MIN-101C07) as monotherapy for negative symptoms in patients diagnosed with schizophrenia.

The trial is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week study to evaluate the efficacy and safety of 32 milligrams (mg) and 64 mg of Roluperidone 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 will be enrolled at approximately 60 clinical sites in the U.S. and Europe, with about 30 percent of patients coming from the U.S. Patients will be initially randomized equally to receive one of the two doses of Roluperidone or placebo for 12 weeks. Thereafter, all patients will continue treatment with active drug for an additional 40 weeks, during which patients initially randomized to the two treatment groups will continue treatment with the same doses, while patients initially randomized to placebo will cross over to one of the two doses.

The primary endpoint of this trial will be improvement in negative symptoms in patients treated with Roluperidone compared to placebo as measured by the change in the Positive and Negative Syndrome Scale (PANSS) Marder negative symptoms factor score (NSFS) over the 12-week double-blind treatment period. The Marder factor score is a widely recognized instrument for quantifying the severity of negative symptoms similar to the White negative sub-score used in the Phase 2b trial. The two factors differ from each other in that the Marder score has eliminated four items and added one on active social avoidance (G16 item). The Company is employing the Marder scale because this item has been shown to be well correlated with patients’ overall functional outcome.

The key secondary endpoint of the trial will be the effect of Roluperidone compared to placebo as measured by the Personal and Social Performance (PSP) total score over the same period. Additional secondary endpoints will be the effect of Roluperidone compared to placebo on the Clinical Global Impression of Severity (CGI-S) score and safety and tolerability.

Our development strategy for Roluperidone 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. No drugs are currently approved to treat the negative symptoms of schizophrenia or negative symptoms present in other conditions, including developmental disorders, affective disorders and neurodegenerative disorders.

Data from the Company’s Phase 2b trial with Roluperidone completed in 2016 have informed the design of the Phase 3 trial. Key findings from the Phase 2b trial include observations of a direct effect on negative symptoms (rather than an indirect or pseudo effect linked to improvements in other symptoms and/or a different side effect profile). The data also support the durability of this effect through the entire 36-week duration of the trial, which included a 12-week double-blind, placebo-controlled core phase and a 24-week, open-label extension phase.

The specificity of Roluperidone’s therapeutic effects on negative symptoms was validated by the stability of positive symptoms observed over the entire duration of treatment and a side effect profile comparable to placebo, particularly as it relates to extra-pyramidal symptoms (EPS). The Company believes that the unique pharmacological profile of Roluperidone (sigma 2 and serotonin 5HT2a receptor antagonism) and the absence of direct binding to post-synaptic dopamine receptors may explain its specific effects on negative symptoms.

The Company’s Phase 3 trial design is intended to replicate the experience of “real world” clinical practice in schizophrenia. Many patients are dissatisfied and not well served by continuous antipsychotic treatment as evidenced by poor compliance with medications. Recent scientific literature points toward the fact that indefinite antipsychotic maintenance treatment in schizophrenic patients (provided by post-synaptic blockade of dopamine receptors) may be responsible for poor long term functional outcomes in addition to well described side effects, including EPS, weight gain, sedation and prolactin increase.

In Phase 4 development, the Company plans to conduct additional trials to expand the profile of Roluperidone. These may potentially include a study comparing the rate of psychosis relapses in patients treated with Roluperidone, standard of care with antipsychotics or placebo. In addition, the Company may conduct a trial in adolescents at high risk for schizophrenia who during the prodromal phase manifest negative symptoms.

While negative symptoms are a core component of schizophrenia and predict poor functional capacity, they are not specific to that disease but are also recognized as a hallmark of other diseases. These include neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, mood disorders, schizophrenia spectrum disorders and autism spectrum disorders. The Company plans to assess these indications as expansion options for Roluperidone in a development program beyond the planned Phase 3 study in schizophrenia.

Learn more about schizophrenia.