INNOVATION & PIPELINE
For the treatment of Schizophrenia
We are developing MIN-101, our lead product candidate, as a treatment for schizophrenia, in particular the negative symptoms of the disease that can persist chronically throughout patients’ lifetimes and contribute to poor quality of life and functional outcomes. MIN-101 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.
MIN-101 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, MIN-101 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 MIN-101.
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.
In May 2017, we announced plans for the Phase 3 and Phase 4 clinical development of MIN-101 following an “end-of-Phase 2” meeting with the U.S. Food and Drug Administration (FDA). Our next step in the development of this compound is the planned initiation of a pivotal Phase 3 trial with MIN-101 in the second half of 2017.
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. 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 MIN-101 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 MIN-101’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 MIN-101 (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.
Key elements of the Phase 2b trial that will be incorporated into the Phase 3 trial include:
- improvement in negative symptoms as the primary endpoint;
- monotherapy administration of MIN-101 and no co-administration with atypical antipsychotics at any stage in the study;
- recruitment of patients with moderate-to-severe negative symptoms expressed as a specified minimum threshold baseline score on the Positive and Negative Syndrome Scale (PANSS) negative sub-scale; and
- a 12-week double-blind, randomized, placebo-controlled core phase followed by an open-label extension phase.
Two doses of MIN-101 or placebo will be administered during the double-blind phase of the Phase 3 trial, which will last 12 weeks, followed by an optional 36-week extension phase in which all patients will receive MIN-101. Approximately 500 patients will be enrolled at approximately 60 clinical sites across the U.S. and Europe, with a significant number of patients recruited at U.S. sites
The primary Phase 3 trial endpoint of improvement in negative symptoms at 12 weeks will be measured by the PANSS negative sub-scale score using the Marder factor, a widely recognized instrument for quantifying severity of negative symptoms. The Marder negative sub-score is 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 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 summary, the Phase 3 trial will seek to confirm clinically meaningful effects on patients’ negative symptoms and to determine whether patients can stay stable in terms of positive symptoms without experiencing the adverse effects of antipsychotics.
In Phase 4 development, the Company plans to conduct additional trials to expand the profile of MIN-101. These may potentially include a study comparing the rate of psychosis relapses in patients treated with MIN-101, 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 MIN-101 in a development program beyond the planned Phase 3 study in schizophrenia.
Learn more about schizophrenia.