Ongoing research by a University of Georgia psychologist reveals that targeting one particular symptom of schizophrenia has a positive effect on other systems, offering significant promise for treating an aspect of schizophrenia that currently has no actual therapeutic options—and costs the U.S. government north of $155 billion per year. However, by treating the symptom of avolition (reduced motivation), the study’s lead, Gregory Strauss, discovers that this has a positive effect on other schizophrenia symptoms. These findings are the result of the outcomes of a Phase IIb clinical trial assessing Minerva Neurosciences’ roluperidone.
A $155+ Billion Per Year Challenge in the U.S. Alone
It is the leading medical cause of functional disability worldwide, according to a number of population health studies, reports Allyson Mann with University of Georgia’s UGA Today. It affects approximately 0.3-0.7% of people at some point in their life, totaling about 20 million worldwide according to the World Health Organization (WHO). According to one report, the mental health condition causes approximately 1% of worldwide disability-adjusted life years (DALYs). The actual rate of schizophrenia actually varies up to threefold depending on how it is diagnosed and defined. Regardless, for an individual struggling with schizophrenia it becomes a struggle—and in some cases impossible—for coping with basic life skills and daily loving.
When considering schizophrenia and associated functional disability, lead investigator Strauss reports, “The government spends a tremendous amount of money every year on functional disability” and continued that with no FDA-approved medication, this patient population and therapeutic target is critically important. How much does the government spend? According to one report back in 2013, the U.S. government was spending $155 billion per year.
The Research: University of Georgia Researcher Quest to Change the Paradigm
Led by Gregory Strauss and team at University of Georgia, the study revealed that successfully treating avolition, a symptom involving reduced motivation, positively impacted other potential negative symptoms of schizophrenia based on the Phase IIb study assessing roluperidone. The study results were published in Schizophrenia Bulletin.
Strauss has established himself as a national, if not global, expert in schizophrenia. He has published more than 125 studies exploring the symptoms, and in a 2018 paper published in JAMA Psychiatry, he demonstrated that adverse symptoms aren’t a single construct but reflect five distinct domains, including 1) avolition 2) anhedonia (reduced pleasure) 3) asociality (reduction in social activity 4) blunted affect (reduction in outwardly expressed emotion in the face and voice) and 5) alogia (reduced speech), reports Ms. Mann at University of Georgia. Each one of these represent a separate treatment target.
By 2019, Strauss was in intense pursuit of these five domains associated with schizophrenia—he sought to understand which one is most critical to target in treatment trials. In applying network analysis, an advanced mathematical approach from the field of engineering and complex systems science, he invited experts in their respective fields, including Hiroki Sayama and Farnaz Zamani from Binghamton University. By employing this network analysis, the Strauss-led team studied the five domains as a system and found causal interactions with each other. Strauss hypothesized that a drug, despite not decreasing the severity of one symptom, could actually impact the interactions among symptoms.
Applying Network Analysis to the Minerva Neurosciences Trial
Strauss’ most recent research applies network analysis on the Minerva Neurosciences’ clinical trial data. The sponsor, Minerva, found that the experimental drug roluperidone significantly reduced negative symptoms associated with schizophrenia. The Strauss network analysis uncovering that avolition represented the nexus of the active treatment group, indicating that as the drug improves avolition, all other symptoms may improve as well.
Phase III Clinical Trial of Roluperidone
In the UGA Today communication, Struss suggests, “There’s a lot of hope that Minerva’s Phase III trial will show a similar improvement in negative symptoms.” He continued, “This could be the first drug that receives an indication for negative symptoms of schizophrenia from the Food and Drug Administration, which is perhaps the biggest in the field of psychiatry. It would be a monumental benefit to the lives of people with schizophrenia.”
Strauss indicates Minerva Neurosciences could be on to something big. The current Phase III trial represents a multicenter, multinational, randomized, double-blind placebo-controlled, parallel-group study to evaluate the efficacy and safety of roluperidone in adult schizophrenia patients. As reported in ClincialTrials.gov, the primary objective of the sponsor centers on the evaluation of 2 fixed doses of the experimental treatment compared to placebo in improving negative symptoms of schizophrenia over 12 weeks of double-blind treatment. The results will be measured by the change in Positive and Negative Syndrome Scale (PANSS) Marder negative symptoms factor score (NSFS) over 12 weeks.
Targeting 501 participants, the study runs from December 2017 through January 2021 with the estimated primary completion date at April 2020. The sponsor selected 30 clinical investigational sites, which are listed in the trial submission. Minerva contracted with contract research organization (CRO) Premier Research to support the operation of the global clinical trial.
Roluperidone (formerly referred to as MIN-010, CYR-101 and MT-210) is Minerva Neurosciences’ lead product candidate and has been shown to block serotonin receptors and sigma receptors, two receptors in the brain active in the regulation of mood, cognition, sleep and anxiety. The experimental treatment 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 side effects associated with antipsychotic treatments, can be minimized. Also, the blocking of 5-HT2A promotes slow wave sleep—a sleeping stage frequently disrupted in patients combating schizophrenia.
Roluperidone also blocks specific subtype of the sigma receptor known as signma2—involved with movement control, psychotic symptom control and learning and memory. For all details, see the link to the company’s well-written description.
Minerva Neurosciences Snapshot
Publicly traded biopharma sponsor Minerva Neurosciences (NASDAQ: NERV) is a clinical-stage venture focusing on the development of a portfolio of product candidates to treat central nervous system (CNS) diseases. The sponsor seeks to transform the lives of patients with improved therapeutic conditions. Founded in 2007 as Cyrenaic Pharmaceuticals, Inc. they entered into a licensing deal with Japan-based Mitsubishi Tanabe Pharma for the lead compound (at the time MT210 and now MIN-101). Minerva Neurosciences as we know it today was actually formed via the merger of two privately held ventures including Cyrenaic Pharmaceuticals and Sonkei Pharmaceuticals in 2013 in what a CNS-focused new company with three late-stage assets was. They then already had development programs for schizophrenia, insomnia, MDD, and Parkinson’s disease. The newly merged entity went public in 2014, raising $32.7 million.
Minerva Neurosciences’ product portfolio:
|Roluperidone (MIN-101)||Schizophrenia negative symptoms||3||Lead candidate; 2.9 million patients worldwide according to Datamonitor|
|Seltorexant (MIN-202)||Insomnia/adjunctive treatment MDD||2||Co-developed with Janssen (J&J); 27.9 million suffer from MDD|
|MIN-117||MDD||2||27.9 million suffer from MDD|
|MIN-301||Parkinson’s Disease||pre||2 million suffer from PD|
Minerva seeks to develop and commercialize “first-in-class” products that address critical unmet needs in the CNS therapeutic area. They seek to develop differentiated products with novel mechanisms of action that target therapeutic areas of high unmet need and significant disease burden.
With a present share price of $8.05, they command a market capitalization of $331 million and hold about $59 million cash in the bank. Over a third of the company is owned by three institutional investors, including Federated investors, Blackrock and FMR, LLC. They are a typical pre-revenue biotech company—losing $41 million in 2017 and $51.7 million in 2018. Of their four primary pipeline investigational products, roluperidone incurs the greatest cost representing $25 million—over 50% of their costs in 2018. As we have discussed, that product is in Phase III and will be completed in 2021 with insight by the spring.
A low-overhead concern, they employ only between 15 and 20 and depend on CROs, such as Premier Research, for the ongoing execution of clinical trials.
Gregory Strauss, Assistant Professor, Clinical Program, Department of Psychology, University of Georgia. Note, Strauss serves as a consultant to Minerva Neurosciences, actually working with them to co-develop and validate a key clinical outcome measure used in their clinical trial—he was not involved with developing roluperidone, which was mentioned earlier as licensed from Mitsubishi Tanabe Pharma.
Research is a team sport. Strauss led a team including the previously mentioned Hiroki Sayama and Farnaz Zamani from Binghamton University as well as Brian Kirkpatrick (University of Nevada, Reno), Remy Luthringer (Minerva Neurosciences), Mark Opler (Medavante-Prophase LLC) and Michael Davidson (with both Minerva and Tel Aviv University).
Call to Action. Keep an eye on the Phase III study results for MIN-101—if this goes well and Minerva Neurosciences successfully files a New Drug Application (NDA) with the FDA, this will lead to the first treatment for schizophrenia. This is a big deal—a considerable historical milestone in the world of treating CNS-based mental health. From a business perspective, the licensing terms for MIN-101 could determine the value if the drug is eventually approved. Sign up for TrialSite News daily newsletter for updates. Interested in having Professor Strauss on the TrialSite News podcast series? Let us know.