Novel Compound Shows Promise in Treating Negative Symptoms of Schizophrenia

In the search for a medication that lessens the debilitating negative symptoms of schizophrenia that tend to persist long after the psychotic symptoms have been stabilized, a promising new agent has emrged—MIN-101, developed by Minerva Biosciences.

Unlike current antipsychotic medications, MIN-101 has no direct affinity for dopamine receptors, but rather targets neural pathways that rely on glutamate, serotonin, or calcium signals.

In a phase 2b clinical study involving 244 adults with schizophrenia funded by Minerva, MIN-101 at both 32 mg/day and 64 mg/day doses was found to be superior to placebo at improving negative symptom ratings. There were no statistically significant differences in positive symptoms between the MIN-101 and placebo groups. The results were published July 28 in AJP in Advance.

MIN-101 is not the first drug that has shown some potential in managing negative symptoms of schizophrenia. In particular, the FDA-approved antipsychotic cariprazine has produced some favorable data (Psychiatric News, March 17). However, Michael Davidson, M.D., chief medical officer at Minerva, told Psychiatric News that whether cariprazine has direct effects on negative symptomology has not yet been determined.

When it comes to treating negative symptoms, “what the clinical evidence has really proven is that cariprazine is superior to risperidone,” Davidson said. He added that while cariprazine appears to be a promising medication, he believes its effects on negative symptoms are likely the indirect result of fewer positive symptoms and better mood.

Davidson said there are two main findings from the trial that make him feel confident that MIN-101specifically targets negative symptoms. First, patients taking MIN-101 showed significant improvements in negative symptoms such as apathy, social isolation, and blunted emotions on two variations of the Positive and Negative Symptom Scale (PANSS) compared with patients taking placebo. In contrast, there was no difference in positive symptom changes between the MIN-101 and placebo groups.

“Of course, for most antipsychotic trials you can always turn around and say that patients or clinicians were unblinded during the study when adverse effects emerged, which skews the reporting,” Davidson said. For example, if a patient in a clinical study started gaining weight, he might conclude he is not on placebo and then think more favorably about his symptoms.

“In this case, there were no revealing side effects,” Davidson said, making it less likely clinicians or patients knew who was receiving MIN-101 or placebo. No clinically significant changes were observed in vital signs, routine laboratory values, weight, metabolic indices, and Abnormal Involuntary Movement Scale scores between the groups.

“A relevant clinical question is whether the improvement in negative symptoms reported here is specific and clinically meaningful. Indeed, it is possible that MIN-101 has a beneficial effect on mood. However, the effect on negative symptoms was maintained after controlling for depression, which suggests the effect was not synonymous with improvement in mood,” Davidson and colleagues wrote.

“This is definitely a promising advance, when you consider this drug had a good effect size, improved both negative symptoms and CGI scores, and does not involve dopamine,” said Stephen Marder, M.D., who studies the pharmacology of antipsychotics. Marder is a professor of psychiatry and biobehavioral sciences at UCLA’s David Geffen School of Medicine.

“An important qualification of this study, though, is that the investigators had to recruit a specific population with elevated negative symptoms and low positive symptoms. So how these results will translate to the typical schizophrenia population is unclear,” said Marder, who was not involved with this study.

Marder also pointed out that the trial was limited to 12 weeks; this duration might not be long enough to assess the degree to which positive symptoms reemerge. Marder said understanding how MIN-101 affects positive symptoms is important to gauge whether this novel agent could be used as a monotherapy or as an adjunct to a conventional antipsychotic.

Minerva is launching a phase 3 study by the end of 2017. At least 500 participants will be enrolled in sites across Europe and the United States . It will retain the 12-week study design, with an optional 36-week extension phase in which all participants will receive MIN-101.

If all goes well, Davidson envisions big things for this new medication. While negative symptoms are a core component of schizophrenia, they are not specific to this disorder. Dementias, depression, or autism also include strong negative components which might be alleviated by MIN-101.

All of the authors on the AJP study have financial ties to Minerva Neurosciences, manufacturer of MIN-101. ■