A New Drug in Development for Negative Symptoms

- Negative symptoms in schizophrenia, including apathy, anhedonia, blunted affect, poverty of speech, and reduced social drive, are common and persistent despite currently available treatments

- The expert consensus Patient Outcomes Research Team schizophrenia guidelines state, “no pharmacologic treatment for negative symptoms has proved to have sufficient evidence to support a treatment recommendation”[1]

- Well-tolerated medications with efficacy for negative and cognitive symptoms of schizophrenia represent a huge area of unmet need

- MIN-101 has equipotent affinities for sigma-2 and serotonin 5-HT2A receptors, but no direct dopamine affinities

- MIN-101 also has affinity for α1 receptors, but not cholinergic or histaminergic receptors

- In rodent models, MIN-101 has been associated with improvements in social interaction and spontaneous alternation behavior, and reduced hyperlocomotion, and does not have sedative effects

- In a 12-week phase 2a randomized controlled trial (RCT) in patients with acute schizophrenia, MIN-101 was associated with significant improvement in negative symptoms versus placebo[2]

- Davidson and colleagues[3] performed a 12-week phase 2b RCT of MIN-101 versus placebo in patients with symptomatically stable schizophrenia

- The authors enrolled 244 patients (age 18 to 60) with a DSM-5 schizophrenia diagnosis at 36 sites across 6 European countries between May and December 2015 

- Inclusion criteria were: clinically stable according to their psychiatrist; negative symptoms for at least 3 months and a baseline Positive and Negative Syndrome Scale (PANSS) negative subscale score of ≥20; and scores <4 for PANSS excitement, hyperactivity, hostility, suspiciousness, uncooperativeness, and poor impulse control items

- Exclusion criteria were: personal or family history of prolonged QT interval, CYP2D6 poor metabolizers, significant suicide risk, unstable medical disorder, or recent substance use

- Participants were hospitalized and withdrawn from all psychotropic medications for at least 5 days (at least 1 month for long-acting injectable antipsychotics)

- Participants were randomized to placebo or oral MIN-101 at 32 or 64 mg/d in a 1:1:1 ratio for 12 weeks. Assessments were completed at baseline and weeks 2, 4, 8, and 12

- No other psychotropic medications were allowed except for rescue medications for insomnia or agitation, or anticholinergics for treatment-emergent extrapyramidal symptoms

- The primary outcome measure was the PANSS negative factor score (pentagonal structure model)

- Secondary outcomes included PANSS total and subscale scores, Brief Negative Symptom Scale scores, Clinical Global Impressions Scale (CGI) scores, cognition (Brief Assessment of Cognition in Schizophrenia [BACS]), and depression (Calgary Depression Scale for Schizophrenia [CDSS])

- Data for the primary endpoint (change from baseline to week 12 in PANSS negative factor score) were analyzed with mixed-effects models, using all observed data without imputation of missing values

- 244 patients (100% Caucasian; 56% male; median age, 41; mean BMI, 26) were randomized and received at least one dose of study medication

- Subjects had a mean baseline PANSS total score of 80

- At week 12, there was a significant reduction in the PANSS negative factor score in both the 32 mg/d and 64 mg/d groups versus placebo (effect sizes of 0.45 and 0.57, respectively)

- Significant improvements in negative symptoms were seen in both MIN-101 groups at 8 weeks, with benefit maintained at week 12

- Improvement in negative symptoms was not driven by improvements in mood

- The MIN-101 64 mg/d group also had significant improvements in PANSS total, CGI, CDSS, and BACS token motor scores compared with placebo at study endpoint

- There was no change in body weight or routine laboratory values from baseline in any subject groups

- 57% of patients in the MIN-101 groups reported at least one treatment-emergent adverse event

- The most common adverse events were headache, anxiety, and insomnia

-The authors concluded that MIN-101 demonstrated statistically significant efficacy in reducing negative symptoms and good tolerability in stable schizophrenia patients

-The authors noted that at this early stage of development it is difficult to weigh the meaningfulness of study results

1. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010;36:94-103.

2. Staner C, Davidson M, Noel N, et al. Results of an exploratory phase 2a study with MIN-101, a 5-HT2A/sigma-2 antagonist, for the treatment of schizophrenia. Presented at: Sixth Biennial Schizophrenia International Research Society Conference; 2016; Florence, Italy.

3. Davidson M, Saoud J, Staner C, et al. Efficacy and safety of MIN-101: a 12-week randomized double-blind, placebo-controlled trial of a new drug in development for the treatment of negative symptoms in schizophrenia. Am J Psychiatry. 2017. https://doi.org/10.1176/appi.ajp.2017.17010122