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A New Drug in Development for Negative Symptoms

A New Drug in Development for Negative Symptoms

  • Is an effective, well-tolerated treatment for the negative symptoms of schizophrenia on the horizon? View the slides in PDF format.

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  • - Participants were hospitalized and withdrawn from all psychotropic medications for at least 5 days (at least 1 month for long-acting injectable antipsychotics)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

View the slides in PDF format.

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