Notable Late-Phase Developments for Negative Symptoms of Schizophrenia
Schizophrenia, a chronic mental disorder, is characterized by three key symptom domains - positive symptoms, negative symptoms, and cognitive impairment. Though numerous antipsychotics are approved for the treatment of schizophrenia, these therapies are mainly effective in managing patients’ positive symptoms. A high level of unmet need remains in the market for effective therapies to treat negative symptoms, which exist in a sizeable proportion of schizophrenia patients.1 Positive efficacy results noted in the mid- to late-phase clinical studies for Allergan/Gedeon Richter/Recordati’s Vraylar/Reagila (cariprazine) and Minerva Neurosciences’ MIN-101 in patients with predominant negative symptoms of schizophrenia offer some hope that this need could soon be addressed, although questions remain about the approval of these agents for negative symptoms and their use in clinical practice.
Cariprazine, a dopamine D2/D3 receptor partial agonist with preferential selectivity for D3 and a 5-HT2B receptor antagonist, launched in the United States (brand name Vraylar) for the treatment of schizophrenia in March 2016 and was approved in Europe (brand name Reagila) for this indication in July 2017. Though cariprazine is not specifically approved for the treatment of negative symptoms in these regions, the EMA label includes data from a Phase III trial conducted in patients with predominant negative symptoms of schizophrenia in Europe (EudraCT, 2012-005485-36).2 In this 26-week study, cariprazine demonstrated a significantly greater mean change in the PANSS-FSNS from baseline- the primary end point - over the active comparator risperidone (-8.9 vs. -7.4, P = 0.002), along with greater improvements in secondary end points, including the PSP and the CGI scores.3 In the United States, Allergan received a Refusal to File letter from the FDA for cariprazine’s sNDA for the treatment of negative symptoms in September 2017 due to an incomplete application.4 Though the details of the trial data submitted in the application have not been disclosed by the company, we expect that pooled data from the post-hoc analyses of two placebo- and active-controlled studies with trial sites in the United States were included in the application. These analyses demonstrated that, at six weeks, in the subset of patients with predominant negative symptoms, a significantly greater improvement in mean change in baseline PANSS-FSNS score was observed with cariprazine compared with aripiprazole- and placebo-treated patients.5 Allergan planned to have a Type A meeting with the FDA in December 2017 to address the issues in cariprazine’s sNDA.6 No further information related to this meeting have been disclosed by the company as of January 2018 and Allergan does not appear to be planning to conduct an additional study of cariprazine for negative symptoms in the United States.7 Of note, some U.S. psychiatrists interviewed by DRG expect that an additional clinical study among patients with predominant negative symptoms of schizophrenia will need to be conducted in the United States to support regulatory approval, casting doubt on whether cariprazine will be approved specifically for negative symptoms in this region.1 Nevertheless, some interviewed experts have reported prescribing cariprazine off-label to patients with negative symptoms to assess its efficacy on this symptom domain in clinical practice, suggesting that it may be incorporated into physicians’ treatment algorithm for negative symptoms without a formal label expansion.
In December 2017, Minerva Neurosciences initiated a 12-week Phase III study for MIN-101, a 5-HT2A and sigma-2 receptor antagonist with low affinity for α1-adrenergic receptors, in the United States and Europe.8 The trial will evaluate MIN-101’s efficacy and safety as a monotherapy compared with placebo in patients with predominant negative symptoms and stable positive symptoms of schizophrenia. Top-line results are expected in the second half of 2019. A 40-week open-label extension period is also planned to determine MIN-101’s long-term efficacy and safety/tolerability. Data from a completed 12-week Phase IIb trial with 244 patients demonstrated a significant reduction in the PANSS-FSNS at 12 weeks for both doses of MIN-101 (32 gm, 64 mg), administered as a monotherapy, compared with placebo (32 mg: P < 0.024, and 64 mg: P < 0.004).9 Notably, a reduction in drug-treated patients’ negative symptoms continued over a 36-week extension phase, with patients’ positive symptoms remaining stable.10 MIN-101 was well tolerated in the Phase IIb study and, unlike cariprazine, no dopaminergic side effects, such as extrapyramidal symptoms, were reported. Of note, six patients experienced QTcF prolongation in the open-label Phase IIb six-month extension study due to an inactive metabolite, BFB-520. As such, the company will use a gastric-resistant formulation of MIN-101 that provides a lower concentration of BFB-520 in the Phase III study.11 Although psychiatrists would welcome a therapy with demonstrated efficacy for negative symptoms, interviewed experts are skeptical of MIN-101’s use as a monotherapy for negative symptoms given that an adjunctive antipsychotic effective against the positive symptoms of schizophrenia will most likely be required in clinical practice.
Cariprazine and MIN-101 are currently the most advanced agents trying to capitalize on the unmet need of a treatment for negative symptoms of schizophrenia. Although the magnitude of difference between cariprazine and risperidone on the improvement of negative symptoms was small in the Phase III trial among patients with predominant negative symptoms, cariprazine remains the only therapy that has shown statistically significant efficacy among this patient population against an active comparator in a Phase III study. Given the history of sigma antagonists’ failure in the treatment of schizophrenia, Phase III results are needed to confirm MIN-101’s efficacy in patients with predominant negative symptoms of schizophrenia. Such results will determine MIN-101’s commercial potential in this market and the likelihood of a therapy launching specifically for negative symptoms.
CGI: Clinical Global Impression
FSNS: Factor Score for Negative Symptoms
PANSS: Positive and Negative Syndrome Scale
PSP: Personal and Social Performance
sNDA: supplemental New Drug Application
- DRG’s Schizophrenia | Disease Landscape & Forecast, 2017.
- EMA: Reagila, CHMP Assessment Report (accessed December 21, 2017)
- Németh G, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet. 2017;389:1103-1113.
- Allergan, press release, September 22, 2017.
- Earley W, et al. Efficacy of cariprazine on negative symptoms in acutely ill patients with schizophrenia: a pooled, post hoc analysis. 170th Annual Meeting of the American Psychiatric Association; May 22, 2017; San Diego, CA. Abstract # P0-031.
- Allergan, Q3 2017 earnings conference call, November 1, 2017.
- Allergan, J.P. Morgan conference, January 8, 2018.
- Minerva Neurosciences, press release, December 19, 2017.
- Davidson M, 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;174:1195-1202.
- Minerva Neurosciences, corporate presentation, October 2017.
- Minerva Neurosciences, press release, June 22, 2017.
Upcoming content: DRG’s Schizophrenia | Unmet Need | Detailed, Expanded Analysis (Negative Symptoms), 2018: DRG’s Unmet Need provides quantitative insight into U.S. and European physician perceptions of key treatment drivers and goals and the current level of unmet need for a specific disease. Commercial opportunities are analyzed, and the extent to which emerging therapies may capitalize on these opportunities is evaluated.