[UPDATE: MEETING CANCELLED]

Background Analysis: US FDA Advisory Committee to Review Lumateperone, an Investigational Drug Proposed by Intra-Cellular Therapies for the Treatment of Schizophrenia – JUL 31, 2019 (PDAC)

Announcement

The US FDA has scheduled a Psychopharmacologic Drugs Advisory Committee (PDAC) meeting for Wednesday, July 31, 2019. The committee will discuss a new drug application (NDA) for lumateperone tosylate capsules, submitted by Intra-Cellular Therapies, Inc. (ICTI), for the treatment of schizophrenia.

Indication Background

Description of Indication

Schizophrenia is a chronic, severe, and disabling brain disorder that affects around one percent of Americans, according to the National Institute of Mental Health (NIMH). People with the disorder may hear voices other people do not hear. They may believe other people are reading their minds, controlling their thoughts, or plotting to harm them. Treatment often involves a psychosocial intervention (e.g., individual/family therapy, training on social skills, and vocational rehabilitation), in combination with antipsychotic medication.

Product Background

Description of Product

According to ICTI, lumateperone works via dopamine receptor phosphoprotein modulation, or DPPM, acting as a pre-synaptic partial agonist and post-synaptic antagonist at D2 receptors. The company believes this mechanism, along with interactions at 5-HT2A receptors, serotonin transporters, and D1 receptors with indirect glutamatergic modulation, contributes to efficacy across a broad array of symptoms, with improved psychosocial function and favorable tolerability.

Clinical Trials of Proposed Indication

A summary of the design and top-line results of the pivotal trials (trials 005, 301, and 302) are provided below, based on information from an ICTI corporate presentation, dated May 21, 2019. Comprehensive data and detailed analyses by both ICTI and the FDA will be made available two business days prior to the PDAC meeting, in meeting materials posted by the FDA. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. At the time of publishing this report, results of the pivotal trials were not posted to ClinicalTrials.Gov (ClinicalTrials.Gov IDs: NCT01499563; NCT02282761, and NCT02469155).

Overall, ICTI has stated that the NDA submission is supported by data from 20 clinical trials and more than 1,900 subjects exposed to lumateperone.

Pivotal Trial Designs

Trial 005 was a randomized, controlled trial in patients with schizophrenia. Patients (N=325) were randomized to receive either 60 mg or 120 mg lumateperone daily, 4 mg risperidone daily, or placebo daily over 4 weeks. Trial 301 was a randomized, controlled trial in patients with schizophrenia. Patients (N=450) were randomized to receive either 40 mg or 60 mg lumateperone daily or placebo daily over 4 weeks. Trial 302 was a randomized, controlled trial in patients with schizophrenia. Patients (N=695) were randomized to receive either 20 mg or 60 mg lumateperone daily, 4 mg risperidone daily, or placebo daily over 4 weeks. Across the trials, efficacy was assessed based on the change from baseline on the Positive and Negative Syndrome Scale (PANSS) Total Score.

Top-Line Pivotal Trial Results

ICTI reported that, for 2 of the 3 trials, namely trials 005 and 301, the primary efficacy endpoint was met for the cohorts that received the 60 mg daily dose of lumateperone. The safety profile was reported as being well-tolerated and similar to placebo. Based on results for data pooled across trials, the company also reported that lumateperone was superior to risperidone on key safety parameters, namely the following measures: fasting glucose; total cholesterol; triglycerides; body weight; and prolactin. The company also presented results from an open-label switching and long-term safety trial, named Trial 303, which they believe show that patients on standard of care (SOC) antipsychotic medications can be safely switched to lumateperone without dose titration, and that the drug has a favorable long-term safety profile. Data from Trial 303 were presented for 329 patients treated with lumateperone for at least 6 months, and for 109 patients treated for one year. The company also reported that patient improvements on body weight, cardiometabolic, and endocrine parameters worsened when they were switched back to SOC antipsychotic medications.

Regulatory Background

US Regulatory Background

September 27, 2019– PDUFA goal date

September 28, 2018 – ICTI announced completion of the rolling NDA submission (NDA 209500).

June 6, 2018 – ICTI announced initiation of the rolling NDA submission.

Fast track

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US regulatory filings.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Intra-Cellular Therapies Drug Name: lumateperone tosylate Drug Class: dopamine receptor phosphoprotein modulation Indication: schizophrenia

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.