SAFETY PROFILE OF ADJUNCTIVE PIMAVANSERIN IN THE ENHANCE STUDY, A PHASE 3 TRIAL FOR THE POTENTIAL TREATMENT OF SCHIZOPHRENIA IN PATIENTS WITH AN INADEQUATE RESPONSE TO ANTIPSYCHOTIC TREATMENT

Abstract Background Many patients with schizophrenia (SCZ) do not fully respond to antipsychotic (AP) treatment despite adherence and require augmentation, often with an AP with similar mode of action. Evidence supporting polypharmacy is limited and adding another AP increases associated risks of adverse effects, including extrapyramidal symptoms and cardiometabolic disturbances. Pimavanserin (PIM) is a highly selective serotonin 5-HT2A inverse agonist/antagonist approved for the treatment of Parkinson’s disease psychosis. The phase 3 ENHANCE study evaluated adjunctive PIM in patients with SCZ and inadequate response to their current AP. As previously reported (ACNP 2019), the primary efficacy endpoint of ENHANCE (change in Positive and Negative Syndrome Scale [PANSS] total score) did not achieve statistical significance. Other prespecified analyses did yield nominal statistical separation from placebo, including changes in PANSS Negative Symptoms subscale, and in PANSS total score for the subgroup of European patients. Here we describe key safety results. Methods ENHANCE was a 6-week, randomized, double-blind, placebo (PBO)-controlled study of adjunctive PIM in patients with SCZ and inadequate response to their prescribed AP (aripiprazole, olanzapine, risperidone, and others). Patients included were age 18–55 years with PANSS total score of ≥65 and ≤110, and scores of ≥4 on ≥2 items including delusions, hallucinatory behavior, and/or suspiciousness/persecution; Clinical Global Impression-Severity scale score ≥4 was also required. The starting dose of PIM or PBO was 20 mg daily and could be adjusted up to 34 mg or down to 10 mg daily after 1 week based on investigator discretion. Safety was evaluated in all randomized patients who received ≥1 dose of study drug. Results All 396 randomized patients (PIM, n=198; PBO, n=198) were included in the safety analysis set. Treatment-emergent adverse events (TEAEs) were reported in 39.9% and 36.4% of patients in the PIM and PBO groups, respectively; most frequent TEAEs were headache (PIM 6.6%, PBO 9.1%), somnolence (PIM 6.6%, PBO 3.5%), and insomnia (PIM 5.1%, PBO 3.5%). Changes from baseline in Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Scale global clinical assessment of akathisia (GCAA), and Simpson–Angus Scale (SAS) scores were similar in the PIM and PBO groups. No patient developed dyskinesia (defined as a score ≥3 on any, or ≥2 on 2 of the first 7 AIMS items). Akathisia (GCAA score ≥2) in patients without baseline akathisia occurred in 4/186 (2.2%) patients receiving PIM and 1/189 (0.5%) receiving PBO. Parkinsonism (SAS total score >3) in patients without Parkinsonism at baseline occurred in 3/181 (1.7%) patients receiving PIM and 4/182 (2.2%) receiving PBO. No patient in either treatment arm had QTcF prolongation >500 msec or Torsades de Pointes during the study period; 2 (1.1%) patients in the PIM arm and 0 in the PBO arm had post-baseline QTcF prolongation >60 msec. Hypotension was reported in 1 patient in each treatment group; no patient had clinically important changes from baseline in blood pressure during treatment. Weight increase ≥7% from baseline was reported in 5/189 (2.6%) patients in the PIM group and 3/191 (1.6%) in the PBO group. Mean changes from baseline in PIM and PBO groups for fasting glucose were 0.07 mmol/L and 0.01 mmol/L; for triglycerides were -0.007 mmol/L and -0.136 mmoL/L, and for cholesterol were -0.10 mmol/L and -0.03 mmol/L, respectively. Discussion Results of ENHANCE provide evidence that the addition of PIM to frequently used APs is well tolerated in patients with SCZ.