Regulatory Decision Summary for Vraylar

To support their New Drug Submission, the sponsor submitted several pivotal studies to demonstrate safety and efficacy for each indication sought. The designs of all the pivotal studies were considered adequate and all used well-known and validated endpoints, as well as appropriate statistical analyses.

The indication for treatment of schizophrenia was supported by three pivotal, multinational, randomized, double-blind, placebo-controlled, parallel-group clinical trials that evaluated doses of Vraylar from 1.5 to 9 milligrams (mg)/day in adult patients with schizophrenia who were experiencing acute exacerbations of psychotic symptoms (no first episode patients included), who were markedly ill per the baseline efficacy assessments. The trials were all 6 weeks in duration and had a 2-week safety follow-up period. The primary and secondary endpoints in all studies were the change from baseline to endpoint in the Positive and Negative Symptom Scale (PANSS) total score and change from baseline to endpoint in Clinical Global Impression-Severity (CGI-S) score, respectively. The main differences between studies were the doses that were evaluated and whether fixed-dose (2 studies: 1.5, 3, 4.5, 6 mg/day) or fixed-flexible dose ranges (1 study: 3-6 mg/day, 6-9 mg/day) were evaluated. Active control arms (risperidone or aripiprazole) were included in two studies for assay sensitivity. There were statistically significant and clinically relevant improvements in symptoms of schizophrenia with all proposed doses (1.5 to 6 mg/day), starting at the end of week 1 with doses of 3 to 9 mg/day or at the end of week 2 with 1.5 mg/day, and were maintained through week 6.

The efficacy of Vraylar was also demonstrated in a Phase 3, multinational, randomized, placebo-controlled study that used a randomized withdrawal design. The study population was consistent with that of the 6-week pivotal trials. Patients received open label Vraylar for the first 20 weeks of the study. Those who were optimized on a stable dose (3 to 9 mg/day) for the last 14 weeks of the open-label period and met protocol-defined criteria for a stable response at week 20 could be randomized 1:1 to double-blind treatment with either placebo or Vraylar (same dose received at the end of open-label treatment) for observation of relapse, for up to 72 weeks. The primary endpoint was the time to first protocol-defined relapse event. The patients randomized to Vraylar had a statistically significant delay in the time to a protocol-defined relapse event, compared to patients randomized to placebo. By the end of the double-blind period, 47.5% of patients in the placebo group compared to 24.8% in the Vraylar group had a relapse event.

The safety data from controlled schizophrenia clinical trials was based on the data collected in four 6-week placebo-controlled trials (Group 1A Safety Population: 3 pivotal 6-week trials and one supportive 6-week trial) and from the longer-term randomized withdrawal study. In Group 1A, 1317 patients received at least one dose of Vraylar (1.5 to 12 mg/day). Completion rates (6 weeks) were similar for patients treated with Vraylar (61.7%) or placebo (57.2%). In the longer-term study, 765 patients received at least 1 dose of Vraylar in the 20-week open-label phase (3 to 9 mg/day fixed-dose after first 6 weeks for remainder of study); 216 patients completed 20 weeks of open-label treatment; and 200 patients were randomized 1:1 to Vraylar or placebo in the double-blind phase.

At least one treatment emergent adverse event (TEAE) was reported in 74.7% of patients on Vraylar (1.5 to 12 mg/day) and 69% of patients on placebo in Group 1A. In the longer-term study, at least one TEAE was reported in 80% of patients during the 20-week open-label phase and 74% of patients on Vraylar compared to 65% on placebo in the double-blind phase. Many of the reported adverse effects were TEAEs that are known to occur with other atypical antipsychotics and were also reported with Vraylar in the bipolar patient populations. Class-related TEAEs reported in Group 1A at higher frequencies in patients treated with Vraylar compared to placebo included: akathisia; restlessness; extrapyramidal symptoms (EPS, for example [e.g.] tremor, dystonias, parkinsonism, bradykinesia, dyskinesia, hypokinesia, tardive dyskinesia); increased blood creatine phosphokinase (CPK); gastrointestinal AEs (constipation, dry mouth, diarrhea, nausea, vomiting); somnolence and sedation; insomnia; and dizziness. Most TEAEs were dose related. Among the commonly reported class related TEAEs, akathisia and restlessness were reported more frequently with Vraylar at recommended doses than with either active control treatment (aripiprazole and risperidone). Metabolic disturbances (e.g., clinically significant increases in fasting glucose and lipids, weight gain) are also a known adverse effect of atypical antipsychotics, but there were no meaningful differences between patients on Vraylar or placebo in Group 1A with respect to clinically significant changes in these parameters. During longer-term treatment, increased incidences of clinically significant changes were observed for some metabolic parameters. Other TEAEs that were reported more frequently with Vraylar than with placebo, included low incidences of hypertension/increases in blood pressure, increases in heart rate and asymptomatic transaminase elevations. For many of the adverse effects associated with Vraylar, first onset was within the first 2 to 3 weeks of treatment for the majority of patients experiencing them. This is consistent with when total Vraylar plasma concentrations would be approaching steady state. The safety profile in the longer-term randomized withdrawal study was generally consistent with what was observed in Group 1A.

The bipolar depression indication was supported by four clinical trials, with three of them being pivotal multicenter, randomized, double-blind, and placebo-controlled studies.

In the three pivotal studies, fixed doses of 0.75, 1.5, and 3.0 mg/day were evaluated in bipolar I disorder patients undergoing a depressive episode. The evaluation of efficacy was based on the primary and secondary efficacy endpoints, which consisted of the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score and Clinical Global Impressions – Severity (CGI-S) score at week 6. The 0.75 mg dose failed to show efficacy. Only the 1.5 mg dose met the primary endpoint in the three pivotal trials and was clinically meaningful. The secondary endpoint was in line with the primary in 2 out of 3 studies. The 3 mg dose only met the primary endpoint in only one study and was not supported by the secondary endpoint.

Across the four clinical trials, 1,230 patients were exposed to Vraylar. Overall, study completion rates were similar for the Vraylar-treated patients and placebo (77.9% and 79.8%, respectively). TEAEs were reported in 43.4% of Vraylar-treated patients and in 32.5% of placebo-treated patients. The most common TEAEs were reported for the following systems: nervous system disorders (headache, akathisia, somnolence, and dizziness), psychiatric disorders (insomnia, restlessness, anxiety, and agitation) and gastrointestinal (GI) disorder (nausea, diarrhea, and dry mouth). Severe AEs were reported more frequently in the placebo (2.6%) as compared to the Vraylar (1.3%) group and were mostly related to worsening of underlying psychiatric conditions. As part of the four clinical trials, one completed suicide was reported.

The bipolar mania indication was supported by three pivotal studies employing a flexible-fixed daily dosing regimen of Vraylar to evaluate patients suffering from bipolar I disorder and during an ongoing manic or mixed-manic episode (as per Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition [DSM-IV] criteria). Patients received an initial dose of 1.5 mg Vraylar (or placebo) and were allowed to titrate up to efficacy (or down for tolerability issues) during the first 14 days, following which the established dose was fixed for the remaining 7 days (total 21 days of administration). The primary endpoint was change from baseline at week 3 in Young Mania Rating Scale (YMRS). The results between the three studies were consistent and contributed to support the overall efficacy of Vraylar in the acute management of manic (mixed-manic) episodes. Study 33 demonstrated that the most effective range of daily Vraylar dose was 3 to 4.5 mg, while remaining efficacious up to 6 mg. At daily doses ≥6 mg/day, there was no therapeutic benefit, and the incidence and severity of AEs increased markedly.

In addition to the aforementioned pivotal trials supporting the bipolar indications (Group 2A), an open-label, multicenter, 16-week flexible dose safety and tolerability study (Group 2B) supported the bipolar mania safety profile derived from Group 2A. 

A total of 1,025 bipolar mania patients received Vraylar at doses ranging from 3 to 12 mg/day. Completion rates were approximately 70% in the pivotal trials, and 30% in the open-label trial, where the highest reason for discontinuation rates was AEs. TEAE were reported in 79.6% Vraylar-treated Group 2A patients and 67.0% placebo, while in Group 2B (with no placebo group), 83.3% of patients reported a TEAE. The most common TEAEs were reported as follows, for Group 2A and 2B respectively: gastrointestinal (GI) disorders [nausea (11.4% and 10.4%), constipation (9.1% and 10.7%)], eye disorders (vision blurred [3.5% and 2.5%]), nervous system and psychiatric disorders (akathisia [20.2% and 32.6%], extrapyramidal disorder [13.2% and 6.7%], restlessness [6.4% and 6.5%], insomnia [8.3% and 7%] and dizziness [6.4% and 0.2%]) and vascular disorders (hypertension [2.1% and 4.2%]). Severe TEAEs were reported by 7.4% (vs placebo at 4.5% in Group 2A) and 6% of patients in Group 2B. Across the four trials, there was one death and three suicide attempts.

Overall, the efficacy of Vraylar for the treatment of schizophrenia in adults was demonstrated at doses of 1.5 to 6 mg/day and, within this dose range, Vraylar was generally well-tolerated. Efficacy of Vraylar was also demonstrated for the management of depressive or mania/mixed-mania episodes associated with bipolar I disorder, in adult patients. At the recommended doses up to 3 mg/day and 6 mg/day, Vraylar was generally well-tolerated in patients with bipolar depression and bipolar mania, respectively. The long-term efficacy of Vraylar was not evaluated for bipolar mania or bipolar depression.

The Vraylar safety profile shares many similarities with that of other atypical antipsychotics, therefore a similar level of patient monitoring was recommended to manage these harms and uncertainties. All of the warnings and recommendations for close monitoring (e.g., akathisia, EPS, suicidal ideation/suicidal behavior, periodic monitoring of weight, glucose and lipid profiles); dose reductions; treatment discontinuation; or, introducing concomitant medications when appropriate, if the patient will remain on the antipsychotic, which are included in the product monographs (PM) for other atypical antipsychotics to manage or mitigate the known class AEs were included in the Vraylar PM. The less consistently reported adverse effects in this class that were reported with Vraylar, such as hypertension, asymptomatic transaminase elevations, and potential ocular effects were also managed this way.

The benefit-harm-uncertainty profile for Vraylar can be considered acceptable for the treatment of adult patients with schizophrenia, and the acute management of patients with bipolar I disorder (mania/mixed mania and depression) when it is used under the conditions described in the approved PM.