Cariprazine (VRAYLAR, Allergan) Meets Primary Endpoint in Phase 3 Trial

Gary Sachs, MD

Topline results from a phase 3 trial on cariprazine (VRAYLAR, Allergan), a once-daily oral antipsychotic, have shown that the primary endpoint was met in comparison to placebo for the treatment of acute bipolar I depression.

The phase 3, randomized, double-blind, placebo-controlled, parallel group, multicenter, fixed-dose trial, called RGH-MD-54, included 488 patients with acute bipolar I depression. Patients were randomized for 6 weeks to either cariprazine 1.5 mg/day, 3.0 mg/day, or placebo. This was the second successful phase 3 clinical trial for the therapy.

"Report of an efficacious treatment for bipolar depression is welcome news for the more than 5 million Americans with bipolar disorder as well as their families and care providers," Gary Sachs, MD, an associate clinical professor of psychiatry at Harvard Medical School, told MD Magazine. "The depressed phase of the illness is the most common entry point for patients seeking treatment and is associated with most of the disability and risk of suicide associated with bipolar disorder."

“We consider today’s positive results a major milestone in the process of making this promising treatment option available for patients suffering from bipolar depression and also widening the therapeutic scope of cariprazine,“ István Greiner, PhD, MSc, the research director of Gedeon Richter Plc, which discovered and co-developed cariprazine, said in a statement.

Cariprazine showed significant improvement from baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Additionally, the therapy met the primary endpoints for safety and efficacy in both doses (P <.05).

“These phase 3 data provide further support for cariprazine as a potential treatment for adults with bipolar depression, and adds to the growing clinical profile of this compound in mental health disorders,” C. David Nicholson, PhD, the chief research & development officer at Allergan, said in a statement. “Bipolar depression is a serious and impairing condition of bipolar I disorder. At Allergan, we’re committed to supporting underserved populations with limited treatment options, and look forward to submitting an sNDA for cariprazine as a treatment option for patients suffering from bipolar I depression.”

The drug was considered well-tolerated, with sedation, somnolence, dizziness, akathisia, and nausea as the most commonly reported adverse events (AEs). In the trial, 5.0% of cariprazine treated patients chose to discontinue due to AEs, compared to placebo at 2.5%.

"First, for patients with bipolar depression, cariprazine can be added to what is still a rather short list of agents with efficacy proven in a fully powered double-blind clinical trial. That list consists of Olanzapine in combination with Fluoxetine, Olanzapine, Quetiapine, lamotrigine, lurasidone, and now cariprazine," Sachs said. "Positive data from a well-controlled trial enables me to add cariprazine to the menu of reasonable choices I offer my patients."

"Since patients with bipolar disorder may experience transitions directly from depression to mania or mania to depression as well as mixed states, cariprazine, which also has proven efficacy for treatment of mania and mixed episodes, provides a broad spectrum option which can simplify the treatment plan," he added.

Allergan plans to submit a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) in the second half of 2018, according to a company statement. The drug is already approved by the FDA to treat schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults in September 2015.

“There are a limited number of products approved to treat bipolar depression and even fewer products that have been studied and approved to treat the full spectrum of bipolar disorder, from mania through depression. Having another product proven to treat the full range of bipolar disorder would be a welcome addition to the treatment options currently available to the psychiatry community and patients,” Sachs said in a statement.

As to how it compares to other drugs on the market, it's still hard to tell without head-to-head evidence, Sachs noted. "[However] cariprazine appears to have an adverse effect profile with relatively little sedation or weight gain compared to quetiapine and olanzapine. Cariprazine’s long half-life may also make it more user-friendly to patients," he said.