HOLLYWOOD, FLA. – The novel oral antipsychotic agent cariprazine showed efficacy across the broad spectrum of schizophrenia manifestations – including negative symptoms – in a multicenter phase III clinical trial.
This is welcome news. Current antipsychotic agents are only modestly effective in treating the negative symptoms, mood disturbances, and neurocognitive dysfunction that so often hamper recovery in patients with schizophrenia. In contrast, the investigational agent cariprazine demonstrated efficacy in all these domains, Dr. John M. Kane reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.
Cariprazine is a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors. As such, it would be expected to have broad efficacy across the spectrum of schizophrenia symptoms. This has been borne out, first in animal studies and now in this phase III randomized trial, noted Dr. Kane, chairman of psychiatry at Zucker Hillside Hospital in Glen Oaks, N.Y., and professor of psychiatry, neurology, and neuroscience at the Albert Einstein College of Medicine in New York.
Dr. John M. Kane
Forest Pharmaceuticals filed an application with the Food and Drug Administration last fall for marketing approval of cariprazine in the treatment of schizophrenia as well as for treatment of bipolar mania. The company expects a decision from the regulatory agency before year’s end.
Dr. Kane reported on 446 patients with acute exacerbation of schizophrenia placed on 6 weeks of double-blind placebo or cariprazine at either 3-6 mg/day or 6-9 mg/day. Sixty-one percent of subjects completed the study. The mean daily dosage of cariprazine in the lower-dose study arm was 4.2 mg/day, versus 6.6 mg/day in the higher-dose arm.
The primary study endpoint was improvement in Positive and Negative Syndrome Scale (PANSS) total score. From a baseline mean PANSS score of 96, indicative of marked illness, patients in the lower-dose cariprazine group showed a placebo-subtracted net 6.8-point improvement. Those on higher-dose therapy had a net 9.9-point improvement. Both dosing strategies were significantly more effective than was placebo. Patients on cariprazine at the more effective dosing regimen of 6-9 mg/day showed a significant advantage over placebo starting at week 1.
To more closely examine the drug’s efficacy in domains other than positive symptoms such as delusions and hallucinations, Dr. Kane and his coinvestigators conducted a post hoc analysis focusing on cariprazine’s impact on each of the five PANSS-derived Marder symptom factor groups. These five groupings are negative symptoms, positive symptoms, uncontrolled hostility/excitement, disorganized thought, and anxiety/depression.
Cariprazine at 6-9 mg/day proved superior to placebo in all five Marder factor groupings. Cariprazine at 3-6 mg/day outperformed placebo in all but the Marder negative symptom factor grouping, where a trend favoring the drug fell short of statistical significance.
Of the 30 individual items that make up the PANSS, higher-dose cariprazine was significantly more effective than was placebo in 21. These included most positive symptom factor items as well as others where conventional antipsychotic agents typically don’t fare very well, such as emotional withdrawal, active social avoidance, poor rapport, anxiety, depression, tension, poor impulse control, hostility, excitement, uncooperativeness, disturbance of volition, and conceptual disorganization.
Cariprazine at 3-6 mg/day outperformed placebo on 11 of the 30 individual PANSS items.
Long-term cariprazine in bipolar I
Also at the NCDEU meeting, Dr. Terence A. Ketter presented a phase III, open-label, 16-week, study of flexibly dosed cariprazine in 402 patients with bipolar I disorder.
Dosing of cariprazine was permitted at 3-12 mg/day. The actual mean dose used in the study was 6.2 mg/day. The primary study endpoints involved safety and tolerability, since the drug already had demonstrated efficacy in three separate 3-week-long studies in acute mania.
This 16-week study was undertaken in recognition that the real challenge in bipolar I disorder is long-term management. Nearly half of all patients who respond to initial conventional therapies relapse within 2 years, mainly because of high rates of nonadherence, explained Dr. Ketter, professor of psychiatry and behavioral sciences and chief of the bipolar disorders clinic at Stanford (Calif.) University.
Just 33% of participants completed the 16-week study. Sixteen percent of subjects withdrew because of adverse events, roughly the same number as for protocol violations.
The major tolerability issue in the phase III trial was treatment-emergent akathisia, which occurred in 37% of participants. In addition, 7% experienced treatment-emergent extrapyramidal symptoms as defined by a Simpson-Angus Scale score of 3 or less at baseline rising to greater than 3 on treatment.
Ninety-eight percent of these cases of treatment-emergent akathisia or extrapyramidal symptoms were rated as mild to moderate in intensity. Five percent of subjects dropped out of the trial because of treatment-emergent akathisia, making this the No. 1 reason for discontinuation because of adverse events, followed by depression at 2%. Only 0.7% of subjects dropped out because of extrapyramidal symptoms, the same small number as quit because of worsening mania.