Schizophrenia: Lumateperone safe and tolerable, achieved reduction in symptoms

Results of a long-term, open-label study presented at the annual congress of the European College of Neuropsychopharmacology showed safety and tolerability of Lumateperone, a novel investigational drug for schizophrenia, in reducing schizophrenia symptoms.

According to the results, the drug with a unique triple mechanism of action demonstrated impressive tolerability and safety and also helped achieve a continuous decline in schizophrenia symptoms over the course of a year.

Suresh Durgam, a psychiatrist and senior vice president for late-stage clinical development and medical affairs at Intra-Cellular Therapies, presented the findings at the conference. Intra-Cellular Therapies is the New York-based company developing lumateperone as its lead product.

It was also found that the patients on lumateperone at the 1-year mark showed significant reductions in LDL cholesterol, total cholesterol, serum prolactin, and body weight, compared with baseline values recorded when participants were on various standard-of-care antipsychotics prior to switching. However, other cardiometabolic parameters, including fasting blood glucose, insulin, triglycerides, and HDL cholesterol, showed only negligible change over the course of study.

This favourable cardiometabolic profile contrasts sharply with those of currently available antipsychotic agents, many of which worsen cardiometabolic risk factors.

Three-phase 3, double-blind, placebo-controlled randomized clinical trials of 4-6 weeks duration have been completed in a total of 1,481 patients with acute exacerbation of schizophrenia. Two trials were positive, with lumateperone achieving significantly greater mean reductions in the Positive and Negative Syndrome Scale (PANSS) total score than placebo, while the third was negative, with no significant between-group difference. Of note, the safety profile of lumateperone was indistinguishable from placebo with the sole exception of somnolence, where the 20% incidence was twice that of placebo-treated controls. However, in the open-label program, dosing was switched from morning to evening, with a resultant drop in somnolence to the placebo level, Dr. Durgam said.

The open-label program has two parts. Part 1 was conducted in 302 patients with stable, generally mild schizophrenia symptoms while on risperidone, olanzapine, or various other antipsychotics commonly prescribed in the United States. They were switched to lumateperone at 42 mg once daily for 6 weeks, at which point they demonstrated significant reductions in body weight, serum prolactin, insulin, total cholesterol, and LDL cholesterol. They then were switched back to their former medications, with a resultant worsening of those parameters to prelumateperone levels, providing evidence of a cause-and-effect relationship with cardiometabolic risk factors.

Part 2 of the open-label program is the long-term study, in which 603 patients with stable symptoms on standard-of-care antipsychotics were switched to lumateperone at 42 mg/day, to be followed for 1 year or more. Dr. Durgam presented an interim analysis focused on the first 107 patients to achieve the 1-year treatment milestone. Most were obese at baseline: the group’s mean body mass index was 31.3 kg/m2. They experienced progressive weight loss, with a mean reduction of 1.82 kg on day 175 and 3.16 kg on day 350. About 24% of subjects had a 7% or greater reduction in body weight, while 8% had at least a 7% weight gain. Waist circumference decreased by an average of 5.2 cm from a baseline of 103.2 cm in men and by 1.9 cm in women.

At 150 days of treatment in 340 patients, 30% had achieved a PANSS response, defined as at least a 20% improvement in PANSS total score, compared with baseline. At 300 days in the smaller group who had reached that milestone at the time of the interim analysis, the PANSS response rate had grown to 41%.

Among patients with schizophrenia and comorbid depression as defined by a Calgary Depression Scale for Schizophrenia (CDSS) score of 6 or more at baseline, lumateperone at 42 mg/day improved depressive symptoms, such that 60% of those patients achieved a CDSS response – that is, at least a 50% reduction in the score – by day 75. This finding supports data from earlier short-term studies and suggests that lumateperone’s multiple mechanisms of action and high tolerability make it a promising candidate for the treatment of depression and other symptom domains of schizophrenia that are currently inadequately treated, according to Dr. Durgam.

Dr. Durgam also presented an update on the lumateperone program for bipolar depression, which consists of three-phase 3, double-blind, placebo-controlled, 6-week-long clinical trials totalling 1,455 patients. Two have been completed: one positive and the other negative with an unusually high placebo response rate. The ongoing third trial will be the tiebreaker. Safety and tolerability have been as noted in other lumateperone studies.

In the positive trial, the primary efficacy endpoint was a change in Montgomery-Åsberg Depression Rating Scale, which improved in lumateperone-treated patients by an average of 16.7 points from a baseline score of just over 30, a significantly better result than the 12.1-point reduction in placebo-treated controls. The treatment benefit was similar in bipolar I and bipolar II patients.

The drug also is well into phase 3 for treatment of agitation in patients with Alzheimer’s disease and other dementias. And lumateperone is an ongoing phase 2 trials for sleep disturbances associated with neuropsychiatric disorders. Phase 2 studies in major depressive disorder and autism are about to get underway.

Lumateperone is an oral once-daily drug that doesn’t require titration. Its high degree of tolerability is thought to be attributable to the drug’s mechanism of action, which involves simultaneous modulation of three different neurotransmitter pathways: serotonin, dopamine, and glutamate. The drug is a potent serotonin 5-HT2a antagonist and serotonin reuptake inhibitor, a dopamine D2 presynaptic partial agonist and postsynaptic antagonist, and it also modulates glutamate via activation of the D1 receptor.