COPENHAGEN – Lumateperone, a novel investigational drug for schizophrenia with a unique triple mechanism of action, showed impressive safety and tolerability while achieving a continuous decline in schizophrenia symptoms over the course of a year in a long-term, open-label study, Suresh Durgam, MD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, 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. Other cardiometabolic parameters, including fasting blood glucose, insulin, triglycerides, and HDL cholesterol, showed only negligible change over the course of study, according to, a psychiatrist and senior vice president for late-stage clinical development and medical affairs at Intra-Cellular Therapies, the New York–based company developing lumateperone as its lead product.
This favorable cardiometabolic profile contrasts sharply with those of currently available antipsychotic agents, many of which worsen cardiometabolic risk factors. That would seem to be a major advantage for lumateperone and is likely to be a factor in the Food and Drug Administration’s ongoing deliberation over the company’s new drug application.Dr. Durgam said.
Intra-Cellular Therapies’ stock price took a hit in July 2019, when the FDA abruptly canceled an advisory committee meeting scheduled to consider lumateperone. The agency sought additional information on animal toxicology studies. Having received it from the company, the FDA now no longer plans to schedule an advisory committee meeting before issuing its marketing approval decision.
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.
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 () 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.
The primary focus of the ongoing long-term study is safety. The most common treatment-emergent adverse events during a full year of therapy were dry mouth, headache, and diarrhea, each occurring in about 7% of patients. Only 0.8% of patients developed extrapyramidal symptoms.
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 () 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 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 totaling 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 change in , 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 phase 3 trial* for treatment of agitation in patients with Alzheimer’s disease and other dementias was stopped early for lack of efficacy in an interim analysis. And lumateperone is in ongoing phase 2 trials for sleep disturbances associated with neuropsychiatric disorders. The phase 2 study* in major depressive disorder has been completed.