In the JournalsPerspective

Lumateperone safe, effective for patients with schizophrenia

Kimberly E. Vanover

Results of a randomized clinical trial demonstrated a favorable safety profile and efficacy of lumateperone for patients with schizophrenia.

Treatment with 42 mg of lumateperone met the primary efficacy objective in this study, significantly improving symptoms in adult patients with schizophrenia,” Kimberly E. Vanover, PhD, of Intra-Cellular Therapies Inc. in New York, told Healio Psychiatry. “Importantly, the agent's weight, metabolic and motor side effect profile was similar to placebo.”

Current antipsychotic therapy can effectively improve positive symptoms of schizophrenia, such as delusions and hallucinations, but it retains limited efficacy for negative symptoms, social functioning and cognitive impairment, Vanover and colleagues noted. Further, available treatments feature an array of adverse effects that “add to the already increased morbidity and mortality associated with schizophrenia.” Lumateperone offers a new avenue for treatment because it simultaneously modulates serotonin, dopamine and glutamate neurotransmission while also lacking interaction with off-target receptors potentially associated with the adverse effects of other antipsychotics, the researchers wrote.

The researchers conducted a randomized, double-blind, placebo-controlled, phase 3 clinical trial in 450 patients with schizophrenia aged 18 to 60 years who experienced an acute exacerbation of psychosis. As the pre-specified primary efficacy endpoint of lumateperone, they tested the mean change from baseline to day 28 in the Positive and Negative Syndrome Scale total score vs. placebo. The Clinical Global Impression-Severity of Illness (CGI-S) score was used as the key secondary efficacy measure.

According to a pre-specified modified intent-to-treat efficacy analysis, 42 mg of lumateperone met the primary and key secondary efficacy objectives. Thus, it demonstrated a statistically significant improvement vs. placebo from baseline to day 28 according to PANSS total score and the CGI-S. The least squares mean difference from baseline to day 28 for 28 mg of lumateperone was 2.6 (95% CI, 6.2 to 1.1) on the PANSS total score and 0.2 (95% CI, 0.5 to 0) on the CGI-S. Lumateperone demonstrated tolerability in both dosage amounts and its use did not result in clinically significant treatment-emergent motor adverse effects or changes in endocrine or cardiometabolic features compared with placebo.

The efficacy and safety profile of lumateperone, as shown in this study and described in the prescribing information now approved by the FDA for adults with schizophrenia, offers health care providers an important new option for treating people living with schizophrenia,” Vanover said.

In a related editorial, Joshua T. Kantrowitz, MD, of the department of psychiatry at Columbia University, expressed a positive outlook for lumateperone’s continuing journey through the drug-approval pipeline.

“Moving from a positive phase 2 to a positive phase 3 study is often hazardous and unsuccessful,” Kantrowitz wrote. “Although we do not know what the ultimate comparative advantages of lumateperone will be, it is encouraging and potentially exciting to see a new drug with novel pharmacologic properties progressing through the gauntlet of drug development and [FDA] approval.” – by Joe Gramigna

Disclosures: Correll reports receiving personal fees from Intra-Cellular Therapies during the conduct of the study, as well as grants from Janssen and Takeda and personal fees from numerous pharmaceutical companies outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.

Kimberly E. Vanover

Results of a randomized clinical trial demonstrated a favorable safety profile and efficacy of lumateperone for patients with schizophrenia.

Treatment with 42 mg of lumateperone met the primary efficacy objective in this study, significantly improving symptoms in adult patients with schizophrenia,” Kimberly E. Vanover, PhD, of Intra-Cellular Therapies Inc. in New York, told Healio Psychiatry. “Importantly, the agent's weight, metabolic and motor side effect profile was similar to placebo.”

Current antipsychotic therapy can effectively improve positive symptoms of schizophrenia, such as delusions and hallucinations, but it retains limited efficacy for negative symptoms, social functioning and cognitive impairment, Vanover and colleagues noted. Further, available treatments feature an array of adverse effects that “add to the already increased morbidity and mortality associated with schizophrenia.” Lumateperone offers a new avenue for treatment because it simultaneously modulates serotonin, dopamine and glutamate neurotransmission while also lacking interaction with off-target receptors potentially associated with the adverse effects of other antipsychotics, the researchers wrote.

The researchers conducted a randomized, double-blind, placebo-controlled, phase 3 clinical trial in 450 patients with schizophrenia aged 18 to 60 years who experienced an acute exacerbation of psychosis. As the pre-specified primary efficacy endpoint of lumateperone, they tested the mean change from baseline to day 28 in the Positive and Negative Syndrome Scale total score vs. placebo. The Clinical Global Impression-Severity of Illness (CGI-S) score was used as the key secondary efficacy measure.

According to a pre-specified modified intent-to-treat efficacy analysis, 42 mg of lumateperone met the primary and key secondary efficacy objectives. Thus, it demonstrated a statistically significant improvement vs. placebo from baseline to day 28 according to PANSS total score and the CGI-S. The least squares mean difference from baseline to day 28 for 28 mg of lumateperone was 2.6 (95% CI, 6.2 to 1.1) on the PANSS total score and 0.2 (95% CI, 0.5 to 0) on the CGI-S. Lumateperone demonstrated tolerability in both dosage amounts and its use did not result in clinically significant treatment-emergent motor adverse effects or changes in endocrine or cardiometabolic features compared with placebo.

The efficacy and safety profile of lumateperone, as shown in this study and described in the prescribing information now approved by the FDA for adults with schizophrenia, offers health care providers an important new option for treating people living with schizophrenia,” Vanover said.

In a related editorial, Joshua T. Kantrowitz, MD, of the department of psychiatry at Columbia University, expressed a positive outlook for lumateperone’s continuing journey through the drug-approval pipeline.

“Moving from a positive phase 2 to a positive phase 3 study is often hazardous and unsuccessful,” Kantrowitz wrote. “Although we do not know what the ultimate comparative advantages of lumateperone will be, it is encouraging and potentially exciting to see a new drug with novel pharmacologic properties progressing through the gauntlet of drug development and [FDA] approval.” – by Joe Gramigna

Disclosures: Correll reports receiving personal fees from Intra-Cellular Therapies during the conduct of the study, as well as grants from Janssen and Takeda and personal fees from numerous pharmaceutical companies outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Oliver Freudenreich

    Oliver Freudenreich

    The antipsychotic lumateperone was just approved at the end of 2019 by the FDA for the treatment of schizophrenia. The study by Correll and colleagues published in JAMA Psychiatry describes one of the pivotal phase 3 registration trials conducted at 12 sites in the United States that ultimately led to lumateperone’s approval. Publishing these pharmacy trials in high-profile journals is welcome, allowing physicians to assess the potential value of new medications, without influence of pharmaceutical industry marketing.

    In this short-term, 28-day, acute treatment trial, lumateperone outperformed placebo with regards to symptom reduction at the FDA-approved dose of 42 mg but not for the lower dose of 28 mg. The effect size of 0.3 was low but in line with effect sizes seen for other antipsychotics in these types of registration trials. Encouragingly, the side effect profile of lumateperone was similar to placebo. Lumateperone’s propensity for side effects including weight gain and metabolic problems, however, will only become apparent with long-term use, particularly in antipsychotic-naive patients. Its risk for development of tardive dyskinesia will similarly require longer-term investigation. 

    Sometimes, a drug’s mechanism of action provides clues how it may be similar to or different from other drugs in the same class. One could argue that lumateperone at its core represents a rather pedestrian antipsychotic as it still binds to (post-synaptic) dopamine-2 receptors. On the other hand, a very high affinity for the 5-HT2a receptor coupled with a low D2 receptor occupancy of 40% sets lumateperone apart from other antipsychotics and may explain the observed lack of extrapyramidal symptoms. Whether other receptor bindings and downstream effects on other neurotransmitter systems described in animal studies (eg, affinity for the dopamine-1 receptor) actually translate into broader clinical efficacy (eg, for negative symptoms or for treatment-resistant patients) can only be answered by trials designed to answer such questions.

    When a new drug comes to market, clinicians and patients should have three clinical questions: 1) does it work? 2) is it safe? and 3) is it better than older medications? Short-term, clinical registration trials like this one can only begin to answer these questions.  Long-term clinical use and further trials will be required to fully evaluate the potential for this new antipsychotic. It remains to be seen if lumateperone will offer something better for patients with schizophrenia who struggle with ongoing symptoms despite treatment or who tolerate their current antipsychotic poorly.

    • Oliver Freudenreich, MD, FACLP
    • Co-director, MGH Schizophrenia Clinical and Research Program
      Massachusetts General Hospital
      Boston

    Disclosures: Freudenreich reports research grants and honoraria from several pharmaceutical companies, as well as honoraria and royalties from several medical publishers.