Intra-Cellular Therapies Submits sNDA to FDA for Lumateperone as an MDD Adjunctive Therapy

Intra-Cellular Therapies announced this morning that they recently submitted a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) for lumateperone (CAPLYTA) as an adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder (MDD).

“MDD is a highly prevalent condition with a significant need for efficacious, safe, and well-tolerated medicines, as more than half of patients do not adequately respond to an antidepressant alone,” said Suresh Durgam, MD, executive vice president and chief medical officer of Intra-Cellular Therapies, in a press release.

Approximately 21 million US adults live with MDD, and this mental disorder can lead to severe functional impairment and impact interpersonal relationships and quality of life. About two-thirds of patients with depression do not reach remission with first-line treatment.

Thus, lumateperone (10.5 mg, 21 mg, and 42 mg), an oral, once-daily atypical antipsychotic already approved in adult schizophrenia and bipolar depressive episodes as a monotherapy and as adjunctive therapy with lithium or valproate, is now being studied for the treatment of MDD. Lumateperone does not have a known mechanism of action, but Intra-Cellular Therapies wrote in a statement that lumateperone could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors. If the FDA approves the sNDA for MDD, it will expand the on-label use of lumateperone beyond the indications for schizophrenia and bipolar depression.

The submission included 2 positive Phase 3 global, double-blind, placebo-controlled studies with patients who had a primary diagnosis of MDD, based on the DSM-5, and did not respond well to their current anti-depressant therapy. Participants were randomized to receive lumateperone or placebo as an adjunctive therapy to antidepressants.

The trials demonstrated that patients who took lumateperone alongside an antidepressant had meaningful improvements in MDD symptoms, as seen with the change from baseline at week 6 on the Montgomery Asberg Depression Rating (MADRS) total score. Compared with placebo, participants on lumateperone had a 4.9-point and 4.5-point reduction (P < .0001; Cohen’s d effect = 0.56) on the MADRS total score in the first and second phase 3 trials, respectively. Improvement in the MADRS score was seen as early as week 1 (P = .0504), with a statistically significant separation on the Clinical Global Impression Scale for Severity of Illness beginning at week 3.

The efficacy of lumateperone was reflected in the Quick Inventory Depressive Symptomatology Self-Report scale (P < .0001), which assesses symptoms of depression, insomnia, low mood, appetite or weight changes, impaired self-perception, concentration difficulties, loss of interest or pleasure, suicidal ideation, psychomotor agitation, and fatigue.

Moreover, lumateperone demonstrated a favorable safety and tolerability profile, with those on this drug having low rates of extrapyramidal symptoms. The most reported adverse events that were observed at a rate ≥ 5% and more than twice the rate of placebo were dizziness, dry mouth, somnolence/sedation, nausea, and fatigue. The studies also observed similar metabolic and weight changes between patients on lumateperone and placebo.

“Given CAPLYTA’s efficacy and safety profile, we believe CAPLYTA can become a first-choice treatment for the adjunctive treatment of MDD pending FDA approval, and we look forward to working with the FDA during this review process,” Durgam said.

References

1. ^{Intra-Cellular Therapies Submits Supplemental New Drug Application (sNDA) to FDA for CAPLYTA® (lumateperone) for the Treatment of Major Depressive Disorder as Adjunctive Therapy. Intra-Cellular Therapies. December 3, 2024. https://www.globenewswire.com/news-release/2024/12/03/2990492/30597/en/Intra-Cellular-Therapies-Submits-Supplemental-New-Drug-Application-sNDA-to-FDA-for-CAPLYTA-lumateperone-for-the-Treatment-of-Major-Depressive-Disorder-as-Adjunctive-Therapy.html. Accessed December 3, 2024.}
2. ^{Derman, C. Lumateperone Significantly Enhances Antidepressant Effects in Phase 3 Trial. HCPLive. June 18, 2024. https://www.hcplive.com/view/lumateperone-significantly-enhances-antidepressant-effects-in-phase-3-trial. Accessed December 3, 2024.}