Data presentations for lumateperone and preclinical ITI 1549 at the American College of Neuropsychopharmacology Annual Meeting – Intra-Cellular Therapies

Intra-Cellular Therapies, Inc. announced data presentations at the American College of Neuropsychopharmacology (ACNP) 62nd Annual Meeting . Poster M91 : “Lumateperone in the Treatment of Patients With Major Depressive Disorder and Bipolar Disorder with Anxious Distress and Mixed Features”. The poster presented at ACNP reports on an important post-hoc analysis from Study 403 evaluating the antidepressant effects of lumateperone in a pre-specified subgroup of patients with mixed features exhibiting anxious distress (commonly known as anxious depression).

Lumateperone improved change from baseline for MADRS total score at Day 43 compared with placebo in all three populations with anxious distress: combined major depressive disorder (MDD)/bipolar depression population (6.1 point reduction v. placebo; Cohen’s d effect size (ES) = 0.67), MDD individual population (6.8 point reduction v. placebo; ES= 0.79), and bipolar depression individual population (5.5 point reduction v. placebo; ES= 0.59). Greater improvements vs placebo in MADRS Total score occurred by Day 15 and persisted throughout the study. Similarly, in the Clinical Global Impression Scale-Severity (CGI-S) lumateperone was superior versus placebo in all three patient populations. Cohen-D effect sizes on the CGI-s ranged from 0.48 to 0.66.

In DSM-5 anxious distress is defined as the presence of greater than 2 anxious symptoms (feeling tense, feeling restless, difficulty concentrating, fearful something awful may happen, or feeling out of control) during the majority of days during the current or most recent major depressive episode. Using this definition, anxious distress was present in 73.9% in MDD and 54.3% in bipolar depression patients enrolled in the study, highlighting its high prevalence, consistent with the literature. Inner tension is an item within the MADRS which is often used as a surrogate marker for anxiety. With respect to the MADRS inner tension single-item score, lumateperone improved change from baseline at Day 43 compared with placebo for all three populations with anxious distress, demonstrating the consistency of the results.

The data presented in this poster represent further analyses from Study 403. Study 403 evaluated lumateperone 42mg as monotherapy in the treatment of major depressive episodes in patients with MDD with mixed features and in patients with bipolar depression with mixed features. Topline results for Study 403 are shown in Poster M88 and described below .
Both DSM-5 specifiers, mixed features and anxious distress, are common in patients with MDD and bipolar depression and their presence is associated with more pernicious forms of depressive illness (symptom severity, more comorbidities, increased suicide risk) and poor treatment response. In this analysis, lumateperone improved depression symptoms and severity score versus placebo in patients with MDD or bipolar depression with anxious distress and mixed features.

Poster M131 : “Discovery and Characterization of ITI 1549, a Novel Non-hallucinogenic Psychedelic For the Treatment of Neuropsychiatric Disorders” We are developing novel non-hallucinogenic psychedelics that allow exploration of this psychoactive drug class in neuropsychiatric conditions including mood disorders without the liabilities of known psychedelics, such as induction of hallucinations and risks for cardiac valvular pathologies. The lead molecule in this program, ITI 1549, is advancing through IND enabling studies and is expected to enter human testing in late 2024 or early 2025. This poster describes the in-vitro and in-vivo preclinical characterization of ITI 1549. In vitro, similar to known hallucinogenic psychedelics, ITI 1549 exhibits high affinity binding to 5-HT2a receptors. Functionally, ITI-1549 acts as an agonist at 5-HT2A receptors favoring postsynaptic signaling within the beta-arrestin pathway over G-protein coupled pathways.

Activation of the 5-HT2a receptor coupled Gq signaling pathway has been linked to hallucinogenic properties of psychedelic compounds. By preferentially activating the beta-arrestin pathway, ITI 1549 and compounds in this chemical series may retain the beneficial therapeutic effects of psychedelics without hallucinogenic effects. Importantly, unlike most psychedelics, ITI 1549 is not a 5-HT2b agonist which has been associated with heart valve pathologies.

In animal models, we have shown that ITI 1549 does not elicit head twitch behaviors in mice, which are predictive of hallucinogenic potential in humans; based
on these data ITI 1549 can be classified as a non-hallucinogenic agent. ITI 1549 has also shown to increase social interaction and reduce anxiety and depressive symptoms in preclinical models. It also activates the mTOR pathway in the prefrontal cortex, which is associated with increased neuroplasticity and rapid antidepressant activity in preclinical models. In conclusion, ITI 1549 may be a safe, non-hallucinogenic psychedelic without the liability to induce hallucinations and cardiac pathologies while retaining the potential as an acute or chronic treatment of mood, anxiety and other neuropsychiatric disorders.

Poster M88 : “Lumateperone Treatment for Major Depressive Episodes with Mixed Features in Major Depressive Disorder and Bipolar I or Bipolar II Disorder”. This poster describes further data analyses from Study 403 in mixed features. In this study, lumateperone 42mg was statistically significant on the primary endpoint of symptom reduction on the MADRS for the combined mixed features patient population of MDD and bipolar depression (5.7 point reduction v. placebo; p<0.0001; Cohen’s d effect size (ES) of 0.64) and the individual patient populations of MDD with mixed features (5.9 point reduction v. placebo; p<0.0001; ES= 0.67) and bipolar depression with mixed features (5.7 point reduction v. placebo; p<0.0001; ES= 0.64). Lumateperone 42mg also met the key secondary endpoint by demonstrating a statistically significant and clinically meaningful reduction in the Clinician’s Global Impression scale or CGI compared to placebo at Week 6 in all three patient populations. Lumateperone was generally safe and well tolerated, with a side effect profile consistent with prior lumateperone trials. The most common adverse events in the study were somnolence, dizziness and nausea. There were no notable changes in weight, body mass index, or waist circumference and no clinically relevant changes in metabolic parameters.