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BioXcel SERENITY I & SERENITY II phase 3 trial of BXCL501 to treat schizophrenia and bipolar disorder meets primary & secondary endpoints

New Haven, Connecticut
Wednesday, July 22, 2020, 16:30 Hrs  [IST]

BioXcel Therapeutics, a clinical-stage biopharmaceutical company, announced that BXCL501, the company’s proprietary sublingual thin film of dexmedetomidine, met the primary and secondary endpoints of SERENITY I and SERENITY II, demonstrating a robust treatment effect in the trials. Results demonstrated that BXCL501 was well tolerated, with rapid and durable reductions in agitation.

In patients with schizophrenia (SERENITY I) and a second study of bipolar disorder (SERENITY II), highly statistically significant and clinically meaningful reductions in the Positive and Negative Syndrome Scale, Excitatory Component (PEC) score at two hours, the primary endpoint, were reported for both high and low dose cohorts of BXCL501 compared to placebo (p<0.0001). Both studies also met the key secondary endpoint, demonstrating improvement in PEC scores beginning as early as 20 minutes in patients with bipolar disorder, at both dose levels, and as early as 20 minutes in patients with schizophrenia for the 180 mcg dose level. Exploratory efficacy endpoints confirmed the primary endpoint, with duration of response lasting at least four hours after treatment.

“These compelling phase 3 results show that BXCL501, if approved, has the potential to become an important new treatment option for patients suffering from acute agitation,” commented Vimal Mehta, Ph.D., chief executive officer of BTI. “We are extremely pleased that rapid and robust reductions in agitation were demonstrated in both patient populations despite differing neuropsychiatric diagnoses. We believe these results suggest that BXCL501 may have potential to treat agitation across a wide range of conditions. As we initiate steps toward regulatory submissions in these first two indications, we are also rapidly advancing the investigation of BXCL501 in additional disorders with significant unmet medical need including dementia, hyperactive delirium and opioid withdrawal symptoms.”

The secondary endpoint was highly statistically significant at 30 minutes, 45 minutes, 60 minutes, and 90 minutes in both studies. At 20 minutes, both doses were statistically significant in patients with bipolar disorder (p<0.025), and in patients with schizophrenia who received the higher 180 mcg dose.

Efficacy was further evaluated using two additional measures of agitation—the Agitation and Calmness Evaluation Scale (ACES), and Clinical Global Impression – Improvement Scale (CGI-I)—each of which showed statistically significant improvements for both doses of BXCL501 compared to placebo.

BXCL501 was well tolerated in both SERENITY trials. Overall, the most commonly reported adverse events from both trials were somnolence (22% for 180 mcg dose arms, 21% for 120 mcg dose arms and 6% for placebo arms; >75% of these events were classified as mild), dry mouth (4.4%, 7.5% and 1.2%, respectively), and dizziness (6.0%, 3.9%, and 0.8%, respectively). All adverse events were mild to moderate in severity, with none categorized as severe or requiring further intervention or monitoring. Few subjects discontinued the trials due to adverse events (SERENITY I: 0 for 180 mcg dose, 2 for 120 mcg dose and 0 for placebo arm; SERENITY II: 0, 1, and 0, respectively).

“I am impressed by the robust and consistent effects of BXCL501 across the SERENITY I and II studies, where it rapidly reduced agitation in patients with schizophrenia and bipolar disorder,” said Professor John Krystal, M.D., Chairman, Department of Psychiatry, and Yale University School of Medicine. “Managing agitation has always been a major challenge for health care providers. We would welcome an oral treatment option that is safe, has a quick onset of action, and reduces agitation with a minimum of sedation.”

“In clinical studies, BXCL501’s mechanism of action in treating patients with agitation appeared to be independent of underlying neuropsychiatric disease conditions,” said Robert Risinger, M.D., vice president, Clinical Development of BTI. “As a result, the Company believes that BXCL501 has significant potential to treat agitation associated with other disorders, and is actively advancing programs in dementia (TRANQUILITY), opioid withdrawal symptoms (RELEASE) and delirium (planned study). The Company is also exploring the potential of BXCL501 in other hyperarousable disease states, such as post-traumatic stress disorder, traumatic brain injury, alcohol withdrawal and as a treatment for phobias.”

The SERENITY studies were randomized; double-blinded, placebo-controlled parallel group adaptive trials in a total of 759 patients, 18 to 75 years of age. SERENITY I (n=381) enrolled patients with agitation associated with schizophrenia or schizoaffective disorder, with arms randomized to receive BXCL501 at 120 micrograms, or 180 micrograms or matching placebo, respectively. SERENITY II (n=378) enrolled patients with agitation associated with bipolar disorders, in three treatment arms randomized to receive BXCL501 at 120 micrograms, 180 micrograms or placebo, respectively. The primary endpoint of the trials was the reduction in acute agitation measured by the Positive and Negative Syndrome Scale - Excitatory Component (PEC) change from baseline compared to placebo. The secondary endpoint was determination of the earliest time where an effect on agitation is apparent as measured by the change from baseline in PEC total score.

Agitation is a common and difficult to manage symptom associated with a number of psychiatric conditions, including schizophrenia and bipolar disorder. It is estimated that approximately 22 million people are at risk of agitation, and 13 million in the US suffer from agitation each year, costing approximately US$ 40 billion annually in treatment related expenses. Early identification and prompt intervention to relieve agitation are essential to avoid symptomatic escalation and emergence of aggression. Recent consensus guidelines emphasize the need for non-coercive management strategies to protect the therapeutic alliance between patients and their health care providers—an alliance that is critical for the effective management of chronic psychiatric conditions. A non-invasive therapy that causes rapid symptom relief and de-escalates agitation may be necessary to avoid the costly and traumatic use of coercive techniques, like physical restraint and seclusion, which require admission and prolonged hospitalization.

BXCL501 is an investigational proprietary sublingual thin film of dexmedetomidine, a selective alpha-2a receptor agonist for the treatment of acute agitation. BTI believes that BXCL501 directly targets a causal agitation mechanism, and the Company has observed anti-agitation effects in multiple clinical studies across multiple neuropsychiatric indications. BXCL501 has been granted Fast Track Designation by the US Food and Drug Administration for the acute treatment of agitation. BXCL501 is also being evaluated in a phase 1b/2 trial (TRANQUILITY) for the treatment of agitation associated with dementia, and in a phase 1b/2 study (RELEASE) for the treatment of opioid withdrawal symptoms.


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