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BTAI: Positive Results in SERENITY Trials Puts NDA Filing on Track for 1Q21…


By David Bautz, PhD



Positive Results in Phase 3 SERENITY Trials

On July 20, 2020, BioXcel Therapeutics, Inc. (NASDAQ:BTAI) announced positive results from the SERENITY (Sub-Lingual DExmedetomidine in Agitation Associated With SchizophRENIa and Bipolar Disorder STudY) trials of BXCL501 for treating agitation in patients with schizophrenia and bipolar disorder. The SERENITY I trial was a randomized, double blind, placebo controlled parallel group adaptive trial in patients with schizophrenia or schizoaffective disorder (n=381) that were randomized to receive 120 μg BXCL501, 180 μg BXCL501, or placebo. The SERENITY II trial was a randomized, double blind, placebo controlled parallel group adaptive trial in patients with bipolar disorders (n=378) that were randomized to receive 120 μg BXCL501, 180 μg BXCL501, or placebo.


The following graph shows the robust response seen in decreasing PEC scores in schizophrenia patients treated with BXCL501 compared to placebo. The results for the 180 μg arm became significant starting at 20 minutes after dosing and the separation from placebo continued to increase out to 120 minutes.

Clinically meaningful responses were also seen in the clinical global impression improvement scale (CGI-I) and the agitation and calmness evaluation scale (ACES), as shown in the following figures. The results from these secondary endpoints lend further support to the clinically meaningful effect that BXCL501 has on agitated patients.


Very similar results were seen in SERENITY II, with patients administered BXCL501 experiencing a robust and highly statistically significant decrease in PEC compared to placebo. Similar to SERENITY I, the difference from placebo became statistically significant at the 20-minute mark.

Just as in SERENITY I, results from SERENITY II showed clinically meaningful responses in the CGI-I and the ACES, as shown in the following figures.

Importantly, there were no serious adverse events reported and the tolerability was comparable in both of the SERENITY trials. In addition, all patients were able to self-administer the treatments.

BioXcel will be meeting with the FDA in the coming months for a Pre-NDA meeting where we anticipate the company learning whether BXCL501 will qualify for Priority Review (which could reduce the review time from 10 months to 6 months). We anticipate the NDA being filed in the first quarter of 2021, with an approval possible in the fourth quarter of 2021 or the first quarter of 2022 (depending upon if it is granted Priority Review).

BXCL501 Compares Favorably with Adasuve®

Adasuve® (loxapine) inhalation powder was approved in 2012 for the treatment of agitation associated with schizophrenia or bipolar disorder. It is administered using a handheld, single-use inhaler. It was approved based on the results of two Phase 3 trials in schizophrenia and bipolar patients with agitation (Lesem et al., 2011; Kwentus et al., 2012; Faden et al., 2019).

The following table gives a comparison between the 10 mg dose of inhaled loxapine and the two doses of BXCL501. The 180 μg dose of BXCL501 is superior to Adasuve® in both change in PEC score as well as the percentage of PEC responders (defined as a ≥40% improvement in PEC score) while the 120 μg dose of BXCL501 is highly comparable.

While clinically successful, Adasuve® has yet to be commercially successful based on the fact that it has a black box warning and Risk Evaluation and Mitigation Strategy (REMS) associated with its potential to cause bronchospasm. In addition, there is a black box warning for an increased risk of death in elderly patients with dementia-related psychosis treated with antipsychotic drugs.

In discussing the potential for inhaled loxapine to treat acute agitation associated with schizophrenia or bipolar disorder, Faden et al. state that:

“An ideal medication for the treatment of agitation would be efficacious, tolerable, non-painful, and have a rapid onset of action” (Faden et al., 2019).

Based on the SERENITY data we believe this perfectly describes BXCL501 and clinicians would welcome the opportunity to treat agitated patients with the drug.

TRANQUILITY Data Anticipated Soon

We anticipate data from the company’s Phase 1b/2 TRANQUILITY trial to be reported in the next month or two. The TRANQUILITY trial is testing BXCL501 for the acute treatment of agitation in patients with dementia, including Alzheimer’s disease (AD). The multicenter, randomized, double blind, placebo controlled, ascending dose trial is designed to evaluate the safety, efficacy, tolerability, and pharmacokinetics of BXCL501 in patients age 65 and older who exhibit acute agitation associated with all forms of dementia. It is an adaptive trial design and will evaluate multiple doses of BXCL501 or matching placebos. Following the completion of each dosing cohort, a safety and tolerability review will be conducted to determine the next tested dose. An outline of the trial is below. Topline data is expected in mid-2020.

The TRANQUILITY data is likely a bigger inflection point for the company than the SERENITY data was. We were very confident that the SERENITY data would be positive, and we were pleasantly surprised by just how positive it turned out to be. There is a bit more risk in the TRANQUILITY data as 1) the company will be testing lower doses of BXCL501 due to the older patient population in an effort to decrease potential side effects (although we note there is no limit to how high dosing can go as TRANQUILITY is a dose-ranging study); and 2) the placebo response is likely to be high in TRANQUILITY, which we base off of Axsome Therapeutics (AXSM) experience with AXS-05 in the treatment of Alzheimer’s disease agitation (38% reduction in CMAI and 57% response rate in placebo patients). However, the strong efficacy results and safety profile of BXCL501 in the SERENITY trials are positive indications heading into the TRANQUILITY data readout. In addition, the fact that similar positive results were seen in patients suffering from schizophrenia or bipolar disorder indicates that BXCL501 is likely to have an effect on agitation regardless of the patients’ underlying medical diagnosis.

Compassionate Use Program for BXCL501 to Treat Delirium in COVID-19 Patients

On July 9, 2020, BioXcel announced that the company has initiated a compassionate use program for BXCL501 to investigate its use in treating delirium in patients suffering from COVID-19 in the intensive care unit (ICU). There have been numerous reports in the media about COVID-19 patients suffering from delirium and agitation after having been admitted to the ICU, particularly in patients that were put on ventilators (see here and here). Treating delirium represents another large potential market opportunity and we look forward to updates from the company regarding the use of BXCL501 in COVID-19 patients.


With the positive results from the Phase 3 SERENITY trials we have increased our probability of approval, the potential peak market share for BXCL501 in agitated patients with schizophrenia or bipolar disorder, and the price per dose as we believe the drug’s attributes will allow for higher pricing than Adasuve®. We have also pushed out the first revenues for the drug until 2022 based on an NDA filing in the first quarter of 2021. These changes have resulted in an increase to our valuation to $118. We anxiously await the results of the Phase 1b/2 TRANQUILITY trial and note that positive results in that study are likely to cause a significant revaluation in the company’s shares.

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