Statistically significant, clinically meaningful, rapid and durable reductions in agitation achieved with the 60 mcg dose as measured by multiple agitation scales
BXCL501 was well tolerated with no severe or serious adverse events
Results provide a clear path toward initiating a pivotal program for BXCL501 in dementia
Agitation associated with dementia affects an estimated 4 million patients in the
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The TRANQUILITY Phase 1b/2 randomized, placebo controlled, adaptive, ascending dose finding study enrolled 54 patients in assisted living facilities with agitation related to dementia, 87 percent of which had Alzheimer’s disease. Patients received BXCL501 at either 30 mcg (n=16), 60 mcg (n=20), 90 mcg (n=4) or placebo (n=14). The study’s primary safety and tolerability endpoints were met, with no severe or serious adverse events reported. Adverse events in the trial included hypotension (10%, 0% and 0%, for 60 mcg, 30 mcg and placebo, respectively), orthostatic hypotension (5%, 6.3% and 0%, respectively) and dizziness (5%, 6.3% and 0%, respectively). The most common adverse event was somnolence characterized as either mild (55% for 60 mcg, 50% for 30 mcg and 7.1% for placebo) or moderate (5%, 0% and 0%, respectively). Orthostasis and dizziness were observed in some patients receiving the highest 90 mcg dose. Higher exposure levels of BXCL501 were observed in this elderly patient population compared to earlier trials and, as a result, the Company focused on studying the 30 and 60 mcg doses. Notably, there were no reported cases of syncope or falls in any of the patients studied.
The trial met its secondary efficacy endpoints with the 60 mcg dose compared to placebo in all three primary agitation scales—the Positive and Negative Syndrome Scale-Excitatory Component (“PEC”), the Pittsburgh Agitation Scale (“PAS”), and the Modified Cohen-Mansfield Agitation Inventory (“Mod-CMAI”)—demonstrating statistically significant and clinically meaningful reductions in total scores at two hours post-dosing. The reductions were both rapid and durable with numerical separation from placebo in PEC total score seen as early as 30 minutes, and with statistically significant separation from placebo in both PEC and PAS total scores observed at 60 minutes* and lasting through eight hours post-dosing. The 30 mcg dose cohort showed numerical improvements at all three measures.
Outcomes from the PEC, PAS, and Mod-CMAI for the 60 mcg, 30 mcg and placebo cohorts are below.
Summary of Topline Efficacy Results at 120 Minutes
60 mcg (n=20) | 30 mcg (n=16) | Placebo (n=14) | ||||
Reduction in PEC Total Score vs. Baseline | -7.1 (P=0.0011) | -5.4 (P=0.0813) | -2.9 | |||
Response Rate (% of Patients Achieving >40% Reduction in PEC Scores) | 70 | % | 25 | % | 7% | |
Reduction in PAS Total Score vs. Baseline | -5.9 (P<0.0001) | -3.9 (P=0.0961) | -2.5 | |||
Reduction in Mod-CMAI Total Score vs. Baseline* | -14.0 (P<0.0001) | -8.0 (P=0.0591) | -3.2 |
* Mod-CMAI was not measured at 60 minutes
Efficacy was further evaluated using two additional measures of agitation-— the Agitation and Calmness Evaluation Scale (“ACES”; P=0.0006) and Clinical Global Impression – Improvement Scale (“CGI-I”; P<0.0001; 90% responder rate)—each of which showed statistically significant improvements in ratings with the 60 mcg dose level compared to placebo at two hours post-dosing. The 30 mcg dose cohort showed numerically greater rates of clinical response versus placebo.
“We are very encouraged by the promising topline results from the TRANQUILITY study, which was designed to identify a recommended dose of BXCL501 for a potential pivotal study in dementia patients suffering from agitation. Following decades of research, there are still no effective treatments that directly target agitation commonly seen with dementia patients, and we are thrilled by the potential of being the first to develop a therapy designed to address this significant patient and caregiver need,” said
About TRANQUILITY
The randomized, double-blind, placebo-controlled, ascending dose, adaptive Phase 1b/2 study was designed to evaluate the efficacy, pharmacokinetics, safety, and tolerability of BXCL501 in adults 65 years and older who exhibit acute agitation associated with all forms of dementia, including Alzheimer's disease. Following the completion of each dose cohort, a safety and tolerability review was performed to determine the next tested dose. The study is designed to assess agitation as measured by the changes from baseline in PAS and PEC total scores, as well as by improvements from baseline in the Mod-CMAI total score.
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About Agitation Associated with Dementia
Dementia is a neurocognitive condition caused by damage to brain cells that leads to a decline in cognitive abilities and independent function. It affects approximately 6 million individuals in
About the Positive and Negative Syndrome Scale-Excitatory Component Score (PEC or PANSS-EC)
The PEC total score is a validated endpoint for measuring acute agitation in schizophrenia and bipolar patients. This scale is used in clinical research to quantify the severity of a patient’s acute agitation. The PEC rating evaluates 5 elements associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). The PEC total score is the sum of these 5 elements and thus ranges from 5 to 35.
About the Pittsburgh Agitation Scale (PAS)
PAS is a validated instrument used to monitor the severity of agitation associated with dementia. The PAS measures 4 behavior groups: aberrant vocalization, motor agitation, aggressiveness, and resisting to care. The groups are evaluated on a scale from 0 to 4, with 0 defined as no agitation present and 4 defined as the highest form of agitation. The PAS total score ranges from 0 to 16.
Modified Cohen-Mansfield Agitation Inventory (Mod-CMAI)
Mod-CMAI is an inventory consisting of 29 behaviors, each rated on a 7-point scale of frequency with 1 defined as never occurring and 7 defined as several times an hour. Only behaviors manifested by the subject at baseline were assessed throughout the study.
About BXCL501
BXCL501 is an investigational, proprietary, orally dissolving thin film formulation of dexmedetomidine, a selective alpha-2a receptor agonist for the treatment of agitation and opioid withdrawal symptoms.
Forward-Looking Statements
This press release includes “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release include but are not limited to the timing and data from clinical development initiatives and trials for BXCL501, dialogue with the FDA and the future development of BXCL501, and the Company’s corporate strategy. When used herein, words including “anticipate,” “being,” “will,” “plan,” “may,” “continue,” and similar expressions are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance, or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon
These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While
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Source: BioXcel Therapeutics
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