Source – BioXcel Therapeutics
On June 29, 2023, a potential breakthrough in the treatment of agitation episodes in Alzheimer’s disease was overshadowed by protocol violations committed by a principal trial investigator. BioXCel, the company behind an orally dissolving formulation of dexmedetomidine (originally Pfizer’s Precedex), revealed Phase III trial data for its Alzheimer’s-related agitation treatment, but also disclosed serious missteps in a filing with the Securities and Exchange Commission (SEC).
During an FDA inspection of a trial site that enrolled approximately 40% of the study participants, three significant issues related to adherence to the trial’s framework were discovered. The investigator failed to follow the informed consent plan for four trial subjects, and there were instances where the investigative plan was not followed and adequate patient case histories were not maintained. Additionally, the principal investigator allegedly fabricated email correspondence regarding a serious adverse event from the placebo arm, falsely indicating that it had been reported in a timely manner and had received confirmation of receipt.
Upon discovering these irregularities in May, BioXCel promptly initiated an investigation, which confirmed the cover-up. Although the serious adverse event was entered into the data system within the required timeframe, it had not been reported to the correct authority, the pharmacovigilance safety vendor, within 24 hours. The company is still conducting its ongoing investigation, focusing on data integrity and protocol adherence at the site. It plans to secure an independent third party to audit the site’s data, which may reveal additional findings regarding the accuracy of the trial results and their suitability for marketing authorization.
“We believe these results represent a significant milestone for BioXcel Therapeutics and a potential important step forward in our goal to helping those impacted by Alzheimer’s disease. Today, there are approximately 100 million Alzheimer’s-related agitation episodes in the US annually, and there are no episodic treatment options for these patients. We believe that our data from TRANQUILITY II show that BXCL501 has the potential to treat acute episodes of agitation in patients with mild to moderate Alzheimer’s disease, if approved. This is particularly critical as the prevalence of this disease is expected to nearly double over the next 15 to 20 years. We are excited at the prospect of continuing to expand BXCL501’s market potential.”
– Vimal Mehta, CEO of BioXcel Therapeutics
In addition to the potential data inaccuracies, the Phase III trial also failed to meet a secondary endpoint. The study showed a 7.5 reduction from baseline on the Positive and Negative Syndrome Scale-Excitatory Component (PEC) score at two hours with a 60mg dose, compared to placebo’s 5.4. The drug demonstrated a reduction in agitation symptoms after 1 hour during the first episode, but did not show a change in the baseline PEC score at 30 minutes, which was a key secondary endpoint. The 40mg dose did not meet the primary endpoints, but the 60mg dose consistently reduced PEC scores with repeated dosing, demonstrating efficacy in all 443 treated episodes at I and II hours compared to placebo.
Although the situation may impact potential approval, BioXCel’s Chief Medical Officer, Robert Risinger, believes that the entire data set may not be rendered unusable. An analysis excluding data from the site in question still showed a similar positive efficacy effect, albeit with some differences. However, the news of the protocol violations led to a significant decline in the company’s shares, with a decrease of over 60%.
“I believe that the results from the TRANQUILITY II trial are an exciting development for potentially addressing Alzheimer’s disease-related agitation. In this trial, BXCL501 showed a desirable onset of action and a meaningful reduction in agitation at 2 hours with the 60 mcg dose, and was well tolerated in this patient population. I believe it has potential to be a new treatment option for a condition that not only impacts patients but also caregivers and families.”
– George Grossberg, M.D., Professor and Director Division of Geriatric Psychiatry in the Department of Psychiatry & Behavioral Neuroscience at St. Louis University School of Medicine
The treatment has been granted breakthrough designation and the company is working closely with the FDA on “every aspect of this trial, down to the nitty-gritty details,” Risinger said. BioXCel noted in its release that it plans to “develop a path” to potential filing during the second half of this year.
