An investigational therapy, BNC210, for post-traumatic stress disorder (PTSD) has shown promising results in a recent phase IIb trial, demonstrating improved symptom severity as early as one month into the 12-week study. The trial, involving 182 patients, revealed that BNC210, a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, had a significant impact compared to placebo.
Early and Sustained Symptom Improvement
According to Spyridon Papapetropoulos, MD, PhD, of Bionomics, and colleagues, treatment effects with BNC210 were observed as early as week 4, with a least squares mean difference of -4.11 based on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). The overall improvement in symptom severity scores at week 12 versus placebo was notable (LSMD -4.03, Cohen's d effect size 0.40, P = 0.048), as reported in NEJM Evidence. These findings were simultaneously presented at the American College of Neuropsychopharmacology annual meeting in Phoenix.
Limitations and Adverse Events
The study authors acknowledged limitations, including the short treatment period and a higher rate of early trial discontinuation in the BNC210 group (46.2%) compared to the placebo group (37.7%), primarily due to adverse events (AEs). This may have introduced bias, despite efforts to correct for missing data. It remains to be seen if the 4-week onset of improvement can be replicated in future trials. Nevertheless, the trial achieved its primary and several secondary endpoints, highlighting the potential of BNC210 to improve key symptoms experienced by patients with PTSD.
Unmet Needs in PTSD Treatment
Existing treatment options for PTSD are limited, with no new pharmacological treatments approved in over 20 years. Current FDA-approved treatments like sertraline and paroxetine (SSRIs) offer only modest efficacy and come with adverse effects such as delayed onset, potential for induced anxiety, discontinuation syndrome, and sexual dysfunction. Less than 50% of patients with PTSD show a beneficial response to these treatments, and only 20-30% achieve remission, underscoring the need for new and more effective treatment options.
Trial Details and Patient Population
The ATTUNE trial, conducted at 28 sites in the U.S. and seven in the U.K. between July 2021 and April 2023, involved a patient population with a mean age of 42.3, predominantly white females. The mean time since the trauma event was 101.9 months, with physical assault (20.1%) and sexual assault (17.7%) being the most common index trauma events. The mean CAPS-5 total score was 41.5.
Patients were randomly assigned 1:1 to receive either a 900-mg dose of BNC210 twice daily or a placebo. Efficacy assessments were completed every 4 weeks, and safety assessments every 2 weeks, with a final follow-up visit at week 15.
Additional Benefits and Adverse Effects
Patients treated with BNC210 also experienced reduced depressive symptoms (LSMD -3.19 on the Montgomery-Åsberg Depression Rating Scale) and improved sleep disorder symptoms (LSMD -2.19 on the Insomnia Severity Index) compared to placebo. However, treatment-emergent AEs occurred in 66.7% of the BNC210 group and 53.8% of the placebo group. Common AEs included nausea, fatigue, hepatic enzyme elevations, and headache. Discontinuation rates due to AEs and loss to follow-up were higher in the BNC210 group (19.8% vs 12.3%).
Future Directions
Bionomics, the developer of BNC210, announced in July 2024 that the FDA had granted the agent fast track designation for PTSD and social anxiety disorder. A planned phase III trial will evaluate two dose levels of BNC210 in a 12-week randomized, double-blind, placebo-controlled trial with a 52-week open-label extension.
