Investigational therapy may be effective for amygdala-driven mental health conditions

Key takeaways:

• BI-1358894 was tested in five phase 1 clinical trials and found to be safe and well-tolerated.
• The mechanism of action reduced hyperreactivity in the amygdala in response to negative stimuli.

MIAMI BEACH, Fla. — An emerging investigational therapeutic may be effective while being safe and generally well-tolerated for the treatment of mental health conditions driven by activity in the amygdala, according to research presented here.

“The amygdala is a crucial regulator of our emotional responses to our environment,” Brittney Starling, PharmD, director of clinical development and medical affairs at Boehringer Ingelheim Pharmaceuticals Inc., said in a presentation at the American Society of Clinical Psychopharmacology annual meeting. “Hyperreactivity contributes to anxiety, stress reactivity and mood disorders.”

Starling and colleagues sought to examine the safety, tolerability and pharmacokinetic profile of BI-1358894, an investigational therapeutic that may offer a novel mechanism of moderating amygdala hyperreactivity to improve regulation of emotions and reduce key symptoms of certain mental health conditions.

They conducted five randomized phase 1 studies of BI-1358894 at doses no higher than 200 mg, including a single blind trial of ascending doses including 87 individuals (24 healthy male volunteers) depending on feeding or fasting, a double-blind, 14-day trial with 50 healthy male volunteers, a single-dose trial of 100 mg of the novel therapeutic, 20 mg citalopram or placebo in 73 individuals with major depressive disorder asked to complete functional MRI faces and scene tasks, a double-blind, parallel-group, single-rising dose trial (50 mg, 100 mg and 200 mg) of 24 healthy Japanese male volunteers, and a pharmacodynamic examination of once-daily 100 mg dose of BI-1358894 in 20 healthy male participants after administration of cholecystokinin tetrapeptide (CCK-4) to induce symptoms consistent with those of panic or anxiety.

The researchers reported that BI-1358894 was generally well-tolerated across all studies, with headache, dizziness and fatigue the most frequently reported adverse events. Pharmacokinetic analyses indicated that exposure increased dose-dependently, but less than dose-proportionally, after single doses in the fed state and multiple doses in the fasted state.

Researchers found that, compared with placebo, BI-1358894 significantly reduced both physiological and psychological responses to CCK-4 measured by the Panic Symptom Scale and the Emotional Faces Visual Analog scale, indicating target engagement and functional mechanistic effects.

Additionally, the fMRI study in those with MDD showed BI-1358894 attenuated activity in the amygdala when the participants took part in a task that required them to viewed negative emotional faces and scenes.

“BI-1358894 significantly reduced amygdala activation in response to negative stimuli, suggesting a potentially useful mechanism of action with a wide range of possible applications,” Starling said.