AbbVie’s schizophrenia candidate fails in two phase 2 trials
AbbVie acquired Cerevel Therapeutics and the rights to emraclidine in a US$8.7 billion deal announced in December last year.
When AbbVie acquired Cerevel, emraclidine was in the process of being tested in two phase 2 trials called EMPOWER-1 and EMPOWER-2. These results of these trials were announced this week and neither trial met its primary endpoint of a statistically significant reduction in the Positive and Negative Syndrome Scale (PANSS) total score compared to the placebo group at week 6.
The two trials were similar but tested a slightly different dosing strategy. EMPOWER-1 enrolled 379 and EMPOWER-2 373 patients with schizophrenia who were experiencing an acute exacerbation. The participants were then randomly assigned in a 1:1:1 fashion into the placebo, 10mg/day or 30mg/day groups in EMPOWER-1 and placebo, 15mg/day or 30mg/day groups in EMPOWER-2.
In EMPOWER-1 the reductions in the PANSS score were slightly greater in the 10mg/day and 30mg/day groups at 14.7 and 16.5, respectively, than in the placebo group, which had a reduction of 13.5 points, but the difference was not significant.
In EMPOWER-2, the placebo group had a reduction of 16.1 points versus 18.5 and 14.2 points in the 15mg/day and 30 mg/day groups, respectively. Similar to EMPOWER-1, the additional reduction in the 15mg/day group versus placebo was not significant.
Side effects were low in both trials and emraclidine was generally well tolerated with headache, dry mouth and indigestion being the most common adverse effects.
"While we are disappointed with the results, we are continuing to analyze the data to determine next steps," said Roopal Thakkar, executive vice president, research and development, chief scientific officer, AbbVie.
"We would like to extend our gratitude to the study participants and their loved ones as well as to our network of clinical investigative sites for their participation in these trials. We are confident that our innovative pipeline will continue to bring meaningful therapies to patients, and we remain committed to finding better treatments for people living with psychiatric and neurological disorders."
The emraclidine trial program is also supposed to include a 52-week open label extension trial EMPOWER-3 to assess the efficacy of emraclidine in stable schizophrenia patients not experiencing acute exacerbation of psychotic symptoms, but AbbVie did not comment on its status.
With emraclidine now unlikely to reach the market, AbbVie will be hoping that Cerevel’s other assets fare better. One asset, tapavadon, for treatment of Parkinson’s disease has already succeeded with a positive phase 3 readout in September.
A new treatment pathway for schizophrenia
First-generation anti-psychotics block the dopamine type two receptor. The second generation also do the same thing, but also trigger the serotonin 2A receptor. While that can be effective for stopping hallucinations, it causes a lot of adverse effects. For example, acting on dopamine receptors can cause Parkinsonian-like motor symptoms called extra pyramidal side effects. Antipsychotics can also cause weight gain, metabolic dysfunction, and hormonal problems.
Activating muscarinic receptors in the brain can help schizophrenia symptoms. Emraclidine acts on the muscarinic acetylcholine receptor M4 subtype and is highly selective for only that receptor, which could explain the drop in efficacy seen in these trials. Cobenfy also acts through the muscarinic system through its active constituent xanomeline, but xanomeline is less selective and acts on all five muscarinic acetylcholine receptor subtypes with most affinity for M1 and M4.
Activating muscarinic receptors outside of the brain can cause intestinal side effects.
Due to xanomeline being non-specific, it is combined with another drug called trospium, which blocks the muscarinic receptors outside the brain. Xanomeline and trospium cancel each other out outside of the brain, and inside the brain, xanomeline helps schizophrenia symptoms, as shown by Cobenfy’s recent approval.
