The drug candidate at the center of AbbVie’s $8.7 billion acquisition of Cerevel Therapeutics has failed a pair of phase 2 trials, dealing a blow to the program and a boost to rival Bristol Myers Squibb.
The concept of using M4-selective positive allosteric modulators to treat schizophrenia looked de-risked by the time AbbVie made its play for Cerevel 11 months ago. By then, Karuna Therapeutics had reported phase 3 data on KarXT, a drug that contains an M4 modulator, in the disease and was on its way to winning approval and attracting a $14 billion buyout bid from BMS
Yet, AbbVie’s emraclidine has floundered where Karuna prospered. AbbVie’s phase 2 trials tested emraclidine as a once-daily, oral monotherapy in adults with schizophrenia experiencing an acute exacerbation of psychotic symptoms.
Both trials missed their primary endpoints. The studies compared the change in the Positive and Negative Syndrome Scale (PANSS) total score, a measure of schizophrenia symptoms, after six weeks of receiving placebo or one of two doses of emraclidine.
In the first trial, AbbVie tracked numerically bigger reductions in PANSS scores, 14.7 and 16.5 points, in the emraclidine arms than in the placebo group, 13.5 points. However, the difference fell short of statistical significance. In the second trial, placebo beat one of the two emraclidine doses numerically, racking up a 16.1-point improvement compared to the 14.2-point reduction in the treatment group.
Emraclidine performed worse than in Cerevel’s phase 1b trial, when the biotech tracked improvements on PANSS of 19.5 and 17.9 points, but placebo response was the main difference between the studies. In the phase 1b trial, patients on placebo improved by 6.8 points after six weeks. A high placebo response has sunk many neuroscience prospects, but AbbVie believed Cerevel had mitigated the risk.
On an earnings call last month, Roopal Thakkar, M.D., chief scientific officer at AbbVie, said the potential for efficacy to erode was a major focus during due diligence on the Cerevel takeover. AbbVie concluded the biotech had countered the risk by limiting the number of countries and sites, performing central review for eligibility criteria, training, certifying and recertifying raters and monitoring blinded data.
“What we observed was, we would say, a good control, or at least the best one could do to manage placebo responses,” Thakkar said. “The effect size that we did see in the phase 1b was a little over 12 points, so we think that was a strong separation. Even if that were to go down a little bit, we still feel that based on the safety profile and tolerability profile, this could still be very, very competitive.”
AbbVie is now analyzing the data to determine the next steps, but the likelihood of emraclidine being at all competitive has taken a major hit. Two share prices tell the story this morning—AbbVie’s stock plunged 12%, while BMS’ jumped 11%.
With emraclidine on the ropes, AbbVie highlighted the fact the Cerevel acquisition also included multiple clinical-stage and preclinical candidates. One of the candidates, Parkinson’s disease prospect tavapadon, hit the primary endpoint in phase 3 recently.