Karuna's resurrection of Lilly drug delivers phase 3 schizophrenia success, teeing up 2023 filing

Karuna Therapeutics’ multi-year mission to resurrect an old Eli Lilly drug has ended in clinical success. The biotech has emerged from the phase 3 Emergent-2 trial with evidence showing its therapy works in schizophrenia, positioning it to seek FDA approval next year.

The clinical trial studied KarXT, a xanomeline formulation designed to address the problems that led Lilly to give up on the molecule despite generating evidence of efficacy. Lilly found the M1 agonist improved cognition in Alzheimer’s disease patients in the 1990s, only for tolerability to stop the program. Karuna sought to address the tolerability problems by giving xanomeline with a peripherally restricted molecule that blocks receptors at the root of the issues without crossing the blood-brain barrier to limit efficacy.  

Now, Karuna has evidence of the effectiveness of its approach. Investigators randomized 252 adults with schizophrenia and psychosis symptoms to receive KarXT or placebo orally twice a day for five weeks. At the end of the treatment period, participants on KarXT had experienced a 21.2 reduction on the Positive and Negative Syndrome Scale (PANSS), compared to an 11.6 reduction in the placebo cohort.

The 9.6-point placebo-adjusted improvement is in line with the phase 2 data that emboldened Karuna to move into the pivotal study, despite the biotech seeing a stronger response in the control group this time around. 

KarXT outperformed placebo in terms of both its effect on positive symptoms, such as hallucinations, and negative symptoms, such as difficulty enjoying life. On the PANSS positive and negative subscales, KarXT beat placebo by 2.9 points and 1.8 points, respectively. Both of the differences were statistically significant. 

On the tolerability front, KarXT performed comparably to placebo. The discontinuation rates because of treatment-emergent adverse events (TEAEs) in the KarXT and control arms were 7% and 6%, respectively. The rate of serious TEAEs was 2% in each cohort and none of those events were deemed to be related to the drug. The most common TEAEs in the KarXT arm were all mild to moderate in severity and included constipation, indigestion, nausea and vomiting.

With the first two studies in its Emergent clinical trial program hitting the mark, Karuna plans to file for FDA approval around the middle of next year. By then, the biotech should have topline data from a third clinical trial, Emergent-3, which is one of the three studies it is running to assess the acute efficacy and long-term safety of KarXT.

Karuna is on track to file for approval next year despite Russia’s invasion of Ukraine disrupting some of its activities. Emergent-2 only recruited at sites in the U.S. but the third clinical trial has 12 sites in Ukraine. Karuna has added U.S. sites since the invasion, helping it to keep its anticipated completion date despite the cessation of enrollment at the Ukraine centers.