KarXT: PDUFA Date Approaches for Potential Treatment for Schizophrenia

CLINICAL CONVERSATIONS

The US Food and Drug Administration will issue a response by September 26, 2024, to the New Drug Application for Bristol Myers Squibb and Karuna Therapeutic’s highly-anticipated schizophrenia drug, KarXT. In advance of this decision, Psychiatric Times sat down with experts like Gil Lichtshein, MD, to learn more about how mental health clinicians feel about this possible treatment.

Psychiatric Times: There has been much excitement about the potential approval of KarXT for the treatment of schizophrenia. Why should clinicians care about this agent? What are you most excited about regarding this agent?

Gil Lichtshein, MD: This could be a very important development. First, it is essential to note that postmortem studies show lower levels of M1 and M4 receptor expression in brain regions implicated in schizophrenia.¹ Additionally, 25% of patients with schizophrenia have greater than 75% fewer M1 receptors than healthy patients.² M1/M4 receptor knockout models replicate the phenotype of schizophrenia in mice, and muscarinic agonists, especially for M4, improve positive and negative symptoms of schizophrenia in mice and humans.³

This is where xanomeline-trospium (KarXT) comes in. Xanomeline is a muscarinic M1/M4 agonist that improved Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome (PANSS) scores in patients with schizophrenia. While gastrointestinal adverse effects limited further clinical development, ultimately, the addition of trospium made xanomeline-trospium viable. Trospium is a muscarinic receptor antagonist that has minimal, if any, penetration of the blood brain barrier, blocking unwanted peripheral cholinergic adverse effects of xanomeline.

PT: How does the unique mechanism of action of KarXT, targeting muscarinic receptors, impact the positive and negative symptoms of schizophrenia?

Lichtshein: In terms of efficacy advantages, the effect sizes of xanomeline-trospium for symptom reduction are as high or higher than agents approved for schizophrenia in the past 25 years, and have been replicated in 3 clinical trials.

In terms of tolerability, there are no metabolic, endocrine, or motor adverse effects. Xanomeline-trospium does require titration in the first week to mitigate its pro-cholinergic adverse effects. As to practical issues, concurrent use of centrally acting anticholinergics (eg, benztropine) and possibly strongly anticholinergic antipsychotics (eg, olanzapine) can interfere with the mechanism of action for muscarinic agonists or positive allosteric modulators. Since KarXT has much less motor adverse effects, the need for use of centrally acting anticholinergics would be less likely.

PT: How might the approval of KarXT influence the current guidelines for schizophrenia treatment, and where do you see it fitting in the treatment algorithm?

Lichtshein: Muscarinic agents may be considered first-line treatments along with standard serotonin/dopamine antagonists. They certainly will be options in patients who have not responded to 1 or 2 serotonin/dopamine antagonists and could undoubtedly improve patients who have not done well on current atypical antipsychotics.

PT: If approved, what practical advice would you give to clinicians who are considering including KarXT in their treatment plans for patients with schizophrenia?

Lichtshein: This is what I do with new medications: I try to learn as much as I can about any new medicines by attending conferences or doing CME articles and understanding the positives and negatives of any new medication, what it is indicated for, and how it could be best utilized in treating patients. In this case, treating patients with schizophrenia, I may consider M1 M4 muscarinic agents as first-line treatments. I might use them initially in new patients with schizophrenia given their more benign adverse effect profile as the potential development of metabolic syndrome is a significant concern and patients with schizophrenia are already at an increased risk of developing metabolic syndrome.

PT: If approved, what types of patients do you think will benefit the most from this agent?

Lichtshein: Once approved, I believe that these types of medications will potentially benefit patients who have not responded to standard, atypical antipsychotics and ones who are being considered for clozapine as a potential option before choosing the route of clozapine.

PT: You recently attended a conference where this agent was being discussed. What was the sense from your colleagues about it? What did you take away from that discussion?

Lichtshein: I attended a conference on psychopharmacology at the University of Cincinnati about 1 year ago, and they were very excited about discussing muscarinic agents and the treatment of schizophrenia, which provides some shift in the treatment focusing away from dopaminergic agents to cholinergic agents.

PT: Is there anything else you want to share with your colleagues?

Lichtshein: This is exciting because it provides another treatment option for patients who are not responding to atypical antipsychotics, and many atypical psychotics cause weight gain and increase the risk for metabolic syndrome and KarXT as reduced risk for weight gain and subsequent development of metabolic syndrome.

The main feature of the M1 M4 muscarinic agents is that they modulate dopaminergic activity without causing motor or metabolic adverse effects.

PT: Thank you!

Dr Lichtshein is a board-certified psychiatrist in Boca Raton, Florida.

References

1. Scarr E, Hopper S, Vos V, et al. Low levels of muscarinic M1 receptor–positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia. J Psychiatry Neurosci. 2018;43(5):338-346.

2. Money TT, Scarr E, Udawela M, et al. Treating schizophrenia: novel targets for the cholinergic system. CNS Neurol Disord Drug Targets. 2010;9(2)241-256.

3. Foster DJ, Bryant ZK, Conn PJ. Targeting muscarinic receptors to treat schizophrenia. Behav Brain Res. 2021;405:113201.