Much Ado About Something: Why There’s Excitement Behind Novel Mechanism of Action in Schizophrenia

CLINICAL CONVERSATIONS

Sam Clark, MD, PhD

Later this month, the US Food and Drug Administration is scheduled to share results of the New Drug Application for Bristol Myers Squibb’s KarXT for the treatment of schizophrenia; the acceptance of the NDA was announced last year. As the date approaches, there is a growing sense of optimism for the drug and its novel mechanism of action, which could be the next breakthrough in the treatment of schizophrenia.

As Psychiatric Times continues its comprehensive coverage, we spoke with Sam Clark, MD, PhD, founder and chief executive officer of Terran Biosciences, about the drug, its novel mechanism of action, and what this approval could mean for psychiatry.

Psychiatric Times: Can you explain the significance of muscarinic receptors in the pathophysiology of schizophrenia?

Sam Clark, MD, PhD: Schizophrenia has a complicated pathophysiology affecting multiple receptor systems. Glutamate is one of the primary neurotransmitters in the brain and its signaling is modulated by other neurotransmitters. Patients with schizophrenia have shown dysfunction in dopamine, a neurotransmitter that modulates glutamate. However, the acetylcholine neurotransmitter system, which binds to muscarinic receptors (including M1 and M4), also plays a role in modulating glutamate, dopamine, and other neurotransmitters.¹ Postmortem studies have shown reduced levels of M1 receptors in the brain cortex of patients with schizophrenia² and it has been hypothesized that activation of M1 receptors may improve cognitive dysfunction while activation of M4 receptors may improve psychotic symptoms.³ Importantly, xanomeline, the active ingredient in KarXT, activates both the M1 and M4 receptors and thus may represent a uniquely effective therapeutic.

Psychiatric Times: How does this novel mechanism of action impact the adverse effect profile?

Sam Clark, MD, PhD: Remarkably, KarXT has not shown the severe adverse effects that have been seen with other traditional antipsychotics. Traditional antipsychotics directly affect the dopamine system by binding to the dopamine type 2 receptor, which can lead to adverse effects on the motor system related to dysfunction in dopaminergic signaling. These symptoms of motor dysfunction, known as extrapyramidal side effects, include disorders such as tardive dyskinesia. KarXT has also been shown to lack some of the other side effects seen with traditional antipsychotics such as endocrine dysfunction leading to increases in prolactin and metabolic dysfunction and weight gain.

The adverse effect profile of KarXT is related to its peripheral cholinergic effects rather than the primarily dopaminergic side effects seen with typical antipsychotics. Because of this differentiated safety profile, patients who may be at risk for metabolic disorders or suffer from movement disorders such as dyskinesias may be good candidates for KarXT.

Psychiatric Times: KarXT is a combination of 2 agents, one specifically designed to reduce the adverse effects of the other. Can you explain how that works?

Sam Clark, MD, PhD: KarXT is a combination of xanomeline tartrate and trospium chloride. The beneficial effects of KarXT in schizophrenia are due to the ability of xanomeline to activate the muscarinic M1 and M4 receptors in the brain. However, muscarinic receptors are also present outside the brain in the peripheral nervous system, where activation can lead to gastrointestinal side effects.

To fix this, KarXT contains a second drug, trospium chloride, which is unable to cross the blood brain barrier and blocks the muscarinic receptors in the peripheral nervous system. The addition of trospium to xanomeline essentially cancels out xanomeline’s effects in the peripheral nervous system while allowing it to exert its beneficial effects on the brain.

Psychiatric Times: Adherence is always an important issue for patients with schizophrenia. What do the studies say about adherence rates for KarXT? LAIs have grown in popularity due to their convenience and impact on adherence. Do you surmise a twice daily medication will be of enough interest to patients and clinicians?

Sam Clark, MD, PhD: As a drug that needs to be dosed twice daily, KarXT presents a unique challenge. The leading antipsychotics currently on the market are dosed once daily and most also have a long acting injectable (LAI) form. Some of the most successful antipsychotics, such as aripiprazole (Abilify) and paliperidone (Invega), were later improved over their initial forms by taking a prodrug approach to enable the longer acting forms. In these cases, the prodrug approach involves modifying the molecules to create an inactive form that has improved absorption into the body, and once absorbed, is modified by enzymes in the blood back to its active form.

Although adherence to KarXT was generally good in the highly controlled clinical studies, we don’t have enough information yet on use in the real world, which often presents new challenges not completely captured in the controlled clinical trial setting. Due to KarXT’s unique first-in-class mechanism and differentiated safety profile, I believe that there will be significant interest in the drug, especially for patients who have tried many other medications without success.

To truly address the patients’ needs in the real world, I believe there is a need for a longer acting, once-daily oral version and an LAI version. TerXT is a combination of novel optimized prodrugs of xanomeline and trospium, which is designed to improve the patient experience and adherence through once-daily dosing and long-acting injection (LAI) options.

Psychiatric Times: What are you most excited about if KarXT gets approved and why?

Sam Clark, MD, PhD: KarXT represents the first new mechanism for schizophrenia in over 50 years. We hope an approval of this first-generation muscarinic modulator KarXT will open the door to further innovation and other follow-on breakthroughs.

Xanomeline and trospium are older compounds first invented in the 1990s and 1960s, respectively, and so there is room to improve the dosing protocol. With the approval of KarXT, we hope TerXT will be able to reference the promising safety and efficacy data generated with KarXT via the FDA’s 505(b)(2) accelerated regulatory pathway to bring an improved version to patients much more quickly than the typical industry standard.

Psychiatric Times: Is there anything else you want to share with readers regarding the upcoming FDA decision?

Sam Clark, MD, PhD: We expect that KarXT is the first of many such new approvals in the schizophrenia space over the next few years. Currently, no singular therapy is able to fully cure schizophrenia, but each new innovation and new drug mechanism brings us closer to that goal.

In the end, patients simply need access to safe, effective, and affordable medications that are easy for them to use. That has been our goal since day one at Terran, and as we develop our novel schizophrenia therapeutics, we are proud to be playing a role in the growing renaissance in psychiatry.

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References

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

2. Dean B, McLeod M, Keriakous D, McKenzie J, Scarr E. Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2002;7(10):1083-1091.

3. Dean B, Scarr E. Muscarinic M1 and M4 receptors: Hypothesis driven drug development for schizophrenia. Psychiatry Res. 2020;288:112989.