Schizophrenia Pharmacology: Version 2.0

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September 26, 2024, turned out to be a paradigm-changing day for the treatment of individuals with schizophrenia. KarXT (Cobenfy) was approved by the US Food and Drug Administration (FDA) after a 15-year journey that started with a young scientist’s remarkable vision for developing a medication with the first new mechanism of action since 1954 to treat individuals with schizophrenia. The name KarXT defines the story: a small start-up company named Karuna Therapeutics, Inc, hypothesized that by combining 2 well-established molecules—xanomeline and trospium—brain circuits associated with schizophrenia could be modulated by a novel nondopaminergic mechanism to improve symptoms and have an entirely different pharmacology than all the other medications currently approved to treat schizophrenia that were developed over the past 70 years.

The Visionary

At age 27, Andrew Miller, who had just completed his chemical engineering doctorate, began to explore possible innovations for unmet needs in medicine. With no background in pharmacology or medicine, after much effort and investigation, Dr Miller became passionate about developing a new treatment for schizophrenia. Researching the existing literature on possible novel mechanisms of action, he identified an established model of treating cognitive and psychotic symptoms by agonizing 2 specific muscarinic cholinergic receptors (mAChRs) in the brain: M1 and M4. Back in the 1990s, Eli Lilly and Company studied xanomeline, a molecule that binds tightly to all 5 of the mAChRs and has significant agonism activity at the M1 and M4 receptors, as a possible treatment for cognitive function in Alzheimer disease. Significantly, xanomeline demonstrated improvement compared with placebo in cognitive function, and in an astounding and serendipitous finding, it also demonstrated improvements in psychotic symptoms in patients with Alzheimer disease. Subsequently, data from a study demonstrated improvement in psychosis and cognition in patients with schizophrenia. However, further development of xanomeline was abandoned due to the poor tolerability that is expected from a medication that agonizes the mAChRs in the peripheral nervous system, specifically nausea, vomiting, diarrhea, sweating, and salivation.

Thinking outside the metaphorical box, Dr Miller asked himself if adding an anticholinergic medication that could not cross the blood-brain barrier might just allow for the central M1 and M4 agonism while mitigating the peripheral mAChR adverse effects. Dr Miller and colleagues created a list of all existing candidate medication combinations, which numbered 7410. The first combination on that list was xanomeline and trospium—an anticholinergic medication the FDA approved in 2004 for overactive bladder. Dr Miller hypothesized that finding an optimal dosing combination of xanomeline and trospium could provide the central benefits for psychosis and cognition while minimizing the peripheral adverse events. The final obstacle in testing this hypothesis was a lack of financial resources, with only $4000 left in the bank account. At this point in the journey, Dr Miller was the only employee of Karuna, which was founded around the development of KarXT. He applied for funding from the Wellcome Trust, a philanthropic organization based in the United Kingdom, which awarded Karuna funding for the initial clinical trial with KarXT. With $5.5 million in hand, Dr Miller could assemble a team to investigate whether or not the xanomeline/trospium combination had a future in the treatment of individuals with schizophrenia.

KarXT Clinical Development

The phase 2 clinical trial, named EMERGENT-1, was a 5-week double-blind placebo-controlled trial of KarXT in individuals with schizophrenia experiencing a significant relapse of symptoms, with an average Positive and Negative Syndrome Scale (PANSS) total score of 97, which places these patients in the “markedly ill” category. At the end of 5 weeks, the least square mean (LSM) improvement in total PANSS score, the primary outcome, in the KarXT group was 11.6 points greater than in the placebo group, with an effect size of 0.81.¹ This robust outcome paved the way for 2 more identically designed phase 3 trials (EMERGENT-2 and -3), the findings of which demonstrated a similar improvement in the total PANSS score compared with placebo, as well as strong effect sizes (LSM improvements, 9.6 points and 8.4 points; effect sizes, 0.61 and 0.60, respectively).^2,3 Finally, 2 open-label, 52-week phase 3 studies designed to further assess the long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia were completed. Data from those studies, EMERGENT-4 and -5, supported the findings of the 5-week studies.^4,5

Not an Antipsychotic

Significantly, in the FDA product insert (PI), Cobenfy is defined as being “indicated for the treatment of schizophrenia in adults.”⁶ Throughout the PI, it is never referred to as an antipsychotic medication. This is notable, as the FDA has described all other medications currently approved to treat schizophrenia, from chlorpromazine (Thorazine) in 1954 to lumateperone (Caplyta) in 2019, as antipsychotics. A common property of all these antipsychotic medications is antagonism or antagonism/partial agonism of the dopamine-2 receptor (D2R), which has been hypothesized to be the mechanism that decreases the positive symptoms of schizophrenia, such as auditory hallucinations and delusions.

Schizophrenia has been well established as a syndrome with 3 primary symptom clusters—positive, negative, and cognitive symptoms. However, from 1954, when chlorpromazine became available in the United States, the treatment focus turned almost entirely to treatment of the positive symptoms because these responded to D2R blockade. Unfortunately, the antagonism of D2Rs in other parts of the brain comes at quite a cost, worsening the cognitive and negative symptoms (called secondary),⁷ muscle dystonia, akathisia, drug- induced parkinsonism, tardive dyskinesia, weight gain, sedation, prolactin elevation, neuroleptic malignant syndrome, and others. Cobenfy has not demonstrated any of these adverse events. It remains to be seen if Cobenfy improves cognitive and/or negative symptoms in schizophrenia. Additionally, Cobenfy has no boxed warnings from the FDA, and its adverse events, contraindications, warnings, and precautions documented in its PI are quite different from the antipsychotic medications we have been prescribing for the past 70 years. As a result, the prescriber has much to learn about this novel treatment option for individuals with schizophrenia. The interested reader can learn more about the putative mechanism of action of Cobenfy in reference 8.⁸

Adverse Events, Warnings

Both xanomeline and trospium target the muscarinic cholinergic system, albeit oppositional to each other. Xanomeline has a strong affinity to all 5 mAChRs but significantly agonizes only 2: the M1 and the M4. Its action at these 2 mAChRs in the brain is hypothesized to decrease presynaptic dopamine release in the circuits relevant to schizophrenia while not affecting the circuits involved in motor function or hormones. In the peripheral nervous system, xanomeline demonstrates the expected adverse effects of nausea, vomiting, diarrhea, hypersalivation, and sweating. Trospium, which poorly crosses the blood-brain barrier, has minimal effects on the central nervous system but mitigates the procholinergic adverse effects of xanomeline in the peripheral nervous system through its anticholinergic activity. Not surprisingly, the common adverse events result from either procholinergic or anticholinergic activity, demonstrating the delicate balance that results from optimally dosing these 2 opposing mechanisms. Table 1 lists the common adverse events of Cobenfy.

Table 1. Common Adverse Reactions to Cobenfy⁶

Xanomeline is extensively metabolized by the liver, and as a result, Cobenfy is contraindicated in the presence of moderate to severe hepatic impairment. CYP2D6 also metabolizes it, and the dose may need to be decreased in the presence of potent CYP2D6 inhibitors. Trospium, on the other hand, is minimally metabolized in the body, and approximately 90% of it is excreted unchanged in the urine. Hence Cobenfy is contraindicated in patients with urinary retention and is not recommended in patients with moderate to severe renal impairment. In these conditions, trospium serum levels are likely to increase, increasing the anticholinergic load. Table 2 lists the contraindications for Cobenfy.

Table 2. Contraindications of Cobenfy⁶

It is important to know about the presence of any other medication, prescribed or over the counter, that has anticholinergic activity. Benztropine, diphenhydramine, tricyclic antidepressants, clozapine, olanzapine, quetiapine, and chlorpromazine are some of the common medications our patients may be taking that have significant anticholinergic effects. Patients should be warned about the signs and symptoms of increased anticholinergic load.

It is crucial to instruct the patient to take Cobenfy on an empty stomach, either 1 hour before or 2 hours after a meal. Food will decrease the absorption of trospium and can lead to increased procholinergic adverse events from xanomeline. With half-lives of 5 hours for xanomeline and 6 hours for trospium, Cobenfy is prescribed twice a day, commonly upon awakening and at bedtime, to maximize adherence.

Before starting Cobenfy, liver function tests and a bilirubin level should be checked, as well as baseline heart rate. These should be monitored during treatment as clinically indicated. Prior to prescribing Cobenfy, the entire PI should be read and understood.

The Pipeline

Cobenfy is the first in a novel class of medications that provide a muscarinic cholinergic mechanism of action for the treatment of individuals with schizophrenia. Two other drug candidates with similar mechanisms have recently completed phase 2 clinical trials. Emraclidine, an M4-selective positive allosteric modulator, is being evaluated in 2 placebo-controlled phase 2 trials in schizophrenia, EMPOWER-1 and EMPOWER-2, as well as in a 52-week open-label safety extension study, EMPOWER-3; trial results are expected to be released in late 2024. NBI-1117568 is a highly selective M4 agonist for the potential treatment of adults with schizophrenia and was evaluated in a recently completed phase 2 study. If FDA approved, these 2 molecules will help us understand the role of M1 agonism in the treatment of adults with schizophrenia, as this property is unique to Cobenfy.

Concluding Thoughts

The medication treatment of schizophrenia has finally diversified to a novel neurotransmitter system, the muscarinic cholinergic system, with the FDA approval of Cobenfy on September 26, 2024. Our clinical experience with Cobenfy over the next several years will educate us on how this mechanism compares with the traditional blockade of D2Rs. Prescribers should familiarize themselves with all aspects of Cobenfy before using it, as it is a novel mechanism with important properties that are very different from the D2R antagonists. It is exciting and refreshing that after 70 years of domination by D2R antagonists, we have a novel neurotransmitter target for the treatment of individuals with schizophrenia.

Dr Miller is medical director of Brain Health in Exeter, New Hampshire; editor in chief of Psychiatric Times; staff psychiatrist at Seacoast Mental Health Center, Exeter; and consulting psychiatrist at the Insight Meditation Society in Barre, Massachusetts.

Dr Miller would like to disclose that he was on the Advisory Board for Karuna and is part of the Speakers’ Bureau for Bristol Myers Squibb.

References

1. Brannan SK, Sawchak S, Miller AC, et al. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;25;384(8):717-726.

2. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;13;403(10422):160-170.

3. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2024;81(8):749-756.

4. An extension study to assess long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia (EMERGENT-4). ClinicalTrials.gov. Updated November 29, 2023. Accessed October 14, 2024. https://clinicaltrials.gov/study/NCT04659174

5. An open-label study to assess the long-term safety, tolerability, and efficacy of KarXT in adult patients with schizophrenia (EMERGENT-5). ClinicalTrials.gov. Updated August 20, 2024. Accessed October 14, 2024. https://clinicaltrials.gov/study/NCT04820309

6. Cobenfy. Prescribing information. Bristol Myers Squibb; 2024. Accessed October 14, 2024. https://packageinserts.bms.com/pi/pi_cobenfy.pdf

7. Mosolov SN, Yaltonskaya PA. Primary and secondary negative symptoms in schizophrenia. Front Psychiatry. 2022;12:766692.

8. Miller JJ. Medication pipeline: schizophrenia and PTSD. Psychiatric Times. 2024;41(1).