5 Competitors Targeting BMS’ KarXT

As the FDA readies itself to make a ruling on Bristol Myers Squibb's potential breakthrough schizophrenia medication, KarXT, a new chapter in treating this complex disorder may be on the cusp of unfolding. If approved, KarXT could be the first innovative treatment for schizophrenia in decades, providing hope for patients and a new direction for therapeutic approaches.

Schizophrenia, a neuropsychiatric condition, involves a range of symptoms: positive symptoms like psychosis, negative symptoms such as social withdrawal and lack of motivation, and cognitive impairments. Affecting over 3.5 million individuals in the U.S., the market for schizophrenia treatments is projected to exceed $7 billion by 2028, highlighting the significant need for advancements in this field.

Historically, schizophrenia treatment has relied on antipsychotics developed in the 1960s and 1970s, which primarily target dopamine and serotonin receptors. First-generation antipsychotics were followed by second-generation drugs, both of which have been essential in managing the disorder but often come with considerable side effects.

KarXT, which Bristol Myers Squibb acquired through a $14 billion purchase of Karuna Therapeutics in December 2023, represents a novel class of drugs called muscarinic receptor acting modulators. Unlike traditional antipsychotics, KarXT does not directly block dopamine receptors. Instead, it activates the M1 and M4 muscarinic acetylcholine receptors in the central nervous system. This mechanism has shown promise in improving all three symptom domains of schizophrenia—positive, negative, and cognitive—while potentially avoiding the common adverse effects like excessive sleepiness and weight gain.

The muscarinic class, where KarXT belongs, has demonstrated strong efficacy and a favorable safety profile, fueling optimism for its approval. This has created a pent-up demand for such innovative treatments in the schizophrenia space.

Following KarXT, several other drugs are in development, targeting the same symptom domains via different pathways. Neurocrine Biosciences' NBI-1117568, an oral muscarinic M4 selective agonist, recently showed symptom improvement in a Phase II trial, though only at the lowest dose tested. Despite mixed investor reactions, the company plans to proceed with a Phase III trial in early 2025.

Similarly, AbbVie's emraclidine, targeting the M4 receptor, is in Phase II development. Acquired through an $8.7 billion deal with Cerevel that closed in August 2023, emraclidine has shown significant improvement in PANSS total scores in a Phase Ib trial. These studies are designed to be potentially registrational, given their large scale.

Reviva Pharmaceuticals is taking a different approach with brilaroxazine, a serotonin-dopamine signaling modulator. According to Laxminarayan Bhat, Reviva’s CEO, balancing serotonin and dopamine levels is crucial for treating schizophrenia. Brilaroxazine has shown a significant reduction in PANSS total scores in a Phase III trial, meeting its primary endpoint. The drug was well-tolerated, with further studies planned in alignment with FDA requirements.

Boehringer Ingelheim is focusing on cognitive symptoms with iclepertin, a glycine transporter 1 inhibitor. The company is conducting three large-scale studies expected to yield results by 2025. Addressing cognitive symptoms, often overlooked by traditional treatments, represents a significant unmet need.

Additionally, Boehringer made a significant deal in March, worth up to $732 million, with Sosei Heptares to develop treatments for the full spectrum of schizophrenia symptoms using GPR52 agonists.

Alto Neuroscience is also targeting cognitive impairments with ALTO-101, a phosphodiesterase 4 inhibitor. This enzyme is linked to cognition and neuroplasticity. Alto initiated a Phase II study in June 2024, looking to enroll around 70 individuals with schizophrenia and cognitive deficits. Initial data are anticipated in late 2025.

In summary, the landscape of schizophrenia treatment is poised for potentially transformative changes with these advanced therapies in development. As these drugs progress through clinical trials, they offer hope for more effective and safer treatment options for millions living with this challenging disorder.