5 Upcoming Schizophrenia Drugs Competitors for Newly Approved BMS’ KarXT (COBENFY)

After years of little progress in the field of schizophrenia drug treatment, Bristol Myers Squibb’s $14 billion acquisition of Karuna Therapeutics has paid off with the approval of a groundbreaking new drug. BMS’s novel medication, KarXT—now named COBENFY—received significant FDA approval on 26 September 2024 for the treatment of adults with schizophrenia. COBENFY is the first muscarinic agonist approved for schizophrenia, marking the first new treatment class for the condition since the FDA approved CLOZARIL (clozapine) 35 years ago.

Schizophrenia is a severe mental illness that impacts thinking, emotions, decision-making, and social interaction. Onset typically occurs in late teens to early 20s for men and late 20s to early 30s for women. As per DelveInsight analysis, in 2023 the total diagnosed prevalent cases of schizophrenia in the 7MM were found to be 3.8 million cases out of which the US accounted for nearly 1.4 million cases. It is anticipated that these numbers will rise by 2034 

The FDA approval of COBENFY is based on findings from the EMERGENT clinical program, which includes three placebo-controlled studies assessing efficacy and safety, along with two open-label trials focused on the drug’s long-term safety and tolerability over one year. In Phase III EMERGENT-2 and EMERGENT-3 trials, COBENFY achieved its primary goal by showing statistically significant reductions in schizophrenia symptoms compared to placebo, measured by the change in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to week five. 

Specifically, COBENFY resulted in a 9.6-point reduction (-21.2 for COBENFY vs. -11.6 for placebo, p<0.0001) in EMERGENT-2 and an 8.4-point reduction (-20.6 for COBENFY vs. -12.2 for placebo, p<0.0001) in EMERGENT-3. Additionally, in EMERGENT-2, COBENFY showed a statistically significant improvement in illness severity from baseline to week five, as measured by the Clinical Global Impression-Severity (CGI-S) score, a secondary endpoint.

Unlike older schizophrenia drugs that focus on dopamine receptors, COBENFY selectively affects the muscarinic receptors M1 and M4, which play roles in learning, memory, and cognition. In contrast to dopamine receptors, M1 and M4 receptors address both the positive symptoms of schizophrenia—such as hallucinations and delusions—as well as the negative symptoms, including diminished emotional expression, speech, motivation, and pleasure.

BMS intends to launch COBENFY in approximately a month, with the product anticipated to be available by late October. The approval of the schizophrenia drug COBENFY has also sparked competition among the pharma companies. 

Discover the latest innovations and updates in the schizophrenia treatment space

Several schizophrenia drugs targeting the positive, negative, and cognitive symptoms of schizophrenia through the muscarinic pathway, as well as other mechanisms, are trailing KarXT in the development pipeline. Let’s take an in-depth review of 5 of these upcoming schizophrenia drugs.

Reviva Pharmaceuticals’ Brilaroxazine

Brilaroxazine (RP5063) is a novel compound with strong affinity and selectivity for important serotonin and dopamine receptors involved in schizophrenia and other psychiatric conditions. It acts as a multimodal modulator for several serotonin receptors (5-HT1A, 5-HT2A, 5-HT2B, and 5-HT7) and dopamine receptors (D2, D3, and D4). Currently in clinical development for various neuropsychiatric indications, including schizophrenia, the company expects to release long-term data from its open-label extension (OLE) trial in the fourth quarter of 2024. 

Reviva Pharmaceuticals also plans to begin the Phase III registration trial, RECOVER-2, in the second quarter of 2024, with initial data anticipated in Q3 2025. Most non-clinical activities are completed, and preparations are underway for an NDA submission for brilaroxazine in schizophrenia, aimed for Q4 2025. Additionally, the drug is being studied for bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder, and various inflammatory conditions, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, and psoriasis.

Reviva Pharmaceuticals recently showcased the results of the RECOVER Phase III clinical trial for brilaroxazine in schizophrenia at the 2024 annual meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in Colorado, USA. The findings indicated that brilaroxazine successfully met all primary and secondary endpoints, demonstrating significant reductions in major symptoms associated with schizophrenia. In September 2024, Reviva Pharmaceuticals unveiled new vocal biomarker data from the Phase III RECOVER trial of brilaroxazine during a virtual event featuring key opinion leaders hosted by the company.

Boehringer Ingelheim’s Iclepertin

Iclepertin (BI 425809) is an experimental drug that functions as a glycine transporter 1 (GlyT1) inhibitor, specifically targeting brain mechanisms associated with cognitive symptoms in schizophrenia (CIAS). Disruptions in glutamatergic signaling following neuronal NMDA receptor activity are linked to cognitive deficits in both conditions. Enhancing NMDA receptor function may improve synaptic plasticity and cognitive abilities. 

Glycine, an amino acid neurotransmitter, acts as a necessary co-agonist for NMDA receptors. GlyT-1 and GlyT-2 transporters are found in presynaptic and astrocytic membranes, where they absorb glycine into nerve terminals and surrounding glial cells, thereby regulating glycine concentrations in the synaptic cleft. By inhibiting these transporters, BI 425809 is expected to elevate glycine levels and enhance NMDA receptor function. The US FDA has granted Iclepertin Breakthrough Therapy Designation.

This powerful and selective GlyT1 inhibitor, taken orally, is also being investigated for Alzheimer’s disease. However, the initial results from its Phase II trial in early 2020 did not support further development for this condition. As a result, the emphasis has now shifted to exploring the compound for schizophrenia. Currently, there are multiple Phase III clinical trials for Iclepertin (BI-425809) at various stages, including those that are recruiting and those that are active but not recruiting specifically for schizophrenia. 

Boehringer Ingelheim and Sosei Group Corporation have formed a global partnership and an exclusive option-to-license agreement to develop and commercialize Sosei Heptares’ innovative portfolio of GPR52 agonists, aiming to enhance patient outcomes by addressing positive, negative, and cognitive symptoms of schizophrenia concurrently.

Alto Neuroscience’s ALTO-101

ALTO-101 is an innovative small molecule PDE4 inhibitor being developed to address cognitive impairment linked to schizophrenia, a condition characterized by negative and cognitive symptoms that currently lack targeted treatment options. Utilizing a unique transdermal delivery system, ALTO-101 aims to maintain consistent drug concentrations, enhancing safety, tolerability, and pharmacokinetics. This specialized delivery system was developed in collaboration with MEDRx. 

In June 2024, Alto Neuroscience announced the start of a Phase II double-blind, placebo-controlled trial for its transdermal formulation of ALTO-101. The company anticipates releasing top-line results from this Phase 2 study in the latter half of 2025. Recently, Alto completed a Phase I trial of ALTO-101 involving healthy adults, which showed promising effects on cognitive performance and electroencephalography (EEG) metrics associated with cognitive function. Additionally, Alto’s innovative transdermal formulation of ALTO-101 provided higher systemic drug exposure compared to the oral version, while also resulting in fewer typical class-related side effects.

The announced Phase II study is a cross-over, double-blind, placebo-controlled trial that involves dose escalation of ALTO-101 and placebo in patients with Cognitive Impairment Associated with Schizophrenia. Alto aims to enroll about 70 adult participants aged 21 to 55 who have schizophrenia and exhibit a noticeable degree of cognitive impairment. The study will assess the impact of ALTO-101 on EEG markers related to cognitive function and will also investigate its effects on cognitive performance. The primary outcome measure is the influence of ALTO-101 on theta band activity, which will be evaluated using EEG after each dosing period.

Alto recently shared data at the Society of Biological Psychiatry (SOBP) Annual Meeting showing that theta band activity correlates most strongly with cognitive function in schizophrenia patients, compared to a wide range of EEG measures, and also exhibits the highest case-control sensitivity. These results, which were confirmed through prospective replication, validate the primary outcome measure being assessed in the current study, providing strong proof-of-concept for ALTO-101 as a potential treatment for CIAS.

Neurocrine Biosciences’ NBI-1117568

NBI-’568 is the first and only M4 selective orthosteric agonist currently in clinical development. Five muscarinic acetylcholine receptors play a role in neurotransmission. These muscarinic receptors are crucial for brain function and have been established as valid targets for drugs treating psychosis and cognitive disorders. As an M4 selective orthosteric agonist, NBI-’568 presents the potential for a new mechanism with an enhanced safety profile, eliminating the need for combination therapy to reduce off-target pharmacological side effects, and it does not rely on the presence of acetylcholine to be effective.

In August 2024, Neurocrine Biosciences reported encouraging top-line results from its Phase II clinical trial of NBI-1117568 (NBI-’568) in adults with schizophrenia. The NBI-’568-SCZ2028 dose-finding study achieved its primary objective with the once-daily 20 mg dose, showing a clinically meaningful and statistically significant decrease from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 6. This resulted in a placebo-adjusted mean reduction of 7.5 points (p=0.011, effect size of 0.61) and an overall reduction of 18.2 points from baseline. Additionally, the 20 mg dose exhibited significant improvements in other measures, such as the Clinical Global Impression of Severity (CGI-S) scale, Marder Factor Score for Positive Symptom Change, and Marder Factor Score for Negative Symptom Change.

NBI-’568 was found to be generally safe and well tolerated across all doses tested in the Phase II clinical trial. The rates of treatment discontinuation due to adverse events were comparable between NBI-’568 and the placebo group. The most commonly reported adverse events included somnolence, dizziness, and headache. Gastrointestinal issues such as nausea and constipation occurred infrequently and were similar to those in the placebo group. Cardiovascular-related events were also rare and were not considered clinically significant at any dose. NBI-’568 did not lead to a greater increase in weight compared to the placebo. Only a few instances of extrapyramidal symptoms were reported.

AbbVie’s Emraclidine

Similar to KarXT and NBI-1117568, emraclidine acts on the M4 receptor. AbbVie gained ownership of emraclidine through its $8.7 billion acquisition of Cerevel in December 2023, with the deal finalized on August 1, 2024.

Emraclidine is a positive allosteric modulator specifically designed to target the M4 muscarinic receptor subtype. Recent findings indicate that activating M4 muscarinic acetylcholine receptors can decrease striatal dopamine signaling and alleviate psychotic symptoms, without directly inhibiting dopamine receptors. Most current schizophrenia treatments work by directly antagonizing postsynaptic dopamine D2 receptors to reduce heightened striatal dopaminergic activity.

In December 2022, Cerevel Therapeutics announced the publication of data from its Phase Ib clinical trial of emraclidine, a novel muscarinic M4-selective positive allosteric modulator, in adults with schizophrenia, in The Lancet.

The trial evaluated two dosing regimens of emraclidine (30 mg once daily and 20 mg twice daily), both of which showed clinically significant and statistically meaningful improvements in symptom severity, as measured by the Positive and Negative Syndrome Scale (PANSS) total score. Emraclidine was also generally well-tolerated compared to placebo over the six-week treatment period. Currently, AbbVie is evaluating emraclidine in the phase II stage of development.

The expected launch of these schizophrenia drugs in the coming years will bring stiff competition in the space. Additionally, the future of schizophrenia treatment, with ongoing research and advancements in understanding disease mechanisms, is promising. Moreover, the development of novel therapies, such as those targeting neuroplasticity and inflammation in schizophrenic patients, is expected to revolutionize the market.