5 schizophrenia candidates chase BMS' KarXT

A new era of schizophrenia treatment may be on the horizon as Bristol Myers Squibb awaits the FDA's decision on its recently acquired drug KarXT. If approved, KarXT would be the first novel approach for schizophrenia over several decades.

“We are on the verge of the first approval of a brand new, novel mechanism of action,” said Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity analyst at Mizuho Americas BioSpace.

Schizophrenia is a neuropsychiatric disorder that includes positive symptoms of psychosis as well as negative symptoms such as social withdrawal and lack of motivation as well as cognitive symptoms. It affects more than 3.5 million people in the US, with the treatment market expected to 7 billion US dollars by 2028, according to The Business Research Company.

The first generation of antipsychotics came on the market in the 1960s and 1970s, Suvannevejh said. Then came second-generation antipsychotics. Both work by attacking the dopamine and serotonin receptors, he explained.

KarXT, which is funded by the $14 billion Acquisition by Karuna Therapeutics in December 2023, belongs to a class called muscarinic receptor-acting modulators. Unlike existing schizophrenia treatments, KarXT does not block dopamine receptors directly. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism that has been shown to improve positive, negative, and cognitive symptoms in schizophrenia without the side effects associated with antipsychotics.

Antipsychotics can cause excessive sleepiness and weight gain, among other side effects, which can lead to discontinuation of treatment, Suvannevejh said. The muscarinic class, on the other hand, has shown “best-in-class efficacy” and “potentially best-in-class safety and tolerability. . . . Therefore, we believe there is a lot of pent-up demand for this new class of medication.”

Following KarXT in the schizophrenia pipeline are several drugs that target the positive, negative and cognitive symptoms of the disease via the muscarinic pathway and other pathways. BioSpace takes a closer look at five of these experimental therapies.

Neurocrine Biosciences

NBI-1117568

Recent results from a Phase II study of Neurocrine's NBI-1117568, an oral muscarinic M4-selective agonist, sparked further interest in the schizophrenia space – albeit without much recognition from investors.

Although the drug improved the symptoms of schizophrenia, this only happened at the lowest dose tested, Neurocrine. reported. Notably, NBI-1117568 met the study's primary endpoint of improving positive and negative symptoms of the psychiatric disorder at a dose of 20 mg after six weeks. The severity of the disorder was also improved at this dose. All other doses – 30 mg, 40 mg and 60 mg – did not meet the study's primary endpoint.

Investors were unimpressed, and the company's shares fell 20% after the results were announced, partly due to a lower Positive and Negative Syndrome Scale (PANSS) score than competitors.

Neurocrine plans to proceed with a Phase III trial in early 2025, according to a Press release Announcement of the results.

AbbVie

Emraclidine

Like KarXT and NBI-1117568, Emraclidine targets the M4 receptor. AbbVie came into possession of Emraclidin if it acquired Cerevel in December 2023 for $8.7 billion in a deal that closed August 1st.

Emraclidine is currently in Phase II developmentHowever, Suvannevejh said the trials were designed to be “potentially registration-relevant” because they are much larger than average Phase II trials.

“Based on the strong data we have seen with drugs like KarXT … I think the expectation [for emraclidine] is that you can also count on very good efficacy and, equally if not more importantly, very good safety and tolerability,” he added.

A Phase Ib study of emraclidine in adults with schizophrenia showed a “clinically meaningful and statistically significant improvement” in the PANSS total score after six weeks, according to a Press release Announcement of the publication of the study in The Lancet.

Reviva Pharma

Brilaroxazine

Reviva Pharmaceuticals is taking a different approach and developing brilaroxazine, a serotonin-dopamine signaling modulator for the treatment of schizophrenia.

“Schizophrenia is primarily caused by an imbalance of [the] serotonin and dopamine signaling cascade,” said Laxminarayan Bhat, Founder, President and CEO of Reviva, BioSpace. An effective treatment should balance the concentration of these neurochemicals by directly or indirectly modulating both the dopamine and serotonin signaling cascades, he explained. “The difference of our drug with respect to the dopamine signaling cascade is that we have a stronger activity for D4, [which is] “It is highly expressed in the frontal cortex” and is involved in the negative and cognitive symptoms of schizophrenia, Bhat said.

Revival announced Topline results from the pivotal Phase III RECOVER trial of brilaroxazine in October 2023. The treatment met the trial's primary endpoint, showing a “statistically significant and clinically meaningful” 10.1-point reduction in the PANSS total score compared to placebo after four weeks at a dose of 50 mg. According to Reviva, brilaroxazine at this dose also resulted in reductions in all key symptom domains and secondary endpoints. The drug was “generally well tolerated” and had a side effect profile comparable to placebo at both the 50 mg and 15 mg doses.

In April announced An agreement has been reached with the FDA for a Phase III program to approve brilaroxazine, where two positive four-week studies and a one-year safety study could support a New Drug Application. Topline data from a one-year open-label extension are expected in the fourth quarter of this year.

Boehringer Ingelheim

Iclepertin

Boehringer Ingelheim develops Subscribean inhibitor of glycine transporter 1 (GlyT1), for the treatment of cognitive symptoms associated with schizophrenia. GlyT1 It is believed to play an important role in regulating both inhibitory and excitatory neurotransmission.

Iclepertin is Boehringer's lead small molecule candidate for the treatment of schizophrenia – the company is also working on a digital therapeutic for negative symptoms – and is currently being studied in three large, randomized, controlled trials, with results expected in 2025, according to Mike Jablonski, vice president of clinical development and medical affairs at Boehringer.

The cognitive symptoms of schizophrenia, which include memory impairment, short attention span and forgetfulness, are “often overlooked,” Jablonski said. BioSpace. “Even if [the] Positive symptoms are controlled by taking antipsychotics, but cognitive symptoms are not treated by them,” he said, calling this a real unmet need.

Boehringer looked more closely at the topic of schizophrenia in March. Coloring a contract worth up to $732 million with Sosei Heptares (now Nxera Pharma) to treat the positive, negative and cognitive symptoms of the disease. Under this contract, the German multinational has the exclusive option to license Sosei Heptares' portfolio of GPR52 agonists.

Alto Neuroscience

ALTO-101

Alto Neuroscience is also targeting cognitive symptoms with ALTO-101, a novel inhibitor of phosphodiesterase 4 (PDE4) enzymes. Disorders in which may play a role in schizophrenia.

“PDE4 is an enzyme that degrades cAMP, an intracellular signaling molecule important for cognition and neuroplasticity that has long been of interest for its putative procognitive and antidepressant effects,” said Amit Etkin, founder and CEO of Alto, BioSpace in an email.

Alto launched a Phase II study of ALTO-101 in June 2024. The goal is to enroll approximately 70 people between the ages of 21 and 55 with schizophrenia and “demonstrable cognitive impairment.” Topline data are expected in the second half of 2025.

In a Phase I study, Alto said the candidate demonstrated positive effects on cognitive abilities and on electroencephalography (EEG) measures relevant to cognitive function. A transdermal formulation of ALTO-101 achieved greater systemic drug exposure than an oral version of the drug, the company reported. Transdermal ALTO-101 is being tested in the Phase II study.