M4 receptor

iStock/ Evgeny Gromov As the FDA prepares to render a verdict on BMS’ closely watched schizophrenia drug, BioSpace takes a closer look at the late-stage pipeline for this neuropsychiatric disorder. A new era of schizophrenia treatment could be on the horizon as Bristol Myers Squibb awaits the FDA’s decision on the company’s recently acquired drug KarXT. If approved, KarXT would represent the first novel approach for schizophrenia in several decades. “What we’re on the cusp of is the first approval for a brand new, novel mechanism of action,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace . Schizophrenia is a neuropsychiatric disorder comprising positive symptoms relating to psychosis as well as negative symptoms such as social withdrawal and lack of motivation, in addition to cognitive symptoms. It affects more than 3.5 million people across the U.S., with the treatment market expected to top $7 billion by 2028, according to The Business Research Company. First-generation antipsychotics made their debut in the 1960s and 1970s, Suvannevejh said. They were then followed by second-generation antipsychotics. Both work by targeting the dopamine and serotonin receptors, he explained. KarXT, which came into BMS’ possession with the $14 billion acquisition of Karuna Therapeutics in December 2023, belongs to a class called muscarinic receptor acting modulators. Unlike existing schizophrenia treatments, KarXT does not directly block dopamine receptors. Instead, it works through the dual activation of the M1 and M4 muscarinic acetylcholine receptors in the central nervous system, a mechanism shown to improve positive, negative and cognitive symptoms in schizophrenia without the side effects associated with antipsychotics. Antipsychotics can induce excessive sleepiness and weight gain, among other adverse effects, which can lead to discontinuation, Suvannevejh said. The muscarinic class, on the other hand, has shown “best in class efficacy” and “potentially best in class safety and tolerability. . . . That’s why we think there is a lot of pent-up demand for this new class of drugs.” Following behind KarXT in the schizophrenia pipeline are several drugs targeting the positive, negative and cognitive symptoms of the disease via the muscarinic pathway and others. BioSpace takes a closer look at five of these investigational therapies. Neurocrine Biosciences NBI-1117568 A recent readout from a Phase II trial of Neurocrine’s NBI-1117568, an oral muscarinic M4 selective agonist, sparked further interest in the schizophrenia space—though few accolades from investors. While the candidate improved symptoms of schizophrenia, it did so only at the lowest dose tested, Neurocrine reported . Specifically, NBI-1117568 met the trial’s primary endpoint, improving the positive and negative symptoms of the psychiatric disease, at the 20-mg dose after six weeks. The severity of the disorder was also improved at this dose level. All other doses—30 mg, 40 mg and 60 mg—failed to meet the trial’s primary endpoint. Investors were unimpressed, and the company’s shares dropped 20% following the results, due partly to a lower Positive and Negative Syndrome Scale (PANSS) score than its competitors. Neurocrine plans to move forward with a Phase III trial in early 2025, according to a press release announcing the results. AbbVie Emraclidine Like KarXT and NBI-1117568, emraclidine targets the M4 receptor. AbbVie came into possession of emraclidine when it acquired Cerevel in December 2023 for $8.7 billion in a deal that closed Aug. 1. Emraclidine is currently in Phase II development . However, Suvannevejh said the studies have been designed as “potentially registrational” as they are much larger than average Phase II trials. “Because of the strong data we’ve seen with drugs like KarXT . . . I think the expectation [for emraclidine] is you should also expect to see very good efficacy and equally, if not more importantly, very good safety and tolerability,” he added. A Phase Ib trial of emraclidine in adults with schizophrenia demonstrated a “clinically meaningful and statistically significant improvement” in PANSS total score at six weeks, according to a press release announcing the trial’s publication in The Lancet . Reviva Pharmaceuticals Brilaroxazine Taking a different tack, Reviva Pharmaceuticals is developing brilaroxazine, a serotonin-dopamine signaling modulator, for schizophrenia. “Schizophrenia is primarily caused by imbalance of [the] serotonin and dopamine signaling cascade,” Laxminarayan Bhat, founder, president and CEO of Reviva, told BioSpace . An effective treatment is expected to balance the levels of these neurochemicals by directly or indirectly modulating both dopamine and serotonin signaling cascades, he explained. “The difference with our drug with respect to dopamine signaling cascade is we have more potent activity for D4, [which is] highly expressed in the frontal cortex” and implicated in the negative and cognitive symptoms of schizophrenia, Bhat said. Reviva 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 PANSS total score vs. placebo after four weeks when dosed at 50 mg. Brilaroxazine at this dose also elicited reductions in all major symptom domains and secondary endpoints, according to Reviva. The drug was “generally well-tolerated” with a side effect pro to placebo at both the 50 mg and 15 mg doses. In April, the company announced it had reached alignment with the FDA on a registrational Phase III program for brilaroxazine where two positive four-week studies plus a year-long 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 is developing iclepertin , a glycine transporter 1 (GlyT1) inhibitor, to treat the cognitive symptoms associated with schizophrenia. GlyT1 is thought to play an important role in regulating both inhibitory and excitatory neurotransmission. Iclepertin is Boehringer’s lead small molecule candidate for schizophrenia—the company is also working on a digital therapeutic for negative symptoms—and is currently being studied in three large, randomized, controlled studies, which are expected to read out in 2025, according to Mike Jablonski, vice president of clinical development and medical affairs at Boehringer. The cognitive symptoms of schizophrenia, which include poor memory, low attention span and forgetfulness, are “often overlooked,” Jablonski told BioSpace . “Even if [the] positive symptoms are controlled through antipsychotic utilization, that doesn’t address the cognitive symptoms,” he said, calling this a real unmet need. Boehringer delved deeper into the schizophrenia space in March, inking a deal worth up to $732 million with Sosei Heptares (now Nxera Pharma) to address the positive, negative and cognitive symptoms of the disease. Under this deal, 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, disruptions in which potentially play a role in schizophrenia. “PDE4 is an enzyme that breaks down cAMP, an intracellular signaling molecule important for cognition and neuroplasticity, which has long been of interest for its putative pro-cognitive and antidepressant effects,” Amit Etkin, founder and CEO of Alto, told BioSpace in an email. Alto kicked off a Phase II study of ALTO-101 in June 2024, intending to enroll approximately 70 individuals between 21 and 55 years of age with schizophrenia and “a demonstrable level of cognitive impairment.” Topline data are expected in the second half of 2025. In a Phase I study, the candidate demonstrated positive effects on cognition and electroencephalography (EEG) measures relevant to cognitive function, according to Alto. A transdermal formulation of ALTO-101 achieved greater systemic drug exposure than an oral version of the drug, the company reported. Transdermal ALTO-101 will be tested in the Phase II trial.

Plus, more news about Circle Pharma, Emergent, Cytokinetics, Nxera Pharma, Neurocrine Biosciences, Simcere Zaiming, TargetRx and Calliditas: Denali Therapeutics to seek accelerated approval in 2025: The decision to seek an expedited OK for its Hunter syndrome program, called DNL310, follows a years-long debate over whether heparan sulfate can serve as an effective surrogate biomarker for certain neurodegenerative diseases. Denali said that the FDA agreed that heparan sulfate levels in the cerebrospinal fluid are “reasonably likely to predict” a clinical benefit. Denali also plans to submit data on the neurofilament biomarker that Biogen used to get an ALS drug approved last year for certain genetic forms of the disease. Regenxbio, with whom Denali is competing in Hunter syndrome, is expected to launch a rolling submission for accelerated approval by the end of this month. — Max Gelman Jazz to launch $850M private offering: The offering , coming in the form of “exchangeable senior notes due in 2030,” will help pay down about $350 million of Jazz’s outstanding loans. — Max Gelman Circle Pharma closes $90M Series C: Circle said in July it was seeking to bring in $117 million when the company raised $54 million as part of its Series C round. The money will be used to fund Circle’s cyclin A/B RxL inhibitor, CID-078, in various tumor types. — Max Gelman Emergent BioSolutions gets $250M loan: The money from Oak Hill Advisors is being used to repay the remaining outstanding loan that Emergent took out in 2018. Emergent’s debt is expected to be reduced by about $200 million by the end of this year, CEO Joe Papa said in a statement. Its stock $EBS was down about 9% on Tuesday morning. — Max Gelman Cytokinetics touts more Phase 3 data for aficamten: In the open-label FOREST-HCM trial, a subgroup of 59 hypertrophic cardiomyopathy patients taking aficamten successfully scaled down their standard of care medication, which is defined as a minimum 50% dose reduction in at least one drug from baseline, according to results presented Sunday at the European Society of Cardiology’s annual meeting. Cytokinetics is currently preparing regulatory filings for the cardiac myosin inhibitor. — Ayisha Sharma Nxera Pharma gets $35M payment from Neurocrine Biosciences: Completing the Phase 2 trial for its candidate in adults with schizophrenia triggered the payment for Nxera, previously known as Sosei Heptares. The trial met the primary endpoint, and Nxera plans to move the muscarinic M4 selective agonist into Phase 3 trials next year. — Katherine Lewin Simcere Zaiming pays $20M to TargetRx for cancer asset: The oncology-focused biopharma is giving $20 million to Shenzhen TargetRx for commercial rights to a Phase 1 antitumor small molecule candidate in China. Simcere will gain marketing rights to TGRX-326 as well as other benefits and will compensate TargetRx for helping to promote the drug. — Anna Brown Calliditas Therapeutics will delist following purchase by Asahi Kasei: Asahi now owns more than 90% of the company’s outstanding shares per its offer to purchase all shares of the Stockholm-based company. The delisting of the American shares is expected to occur around Sept. 23. — Katherine Lewin

2 September 2024 – Nxera Pharma Co., Ltd. (“Nxera” or “the Company”; TSE 4565) – formerly known as Sosei Group or Sosei Heptares – announces that it will receive a US$35 million payment from Neurocrine Biosciences (‘Neurocrine’), triggered by the successful completion of the Phase 2 trial with NBI-1117568 (NBI-‘568) in adults with schizophrenia, as announced on 28 August 2024. Receipt of the US$35 million payment will be recognized as one-time revenue in the third quarter of 2024. The NBI-’568-SCZ2028 dose-finding study met its primary endpoint for the once-daily 20 mg dose and was generally safe and well tolerated at all doses studied, supporting Neurocrine’s intentions to advance NBI-‘568 into Phase 3 clinical trials in early 2025. Please refer to “Nxera Pharma Notes Positive Phase 2 Data for Partnered Schizophrenia Candidate NBI-1117568” dated 28 August 2024 for the full announcement from Nxera on the positive data from the trial. NBI-’568 is the first oral, muscarinic M4 selective agonist in development for the treatment of schizophrenia. The candidate is the most advanced from a broad portfolio of novel clinical and preclinical subtype-selective muscarinic M4, M1 and dual M1/M4 receptor agonists discovered by Nxera and advancing under a 2021 global collaboration with Neurocrine for the treatment of major neurological and neuropsychiatric disorders. To date, Nxera has received multiple, significant payments from Neurocrine including those based on developmental progress of four candidates in clinical trials. Overall, Nxera is eligible to receive up to US$1.5 billion in development milestone payments through to approvals, plus commercial milestones, which together total up to US$2.6 billion, plus product royalties, provided the criteria under the agreement are satisfied. Nxera retains rights to develop M1 agonists advancing under this collaboration in Japan in all indications, subject to certain exceptions. Matt Barnes, EVP, President of Nxera Pharma UK and Head of R&D, commented: “The successful Phase 2 trial with NBI-‘568 delivered positive data in adults with schizophrenia at the 20mg dose. As stated by Neurocrine, these data support advancing NBI-‘568 into Phase 3 trials that would aim to confirm its potential to become a new oral therapy option for patients with a competitive profile based on efficacy, safety and tolerability from a convenient 20mg once-daily administration.” Nxera Pharma and Neurocrine entered a collaboration and licensing agreement in November 2021 to develop a portfolio of novel muscarinic receptor agonists for the treatment of schizophrenia, dementia and other neuropsychiatric disorders. Under the terms of the agreement, Neurocrine gained development and commercialization rights to a broad portfolio of novel clinical and preclinical subtype-selective muscarinic M4, M1 and dual M1/M4 receptor agonists discovered by Nxera. Neurocrine is responsible for development costs associated with the programs globally, except for M1 agonists being developed in Japan. Nxera retains rights to develop M1 agonists in Japan for any indication, subject to certain exceptions, with Neurocrine receiving co-development and profit share options. Nxera is eligible to receive R&D funding plus development, regulatory and commercial milestones of up to US$2.6 billion, with further product royalties, provided the criteria under the agreement are satisfied. The four candidates progressing from the partnership are: About Nxera PharmaNxera Pharma (formerly Sosei Heptares) is a technology powered biopharma company, in pursuit of new specialty medicines to improve the lives of patients with unmet needs in Japan and globally. In addition to several products being commercialized in Japan, we are advancing an extensive pipeline of over 30 active programs from discovery through to late clinical stage internally and in partnership with leading pharma and biotech companies. This pipeline is focused on addressing major unmet needs in some of the fastest-growing areas of medicine across neurology, GI and immunology, metabolic disorders and rare diseases, and leverages the power of our unique and industry leading GPCR-targeted structure-based drug discovery “NxWaveTM” platform to provide a sustainable source of best- or first-in-class candidates. Nxera employs over 350 talented people at key locations in Tokyo and Osaka (Japan), London and Cambridge (UK), Basel (Switzerland) and Seoul (South Korea) and is listed on the Tokyo Stock Exchange (ticker: 4565). The content above comes from the network. if any infringement, please contact us to modify.