Effects of Iclepertin on the QT Interval Following Oral Administration in Healthy Male and Female Subjects (a Double-blind, Randomised, Placebo-controlled, Multiple-dose, Parallel Group With Nested Crossover Design Trial, With Moxifloxacin as Positive Control)

This study aims to evaluate the effects of iclepertin in the range of therapeutic to supra-therapeutic exposures on the (QT/QTc): Electrocardiogram (ECG) time interval from the start of the QRS complex (ECG time interval) to the end of the T wave / QT interval corrected for heart rate, e.g. using the method of Fridericia or Bazett interval and other ECG parameters.

Start Date25 Jan 2024

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT05731895 / CompletedPhase 1

Pharmacokinetics, Safety and Tolerability of BI 425809 (Iclepertin) Following Oral Administration in Male and Female Participants With Different Degrees of Hepatic Impairment (Child-Pugh Classification A and B) Compared With Matched Male and Female Participants With Normal Hepatic Function (an Open-label, Non-randomised, Single-dose, Parallel, Individualmatched Design Trial)

This study is open to people with and without liver problems. People can join the study if they are 18 to 79 years of age and have a body mass index (BMI) between 18.5 and 35 kg/m2.
Iclepertin (also called BI 425809) is a medicine that is being developed to treat diseases of the brain. The purpose of this study is to find out whether having liver problems influences how iclepertin is taken up in the body. All participants take iclepertin once as a tablet.
Participants are in the study for 2 to 3 weeks. During the first part of the study, they stay at the study site for 4 nights. Afterwards, there are 5 visits to the study site and 1 call. The site staff measures the amount of iclepertin in the blood. The doctors also regularly check participants' health and take note of any unwanted effects.

Start Date08 Mar 2023

Sponsor / Collaborator

Boehringer Ingelheim GmbH

NCT05723874 / CompletedPhase 1

The Effect of Multiple Oral Doses of Bosentan on the Steady State Kinetics of BI 425809 After Oral Administration to Healthy Male Subjects (an Open-label, Two-period Fixed Sequence Trial)

The main objective of this trial is to investigate the relative bioavailability of BI 425809 given alone (Reference) compared to a combined administration with the moderate CYP3A4 inducer bosentan (Test) following repeated oral administration.

Start Date06 Mar 2023

Sponsor / Collaborator

Boehringer Ingelheim GmbH

100 Clinical Results associated with Iclepertin

100 Translational Medicine associated with Iclepertin

100 Patents (Medical) associated with Iclepertin

Literatures (Medical) associated with Iclepertin

01 Jan 2025·BIOLOGICAL PSYCHIATRY

Finding the Right Dose: NMDA Receptor–Modulating Treatments for Cognitive and Plasticity Deficits in Schizophrenia and the Role of Pharmacodynamic Target Engagement

Review

Author: Sehatpour, Pejman ; Kantrowitz, Joshua T. ; Kantrowitz, Joshua T

Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are among the leading causes of disability in schizophrenia. Despite this, there are no Food and Drug Administration-approved treatments for CIAS, and the development of treatments has been limited by numerous phase 2/3 failures of compounds that showed initial promise in small-scale studies. NMDA-type glutamate receptors (NMDARs) have been proposed to play an important role in schizophrenia; moreover, the NMDAR has a well-characterized role in cognition, learning, and neuroplasticity. We review previously published clinical trials in CIAS that focused on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We use this discussion of previous studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in phase 3. A range of direct and indirect NMDAR modulators are covered, including D-serine, D-cycloserine, memantine, and glycine and first-generation glycine transport inhibitors (e.g., sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel glycine transport inhibitor, and luvadaxistat, a D-amino acid oxidase inhibitor that increases brain D-serine levels, and indirect noninvasive brain stimulation NMDAR-modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery are emphasized, including the mismatch negativity, auditory steady state, and time-frequency event-related potential approaches.

01 Sep 2024·PHARMACOPSYCHIATRY

Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments

Review

Author: Hart, Xenia ; Hori, Satoko ; Takahashi, Yuna ; Komatsu, Yuki ; Ueno, Fumihiko ; Takehara, Moe ; Uchida, Hiroyuki

Abstract:

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia.

01 Nov 2023·Journal of labelled compounds & radiopharmaceuticals

Stable isotope synthesis of glycine transporter 1 inhibitor Iclepertin (BI 425809) and its major metabolites

Article

Author: Latli, Bachir ; Lee, Heewon ; Chevliakov, Maxim ; Hrapchak, Matt J ; Frutos, Rogelio P ; Samankumara, Lalith P

Stable isotope labeled Iclepertin (BI 425809, 1) and its major metabolites are needed as internal standards in bioanalytical studies. BI 425809 consists of two main building blocks, 5‐methylsulfonyl‐2‐[(1R)‐2,2,2‐trifluoro‐1‐methyl‐ethoxy]benzoic acid (2) and 3‐[(1R,5R)‐3‐azabicyclo[3.1.0]hexan‐5‐yl]‐5‐(trifluoromethyl)isoxazole (3) linked to each other via an amide bond. We used fluoro[13C6]benzene as the starting material in the preparation of [13C6]‐2. This intermediate was then employed to access carbon 13 labeled Iclepertin ([13C6]‐1) and other metabolites. The major metabolite BI 761036 (6), which resulted from cytochrome P450 oxidation and amide hydrolysis of BI 425809, was prepared labeled with carbon 13 and nitrogen 15 via two synthetic routes. In the first route, diethyl [13C3]malonate, [13C]methyl iodide, and hydroxyl[15N]amine were used to provide [13C4,15N]‐BI 761036 ([13C4,15N]‐6a) in 13 steps in 6% overall yield, whereas in the second route, [13C3]propargyl alcohol, potassium [13C]cyanide, and [15N]ammonia were used to furnish [13C4,15N]‐BI 761036 ([13C4,15N]‐6b) in 11 steps in 1% overall yield. The detailed stable isotope synthesis of 1 and its major metabolites is described.

News (Medical) associated with Iclepertin

23 Sep 2024

·www.biospace.com

5 Schizophrenia Candidates Chasing BMS’ KarXT

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.

Clinical ResultPhase 2Phase 3AcquisitionPhase 1

26 Aug 2024

·www.prnewswire.com

Schizophrenia Market: RISVAN's Approval Has Sparked a Competitive Race Among Pharmaceutical Companies | DelveInsight

The recent approval of Rovi Pharmaceuticals Laboratories' OKEDI/RISVAN (risperidone ISM) has spiked the competition among the other pharmaceutical companies that are developing novel therapies to improve the treatment landscape. RISVAN has the potential to become a blockbuster drug. LAS VEGAS, Aug. 26, 2024 /PRNewswire/ -- Schizophrenia is a severe mental illness affecting about 1% of Americans, cognitive functions, emotional responses, decision-making, and social interaction. Onset typically occurs in late teens to early 20s for men and late 20s to early 30s for women. Currently, as per the WHO, the vast majority of schizophrenia patients around the world are not receiving mental health care. Approximately 50% of people in mental hospitals have a schizophrenia diagnosis, and only 31.3% of people with psychosis receive specialist mental health care. As per DelveInsight analysis, in 2023 the total diagnosed prevalent cases of schizophrenia in the 7MM were found to be approximately 4 million cases out of which the US accounted for nearly 1.5 million cases. It is anticipated that these numbers will rise by 2034 due to several factors, including population growth, improved diagnostic techniques, increased awareness, and reduced stigma around mental health issues prompting more individuals to seek diagnosis, and potentially, environmental stressors contributing to a higher occurrence of the disorder. Schizophrenia treatment involves a blend of medication, psychological counseling, and social support. However, nearly one-third of patients do not respond sufficiently to standard treatments. Relapses, characterized by psychotic symptoms and functional impairments, are significant. Schizophrenia treatment mainly consists of antipsychotic medications that target dopamine neurotransmitters. Second-generation medications are favored because they lower the risk of severe side effects. Long-acting injectable antipsychotics can enhance adherence and improve treatment outcomes. High-dose regimens of specific medications may be advantageous for patients with severe, treatment-resistant schizophrenia. Additionally, hospitalization and electroconvulsive therapy might be necessary for patients who do not respond to medication therapy or during severe episodes. First-generation antipsychotics like chlorpromazine, fluphenazine, haloperidol, and perphenazine are effective in treating positive symptoms such as hallucinations and delusions but do not alleviate negative symptoms or cognitive impairments. Second-generation antipsychotics, including REXULTI/RXULTI (brexpiprazole), CAPLYTA (lumateperone), LATUDA (lurasidone hydrochloride), SAPHRIS (asenapine), ABILIFY MYCITE (aripiprazole tablets with sensor), VRAYLAR/REAGILA (cariprazine), SECUADO (asenapine), INVEGA SUSTENNA/TRINZA/HAYFERA (paliperidone palmitate), ARISTADA/ARISTADA INITIO (aripiprazole lauroxil), PERSERIS (risperidone), FANAPT (iloperidone), and LYBALVI (olanzapine and samidorphan), were developed to address both positive and negative symptoms, as well as cognitive symptoms. Although these medications typically have fewer extrapyramidal side effects, they can cause weight gain, sexual dysfunction, and other metabolic disorders. Additionally, elderly patients using FGAs and SGAs are at an increased risk of developing pneumonia. Learn more about the FDA-approved schizophrenia drugs @ Drugs for Schizophrenia Treatment REXULTI (brexpiprazole) is an oral tablet available in strengths from 0.25 mg to 4 mg, containing various inactive ingredients. While its exact mechanism of action is not fully understood, it work as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at serotonin 5-HT2A receptors. REXULTI was first approved in the US in July 2015 for use in adults with MDD and schizophrenia. In January 2022, it received FDA approval for pediatric patients aged 13–17. The EMA approved it in July 2018, and Japan approved it in tablet form in January 2018 and as an oral-disintegrating dose in August 2021. Generic versions of REXULTI have now been approved, which may affect its market presence. Janssen Pharmaceutical's INVEGA SUSTENNA/INVEGA TRINZA/INVEGA HAFYERA (paliperidone palmitate) is an SGA agent that seems to act as a D2 partial agonist and a 5-HT-2A receptor antagonist. INVEGA SUSTENNA is administered monthly, INVEGA TRINZA every three months, and INVEGA HAFYERA twice yearly. Paliperidone is a benzisoxazole derivative. In the EU and Japan, INVEGA SUSTENNA is marketed as XEPLION. In the EU, INVEGA TRINZA is sold as TREVICTA, and in Japan as XEPLION TRI. INVEGA HAFYERA is a long-acting injectable treatment administered in the upper buttocks every six months, providing continuous treatment and symptom control over this period. Additionally, the recent approval of RISVAN (Risperidone ISM) has intensified the competition in the schizophrenia treatment space. Risperidone ISM is a long-acting injectable antipsychotic created and patented by ROVI for treating schizophrenia in adults. From the first injection, it delivers immediate and sustained plasma drug levels without the need for loading doses or additional oral risperidone. This approval is based on the positive outcomes of the pivotal PRISMA-3 study, which assessed the efficacy and safety of Risperidone ISM in patients with schizophrenia. The study's findings demonstrate that the two doses tested (75 mg and 100 mg administered once monthly) successfully met the predetermined primary and secondary efficacy endpoints for treating patients with moderate to severe schizophrenia symptoms. Furthermore, OKEDI (risperidone ISM) was launched in Germany, the UK, and Spain in 2022. The approval was based on the positive results of the pivotal PRISMA-3 study on the efficacy and safety of risperidone ISM in schizophrenia patients. As per the estimates by Delveinsight analysts, this drug has blockbuster potential in the schizophrenia market with medium-fast uptake. To know more about schizophrenia treatment options, visit @ New Treatment for Schizophrenia The schizophrenia market is crowded with so many companies working in the domain. Various potential therapies that are projected to enter during the forecast period include Boehringer Ingelheim's Iclepertin (BI-425809), Sumitomo Pharma/Otsuka's Ulotaront (SEP-363856), Reviva Pharmaceuticals' Brilaroxazine (RP5063), Minerva Neurosciences/Mitsubishi Tanabe Pharma's Roluperidone (MIN-101/MT-210), Karuna Therapeutics (Bristol Myers Squibb)/Royalty Pharma's KarXT (xanomeline-trospium), ACADIA Pharmaceuticals' NUPLAZID (pimavanserin), Teva Pharmaceutical/MedinCell/Royalty Pharma's Olanzapine LAI (mdc-TJK/TV-44749), Neurocrine Biosciences/Mitsubishi Tanabe Pharma's Valbenazine (NBI-98854), Lyndra Therapeutics' LYN-005 (long-acting oral risperidone), Newron Pharmaceuticals' Evenamide (NW-3509), Luye Pharma's LY03010 (ER paliperidone palmitate), and others. Discover which therapies are expected to grab major schizophrenia market share @ Schizophrenia Market Report Iclepertin (BI 425809) is an investigational drug and a glycine transporter 1 (GlyT1) inhibitor aimed at addressing the brain biology related to cognitive symptoms in schizophrenia (CIAS). Abnormalities in glutamatergic signaling downstream of neuronal NMDA receptors contribute to cognitive impairment in this condition. Enhancing NMDA receptor function could potentially improve synaptic plasticity and cognition. Glycine, an essential NMDA receptor co-agonist, is modulated by glycine transporters GlyT-1 and GlyT-2, which are located in presynaptic and astrocyte membranes. These transporters regulate glycine levels by taking it up into nerve terminals and adjacent glial cells, affecting synaptic cleft glycine concentration. By inhibiting these transporters, BI 425809 aims to increase glycine levels, thereby modulating NMDA receptor function. Administered orally, this potent and selective GlyT1 inhibitor is also under investigation for Alzheimer's disease. However, early 2020 Phase II trial results did not support its continued development for this indication, and the focus has now shifted to schizophrenia, with multiple Phase III trials currently underway. Since schizophrenia, patients frequently ignore certain symptoms, such as cognitive impairment. Therefore, if approved, BI-425809 will be the first approved pharmacotherapy for the treatment of CIAS. Ulotaront (SEP-363856), developed by Sumitomo Pharma and Otsuka Pharmaceuticals, is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity. It is a small-molecule oral agent that does not bind to dopamine D2 or serotonin 5-HT2A receptors. Sunovion discovered Ulotaront in collaboration with PsychoGenics using the in vivo phenotypic SmartCube platform and associated artificial intelligence algorithms. Ulotaront is currently in late-stage development for schizophrenia and generalized anxiety disorder (GAD) in Japan and as an adjunctive treatment for major depressive disorder, schizophrenia, and GAD in the US. Top-line results from Phase III DIAMOND 1 and DIAMOND 2 trials in schizophrenia have been released, but the Phase III DIAMOND 3 trial in the US has been halted. Sumitomo Pharma has also stopped a Phase III trial for schizophrenia in Japan and another Phase II/III trial in China, Japan, Taiwan, and the Philippines, citing business strategy reasons. Despite this, two Phase III trials are still ongoing. Recently, Otsuka and Sumitomo revised their licensing agreement, excluding SEP-4199 and SEP-378614. Under this revision, Otsuka gained exclusive rights from SMPA to develop, manufacture, and commercialize ulotaront worldwide. If Otsuka successfully develops and commercializes ulotaront, they will pay up to 30 million USD (approximately 4.5 billion yen) in milestones, along with royalties based on sales, without any upfront payment. Starting January 2024, Otsuka will cover the full cost of studies conducted by both Sumitomo Pharma Group and Otsuka, except for certain studies. KarXT (xanomeline–trospium) is an oral modulator targeting muscarinic receptors found in both the central nervous system (CNS) and various peripheral tissues. This proprietary product combines xanomeline, a novel muscarinic agonist, with trospium, an approved muscarinic antagonist, to preferentially stimulate muscarinic receptors in the CNS. As a dual M1/M4 muscarinic acetylcholine receptor agonist, KarXT aims to improve the positive, negative, and cognitive symptoms of schizophrenia. The US FDA has accepted Karuna Therapeutics' NDA for KarXT for adult schizophrenia treatment, with a PDUFA date of September 26, 2024. Additionally, KarXT is undergoing multiple Phase III trials as an adjunctive treatment with standard-of-care agents for schizophrenia and is being evaluated for psychosis treatment in Alzheimer's disease patients. Following Bristol Myers Squibb's acquisition of Karuna Therapeutics, Karuna is now a wholly-owned subsidiary of BMS. At the Annual Congress of the Schizophrenia International Research Society (SIRS) in April 2024 in Italy, BMS presented promising results from the latest interim analysis of the Phase III EMERGENT-4 open-label extension trial, showing KarXT's efficacy in reducing symptoms in adults with schizophrenia. BMS plans to continue discussions with the US FDA and will release more data from the EMERGENT program later this year. Discover more about drugs for schizophrenia in development @ Schizophrenia Clinical Trials The anticipated launch of these emerging therapies for schizophrenia are poised to transform the market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the schizophrenia market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. DelveInsight estimates that the market size for schizophrenia is expected to grow from USD 2.6 billion in 2023 with a significant CAGR by 2034. This growth can be attributed to the introduction of upcoming therapies and the rising prevalence of the disease. The anticipated launch of these therapies is also expected to attract new entrants to the Schizophrenia market, resulting in increased competition and innovation. DelveInsight's latest published market report titled as Schizophrenia Market Insight, Epidemiology, and Market Forecast – 2034 will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the schizophrenia country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The schizophrenia market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Prevalent Cases of Schizophrenia Total Diagnosed Prevalent Cases of Schizophrenia Gender-specific Diagnosed Prevalent Cases of Schizophrenia Severity-specific Diagnosed Prevalent Cases of Schizophrenia The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM schizophrenia market. Highlights include: 11-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this schizophrenia market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the schizophrenia market. Also, stay abreast of the mitigating factors to improve your market position in the schizophrenia therapeutic space. Related Reports Schizophrenia Pipeline Schizophrenia Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key schizophrenia companies, including Otsuka Pharmaceutical Development & Commercialization, Inc., Gedeon Richter Ltd., Lyndra Therapeutics, Neurocrine Bioscience, Takeda Pharmaceutical Company, Memory Pharmaceuticals, Hoffmann-La Roche, Neurocrine Biosciences, Boehringer Ingelheim, Meiji Seika Pharma Co., Ltd., SK Life Science, Inc., Alkermes, Inc. , Solvay Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation, SyneuRx International (Taiwan) Corp, BioXcel Therapeutics Inc, Cognitive Research Corporation, Amarex Clinical Research, Forum Pharmaceuticals Inc, Amneal Pharmaceuticals, LLC, Recognify Life Sciences, Accutest Research Laboratories (I) Pvt. Ltd., Eli Lilly and Company, Johnson & Johnson Pharmaceutical Research & Development, L.L.C, Janssen, LP, Delpor, Inc., Jiangsu Hansoh Pharmaceutical, Cerevel Therapeutics, LLC, Zogenix, Inc., Luye Pharma, Reviva Pharmaceuticals, Alkermes, Inc., Karuna Therapeutics, Autifony Therapeutics, Neumora Therapeutics, Adex Therapeutics, among others. Schizophrenia Epidemiology Forecast Schizophrenia Epidemiology Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, and schizophrenia epidemiology trends. Dementia Market Dementia Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key dementia companies, including Hoffmann-La Roche, Forest Laboratories, Inc., Janssen Pharmaceuticals, Inc., Merck and Co., Inc., Novartis, among others. Bipolar Depression Market Bipolar Depression Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key bipolar depression companies, including Intra-Cellular Therapies, Sunovion Pharmaceuticals, COMPASS Pathways, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP

Phase 3Phase 2Clinical ResultDrug ApprovalLicense out/in

19 Aug 2024

·www.biopharmadive.com

As Bristol Myers’ schizophrenia drug nears approval, AbbVie and others hope to provide competition

Bristol Myers Squibbs highly anticipated schizophrenia drug KarXT is fast approaching a September deadline for the Food and Drug Administration to decide on approval. Yet competition already looms for a market thats estimated to soon be worth billions of dollars.KarXT, a so-called muscarinic agonist, may become the first new kind of schizophrenia drug in decades. Close behind it is AbbVies emraclidine, which works in a similar fashion.People with schizophrenia experience a broad range of symptoms, from hallucinations and delusions to cognitive impairments and social withdrawal. Clinical testing has shown that, like KarXT, emraclidine, which AbbVie acquired from Cerevel Therapeutics in a multibillion-dollar deal, is effective at controlling symptoms without the debilitating side effects or drawbacks of traditional antipsychotics, which cause almost three-quarters of patients to abandon treatment.But experts say once-daily dosing versus twice-daily treatment, and a potentially more gut-friendly formulation, may give emraclidine an edge over KarXT, which Bristol Myers Squibb acquired in a $14 billion acquisition of Karuna Therapeutics.Emraclidine is designed to reduce the excess dopamine signaling that causes schizophrenic symptoms, but without blocking the receptors altogether. By blocking specific M4 receptors, rather than others more broadly, the drug could help patients deal with symptoms without the side effects that come with less precise treatment.A Phase 1b study found people who received emraclidine for six weeks saw statistically significant improvements on a standardized scale of symptom severity without side effects like weight gain, restlessness and movement disorders.By selectively targeting the M4 receptor, emraclidine resulted in infrequent gastrointestinal side effects, with rates similar to placebo, Dawn Carlson, AbbVies vice president of neuroscience development, wrote in an email.AbbVie is testing the drug in two mid-stage trials that support approval, and expects to release topline data later this year.According to Carlson, the Cerevel acquisition, finalized this month, not only gave AbbVie emraclidine but several preclinical and clinical-stage drugs that fit into the pharma giants existing portfolio.There are multiple programs in Cerevels pipeline across several psychiatric and neurological conditions such as schizophrenia, Parkinsons disease and mood disorders, where there continues to be significant unmet need for patients, she wrote.Emraclidine may also have applications outside of schizophrenia for dementia-related psychosis in diseases like Alzheimer's and Parkinsons.Several other new schizophrenia drugs are advancing through testing. While many have the same dopamine or serotonin targets as traditional antipsychotics, others rely on novel approaches like KarXT and emraclidine.Neurocrine Biosciences is testing a muscarinic agonist in a Phase 2 study with Nxera Pharma. The company also has another mid-stage schizophrenia candidate called luvadaxistat. Boehringer Ingelheim is in Phase 3 with its drug iclepertin, a selective glycine transporter 1 inhibitor.Meanwhile, Terran Biosciences is looking to compete with a prodrug therapy thats meant to improve on KarXTs twice-daily dosing schedule with a once-daily pill. Its also developing a long-acting injection, dubbed TerXT LAI.Its unclear how either KarXT or emraclidine might compare to these investigational drugs. AbbVie has yet to conduct any head-to-head studies comparing emraclidine to other potential therapies.An increasingly competitive market may create hurdles for drug companies, but it could create new options for people with schizophrenia. The condition affects less than 1% of the population, but is among the top 15 leading causes of disability worldwide.There remains a significant unmet need for more therapies with different mechanisms of action in the treatment of schizophrenia, Carlson wrote. '

Phase 2Phase 1AcquisitionPhase 3Clinical Result

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Schizophrenia	Phase 3	US	Boehringer Ingelheim GmbH	09 Aug 2021
Schizophrenia	Phase 3	US	Boehringer Ingelheim International GmbH	09 Aug 2021
Schizophrenia	Phase 3	US	Boehringer Ingelheim Pharma GmbH & Co., KG	09 Aug 2021
Schizophrenia	Phase 3	CN	Boehringer Ingelheim GmbH	09 Aug 2021
Schizophrenia	Phase 3	AR	Boehringer Ingelheim International GmbH	09 Aug 2021
Schizophrenia	Phase 3	AR	Boehringer Ingelheim GmbH	09 Aug 2021
Schizophrenia	Phase 3	AR	Boehringer Ingelheim Pharma GmbH & Co., KG	09 Aug 2021
Schizophrenia	Phase 3	AT	Boehringer Ingelheim GmbH	09 Aug 2021
Schizophrenia	Phase 3	BE	Boehringer Ingelheim Pharma GmbH & Co., KG	09 Aug 2021
Schizophrenia	Phase 3	BE	Boehringer Ingelheim GmbH	09 Aug 2021

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03859973 (CTgov)	Phase 2	Schizophrenia	200	BI 425809 (BI 425809 10 mg + Computerized Cognitive Training)	vwwmmbwcis(qzazldsoog) = ikbhpedyxp vlapwqfrqp (tggtzohcbk, yfzfgfmlhj - emxmdsjwsy) View more	-	18 Nov 2023
				Placebo (Placebo + Computerized Cognitive Training)	vwwmmbwcis(qzazldsoog) = fqivwsmqvs vlapwqfrqp (tggtzohcbk, gqyvverglk - dzzlochbqa) View more
NCT03783000 \| NCT03654170 (Pubmed)	Phase 1	-	6	BI 425809	bdaeiqamhj(hicqvfmkbe) = forcuepckw ndkcsjoyur (lxgfdwvexu )	-	22 Dec 2021
NCT03988803 (CTgov)	Phase 1	-	16	BI 425809 (BI 425809)	hedzeybwfa(sxjpabwuhn) = uhfvtizbjn tbkxbibbvo (htwzmlcgoc, jdbzdwkxmy - kwauhqxhgx) View more	-	17 Mar 2021
				Memantine+BI 425809 (Memantine + BI 425809)	hedzeybwfa(sxjpabwuhn) = soqbgxcoie tbkxbibbvo (htwzmlcgoc, unlewmvszh - frmgwwzccg) View more
NCT02832037 (CTgov)	Phase 2	Schizophrenia	509	BI 425809 (BI 425809 2 mg Once a Day (q.d.))	qzyfqqhdem(umwjmxrzlr) = ouyzzpgrmb noqrcvbzyr (nxgeeecdpn, htagwbdqvt - ldjfurqxpp) View more	-	24 Feb 2021
				placebo+BI 425809 (BI 425809 5 mg q.d.)	qzyfqqhdem(umwjmxrzlr) = uvtsqcmgzj noqrcvbzyr (nxgeeecdpn, slkynykzqv - zclugeuuyn) View more
NCT03905096 (CTgov)	Phase 1	-	32	BI 425809 (BI 425809 Alone Group (Part 1: Treatment A, Reference 1))	ksmqxspunz(kqznmrxtpr) = zuqoyfwlbo awjlmpalzs (vhbrworedu, czcvzlosbq - xalxgzimme) View more	-	17 Feb 2021
				Don+BI 425809 (BI 425809 + Don Group (Part 1: Treatment B, Test 1))	ksmqxspunz(kqznmrxtpr) = mmxdhdabpz awjlmpalzs (vhbrworedu, yzfnilwhmd - nndthgduit) View more
NCT02788513 (CTgov)	Phase 2	Alzheimer Disease \| Cognitive Dysfunction	611	placebo+BI 425809 (2 mg BI 425809)	njovmejpim(rhdaztidvl) = cixosieszd vbjraxhobq (rknvwqjunp, yxhihqvnef - rqiwmrtffp) View more	-	06 Nov 2020
				BI 425809 (5 mg BI 425809)	njovmejpim(rhdaztidvl) = ftllmbitnv vbjraxhobq (rknvwqjunp, iolrhmiigy - ryngypamup) View more
NCT02383888 (Pubmed \| Clin Ther) Manual	Phase 1	-	49	BI 425809	xemvdryhoz(wskpkgilnm) = One drug-related AE of moderate somnolence was reported by a Japanese subject who received placebo. lfgcysrtcu (taonzmtgfw )	Positive	01 May 2019
				Placebo
NCT02337283 (Pubmed) Manual	Phase 1	Alzheimer Disease \| Schizophrenia	12	BI 425809	nupgdivfpq(mqnlbwyvbi) = tdghoroagq iapulfiuay (liqsgqcnqi )	Positive	01 Aug 2018
				BI 425809+BI 425809	-
NCT02068690 (Pubmed \| Eur J Drug Metab Pharmacokinet) Manual	Phase 1	Alzheimer Disease \| Schizophrenia	83	BI 425809	qfqvnijini(lionopyyic) = pdcflnubbx eelojjokod (bytpiyvmbz )	Positive	01 Apr 2018
				Placebo	-
AAIC2016	Not Applicable	Well Aging	-	BI 425809	iakmdggrsw(uhjytnenjx) = kxnxyaamos cdlukitbxd (mtgzpptqnx ) View more	-	01 Jul 2016

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