Chlorpromazine Hydrochloride

iStock/ ktsimage From Eli Lilly to Karuna Therapeutics to current owner Bristol Myers Squibb, the newly approved schizophrenia drug had quite the journey to market. Former Karuna and Lilly executives discuss the “accidental” and “serendipitous” discovery. What began as a therapeutic candidate for Alzheimer’s disease at Eli Lilly completed its development journey Thursday in the hands of Bristol Myers Squibb as Cobenfy, the first novel treatment for schizophrenia in 35 years . Andrew Miller, former CEO of Karuna Therapeutics who co-invented the drug, said this trajectory is not uncommon in neuropsychiatric diseases. “The only treatments we have for schizophrenia was because chlorpromazine, which was an anesthetic drug in the ’50s, was discovered to have antipsychotic effects . . . and that was kind of the parent of all of the currently available treatments for schizophrenia,” Miller told BioSpace . Similarly, he added, the first approved treatment for depression was an anti-tuberculosis medicine. “When you look at the history of psychiatric drug development, the source of innovation, in many respects, is serendipitous, human to human findings,” Miller said. Weight Loss Rivals Were Once Alzheimer’s Partners In the mid-1990s, Lilly and current obesity and diabetes archrival Novo Nordisk were collaborating on a muscarinic acetylcholine receptor stimulator agonist to treat cognitive impairment in Alzheimer’s disease. Acetylcholine is the neurotransmitter through which cholinergic neurons, which are involved in memory and learning, send their messages. Steven Paul People with Alzheimer’s lose these neurons early in the disease process, said Steven Paul, who oversaw the program at Lilly. “So, our idea in those days was if we could stimulate the receptors for acetylcholine, maybe in the absence of those neurons we could still enhance memory and learning,” Paul told BioSpace . This idea birthed xanomeline, an acetylcholine receptor agonist that the partners studied in a large Phase II trial. The results showed xanomeline had a “modest” but “significant” effect in improving memory, Paul said. However, the trial also revealed adverse events such as nausea, vomiting and excess salivation—effects associated with stimulating muscarinic receptors. Ultimately, the companies made the decision not to proceed with xanomeline “because we felt we didn’t have the requisite tolerability safety margin for patients with Alzheimer’s,” Paul said. But, as part of the trial, the companies had also studied xanomeline’s effect on “abnormal behaviors” in Alzheimer’s such as hallucinations and delusions. “The drug seemed to treat these psychotic symptoms, and it seemed to prevent the emergence of these psychotic symptoms in these patients,” Paul said. With the exception of the adverse events, “that was the most striking finding.” Paul and colleagues published their findings in a 1997 paper . “This was by accident,” Paul said. “We didn’t really think this might happen.” A few years later, researchers at Lilly wondered if these same effects might translate to patients with schizophrenia. To answer this question, the company conducted a small study at Indiana University. “And sure enough, the drug seemed to work in those patients as well,” Paul said. But the adverse effects remained, and the companies did not pursue this indication either. KarXT Is Born Enter PureTech Health, where Miller, who was vice president in 2009, had an idea: Instead of tweaking xanomeline for more selectivity and fewer side effects—which Paul said “probably wasn’t going to work anyway”—why not combine it with a muscarinic antagonist molecule that blocks the peripheral side effects while leaving efficacy unaffected? In 2009, PureTech founded Karuna Pharmaceuticals, which later changed its name to Karuna Therapeutics, to take the candidate forward, with Miller at the helm. Andrew Miller “It took a lot of effort to get from that concept to the actual, real matter of KarXT,” Miller said. Perusing the scientific literature, Karuna identified 65 acetylcholine receptor agonist molecules and 114 muscarinic antagonist molecules. “So that gives you 7,410 possible combinations.” Ultimately, Karuna selected 95 parameters, some specific to the agonist molecule, others specific to the antagonist, and still others about how combinations would function. At the end of this process, the researchers stuck with xanomeline as the agonist and selected trospium as the antagonist, and the combination became KarXT. Interestingly, “[Karuna] couldn’t raise any money. There was very little interest,” said Paul, who joined the company as CEO in 2018 after Karuna published Phase I data. “Sometimes these are the best companies, when people turn you down.” The Phase I trial , in which 70 healthy volunteers received either KarXT or xanomeline plus placebo, showed a significant difference in terms of side effects: 64% of patients in the xanomeline/placebo group saw the most common xanomeline-associated side effects vs. 34% in the KarXT cohort. These early results generated some excitement. In 2018, Karuna raised $42 million in a Series A round, followed six months later by a $68 million Series B , which was later topped up to $80 million . That same year, Paul and Miller took the company public . Then, in November 2019, KarXT met the primary efficacy endpoint in the Phase II EMERGENT-1 trial , where it was also found to be generally well-tolerated, “and our stock just went off the roof,” Paul said. According to Biopharma Dive , Karuna’s value increased from around $400 million to nearly $3 billion following this data drop. BMS Buys Karuna for $14B By December 2023, Karuna had two successful Phase III trials under its belt, and BMS came knocking. Paul said they’d actually been in discussions with BMS since the J.P. Morgan Healthcare Conference in January 2023 but it wasn’t until the company submitted the New Drug Application for KarXT in September 2023 that the pharma company was ready to commit to buying Karuna. “I presented to them the story, and we didn’t hear from them afterwards until later that year,” Paul said. “Then, once we filed the NDA with the FDA, we had them and another company kind of beating down our door.” While Paul wouldn’t reveal the name of the other suitor, he did say that Karuna had “narrowed it to a bit of a bake-off with those two companies.” Prior to agreeing to the buyout deal with BMS, Paul said Karuna had intended to launch KarXT itself. “We were building a sales force. We were building a commercial presence.” In the end, however, Karuna decided BMS’ offer was in the best interest of its stakeholders. “When I joined the company, as a private company of maybe $20- $30-, $40 million bucks . . . we went public, and maybe we were worth at most $400 [million]. And then we were offered $14 billion dollars for the company, in less than five years.” He called the decision bittersweet “because if the drug had been approved, if we had ourselves commercialized it, if it became a mega billion-dollar blockbuster drug ourselves, well, the company’s value would be much greater than $14 billion dollars.” Paul calls KarXT “one of my early children” and said he is pleased with its progress. “They’re [BMS] doing a great job with it, so far as I can tell,” he said. While BMS is starting with schizophrenia, KarXT/Cobenfy’s journey may be far from over. A recent post-hoc analysis showed that a subset of patients in the pivotal Phase III EMERGENT-1 and EMERGENT-2 studies with predominantly negative symptoms of schizophrenia—such as apathy and social withdrawal—at baseline saw a larger effect on negative symptoms than the overall trial population. And the drug may also treat the disease’s cognitive symptoms, including poor memory and low attention span, said Paul, adding that another paper on this was recently accepted for publication. In a return to its roots, BMS has also shared plans to test Cobenfy in Alzheimer’s disease psychosis, as well as bipolar disorder. “Our expectation is that KarXT is our first foray into schizophrenia and serious mental illnesses,” Carlos Dortrait, SVP and general manager of U.S. immunology and neuroscience at BMS, previously told BioSpace , “but we are looking at expanding and looking very broadly across many diseases.”

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