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MIAMI LAKES, Fla.--(BUSINESS WIRE)-- #BreakthroughTherapy --Segal Trials is honored to have contributed significantly to the FDA approval of COBENFY™ (xanomeline and trospium chloride), a groundbreaking first-in-class muscarinic agonist developed by Bristol Myers Squibb for the treatment of schizophrenia in adults. This approval marks a critical advancement in schizophrenia care, offering new hope to those living with the condition. A Major Leap Forward in Schizophrenia Treatment COBENFY™ provides a fresh approach to schizophrenia treatment by targeting muscarinic receptors, offering patients a reduction in symptoms of psychosis with fewer metabolic side effects than traditional antipsychotics. This novel pathway represents a major step forward in treatment options, improving both patient outcomes and quality of life (Patient Care Online)(BMS News). Segal Trials’ Longstanding Involvement Segal Trials has been involved with COBENFY™ from its early development under Karuna Therapeutics. Our partnership began during the initial phases of the EMERGENT program and continued after Bristol Myers Squibb acquired Karuna and brought COBENFY™ to market. Throughout this process, Segal Trials provided essential data across multiple phases, contributing to the pivotal clinical trials that led to FDA approval. This enduring partnership highlights Segal Trials’ leadership in schizophrenia research, built on over 20 years of expertise. A Transformative Moment for Mental Health Care Dr. Rishi Kakar, Chief Scientific Officer at Segal Trials, remarked, “The FDA’s approval of COBENFY™ is a monumental step forward in schizophrenia treatment. We are proud to have contributed to this breakthrough, which will offer patients and clinicians a much-needed alternative in mental health care.” Bonnie Segal, President of Segal Trials, added, “Our involvement with this groundbreaking treatment spans many years, from working with Karuna Therapeutics when the drug was originally known as KarXT, to continuing our partnership with Bristol Myers Squibb after the acquisition and rebranding of the drug as COBENFY™. This approval highlights the strength of longstanding collaborations in clinical research, and we are honored to have been part of bringing such an innovative treatment to patients.” Looking Ahead As we celebrate this approval, Segal Trials is reminded of the immense potential that clinical research holds in improving patient outcomes. We remain committed to advancing treatments for mental health conditions through ongoing research and innovation. For more information, visit: Segal Trials and the official Bristol Myers Squibb press release . Contacts marketing@segaltrials.com - 305-722-8444

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.”

COBENFY™ (xanomeline and trospium chloride) Fact Sheet Schizophrenia Fact Sheet COBENFY represents the first new pharmacological approach to treat schizophrenia in decades, with a mechanism of action distinct from current therapies Approval is supported by data from the EMERGENT clinical program demonstrating statistically significant reductions of schizophrenia symptoms The safety and tolerability profile of COBENFY has been established across acute and long-term trials in schizophrenia PRINCETON, NJ, USA I September 26, 2024 I Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has approved COBENFY™ (xanomeline and trospium chloride), an oral medication for the treatment of schizophrenia in adults. 1 COBENFY represents the first new class of medicine in several decades and introduces a fundamentally new approach to treating schizophrenia by selectively targeting M 1 and M 4 receptors in the brain without blocking D 2 receptors. 2,3,4 “Today’s landmark approval of our first-in-class treatment for schizophrenia marks an important milestone for the community, where after more than 30 years, there is now an entirely new pharmacological approach for schizophrenia — one that has the potential to change the treatment paradigm,” said Chris Boerner, PhD , board chair and chief executive officer at Bristol Myers Squibb. “As we reenter the field of neuropsychiatry, we are dedicated to changing the conversation around serious mental illness, beginning with today’s approval in schizophrenia.” Schizophrenia is a persistent and often disabling mental illness affecting how a person thinks, feels and behaves. 5 It is estimated to impact approximately 2.8 million people in the United States. 6 Symptoms typically first appear in early adulthood and present differently in each person, making symptoms difficult to diagnose and manage. 6 While the current standard of care can be effective in managing symptoms of schizophrenia, up to 60% of people experience inadequate improvement in symptoms or intolerable side effects during therapy. 7 “For people living with schizophrenia, it’s often difficult to find a treatment that works for them. Having a variety of treatment options gives patients and healthcare providers the tools to help manage this serious condition,” said Gordon Lavigne, chief executive officer of the Schizophrenia & Psychosis Action Alliance. “People living with schizophrenia want and deserve more. Today’s approval provides a new option as people with schizophrenia move forward with proper support to rebuild their lives.” The FDA approval of COBENFY is supported by data from the EMERGENT clinical program, which includes three placebo-controlled efficacy and safety trials and two open-label trials evaluating the long-term safety and tolerability of COBENFY for up to one year. In the Phase 3 EMERGENT-2 and EMERGENT-3 trials, COBENFY met its primary endpoint, demonstrating statistically significant reductions of schizophrenia symptoms compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week five. COBENFY demonstrated a 9.6-point reduction (-21.2 COBENFY vs. -11.6 placebo, p<0.0001) and an 8.4-point reduction (-20.6 COBENFY vs. -12.2 placebo; p<0.0001) in PANSS total score compared to placebo at week five in EMERGENT-2 and EMERGENT-3, respectively. In EMERGENT-2, COBENFY demonstrated a statistically significant improvement in illness from baseline to week five, as measured by the Clinical Global Impression-Severity (CGI-S) score, a secondary endpoint in the trial. 1 The safety and tolerability profile of COBENFY has been established across acute and long-term trials. In the Phase 3 EMERGENT-2 and EMERGENT-3 trials, the most common adverse reactions (≥5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness and gastroesophageal reflux disease. 1 COBENFY does not have atypical antipsychotic class warnings and precautions and does not have a boxed warning. “Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” said Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials and investigator in the EMERGENT program. “The approval of COBENFY is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, COBENFY offers a new option to manage this challenging condition.” The Company today also announced the launch of COBENFY Cares™, a program designed to support patients who have been prescribed COBENFY. Patients will be able to enroll in the COBENFY Cares program in late October corresponding with product availability. The COBENFY Cares phone number is 1-877-COBENFY. About Schizophrenia Schizophrenia is a persistent and often disabling mental illness impacting how a person thinks, feels and behaves. There are three symptom domains of schizophrenia, which include positive symptoms (e.g., hallucinations, delusions, disordered thinking and speech), negative symptoms (e.g., lack of motivation, lack of emotional expression/flat affect, social withdrawal) and cognitive dysfunction (e.g., impaired attention, deficits in memory, concentration and decision-making). 5 The symptoms of schizophrenia can affect all areas of people’s lives, making it difficult to maintain employment, live independently and manage relationships. 8,9 Schizophrenia affects nearly 24 million people worldwide, including 2.8 million people in the United States, and is one of the top 15 leading causes of disability worldwide. 6,10,11 About COBENFY™ (xanomeline and trospium chloride) COBENFY™ (xanomeline and trospium chloride), formerly KarXT, is an oral medication for the treatment of schizophrenia in adults. COBENFY combines xanomeline, a dual M 1 – and M 4 -preferring muscarinic receptor agonist, with trospium chloride, a muscarinic receptor antagonist that does not appreciably cross the blood-brain barrier, primarily acting in peripheral tissues. While the exact mechanism of action of COBENFY is unknown, its efficacy is thought to be due to the agonist activity of xanomeline at M 1 and M 4 muscarinic acetylcholine receptors in the central nervous system. About EMERGENT Clinical Program The EMERGENT clinical program evaluating COBENFY for the treatment of schizophrenia in adults includes three placebo-controlled efficacy and safety studies, including the Phase 3 EMERGENT-2 and EMERGENT-3 trials, and two open-label studies evaluating the long-term safety and tolerability of COBENFY for up to one year. The Phase 3 EMERGENT-2 and EMERGENT-3 trials were five-week, inpatient trials that evaluated the efficacy, safety and tolerability of COBENFY compared to placebo in adults with schizophrenia. In both trials, COBENFY met its primary endpoint, demonstrating statistically significant reductions of schizophrenia symptoms compared to placebo as measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week five. COBENFY demonstrated a 9.6-point reduction (-21.2 COBENFY vs. -11.6 placebo, p<0.0001) and an 8.4-point reduction (-20.6 COBENFY vs. -12.2 placebo; p<0.0001) in PANSS total score compared to placebo at week five in EMERGENT-2 and EMERGENT-3, respectively. In EMERGENT-2, COBENFY demonstrated a statistically significant 0.6 change (-1.2 COBENFY vs. -0.7 placebo; p<0.0001) in the Clinical Global Impression-Severity (CGI-S) score compared to placebo at week five, a secondary endpoint in the trial. The most common adverse reactions (≥5% and at least twice placebo) of COBENFY compared to placebo were nausea (19% vs. 4%), dyspepsia (18% vs 5%), constipation (17% vs 7%), vomiting (15% vs 1%), hypertension (11% vs 2%), abdominal pain (8% vs 4%), diarrhea (6% vs 2%), tachycardia (5% vs 2%), dizziness (5% vs 2%) and gastroesophageal reflux disease (5% vs. <1%). INDICATION COBENFY™ (xanomeline and trospium chloride) is indicated for the treatment of schizophrenia in adults. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS COBENFY is contraindicated in patients with: WARNINGS AND PRECAUTIONS Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention. COBENFY is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment. In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated. Risk of Use in Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions. COBENFY is contraindicated in patients with moderate or severe hepatic impairment. COBENFY is not recommended in patients with mild hepatic impairment. Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment. Risk of Use in Patients with Biliary Disease: In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage. COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values. Decreased Gastrointestinal Motility: COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis. Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride. Risk of Use in Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring. Increases in Heart Rate: COBENFY can increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment. Central Nervous System Effects: Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation. Most Common Adverse Reactions (≥5% and at least twice placebo): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease. Use in Specific Populations: COBENFY (xanomeline and trospium chloride) is available in 50mg/20mg, 100mg/20mg, and 125mg/30mg capsules. Please see U.S. Full Prescribing Information , including Patient Information . About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , Twitter , YouTube , Facebook and Instagram. REFERENCES SOURCE: Bristol Myers Squibb