Extravasation of Diagnostic and Therapeutic Materials

Trial has met primary endpoints of safety and immunogenicity and secondary endpoint for efficacy based on response rate Trial data published today in Nature Medicine Selected clinical trial data also presented at the 2024 AACR Annual Meeting PHILADELPHIA, April 7, 2024 /PRNewswire/ -- Geneos Therapeutics, a clinical stage biotherapeutics company focused on the development of personalized therapeutic cancer vaccines (PTCVs), today announced the publication of positive safety, immunogenicity, and efficacy data from the full cohort of patients enrolled in its GT-30 clinical trial in Nature Medicine. The paper, titled, "Personalized Neoantigen Vaccine and Pembrolizumab in Advanced Hepatocellular Carcinoma: A phase 1/2 trial," details the GT-30 clinical trial, a 36-patient, single-arm, open-label, multi-center Phase 1/2 study of GNOS-PV02, a DNA plasmid encoded PTCV in combination with DNA plasmid encoded IL-12 (a cytokine adjuvant), and pembrolizumab (a PD-1 inhibitor) in second-line (2L) patients with advanced hepatocellular carcinoma (HCC) previously treated with a multi-tyrosine kinase inhibitor. The study met its primary endpoints of safety and immunogenicity and its secondary endpoint of efficacy based on observed response rate (ORR). PTCV-related adverse events were all limited to Grades 1 and 2 with no dose-limiting toxicities or grade > 3 adverse events observed. The most common adverse events were injection site reactions observed in 41.6% (15/36) of patients. This is in contrast to typical immuno-oncology combination regimens, including those approved for first-line use in advanced HCC, wherein adding a second agent may lead to markedly increased toxicity; here, the addition of a PTCV to a PD-1 inhibitor was not observed to lead to any significant decrease in patient safety and tolerability. The ORR for GT-30 is currently at 30.6% (11/36), including three complete responses (CR) and eight partial responses. This response is statistically significant based on pre-specified criteria at a one-sided p-value = 0.031 (1-sided 90% CI 20.4%-100%) versus a pre-specified historical control of 16.9% for pembrolizumab monotherapy. This historical comparator response rate was modeled on Phase 3 KN-240 data presented at ASCO 2019 and is also consistent with the prior Phase 2 KN-224 study. As an overall class, anti-PD1 monotherapy for 2L advanced HCC has shown response rates of 11%-18% in seven Phase 2 and Phase 3 clinical studies enrolling over 1400 patients. Additionally, the GT-30 CR rate of 8.3% (3/36) compares with a historical anti-PD-1 monotherapy CR rate in 2L of 0% - 3% in the prior studies. As of the data cutoff, the median OS (mOS) in GT-30 was 19.9 months compared to a mOS range of 12.9 – 15.1 months reported for the prior 2L studies of pembrolizumab and other anti-PD-1 monotherapy. 11 of 36 patients remain on treatment and, in total, 17 patients continue to be followed for overall survival (OS). "Other recent industry trials have tested personalized cancer vaccines in patients with highly immune-sensitive tumor phenotypes and no measurable disease. In marked contrast, the GT-30 trial assesses PTCVs in HCC, a cancer with very low tumor mutational burden and an immune-excluded phenotype, and in patients with significant late-stage unresectable and metastatic disease," said Niranjan Sardesai, PhD, CEO and president of Geneos. "Despite the small size of this study, our results are important for the advancement of the field. We have not only met endpoints for safety, immunogenicity, and clinical efficacy based on ORR in this difficult to treat setting, but our mechanism of action data trace and confirm every step, from vaccination to tumor reduction, required to explain the immunological basis for the observed clinical responses." Immunological analyses confirm the induction of new T cell responses to vaccine-encoded neoantigens in 14 of 14 (100%) evaluated patients and the expansion of this TCR repertoire both in the peripheral blood and tumors of PTCV-treated patients. Single cell sequencing analyses show the vast majority of these T cell clones to be CD8 T effector memory cells, a key requirement to induce anti-tumor cytotoxicity. In contrast, while anti-PD-1 monotherapy has been observed to reverse T cell dysfunction in existing neoantigen-specific T cell clones, it is not known to induce any new neoantigen-specific T cell clones. Today Geneos also presented selected GT-30 clinical trial data and updated longitudinal circulating tumor DNA (ctDNA) biomarker data from the trial at the 2024 American Association for Cancer Research (AACR) Annual Meeting in San Diego. Reductions of at least 50% versus baseline in patient ctDNA, an exploratory endpoint, were seen in 40.7% of patients (11 of 27 patients for whom the full data set are available). All such responses correlate with ongoing survival. "To our knowledge, the GT-30 clinical study provides the first definitive demonstration of a personalized cancer vaccine enhancing clinical response to anti-PD-1 therapy by inducing new, neoantigen-specific T cells which traffic to the tumor," said Ildiko Csiki, MD, PhD, chief medical officer of Geneos. "The fact that the PTCV regimen has produced this important result in a form of cancer as immunologically 'cold' as HCC, leading to multiple complete responses and a doubling of objective response versus PD-1, is incredibly promising and shows the therapeutic potential of personalized cancer vaccines for cancer patients." DNA-based PTCVs may include up to 40 neoantigens. The majority of patients in the GT-30 study were administered PTCVs which included all of their targetable neoantigens across a broad range of predicted MHC binding affinity. A correlation was seen in GT-30 between the number of vaccine epitopes and the number of reactive epitopes post-vaccination, suggesting that having more neoantigens in the vaccine increased the effectiveness of tumor control. Other personalized vaccine platforms, especially those not based on DNA, have historically had to target a more limited selection of neoantigens, which may limit their efficacy. About Geneos Therapeutics Geneos Therapeutics, a clinical stage biotherapeutics company, is developing personalized therapeutic cancer vaccines (PTCVs) that may serve an important role in new immunotherapeutic paradigms for cancer. The company's approach, using its proprietary GT-EPIC™ platform, is to target neoantigens (abnormal mutations produced by cancer cells) from individual patient tumors to develop novel and uniquely personalized treatments for cancer. Planning is underway for a potentially registrational clinical trial in advanced hepatocellular carcinoma. For more information, please visit . This press release contains certain forward-looking statements relating to our business, including our plans regarding the development of personalized therapeutic cancer vaccines and the therapeutic potential and clinical benefits of our product candidates. Actual events or results may differ from the expectations set forth herein. There can be no assurance that any product candidate in Geneos' pipeline will be successfully developed, manufactured or commercialized, that final results of clinical trials will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate. Forward-looking statements speak only as of the date of this release, and Geneos undertakes no obligation to update or revise these statements, except as may be required by law. This press release does not constitute an offer to sell or the solicitation of an offer to buy any securities. SOURCE Geneos Therapeutics, Inc.

V-INITIATE trial demonstrates that early initiation with Leqvio, prior to guideline-recommended ezetimibe, for ASCVD patients unable to achieve LDL-C goal on statin therapy alone led to significant LDL-C reduction vs. clinician-determined usual care (60% vs. 7% respectively)1 A significantly greater proportion of the ASCVD patients receiving Leqvio achieved guideline-recommended LDL-C goal vs. the usual care arm while maintaining adherence to statin treatment1 Results from usual care arm reinforce the urgent need for more aggressive LDL-C lowering in ASCVD patients, 92% of whom did not reach their LDL-C goal with statins alone1 The Leqvio safety profile was consistent with the Phase III clinical studies and long-term open-label extension trials for up to 6 years of treatment1-4 EAST HANOVER, N.J., April 6, 2024 /PRNewswire/ -- Novartis today announced new data demonstrating the early addition of twice-yearly* Leqvio® (inclisiran) to maximally tolerated statin therapy, prior to guideline-recommended ezetimibe, in a real-world setting significantly reduced low-density lipoprotein cholesterol (LDL-C) in patients with atherosclerotic cardiovascular disease (ASCVD), including those with a history of an ASCVD-related event, who could not reach their goal on statin therapy alone1. The late-breaking data were presented at the 2024 American College of Cardiology's Annual Scientific Session & Expo and simultaneously published in the Journal of the American College of Cardiology. "V-INITIATE evaluated a solution to the important challenge seen in clinical practice of too many patients with ASCVD not achieving guideline-recommended LDL-C goal on statins alone and effective non-statin therapies being markedly underutilized," said Michael Koren, M.D., Medical Director and CEO of Jacksonville Center for Clinical Research, and the primary investigator of the study. "Given the urgent need to more aggressively manage LDL-C, the results from V-INITIATE show that when added earlier in the treatment continuum, the structured use of effective non-statin therapies like Leqvio can significantly reduce LDL-C for ASCVD patients who are struggling to reach or maintain their LDL-C goal." In the V-INITIATE study, patients receiving Leqvio experienced significant reductions in LDL-C compared to those receiving usual care (60% vs. 7%, respectively; p<0.001), which consisted mostly of statin therapy alone (73%)1. Four in five patients receiving Leqvio achieved the guideline-recommended LDL-C goal of <70 mg/dL compared to just one in five patients receiving usual care (81.8% vs. 22.2%, respectively; p<0.001)1. Notably, patients receiving health care provider (HCP)-administered Leqvio maintained adherence to existing lipid-lowering therapy, and the discontinuation rate of background statin therapy did not differ between the Leqvio and usual care arms (5.8% vs. 16.7%, respectively)1. The safety results from V-INITIATE were consistent with findings from the pivotal Phase III clinical trial program and long-term open-label extension trials, ORION-3 and ORION-8, which demonstrated sustained safety for up to six years of treatment1-4. "The data from V-INITIATE illustrate that earlier initiation of innovative non-statin therapies, like Leqvio, presents a real opportunity to do better for ASCVD patients and improve the way we approach LDL-C lowering," said David Soergel, M.D., Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis. "This study adds data from a real-world setting to the growing body of evidence for Leqvio being generated through our robust VictORION program, and further reinforces the clinical value of this twice-yearly HCP-administered therapy." V-INITIATE is a 12-month Phase IIIb open-label study evaluating the effectiveness of adding Leqvio earlier, following a patient's failure to reach LDL-C goal on maximally tolerated statin therapy, compared to usual care, in a setting that reflects U.S. clinical practice. It was designed to more accurately represent the diversity of the U.S. general population across age, sex, race, ethnicity, insurance status, income level, education, prior medical history and statin intolerance1. Unlike placebo arms in typical double-blind trials, the usual care arm reflected U.S. clinical practice by allowing treating physicians to make changes to lipid-lowering treatment based on LDL-C measurements. Usual care was defined as clinician determined based on the 2018 American College of Cardiology/American Heart Association guideline recommendations1. *After an initial dose and another at three months. Indication LEQVIO (inclisiran) is an injectable prescription medicine used along with diet and other cholesterol-lowering medicines in adults with high blood cholesterol levels called primary hyperlipidemia (including a type of high cholesterol called heterozygous familial hypercholesterolemia [HeFH]) to reduce low-density lipoprotein (LDL-C) or "bad" cholesterol. Important Safety Information: The most common side effects of Leqvio were: injection site reaction (including pain, redness, and rash), arthralgia (joint pain), bronchitis (chest cold). These are not all the possible side effects of Leqvio. Ask your health care provider for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit , or call 1-800-FDA-1088. Please click here for Leqvio full Prescribing Information. About Leqvio Leqvio is a subcutaneous injection given by a health care provider (HCP) with an initial dose, another at three months, and then every six months2,5. As a twice-yearly, HCP-administered treatment, Leqvio may help to circumvent the challenges of treatment adherence, a common issue in cholesterol management. Leqvio is the first and only small interfering RNA (siRNA) therapy to lower LDL-C. It is approved in over 90 countries, including the U.S., EU, Japan and China1,5,6. Novartis has obtained global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics. About V-INITIATE V-INITIATE is a 12-month, randomized, multicenter, open-label Phase IIIb study in 450 atherosclerotic cardiovascular disease (ASCVD) patients in the U.S. with elevated LDL cholesterol (LDL-C) ≥70 mg/dL. The study evaluated the effectiveness of adding HCP-administered Leqvio earlier, following a patient's failure to reach LDL-C goal on maximally tolerated statin therapy, compared to usual care1. Usual care was determined by the clinicians and based on the 2018 American College of Cardiology/American Heart Association guideline recommendations; most patients (73%) in the usual care arm remained on statins only1. The co-primary endpoints were the percentage change in LDL-C from baseline to Day 330 and the discontinuation of statin therapy, defined as no statin use ≥30 days before the end of study visit1. This is the first Novartis trial where all patients have been tokenized with the intention of following their outcomes for two additional years post-trial completion, providing additional insights on the real-world effectiveness of Leqvio7. About VictORION The V-INITIATE trial is part of VictORION, an innovative and robust clinical program for Leqvio, comprising more than 30 trials and enrolling over 60,000 patients in more than 50 countries worldwide7. The program is designed to expand on the foundational evidence of LDL-C reduction with Leqvio in diverse patient populations to include randomized clinical trials, implementation research, real-world evidence, and trials that aim to establish its potential benefits on cardiovascular outcomes in primary and secondary prevention. A growing number of studies are planned to generate a vast array of data with major trials such as ORION-4 (secondary prevention), V(VictORION)-2-PREVENT (secondary prevention), V-1-PREVENT (high-risk primary prevention), V-INCEPTION and V-MONO. About Atherosclerotic Cardiovascular Disease (ASCVD) ASCVD refers to a variety of diseases caused by the development and growth of plaques in the inner lining of the arteries8. The atherosclerotic plaque is mainly composed of low-density lipoprotein cholesterol (LDL-C) which accumulates over time8. Cumulative exposure to LDL-C is proportionally related to arterial plaque growth and progression leads to subsequent risk of cardiovascular events such as a heart attack or stroke8,9. Accounting for 85% of all cardiovascular disease deaths, ASCVD is the primary cause of mortality in the European Union and its burden in the United States is greater than that of any other chronic diseases10-13. ASCVD risk-equivalent corresponds to conditions that confer a similar risk for an ASCVD event (e.g., diabetes and heterozygous familial hypercholesterolemia)4,13. About Novartis in Cardiovascular Cardiovascular disease (CVD) affects hundreds of millions of people and claims more lives globally than cancer, chronic lung disease and diabetes combined14. It is time to change that. Around 80% of premature cardiovascular deaths can be prevented by addressing factors that cause or worsen CVD15. We have a responsibility to make that a reality for more people. Novartis has been advancing the scientific understanding and treatment of CVD for more than four decades. Through early intervention, pioneering science and technological innovation, we are addressing factors that increase the risk of heart attacks and strokes, improving the function of damaged hearts and easing the burden of care for patients. We also collaborate with healthcare professionals, patient communities and diverse organizations to improve preventive CV care worldwide. Together, we will help more people with CVD get the right treatments at the right time and live longer and healthier lives. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people's lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 250 million people worldwide. Reimagine medicine with us: Visit us at and and connect with us on LinkedIn, LinkedIn US, Facebook, X/Twitter, X/Twitter US and Instagram. Novartis previously filed its 2023 annual report with the Swiss SIX exchange in Switzerland, as well as its 2023 Annual Report on Form 20-F with the US Securities and Exchange Commission, and posted these documents on . Novartis shareholders may receive a hard copy of either of these documents, each of which contains our complete audited financial statements, free of charge, upon request. References Koren MJ, Rodriguez F, East CA, et al. Comparison of an "inclisiran first" strategy with usual care in patients with atherosclerotic cardiovascular disease: results from the VICTORION-INITIATE randomized trial. Data presented at: American College of Cardiology Congress; April 6, 2024; Atlanta, GA. Leqvio. Prescribing information. Novartis Pharmaceuticals Corp. Wright RS, Raal FJ, Koenig W, et al. ORION-8: Long-term efficacy and safety of twice-yearly inclisiran in high cardiovascular risk patients. Data presented at: European Society of Cardiology Congress; August 28, 2023; Amsterdam, the Netherlands. Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial. Lancet Diabetes Endocrinol. 2023;11(2):109-119. European Medicines Agency. Leqvio (inclisiran): An overview of Leqvio and why it is authorized in the EU. Last updated June 2021. Accessed March 12, 2024. National Medical Products Administration. Drug approval document delivery information. Published August 24, 2023. Accessed March 12, 2024. Data on file. NCT04929249. Novartis Pharmaceuticals Corp; 2024. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161-172. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156. World Health Organization. Cardiovascular diseases (CVDs). Published June 11, 2021. Accessed March 12, 2024. (cvds) Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220. Kim H, Kim S, Han S, et al. Prevalence and incidence of atherosclerotic cardiovascular disease and its risk factors in Korea: a nationwide population-based study. BMC Public Health. 2019;19(1):1112. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–e1143. American Heart Association. More than half of U.S. adults don't know heart disease is leading cause of death, despite 100-year reign. Published January 24, 2024. Accessed March 12, 2024. World Heart Federation. World Heart Report. Published May 20, 2023. Accessed March 12, 2024. # # # SOURCE Novartis Pharmaceuticals Corporation

PK modeling data provide insights into potential dosing conversions and strategies for switching to UZEDY from a long-acting injectable (LAI) formulation of risperidone microspheres (R064766) Additional UZEDY data include a new analysis from the Phase 3 RISE trial reinforcing its efficacy and safety profile in adults with schizophrenia ADVANCE, a global survey study, will also provide real-world findings on LAI utilization from healthcare professionals, caregivers and patients TEL AVIV, Israel & PARSIPPANY, N.J.--(BUSINESS WIRE)-- Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), today announced the presentation of eight studies from its LAI schizophrenia research program, including data evaluating UZEDY, an extended-release injectable suspension of risperidone for subcutaneous use every one or two months for the treatment of schizophrenia in adults. The data were presented at the 2024 Congress of the Schizophrenia International Research Society (SIRS) taking place from April 3-7, 2024 in Florence, Italy. “As part of Teva’s commitment to advancing treatment innovation for schizophrenia patients, this research provides clinical insights into how healthcare providers may switch appropriate patients to UZEDY, a subcutaneous risperidone LAI option with flexible dosing,” said Eric Hughes, MD, Ph.D, Executive Vice President of Global R&D and Chief Medical Officer at Teva. “Schizophrenia is a complex mental health condition where the treatment needs and preferences of those living with it may evolve over time. These data collectively demonstrate the efficacy and safety profile of UZEDY – reinforcing its potential as a treatment option that may help lower rates of relapse and hospitalization.” Presented data include population pharmacokinetic (PopPK) modeling to investigate dosing conversion strategies for switching patients to a once-monthly or once every two-months subcutaneous dose of UZEDY from a biweekly intramuscular LAI formulation of risperidone microspheres (R064766). The analysis aims to address the knowledge gap as limited clinical data currently exist on optimal strategies for switching between the various available LAI treatment options, which have differing pharmacokinetic (PK) properties. In the PopPK analysis, patient model simulations showed that switching to UZEDY at 4-6 weeks after the last dose of R064766 provided comparable PK exposures by the second dose. Specifically, switching patients to UZEDY 5 weeks after the last dose of R064766 achieved PK exposures similar to those achieved with R064766 at a steady state. The optimal switching strategy should be determined by clinicians on an individual basis, considering factors such as patient preference, scheduling convenience, and potential tolerability issues or risk of symptom breakthrough. Additional key data being presented at the SIRS Annual Meeting include: New data from RISE (Risperidone Subcutaneous Extended-Release Study), the Phase 3 pivotal trial that supported the FDA approval of UZEDY. An analysis estimated the number needed to treat (NNT) and the number needed to harm (NNH), clinically relevant measures that help provide healthcare providers with an understanding of the benefits and risks of UZEDY and inform clinical decision-making. Qualitative data from two ADVANCE (Attitudes Driving Regional Differences in LAI Antipsychotic Utilization for Schizophrenia Among Healthcare Professionals, Patients, and Caregivers) surveys: In the healthcare provider survey, ten psychiatrists (spending an average of 45% of their time at hospital-based outpatient clinics) and seven psychiatric nurses (averaging 47% of time at community mental health centers) were interviewed. Findings suggest that regional differences in LAI utilization rates are likely influenced by a combination of factors, including systemic, HCP, and patient factors. In the patient survey, approximately 20 patients and 19 caregivers completed a 60-minute interview regarding the use of LAIs in schizophrenia. Unfavorable early experiences, especially in the inpatient setting, can negatively impact patients’ perception of and willingness to accept LAIs. The survey findings offer further key insights into addressing global adherence and inconsistent utilization challenges with LAIs. Below is the full set of data presented by Teva at SIRS 2024. AUSTEDO ® XR (deutetrabenazine): (Encore) Occupational Impact of Tardive Dyskinesia (TD): a Cross-Sectional, International Survey Assessing the Perceptions and Experiences of Patients With TD and Physicians Who Treat TD (Encore) Burden and Management of Tardive Dyskinesia (TD): A Cross-Sectional, International Survey Study to Assess the Perceptions and Experiences of Physicians and Patients With TD (De novo) Patient and Caregiver Experiences With Tardive Dyskinesia: Emotions, Challenges, and Unmet Needs in the Patient Journey UZEDY (risperidone): (De novo) Switching Patients With Schizophrenia to TV-46000, a Long-Acting Subcutaneous Antipsychotic (LASCA), From Risperidone Microspheres (R064766): An Exploration of Population Pharmacokinetic (PopPK)–Based Strategies (De novo) Clinical Benefit and Risk Profile of TV-46000 for Patients With Schizophrenia as Assessed by Number Needed to Treat (NNT) and Number Needed to Harm (NNH) TV-44749 (olanzapine): (De novo) TV-44749, a Long-Acting Subcutaneous (sc) Injectable Formulation of Olanzapine is Designed to Provide Sustained Controlled Concentrations and to Eliminate the Causes of Post-Injection delirium/sedation Syndrome (PDSS) (De novo) Population Pharmacokinetic Modeling Following Administration of Olanzapine for Extended-Release Injectable Suspension (TV-44749) for Subcutaneous Use to Support Dose Selection for Phase 3 Clinical Trial (SOLARIS) LAI Real-World Insights: (De novo) Attitudes DriVing regional differences in LAI ANtipsychotic utilization for schizophrenia among healthcare professionals, patients, and CaregivErs (ADVANCE): healthcare professional qualitative interviews (De novo) Attitudes DriVing regional differences in LAI ANtipsychotic utilization for schizophrenia among healthcare professionals, patients, and CaregivErs (ADVANCE): patient and caregiver qualitative interviews (De novo) Initiation Regimens for Long-Acting Injectable Antipsychotics Requiring Oral Supplementation: Impact on Subsequent Maintenance Treatment Adherence and Persistence INDICATION AND USAGE UZEDY (risperidone) extended-release injectable suspension for subcutaneous use is indicated for the treatment of schizophrenia in adults. WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. UZEDY is not approved for use in patients with dementia-related psychosis and has not been studied in this patient population. See below for additional Important Safety Information. TV-44749 (olanzapine) is an investigational extended-release injectable suspension for subcutaneous use and is not approved by any regulatory authority for any use and its safety and efficacy are not established. About Schizophrenia Schizophrenia is a chronic, progressive and severely debilitating mental disorder that affects how one thinks, feels and acts. 1 Patients experience an array of symptoms, which may include delusions, hallucinations, disorganized speech or behavior and impaired cognitive ability. 1,2,3 Approximately 1% of the world’s population will develop schizophrenia in their lifetime, and 3.5 million people in the U.S. are currently diagnosed with the condition. 2,3 Although schizophrenia can occur at any age, the average age of onset tends to be in the late teens to the early 20s for men, and the late 20s to early 30s for women. 3 The long-term course of schizophrenia is marked by episodes of partial or full remission broken by relapses that often occur in the context of psychiatric emergency and require hospitalization. 3 Approximately 80% of patients experience multiple relapses over the first five years of treatment, and each relapse carries a biological risk of loss of function, treatment refractoriness, and changes in brain morphology. 4,5,6 Patients are often unaware of their illness and its consequences, contributing to treatment nonadherence, high discontinuation rates, and ultimately, significant direct and indirect healthcare costs from subsequent relapses and hospitalizations. 1,2,3,4,5,6 About UZEDY UZEDY (risperidone) extended-release injectable suspension, for subcutaneous use, is indicated for the treatment of schizophrenia in adults. In clinical trials, UZEDY significantly reduced the risk of schizophrenia relapse. 7,8 UZEDY administers risperidone through copolymer technology under license from MedinCell that allows for absorption and sustained release after subcutaneous injection. UZEDY is the only long-acting, subcutaneous formulation of risperidone available in both one- and two-month dosing intervals. 7 For full prescribing information, visit https://www.uzedy.com/globalassets/uzedy/prescribing-information.pdf . IMPORTANT SAFETY INFORMATION CONTINUED CONTRAINDICATIONS: UZEDY is contraindicated in patients with a known hypersensitivity to risperidone, its metabolite, paliperidone, or to any of its components. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone or paliperidone. WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions: In trials of elderly patients with dementia-related psychosis, there was a significantly higher incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in patients treated with oral risperidone compared to placebo. UZEDY is not approved for use in patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue UZEDY and provide symptomatic treatment and monitoring. Tardive Dyskinesia (TD): TD, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause TD is unknown. The risk of developing TD and the likelihood that it will become irreversible are believed to increase with the duration of treatment and the cumulative dose. The syndrome can develop, after relatively brief treatment periods, even at low doses. It may also occur after discontinuation. TD may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of TD appear in a patient treated with UZEDY, drug discontinuation should be considered. However, some patients may require treatment with UZEDY despite the presence of the syndrome. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment. Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia and diabetes mellitus (DM), in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics, including risperidone. Patients with an established diagnosis of DM who are started on atypical antipsychotics, including UZEDY, should be monitored regularly for worsening of glucose control. Patients with risk factors for DM (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including UZEDY, should undergo fasting blood glucose (FBG) testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including UZEDY, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including UZEDY, should undergo FBG testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of risperidone. Dyslipidemia has been observed in patients treated with atypical antipsychotics. Weight gain has been observed with atypical antipsychotic use. Monitoring weight is recommended. Hyperprolactinemia: As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Orthostatic Hypotension and Syncope: UZEDY may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope. UZEDY should be used with particular caution in patients with known cardiovascular disease, cerebrovascular disease, and conditions which would predispose patients to hypotension and in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication. Falls: Antipsychotics, including UZEDY, may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other fall-related injuries. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of risperidone. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. Leukopenia, Neutropenia, and Agranulocytosis have been reported with antipsychotic agents, including risperidone. In patients with a pre-existing history of a clinically significant low white blood cell count (WBC) or absolute neutrophil count (ANC) or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of UZEDY at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue UZEDY in patients with ANC < 1000/mm 3 ) and follow their WBC until recovery. Potential for Cognitive and Motor Impairment: UZEDY, like other antipsychotics, may cause somnolence and has the potential to impair judgement, thinking, and motor skills. Somnolence was a commonly reported adverse reaction associated with oral risperidone treatment. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that treatment with UZEDY does not affect them adversely. Seizures: During premarketing studies of oral risperidone in adult patients with schizophrenia, seizures occurred in 0.3% of patients (9 out of 2,607 patients), two in association with hyponatremia. Use UZEDY cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including UZEDY, should be used cautiously in patients at risk for aspiration. Priapism has been reported during postmarketing surveillance for other risperidone products. A case of priapism was reported in premarket studies of UZEDY. Severe priapism may require surgical intervention. Body temperature regulation . Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use UZEDY with caution in patients who experience these conditions. ADVERSE REACTIONS The most common adverse reactions with risperidone (≥5% and greater than placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain. The most common injection site reactions with UZEDY (≥5% and greater than placebo) were pruritus and nodule. DRUG INTERACTIONS Carbamazepine and other strong CYP3A4 inducers decrease plasma concentrations of risperidone. Fluoxetine, paroxetine, and other strong CYP2D6 inhibitors increase risperidone plasma concentration. Due to additive pharmacologic effects, the concomitant use of centrally-acting drugs, including alcohol, may increase nervous system disorders. UZEDY may enhance the hypotensive effects of other therapeutic agents with this potential. UZEDY may antagonize the pharmacologic effects of dopamine agonists. Concomitant use with methylphenidate, when there is change in dosage of either medication, may increase the risk of extrapyramidal symptoms (EPS) USE IN SPECIFIC POPULATIONS Pregnancy: May cause EPS and/or withdrawal symptoms in neonates with third trimester exposure. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including UZEDY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinicaland-research-programs/pregnancyregistry/ . Lactation: Infants exposed to risperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and EPS. Fertility: UZEDY may cause a reversible reduction in fertility in females. Pediatric Use: Safety and effectiveness of UZEDY have not been established in pediatric patients. Renal or Hepatic Impairment: Carefully titrate on oral risperidone up to at least 2 mg daily before initiating treatment with UZEDY. Patients with Parkinson’s disease or dementia with Lewy bodies can experience increased sensitivity to UZEDY. Manifestations and features are consistent with NMS. Please see the full Prescribing Information for UZEDY, including Boxed WARNING. About AUSTEDO ® XR Extended-Release Tablets and AUSTEDO ® Tablets AUSTEDO XR and AUSTEDO are the first vesicular monoamine transporter 2 (VMAT2) inhibitors approved by the U.S. Food and Drug Administration in adults for the treatment of tardive dyskinesia and for the treatment of chorea associated with Huntington’s disease. Safety and effectiveness in pediatric patients have not been established. AUSTEDO XR is the once-daily formulation of AUSTEDO. INDICATIONS AND USAGE AUSTEDO ® XR (deutetrabenazine) extended-release tablets and AUSTEDO ® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington’s disease and for the treatment of tardive dyskinesia. IMPORTANT SAFETY INFORMATION Depression and Suicidality in Patients with Huntington’s Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea . Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression. Contraindications: AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington’s disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine. Clinical Worsening and Adverse Events in Patients with Huntington’s Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity . Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects. QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems. Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington’s disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence. Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO. Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects . Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington’s disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets. Please see accompanying full Prescribing Information , including Boxed Warning. About Teva Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a global pharmaceutical leader with a category-defying portfolio, harnessing our generics expertise and stepping up innovation to continue the momentum behind the discovery, delivery, and expanded development of modern medicine. For over 120 years, Teva’s commitment to bettering health has never wavered. Today, the company’s global network of capabilities enables its 37,000 employees across 58 markets to push the boundaries of scientific innovation and deliver quality medicines to help improve health outcomes of millions of patients every day. To learn more about how Teva is all in for better health, visit www.tevapharm.com . Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, which are based on management’s current beliefs and expectations and are subject to substantial risks and uncertainties, both known and unknown, that could cause our future results, performance or achievements to differ significantly from that expressed or implied by such forward-looking statements. You can identify these forward-looking statements by the use of words such as “should,” “expect,” “anticipate,” “estimate,” “target,” “may,” “project,” “guidance,” “intend,” “plan,” “believe” and other words and terms of similar meaning and expression in connection with any discussion of future operating or financial performance. Important factors that could cause or contribute to such differences include risks relating to: our ability to successfully develop and commercialize UZEDY; our ability to successfully develop and commercialize AUSTEDO XR; our ability to develop and obtain regulatory approvals to our late-stage pipeline assets, including olanzapine LAI (TEV-‘749); our ability to successfully execute our Pivot to Growth strategy, including to expand our innovative and biosimilar medicines pipeline and profitably commercialize the innovative medicines and biosimilar portfolio, whether organically or through business development; and other factors discussed in this press release, and in our Annual Report on Form 10-K for the year ended December 31, 2023, including in the sections captioned "Risk Factors.” Forward-looking statements speak only as of the date on which they are made, and we assume no obligation to update or revise any forward-looking statements or other information contained herein, whether as a result of new information, future events or otherwise. You are cautioned not to put undue reliance on these forward-looking statements. ________________________ 1 Substance Abuse and Mental Health Services Administration. Schizophrenia. https://www.samhsa.gov/mental-health/schizophrenia . Accessed November 2023. 2 Velligan DI, Rao S. The epidemiology and global burden of schizophrenia. J Clin Psychiatry. 2023;84(1):MS21078COM5. https://doi-org.libproxy1.nus.edu.sg/10.4088/JCP.MS21078COM5 . 3 Wander C. (2020). Schizophrenia: opportunities to improve outcomes and reduce economic burden through managed care. The American journal of managed care, 26(3 Suppl), S62–S68. https://doi-org.libproxy1.nus.edu.sg/10.37765/ajmc.2020.43013 4 Emsley, R., & Kilian, S. (2018). Efficacy and safety profile of paliperidone palmitate injections in the management of patients with schizophrenia: an evidence-based review. Neuropsychiatric disease and treatment, 14, 205–223. 5 Emsley, R., Chiliza, B., Asmal, L. et al. (2013) The nature of relapse in schizophrenia. BMC Psychiatry 13, 50. 6 Andreasen, N. C., et al. (2013). Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. The American journal of psychiatry, 170(6), 609–615. 7 UZEDY™ (risperidone) extended-release injectable suspension, for subcutaneous injection Current Prescribing Information. Parsippany, NJ. Teva Neuroscience, Inc. 8 Data on file. Parsippany, NJ: Teva Neuroscience, Inc. View source version on businesswire.com : https://www.businesswire.com/news/home/20240406098130/en/ IR Ran Meir +1 (267) 468-4475 Yael Ashman +972 (3) 914 8262 Sanjeev Sharma +1 (973) 658 2700 PR Kelley Dougherty +1 (973) 832-2810 Eden Klein +972 (3) 906 2645 Source: Teva Pharmaceutical Industries Limited