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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/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/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

感谢关注转发，欢迎学术交流请点击此处链接观看CyberSAR系统详细使用教程急性心肌梗死后，早期再灌注是减少心脏损伤、改善临床预后的最有效策略。然而，恢复缺血心肌的血流本身可能会引起损伤（再灌注损伤），其中，微血管功能障碍是一个促成因素。α2B肾上腺素能受体被认为参与了这一过程。本文通过高通量筛选（HTS）鉴定了一种新型α2B拮抗剂，并在此基础上进行了优化，并最终获得有效的、具有选择性和高水溶性的肾上腺素能α2B受体拮抗剂——BAY-6096。优化的关键方面是引入永久带电的吡啶片段，以实现非常好的水溶性，以防止遗传毒性。BAY-6096剂量依赖性降低α2B激动剂诱导的大鼠血压升高，证明了α2B受体在大鼠血管收缩中的作用。由于急性心肌缺血的发病率和死亡率仍然很高，迫切需要新的治疗方法。尽管在过去的几十年里，这些患者的治疗有了显著的进步，但在最近的一项研究中，一年的死亡率据报道为14%。急性心肌梗死多由动脉粥样硬化斑块破裂引起，目前对闭塞的冠状动脉进行及时再灌注无疑是挽救心肌组织免于细胞死亡的最重要途径。然而再灌注不仅终止心肌缺血，而且自身也造成损伤，即所谓的再灌注损伤。研究表明，冠状动脉血流恢复可能导致血管通透性增加，导致水肿、血管收缩增强、微栓塞和毛细血管破坏并出血。血运重建造成的损伤可导致无再流现象，这种现象在介入性再灌注后经常出现，并与不良预后相关。此外，心肌缺血时观察到的高儿茶酚胺浓度可能导致血管收缩，从而干扰小冠状血管的血流（微血管）功能障碍。研究表明，α-肾上腺素能阻断可减轻血管收缩和缺血后左心室功能障碍，从而支持神经机制在心肌梗死中起重要作用的假设。α-肾上腺素能性冠状动脉血管收缩作为应激性稳定性心绞痛的因果机制的证据更大，因为狭窄后的冠状动脉血管对α-肾上腺素能介导的血管收缩作用特别敏感。然而，对于缺血/再灌注，多种机制导致损伤，α肾上腺素受体的相关性仍有待评估。冠状动脉血流的肾上腺素能调节是主要作为血管收缩剂（α受体）和主要作为血管舒张剂（β受体）的肾上腺素受体之间复杂平衡的结果。冠状动脉中存在α1和α2两种α-肾上腺素能受体亚型，两者都位于血管平滑肌细胞上，介导血管收缩。α1肾上腺素受体在大血管中占优势，而α2肾上腺素受体在微循环中占优势。α2和β2受体主要在心肌代谢需求增加的情况下（如运动时）调节小动脉张力和冠状动脉血流。对于动脉粥样硬化的病理情况，多项研究表明，α-肾上腺素能受体介导的血管收缩作用失衡，β-肾上腺素能血管舒张功能受损，加重了冠状动脉血管收缩。α-肾上腺素受体介导的冠状动脉血流作用长期以来受到的关注有限。在动物实验中，生理条件下，静止时α-肾上腺素能性冠状动脉血管舒缩张力很少，交感神经激活时冠状动脉血流量的增加只是有所钝化。Holtz等人首次证明，在麻醉犬中，选择性α2拮抗剂rauwolscine明显比选择性α1拮抗剂prazosin更能减弱去甲肾上腺素引起的冠状动脉阻力增加。α-肾上腺素受体在冠状动脉内α-肾上腺素受体激动剂和心脏交感神经刺激作用下介导冠状动脉收缩的优势后来在麻醉犬制剂中得到证实。在人体中，α2激动剂刺激可显著减少冠状动脉血流量，主要是通过微血管收缩。最近的实验研究清楚地表明，当冠状动脉循环因内皮功能障碍或严重的冠状动脉狭窄而受损时，α肾上腺素能血管收缩是不受约束的，足以减少冠状动脉血流量并诱导心肌缺血。此外，分别用乌拉地尔或优欣宾阻断α1或α2肾上腺素能受体，可减轻血运重建术后冠状动脉血流损伤的减少，再次表明肾上腺素能系统在限制冠状动脉循环扩张能力方面发挥重要作用。由此得出结论：虽然在静止状态下没有观察到血管张力的限制，但冠状动脉储备可能受到限制，特别是在交感神经激活时，正常冠状动脉循环中的小动脉α2肾上腺素受体。α2受体分为α2A、α2B和α2C三种亚型，属于G蛋白偶联七跨膜受体组。α2B受体亚型在小鼠血管平滑肌细胞外周表达介导血管收缩。此外，在人类小冠状血管中也检测到。最近，α2B受体的一种基因（D，缺失）变异被描述为减少激动剂诱导的受体磷酸化和脱敏，导致受体信号传导延长和激动剂刺激后冠状动脉血流量受损。有趣的是，遗传分析显示纯合携带者（DD）α2BD变异与心肌梗死和心源性猝死的发生有显著关联。此外，对α2-肾上腺素能受体激活的反应与人类G蛋白水平上的单核苷酸多态性密切相关。GNB3基因825T等位基因携带者冠脉血管收缩反应增强，心肌缺血的体征和症状发生率较高。基于已收集的α2肾上腺素能性冠状血管收缩参与心肌缺血加重的知识和α2B受体亚型的遗传证据，假设α2B受体可能在缺血性心脏病中具有病理机制作用，而不考虑基因型。为评估α2B受体在心脏微血管血流调节中的潜在作用，需要有效和选择性的α2B肾上腺素受体拮抗剂。然而，目前还没有α2B拮抗剂处于临床开发阶段，也没有明显的候选药物可以选择。文献检索显示，2003年，Juvantia Pharma获得了α2B拮抗剂专利。选择其专利实例之一和两种市售物质进行表征。这三种化合物被证明都缺乏选择性（图1）。所以此后重新利用高通量筛选确定新的α2B拮抗剂，以此作为先导优化的起点。由于急性冠脉综合征期间的药物通常是静脉给药以实现快速起效，除了效力和选择性外，高溶解度是一个重要的优化目标。综上，本研究成功鉴定出一种强效、选择性、高水溶性肾上腺素能α2B受体拮抗剂BAY-6096，可有效降低α2B受体激动剂诱导的大鼠血管收缩。图1.已知α2B受体拮抗剂的例子及其对α2B和选择性因子的效价效价、选择性和溶解度的优化通过重组α2B报告细胞系的uHTS-campaign，从拜耳公司化合物文库中鉴定出苯并咪唑1是人α2B受体的强效拮抗剂（表1）。α1A(>498x)和α2C(>93x)的选择性较好，所以，α2A的选择性（11x）是首先关注的优化参数。大量酰胺侧链类似物的快速合成表明吡啶取代丙酸2作为拮抗剂具有更高的效价和选择性，而区域异构体3和4则没有进展。二甲胺5表明，链上的叔胺可以被α2B受体耐受，这提供了增加极性的选择，从而提高酰胺的溶解度。表1.酰胺侧链提高对α2A选择性的探索为了提高吡啶取代丙酸2（pH 7：0.02g/L）的溶解度，拜尔公司尝试用2-甲基氨基吡啶与氯乙酸6烷基化合成甲胺类似物，但没有得到任何产物。另一方面，4-甲基氨基吡啶与6的烷基化反应（方案1）得到了可以用制备型高效液相色谱分离的化合物。根据质谱和核磁共振谱（见辅助资料），我们只获得了吡啶盐8，而不是7。方案1.吡啶盐8a的合成有趣的是，与HTS hit 1相比，8对α2B表现出有效的活性，对α2A的选择性也有所提高（表2）。此外，水溶液溶解度显著提高（pH 7：0.3g/L 1, 14g/L 8）。表2.探索残基对α2A的选择性影响因此，保留吡啶部分，并将注意力转向α2B拮抗剂进行进一步优化。表2所示的五元杂芳烃取代邻甲氧基可以显著提高8对α2A的选择性。甲基吡唑9仅表现出中等效价，而相应的n-乙基类似物10对α2B的效价几乎与8相当，α2A选择性显著提高。二甲基异噻唑11和二甲基异恶唑12的效果更好。二甲基异恶唑12在研究中被证明是最有效和选择性最强的α2B拮抗剂，对α1A(>680×)和α2C(>510×)也有很高的选择性，并被选中进行更详细的表征。此后测试了其在溶液中的化学稳定性。在24小时内，在pH值为1、7或10时，没有检测到分解。同样，12在大鼠或人血浆中搅拌或在谷胱甘肽存在时也是稳定的。与微粒体（大鼠、狗）或肝细胞（大鼠、犬、人）孵育后，几乎没有代谢产物形成，可能部分归因于12（Caco-2, PAB 3.6nm/s）的低通透性。由于吡啶取代基的永久电荷（pH 7：19.5g/L），水溶液溶解度很好。对包括肾上腺素能β受体在内的75个靶点进行脱靶筛选，结果显示没有击中靶点。为了评估12与α2B受体的结合是否可逆，进行了洗脱实验。经拮抗剂处理的α2B细胞两次洗涤后，IC50值下降了57倍，表明其结合是可逆的。Ames检测结果呈阳性。假设这可以归因于阳性苯胺13的形成（图2），在血浆、微粒体或肝细胞孵育12后检测到微量苯胺13。图2.Ames试验结果为了排除12的吡啶部分对观察到的遗传毒性负责，对Ames阴性的间甲苯胺（14）的酰胺进行了测试，发现Ames阴性。尽管在降解培养中未观察到15和16，但由于芳香胺通常产生Ames阳性结果，因此对它们进行了筛选。然而，15和16被证明是Ames阴性。据此推断，通过强效诱变13，12酰胺的轻微裂解导致Ames试验呈阳性。因此，下一个优化周期的重点是鉴定Ames阴性、强效、选择性和高水溶性α2B拮抗剂。Ames-阴性α2B拮抗剂的鉴定首先尝试用潜在的比13更缺电子的Ames阴性苯胺取代苯胺13。这以氮杂-苯并咪唑17和氮杂-苯并吡唑18-20为代表。然而，引入一个额外的氮原子，要么导致Ames阳性的吡并咪唑17，要么导致效价的显著丧失。表3.核心修饰及其对α2B和Ames遗传毒性的影响为了使配体结合合理化，利用Schrödinger的Prime Software（3nya）基于α2B受体的X射线结构建立了α2B受体的同源性模型。应用Schrödinger的诱导配合对接（Induced Fit Docking）为化合物12寻找合适的结合姿势。发现12填充疏水结合位点，如图3a所示。中心苯并咪唑的未取代氮与细胞外环2的GLN-168相互作用。带负电的ASP-92与化合物12的永久带正电的吡啶取代基相互作用，并在配体的酰胺桥上附加一个氢键。氨基吡啶取代基上的胺与GLN-409形成氢键。12的异恶唑部分与PHE-388发生π堆积。为了深入了解与化合物12类似的配体的结合，我们模拟化合物12的既定结合姿态构建了这些化合物与受体的配合物。配体放置后，对配合物进行优化,构建的结合模式可以定性地解释表3中描述的SAR，特别是化合物18和19在与GLN-168相互作用的正确位置没有氢键受体的活性丧失。化合物20通过其中心核心的吡啶部分与GLN-168弱相互作用，这可能是受体上保留一些活性的原因（图3b）。图3.（a）化合物12在α2B受体同源模型中的结合位。（b）化合物20在α2B受体同源模型中的结合位。化合物用绿色的碳原子、蓝色的氮原子和红色的氧原子来表示。GLN-168、ASP-92和PHE-388直接与配体相互作用。关键的氢键和电荷相互作用用黄色虚线表示。在第二种策略中，我们合成了不同的酰胺生物异构体，以避免形成Ames阳性苯胺，如13。氟乙烯和含三氟乙胺分子21和22的效价显著下降（图4）。具有延伸烷基链的倒置酰胺23获得了更有希望的结果。23对α2B的拮抗作用略低于酰胺12，对α1A(>169x)、α2A(>169x)和α2C (>169x)具有良好的选择性。最重要的是，23和所有随后合成类似化合物的遗传毒性测试均为Ames阴性。图4. 酰胺生物同分酯和反相酰胺23对α2B效价的影响及Ames试验在这一突破之后，拜耳公司首先尝试在保持选择性的同时恢复效力。以12等苯并咪唑为例，根据同源性模型，双环核心五元环对位对应的sp2杂化氮原子对实现有效的α2B拮抗作用很重要。基于这一思路，合成了核心修饰的化合物24（BAY-6096）和25（图5）。苯并三唑25仅表现出中等效价，而咪唑吡啶24则是一种高效的选择性α2B拮抗剂，而拮抗剂45（24的甲酸酯）对效力和选择性的影响可以忽略不计（图6）。图5.咪唑吡啶与苯并三唑胺的比较图6.α2B拮抗剂(45)对α2B激动剂(44)诱导的血压升高的剂量依赖性抑制作用结果表明，24中的咪唑吡啶核比23中的苯并咪唑核更有效，同时具有较高的选择性。随后在保持24咪唑吡啶不变的情况下进行SAR分析（表4）。表4.含吡啶基团酰胺侧链的探索从24中存在的对甲基胺中省略甲基导致α2B拮抗剂的效力大大降低（26）。使对取代基稍长（27）或用亚甲基（28）交换对甲氨基基的氮也产生比24效力低的化合物。采用对二甲氨基部分（29）产生与24类似的有效化合物，但没有选择性。在（30）中含有的甲基胺部分会使α2B拮抗剂的效力降低，在邻位上额外的甲基也是如此（31）。延长亚甲基链也没有改善（32）。没有发现一个改进的吡啶残基，因此接下来将酰胺部分从24保持不变（表5）。表5.咪唑吡啶羧胺残基的研究根据表2和α2B拮抗剂24，采用二甲基取代的五元杂芳基可以得到强效和选择性的化合物。转移到吡唑上，发现33的效力只比24低2倍，但同样具有选择性。另一方面，区域异构体34几乎没有活性。在35中，我们看到了与化合物8相似的结果，邻甲氧基苯基取代基可以产生一位数纳米摩尔的α2B拮抗剂，尽管对α2A只有中等的选择性。吡啶衍生物36的选择性高于35，但不如含有α2B拮抗剂24和33的五元杂芳基。综上所述，24（BAY-6096）仍然是我们的最佳化合物。BAY-6096抑制活性与药代动力学表征BAY-6096（24）的广泛体外分析开始于对肾上腺素能受体的效价和选择性信息的补充。人α2B受体被抑制的IC50为14nM（图5），而人缺失变体α2BD（19）在25nM浓度下被抑制50%。总之，24足以评估α2B介导的动物药理作用。此外，24与其他肾上腺素能受体相比表现出非常好的选择性（表6）。表6. α2B IC50及其对BAY-6096肾上腺素能受体的选择性（24）BAY-6096（24）在人肝微粒体中的体外代谢稳定性较高。孵育2小时显示低周转率，可能在异恶唑的两个甲基之一上可见一些羟基化。渗透性低(Caco-2, PAB 3.0nm/s)，这可能有助于肝细胞孵育(CLrat 10-4L/kg/h, CLhuman 10-4L/kg/h)中观察到的高代谢稳定性。对大鼠、狗、猴子和人类肝细胞中形成的代谢物的检查显示没有反应性途径。在包括人类在内的一些物种中，24的蛋白结合率很低（未结合的比例:大鼠79%，犬82%，猴子92%，人类85%）。在20μM内对CYP1A2、2C8、2C9、2D6、3A4酶无抑制作用，在211μM内对CYP1A2、3A4酶无诱导作用。对67个非靶点和心脏离子通道的相互作用进行了评估，显示未有额外结合。Ames或微核试验未发现遗传毒性。α2B拮抗剂24的体内药代动力学行为通过大鼠和狗的静脉给药进行评估（表7）。两种动物的清除率都很高，平均停留时间（MRT）也很低。表7.α2B拮抗剂BAY-6096（24）在特定物种中的药动学特征a通过静脉给药（剂量0.3mg/kg）血浆中99%/DMSO 1%（大鼠）或水中50%/PEG400 40%/EtOH 10%（狗）的溶液得出数值；bPlasma间隙；c稳定状态下的分布体积；d静脉注射后平均停留时间BAY-6096（24）在人类中也会显示出高清除率和短MRT（数据未显示）。如果α2B拮抗剂能够减少再灌注损伤，则半衰期短可视为对易感心肌梗死患者有益。如果持续输注24，例如在经皮冠状动脉介入治疗期间，24的浓度应在停止输注后迅速降至相关水平以下，以此增加手术的安全性。BAY-6096的药效学研究α2-肾上腺素能受体介导内源性儿茶酚胺、肾上腺素和去甲肾上腺素的多种生物学效应。携带α2受体亚型编码基因缺失的基因靶向小鼠，揭示了α2B受体作为血管收缩剂的肾上腺素能受体多样性的生理意义。在人体中，α2B受体变异体的受体脱敏性降低和活性延长与急性冠状动脉事件的风险增加有关，这表明抑制α2B可能有利于治疗冠状动脉血管收缩。为了在第一个简单的动物实验中研究化合物的α2B拮抗剂作用，拜耳公司使用了麻醉大鼠的血压记录，与许多其他物种不同，大鼠在输注α2B激动剂后显示出强烈且可重复的血压升高。在这些实验中，大鼠连续三天用利血平预处理，从而使其对肾上腺素能刺激敏感。与基线相比，α2B激动剂44使平均动脉血压升高43%。在使用α2B拮抗剂45之后再使用α2B激动剂44，在45的最高剂量下，血压的升高大约减少了一半（图6）。α2B拮抗剂对α2B激动剂诱导的血压升高的剂量依赖性阻断提示α2B受体在大鼠血管收缩中的作用。然而，观察到的效果很可能不是由于冠状动脉微血管血流的调节。结论综上，这篇文章作者优化了一个低水溶性和低α2A受体选择性的HTS筛选靶点，在此基础上获得水溶性和选择性α2B拮抗剂。所得拮抗剂结构的主要特点是结合了一个永久带电的吡啶片段和一个酰胺反转。对甲氨基吡啶组被证明与α2B的效价兼容，同时提供了大量的水溶性，这对于静脉应用（如急性冠脉综合征治疗中典型使用的应用）非常重要。其中，苯胺酰胺的遗传毒性是通过酰胺转化来规避的，这最初是以降低效力为代价。将核心改为咪唑吡啶，得到了有效的、选择性的、高水溶性的α2B拮抗剂BAY-6096（24）。在利血平预处理大鼠中，BAY-6096（24）剂量依赖性地降低α2B激动剂诱导的血压升高，表明α2B受体在大鼠血管收缩中的作用。文章来源J. Med. Chem. 2023, 66, 4659−4670请点击此处链接观看CyberSAR系统详细使用教程1.药渡CyberSAR结合药物设计思想，挖掘了文献及专利报道的活性的结构，通过CyberSAR以方便快速获得研发人员兴趣靶向结构，以供开拓思路，就本文涉及Adrenergic receptor alpha-2举例如下：2.在靶点界面选中“化学空间”选项标签下级联“聚类结构视图”选项卡，可以将CyberSAR平台收录的文献和专利具有关于靶点相关实验测试活性的分子以“母核结构聚类”的形式展示。其中“绿色字体高亮的”为文献报道的体外酶、细胞活性测试实验中IC50<100nM的活性分子结构、具体实验、实验结果及实验来源。3.在靶点界面选中“化学空间”选项标签下级联“原始结构视图”选项卡，可以将CyberSAR平台收录的文献具有关于靶点相关实验测试活性的分子以“研发阶段时光轴“的形式展示。其中绿色高亮展示了潜力Hit。4.在靶点界面选中“适应症”选项标签，可以可视化直观分析现收集的各类大数据。5.在靶点界面选中“实验设计”选项标签，可以将CyberSAR平台收录的文献相关靶点相关实验设计进行展示，为实验设计提供思路与支持。登录方式CyberSAR在电脑浏览器端登录网址：https://data.pharmacodia.com/cybersar/，欢迎猛烈试用。请点击此处链接观看CyberSAR系统详细使用教程如需进一步沟通，请扫码添加微信联系药渡赵博士或药渡CyberSAR沟通群。