UZEDY™ (risperidone) Extended-Release Injectable Suspension Significantly Prolongs Time to Schizophrenia Relapse in RISE Study Results Published in The Lancet Psychiatry

Rhea-AI Summary

Teva Pharmaceuticals announces efficacy and safety findings from the phase 3 RISE study, supporting the FDA approval of UZEDY as a long-acting injectable antipsychotic treatment for adults with schizophrenia. UZEDY significantly prolonged time to impending relapse by up to 5.0 times versus placebo, with once-monthly dosing showing an 80% decreased risk of relapse. The safety profile of UZEDY was consistent with other formulations of risperidone.

• RISE data show UZEDY to be an effective long-acting injectable (LAI) antipsychotic treatment option for adults with schizophrenia, with a known safety profile consistent with other formulations of risperidone¹
• In the RISE study, UZEDY significantly prolonged time to impending relapse by up to 5.0 times (once-monthly dosing) versus placebo in patients with schizophrenia¹
• The U.S. Food and Drug Administration (FDA) approved UZEDY in April 2023 for the treatment of schizophrenia in adults as a subcutaneous injection dosed every one or two months

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 publication of efficacy and safety findings from the phase 3 Risperidone Subcutaneous Extended-Release (RISE) study in The Lancet Psychiatry. The data supported the FDA approval for UZEDY, which was approved in April 2023 for the treatment of schizophrenia in adults as a subcutaneous injection every one or two months using a pre-filled syringe.

In RISE, UZEDY significantly prolonged time to impending relapse by 5.0 times with once-monthly dosing (HR 0.200, 95% CI 0.109–0.367; log rank p<0.0001) and 2.7 times with once-every-two-months dosing (0.375, 0.227–0.618; log rank p<0.0001) versus placebo in patients with schizophrenia, corresponding to a decreased risk of relapse by 80% and 62.5%, respectively.¹ Study findings also show UZEDY provided clinically relevant plasma concentrations within 24 hours of administration and maintained them over the flexible dosing intervals.^1,2 Additionally, the observed safety profile of UZEDY was consistent with other approved formulations of risperidone – reinforcing its potential role as an effective LAI treatment option for adults living with schizophrenia.¹

“Relapse remains a significant and ongoing challenge for patients with schizophrenia as well as their caregivers and physicians, and these RISE study findings demonstrate UZEDY’s long-acting dosing has the potential to effectively prolong time to relapse,” said Eric Hughes, MD, PhD, Executive Vice President of Global R&D and Chief Medical Officer at Teva. “Importantly, a diverse patient population was enrolled in the study, reflecting Teva’s commitment to health equity in research and development as well as ensuring there are clinical insights into the role of UZEDY for every community impacted by schizophrenia.”

In the RISE study, 544 patients were randomized to receive a subcutaneous injection of UZEDY once-monthly (n=183), once-every-two-months (n=180), or placebo (n=181).¹ In this study population, 59% were Black or African American (n=322), 38% White (n=206), 22% were Hispanic or Latinx (n=117), 1% were Asian (n=7), <1% were Native Hawaiian or other Pacific Islander (n=2), <1% did not report a race (n=3), and <1% were considered other race (n=4).¹

“Helping prevent relapses in my patients who live with schizophrenia is critical to protecting their health and goals,” said Christoph Correll, MD, practicing physician and professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY. “The RISE study demonstrates that a long-acting treatment option of a proven antipsychotic molecule may mitigate the risk of relapse, helping address the needs and preferences of patients with schizophrenia.”

UZEDY utilizes SteadyTeq™, a copolymer technology proprietary to MedinCell, that controls the rate and duration of risperidone release.² With this delivery system, therapeutic blood concentrations are reached within 6-24 hours of a single dose.^{1, 2}

To read more on the RISE study findings published online in The Lancet Psychiatry today, click here.

About Schizophrenia

Schizophrenia is a chronic, progressive and severely debilitating mental disorder that affects how one thinks, feels and acts.³ Patients experience an array of symptoms, which may include delusions, hallucinations, disorganized speech or behavior and impaired cognitive ability.^3-5 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.^4,5 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.^6-8 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.^3-8

About the Risperidone Subcutaneous Extended-Release (RISE) Study

The RISE study was a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy of risperidone extended-release injectable suspension for subcutaneous use as a treatment in patients (ages 13-65 years) with schizophrenia.⁹ 544 patients were randomized to receive a subcutaneous injection of TV-46000 once-monthly (q1M), once-every-two-months (q2M), or placebo in a 1:1:1 ratio.⁹ Additional information can be found at https://clinicaltrials.gov/study/NCT03503318.

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.^{2, 10} 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.² For full prescribing information, visit https://www.uzedy.com/globalassets/uzedy/prescribing-information.pdf.

INDICATION AND USAGE

UZEDY (risperidone) extended-release injectable suspension for subcutaneous use is indicated for the treatment of schizophrenia in adults.

IMPORTANT SAFETY INFORMATION

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.

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 D₂ 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/mm³) 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 Teva

Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) has been developing and producing medicines to improve people’s lives for more than a century. We are a global leader in generic and innovative medicines with a portfolio consisting of over 3,500 products in nearly every therapeutic area. Around 200 million people around the world take a Teva medicine every day, and are served by one of the largest and most complex supply chains in the pharmaceutical industry. Along with our established presence in generics, we have significant innovative research and operations supporting our growing portfolio of innovative and biopharmaceutical products. Learn more at 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 the development and commercial success of UZEDY (risperidone) extended-release injectable suspension for the treatment of schizophrenia in adults; our ability to successfully compete in the marketplace, including our ability to develop and commercialize competition for our innovative medicines, our ability to achieve expected results from investments in our product pipeline, our ability to develop and commercialize additional pharmaceutical products, our ability to successfully launch and execute our new 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 the effectiveness of our patents and other measures to protect our intellectual property rights; our substantial indebtedness; our business and operations in general, including, the impact of global economic conditions and other macroeconomic developments and the governmental and societal responses thereto, and costs and delays resulting from the extensive pharmaceutical regulation to which we are subject; compliance, regulatory and litigation matters, including failure to comply with complex legal and regulatory environments; other financial and economic risks; and other factors discussed in our Quarterly Report on Form 10-Q for the second quarter of 2023 and in our Annual Report on Form 10-K for the year ended December 31, 2022, including in the section 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 Kane J, Harary E, et al (2023). Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised clinical trial in the USA and Bulgaria. The Lancet Psychiatry, 10(12), 935-944. https;//doi.org/10.1016/ S2215-0366(23)00288-2.

² UZEDY™ (risperidone) extended-release injectable suspension, for subcutaneous injection Current Prescribing Information. Parsippany, NJ. Teva Neuroscience, Inc.

³ Substance Abuse and Mental Health Services Administration. Schizophrenia. https://www.samhsa.gov/mental-health/schizophrenia. Accessed November 2023.

⁴ 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.

⁵ 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

⁶ 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.

⁷ Emsley, R., Chiliza, B., Asmal, L. et al. (2013) The nature of relapse in schizophrenia. BMC Psychiatry 13, 50.

⁸ 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.

⁹ Clinicaltrials.gov. Study to Evaluate TV-46000 as Maintenance Treatment in Adult and Adolescent Participants With Schizophrenia (RISE). https://clinicaltrials.gov/study/NCT03503318. Accessed November 2023.

¹⁰ Data on file. Parsippany, NJ: Teva Neuroscience, Inc.

View source version on businesswire.com: https://www.businesswire.com/news/home/20231101627268/en/

IR Contacts

Ran Meir, +1 (267) 468-4475

Yael Ashman, +972 (3) 914 8262

Sanjeev Sharma, +1 (973) 658 2700

PR Contacts

Kelley Dougherty, +1 (973) 832-2810

Eden Klein, +972 (3) 906 2645

Source: Teva Pharmaceutical Industries Limited

FAQ

What is the FDA-approved treatment for schizophrenia in adults?

The FDA-approved treatment for schizophrenia in adults is UZEDY, a long-acting injectable antipsychotic.

What were the findings of the RISE study?

The RISE study found that UZEDY significantly prolonged time to impending relapse by up to 5.0 times versus placebo. Once-monthly dosing showed an 80% decreased risk of relapse.

What is the safety profile of UZEDY?

The safety profile of UZEDY was consistent with other formulations of risperidone.

What is SteadyTeq™?

SteadyTeq™ is a copolymer technology proprietary to MedinCell, which controls the rate and duration of risperidone release in UZEDY.

Who conducted the RISE study?

The RISE study was conducted by Teva Pharmaceuticals.