Teva- Pharmaceutical Industries Ltd. TEVA

• Teva’s presentation of findings from six schizophrenia studies at Psych Congress 2024 highlights its commitment to finding new innovations in neuroscience
• Data show TEV-'749 drug delivery technology resulted in no occurrence of Post-Injection Delirium/Sedation Syndrome (PDSS) events to date
• Real-world analyses of UZEDY (risperidone) subcutaneous long-acting injectable reveal high adherence rates and utilization in adults with schizophrenia who have barriers to treatment
  

TEL AVIV, Israel & PARSIPPANY, N.J., Nov. 01, 2024 (GLOBE NEWSWIRE) -- Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), today announced new, positive data on social functioning and quality of life from the Phase 3 Subcutaneous Olanzapine Extended-Release Injection Study (SOLARIS) trial evaluating TEV-'749 in adult patients diagnosed with schizophrenia. In the acute treatment phase of the study (Period 1), TEV-'749 demonstrated significant improvement in social functioning and quality of life across multiple validated measures from baseline to week 8. The systemic safety profile of TEV-'749 was consistent with other approved oral formulations of olanzapine, with no new safety signals identified and no PDSS events reported to date.¹ In addition, in vitro data and interim results from a Phase 1 study evaluating the pharmacokinetic characteristics of TEV-'749 validate that its route of administration and drug delivery technology may effectively address the risk of PDSS development.¹ These studies, highlighting the patient focused outcomes, were presented at Psych Congress 2024 taking place from October 29 – November 2, 2024, in Boston, MA.

Schizophrenia is a complex medical condition which can severely impact quality of life and social functioning. These new results demonstrate the potential benefits TEV-'749 may have for patients utilizing this form of a long-acting injectable (LAI) treatment option including improving quality life and social functioning.¹

“For people living with schizophrenia receiving treatment, outside of symptom control, potential improvements in social functioning and quality of life are of fundamental importance, so we are delighted to share these encouraging TEV-'749 results,” said Eric Hughes, MD, PhD, Executive Vice President of Global R&D and Chief Medical Officer at Teva. “Similarly, the real-world studies evaluating UZEDY^® will help enable healthcare professionals to better understand the impact of unmet social needs - like housing instability and food insecurity - may have on people living with schizophrenia and their treatment. These efforts reflect Teva’s continued commitment to help address the needs of people living with schizophrenia, as we continue to center our research on the patient.”

SOLARIS study Period 1 is an 8-week, randomized, double-blind, placebo-controlled trial in patients aged 18-64 years diagnosed with schizophrenia, followed by an open-label safety period of up to 48 weeks (Period 2). In the study, TEV-'749 significantly improved social functioning and quality of life by week 8 across all three doses evaluated compared to placebo in a hospitalized population. The results showed:

• The mean difference in change in the Personal and Social Performance Scale, a standard measure of social functioning, from baseline to week 8 was superior with TEV-'749 318mg (4.63), 425mg (3.15), and 531mg (4.93) versus placebo (all P<0.05). The mean difference in change to week 4 was statistically significant for TEV-'749 318mg (P<0.05) and numerically greater for all other TEV-'749 doses versus placebo.¹
• Treatment with TEV-'749 significantly improved Schizophrenia Quality of Life Scores, with greater mean difference in change from baseline to week 8 observed at the 318mg (-3.99), 425mg (-5.39), and 531mg (-5.65) doses versus placebo (all P<0.05).¹
• Changes from baseline to week 8 in EuroQoL-5 Dimensions-3 Levels (exploratory endpoint), another quality-of-life measure, were numerically higher at week 8 with TEV-'749 at the 425mg dose versus placebo.¹
  

As previously announced, efficacy results from the SOLARIS trial showed that by week 8, TEV-'749 met its primary endpoint across all three dosing groups, with statistically significant mean differences in the change in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to week 8 (all P<0.0001). The systemic safety profile of TEV-'749 was consistent with other approved oral formulations of olanzapine, with no new safety signals identified and no PDSS events reported to date.

Beyond the SOLARIS study, Teva presented results from in vitro studies that evaluated TEV-'749 against the currently marketed intramuscular olanzapine long-acting injectable for the risk of PDSS, as well as Phase 1 data evaluating the pharmacokinetic characteristics of TEV-'749.¹ In the studies, TEV-'749 maintained controlled-release properties without any burst in olanzapine concentrations even upon direct contact with plasma.¹

“My patients with schizophrenia have a wide range of social backgrounds and experiences, so it’s important that healthcare professionals are able to consider real-world data that incorporate these aspects of life as we consider appropriate treatment options like UZEDY,” said Christoph Correll, MD, Professor of Psychiatry at the Zucker School of Medicine, Hempstead, NY. “In regard to TEV-'749 and the potential lack of PDSS, we may soon be able to offer schizophrenia treatment for patients taking daily oral olanzapine with a long-acting injectable option that may reduce the risk of this potentially life-threatening side effect. This is an important advancement for those who may benefit from a long-acting treatment approach.”

Teva also announced results of real-world analyses with UZEDY (risperidone), the Company’s extended-release injectable suspension of risperidone for subcutaneous use every one or two months for the treatment of schizophrenia in adults, presented at Psych Congress 2024.

The results provide insight into real-world treatment patterns with UZEDY since its approval for the treatment of schizophrenia in adults by the U.S. Food and Drug Administration in April 2023.

Analyses of U.S. claims data from adults living with schizophrenia who received treatment with UZEDY (n=715) examined social determinants of health (SDOH) as well as patterns of adherence. Results reveal high adherence rates in adults living with schizophrenia who have unmet social needs.

• 41% of patients were covered by Medicaid, 8% had Medicare, and 40% had dual coverage.¹
• Of those patients with available data on SDOH (n=189), over half had low educational attainment, lived in poverty, had experienced food insecurity, and/or had limited access to healthcare. A large minority (44% (n=83/189) were additionally affected by housing instability.¹
• 69% were adherent (defined as proportion of days covered greater than or equal to 80%).¹
• A lines of therapy analysis found that use of UZEDY as a first-line treatment option was at 12%. However, patients prescribed UZEDY had most commonly received oral second-generation antipsychotics as their initial therapy.¹

TEV-'749 is an investigational once-monthly subcutaneous LAI of the 2^nd generation antipsychotic olanzapine 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.² Patients experience an array of symptoms, which may include delusions, hallucinations, disorganized speech or behavior, and impaired cognitive ability.^2,3,4 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.^3,4 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.⁴ 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.⁴ 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 with a significant number of patients never achieving full remission.^5,6,7 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.^2,3,4,5,6,7

About Subcutaneous OLAnzapine Extended-Release Injection Study (SOLARIS)
SOLARIS is a multinational, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy, safety and tolerability of olanzapine extended-release injectable suspension for subcutaneous use as a treatment in patients (ages 18-64 years) with schizophrenia. For Period 1 of the study (first 8 weeks), 675 patients were randomized to receive a subcutaneous injection of once-monthly TEV-'749 (low, medium or high dose) or placebo in a 1:1:1:1 ratio. For Period 2, which will last for up to 48 weeks, patients who completed Period 1 were re-randomized and equally allocated to one of the three TEV-'749 treatment groups. The end-of-treatment and follow-up visits will be at 4 and 8 weeks after administration of the last treatment dose, respectively. The primary objective of the Phase 3 SOLARIS study was to evaluate the efficacy of TEV- '749 in adult patients with schizophrenia. A key secondary objective was to further evaluate the efficacy of TEV-'749 based on additional parameters in adult patients with schizophrenia. Assessment of the secondary objective that is still ongoing through Period 2 of the study is to evaluate the safety and tolerability of TEV-'749 in adult patients with schizophrenia.

About olanzapine LAI (TEV-'749)
TEV-'749 (olanzapine) extended-release injectable suspension, for subcutaneous use, is the second product developed by Teva to utilize SteadyTeq™, a copolymer technology proprietary to MedinCell that allows for sustained release of olanzapine at a therapeutic dose over the full one-month dosing interval. SteadyTeq technology is also utilized in UZEDY^® (risperidone) extended-release injectable suspension for subcutaneous use, which was approved by the FDA for the treatment of schizophrenia in adults in April 2023.

Teva leads the clinical development and regulatory process and is responsible for commercialization of these products.

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.^1,8 UZEDY administers risperidone through SteadyTeq™ 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.⁸ 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.

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.

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 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) 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 TEV-'749 (olanzapine LAI) in adult patients diagnosed with schizophrenia; our ability to successfully develop and commercialize UZEDY (risperidone) extended-release injectable suspension for the treatment schizophrenia; our ability to successfully compete in the marketplace, including our ability to develop and commercialize additional pharmaceutical products; 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 our Quarterly Report on Form 10-Q for the second quarter of 2024 and in our Annual Report on Form 10-K for the year ended December 31, 2023, 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. Data on file. Parsippany, NJ: Teva Neuroscience, Inc.
2. ubstance Abuse and Mental Health Services Administration. Schizophrenia. https://www.samhsa.gov/mental-health/schizophrenia. Accessed November 2023.
3. 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.
4. Wander C. (2020). Schizophrenia: Opportunities to Improve Outcomes and Reduce Economic Burden Through Managed Care. The Am J Manag Care. 26(3 Suppl), S62–S68. https://doi.org/10.37765/ajmc.2020.43013.
5. 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 Dis. Treat., 14, 205–223.
6. Emsley, R., Chiliza, B., Asmal, L. et al. (2013) The nature of relapse in schizophrenia. BMC Psychiatry 13, 50.
7. Andreasen, N. C., et al. (2013). Relapse duration, treatment intensity, and brain tissue loss in schizophrenia: a prospective longitudinal MRI study. The Am J Psychiatry, 170(6), 609–615.
8. UZEDY^® (risperidone) extended-release injectable suspension, for subcutaneous injection Current Prescribing Information. Parsippany, NJ. Teva Neuroscience, Inc.

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