Findings published in CNS Drugs from Open-Label Extension Study Add to Safety and Tolerability Profile Observed in Earlier Studies

Teva Pharmaceuticals, a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), today announced results from the ARC-HD (Alternatives for Reducing Chorea in Huntington’s Disease) trial, an approximately 3-year open-label, single-arm, 2-cohort, multicenter extension study evaluating the safety and tolerability of long-term treatment with AUSTEDO^® (deutetrabenazine) tablets for chorea associated with Huntington’s Disease (HD). The ARC-HD study was conducted by Teva in partnership with the Huntington Study Group (HSG).

ARC-HD results showed that treatment with AUSTEDO had a safety and tolerability profile comparable with the First-HD randomized, double-blind, placebo-controlled, 12-week study. In ARC-HD medication compliance rates were greater than 90% over the ~3 year open-label extension period. Over this full period, AUSTEDO improved and maintained chorea control in both the Rollover cohort and the Switch cohort, as measured by the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score.¹

“These data provide important insight into the long-term use of deutetrabenazine for the treatment of chorea associated with Huntington’s disease, which can have a significant functional impact on people’s lives,” said Samuel Frank, MD, Associate Professor of Neurology and Director of HDSA Center of Excellence at Beth Israel Deaconess Medical Center, Boston, and lead author of the study. “Results of this study add to the safety and tolerability profile and support deutetrabenazine as a treatment choice for this progressive condition. We are deeply grateful to the researchers, patients and their families who played an integral role in this study.”

The analysis included a total of 119 patients: 82 patients who completed the randomized, double-blind placebo-controlled First-HD trial (Rollover cohort), and 37 patients who converted overnight from a stable tetrabenazine dose to AUSTEDO with subsequent dose adjustments (Switch cohort). The average mean daily dose of AUSTEDO at the conclusion of the study was 45.7 mg. The findings were published online in CNS Drugs.

“Chorea is one of the most striking physical manifestations of Huntington’s Disease that occurs in approximately 90% of HD patients,” said Eran Harary, MD, SVP, Global Head of Specialty R&D at Teva. ² “As a disease that can have significant functional impact on patients’ and caregivers’ lives, we’re proud to share these new data to provide valuable insights for this community of patients and for those who provide care to them each day.”

3 Year Safety Results

Exposure-adjusted incidence rates (EAIRs) were used to compare the frequency of adverse events (AEs) in this long-term open-label extension study with those in the short-term First-HD study. EAIRs related to AEs were comparable to those in the pivotal First-HD trial.

Common AEs (≥4% in either cohort) in the Rollover and Switch cohorts, respectively, included: fall, depression, anxiety, insomnia, somnolence, and akathisia. There were no new safety concerns.

3 Year TMC and Total Motor Score (TMS) Findings

The study showed that mean TMC scores decreased from baseline to Week 8 and maintained chorea control through ~3 years.

Key results include:

• In patients who rolled over from the pivotal study, from baseline to Week 8 there was a:
  • 4.5-point reduction in mean chorea scores (SD: 3.1; 95% CI: –5.2, –3.7);
  • 7.1-point reduction in mean TMS (SD: 7.3; 95% CI: –8.8, –5.5);
• In patients who switched overnight from tetrabenazine, from baseline to Week 8 there was a:
  • 2.1-point reduction in mean chorea scores (SD: 3.3; 95% CI: –3.1, –1.0).
  • 2.4-point reduction in mean TMS (SD: 8.7; 95% CI: –5.4, 0.5).
• Reductions in TMC were maintained for all subjects in both cohorts from Week 8 to Week 145 (or to the end of treatment, whichever was earlier; –0.5 [SD: 5.2; 95% CI: –1.9, 1.0]).

HD is a rare and fatal neurodegenerative disorder, affecting approximately 35,000 people in the United States.^3,4 Chorea is associated with involuntary, random and sudden, twisting and/or writhing movements and is one of the most striking physical manifestations of this disease.² Chorea can interfere with daily function, cause social isolation, and increase risk of injury, leading to decreased quality of life for patients with HD.¹

About AUSTEDO (deutetrabenazine) Tablets

AUSTEDO is the first and only vesicular monoamine transporter 2 (VMAT2) inhibitor approved by the U.S. Food and Drug Administration for the treatment of tardive dyskinesia (TD) in adults and for the treatment of chorea associated with Huntington’s disease. TD is a movement disorder that is characterized by uncontrollable, abnormal, and repetitive movements of the face, torso, and/or other body parts, which may be disruptive and negatively impact individuals. Chorea – involuntary, random and sudden, twisting and/or writhing movements – is one of the most striking physical manifestations of Huntington’s disease and occurs in approximately 90% of patients. Chorea can have a significant impact on daily activities and progressively limit peoples’ lives. Safety and effectiveness in pediatric patients have not been established.

Indications and Usage

AUSTEDO (deutetrabenazine) tablets is 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 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 is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.

Contraindications: AUSTEDO is contraindicated in patients with Huntington’s disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO is 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 (Xenazine^®) or valbenazine (Ingrezza^®).

Clinical Worsening and Adverse Events in Patients with Huntington’s Disease: AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.

QTc Prolongation: AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO is administered within the recommended dosage range. 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; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.

Akathisia, Agitation, and Restlessness: 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 dose should be reduced; some patients may require discontinuation of therapy.

Parkinsonism: 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 dose should be reduced; some patients may require discontinuation of therapy.

Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of 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 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.

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.

Please see accompanying full Prescribing Information, 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 specialty 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 specialty and biopharmaceutical products. Learn more at www.tevapharm.com.

About Huntington Study Group

Founded in 1993, the Huntington Study Group (HSG), a global not-for-profit organization, together with its wholly owned for-profit subsidiary, HSG Clinical Research, Inc., designs, implements, manages, and conducts clinical research trials. The HSG, a leader in conducting clinical trials for HD, has more than 800 HD experts at over 130 HSG Credentialed Research Sites worldwide. The mission of the HSG is seeking treatments that make a difference for those affected by HD. The HSG also offers educational services like CME4HD™ for healthcare professionals and care providers on treating patients with HD. For more information, visit our website www.huntingtonstudygroup.org. 

The ARC-HD study was conducted in cooperation between the HSG and the Clinical Trials Coordination Center (CTCC) at the University of Rochester Medical Center's Center for Health + Technology (CHeT). For more information, visit the CTCC website https://www.urmc.rochester.edu/health-technology/our-expertise/clinical-trials-coordination.aspx.

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 commercial success of AUSTEDO; our ability to successfully compete in the marketplace, including our ability to develop and commercialize biopharmaceutical products, competition for our specialty products, including AUSTEDO, AJOVY^® and COPAXONE^®; our ability to achieve expected results from investments in our product pipeline, our ability to develop and commercialize additional pharmaceutical products, 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 uncertainty regarding the COVID-19 pandemic and the governmental and societal responses thereto; our ability to successfully execute and maintain the activities and efforts related to the measures we have taken or may take in response to the COVID-19 pandemic and associated costs therewith; costs and delays resulting from the extensive pharmaceutical regulation to which we are subject or delays in governmental processing time due to travel and work restrictions caused by the COVID-19 pandemic; 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 2022 and in our Annual Report on Form 10-K for the year ended December 31, 2021, 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 Frank, S. Testa C, Edmondson, M. et al. The Safety of Deutetrabenazine for Chorea in Huntington Disease: An Open-label Extension Study. CNS Drugs. 2022. [to be updated upon publication]

² A Physician’s Guide to the Management of Huntington’s Disease (3rd edition). Huntington’s Disease Society of America (HDSA) website.

³ Fisher E, Hayden R. Multisource ascertainment of Huntington disease in Canada: prevalence and population at risk.; Mov Disord. 2014;29(1):105-114.

⁴ Huntington’s disease: a family guide. HDSA website. http://hdsa.org/wp-content/uploads/2015/03/HDSA_FamilyGuide.pdf. Published 2016. Accessed September 2022.

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