Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) today announced the Phase 2/3 ARTISTS 1 and Phase 3 ARTISTS 2 trials designed to evaluate deutetrabenazine compared to placebo for the treatment of tics in pediatric patients with moderate to severe Tourette Syndrome failed to meet the primary endpoint of reduction in motor and phonic tics as assessed by the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS).
In the data received this week, the most commonly reported adverse event in the ARTISTS 1 and ARTISTS 2 studies were headache, somnolence and fatigue. In this population, no new safety signals were identified that were inconsistent with the known safety profile of deutetrabenazine.
“The results of the trials are disappointing, especially as there is such an unmet need for this community of pediatric patients,” said Dr. Hafrun Fridriksdottir, Executive Vice President, Global R&D, at Teva. “As we assess a path forward, Teva is especially grateful to the investigators, patients and families who contributed to these studies for such an important patient population.”
The studies were conducted in partnership between Teva and Nuvelution Pharma, Inc.
Deutetrabenazine was approved by the FDA as AUSTEDO® (deutetrabenazine) tablets for the treatment of chorea associated with Huntington’s disease in April 2017 and for tardive dyskinesia in adults in August 2017.
About ARTISTS 1
The ARTISTS 1 study was a multicenter, randomized, double-blind, placebo-controlled, Phase 2/3 study to evaluate the safety, tolerability and efficacy of deutetrabenazine in 119 pediatric patients (6-16 years) with moderate to severe Tourette Syndrome. Patients received either deutetrabenazine or placebo using a 1:1 randomization over 12 weeks of dosing. The primary endpoint was the change in the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) from baseline to week 12 between placebo and active treatment groups.
About ARTISTS 2
The ARTISTS 2 study was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study to evaluate the safety, tolerability and efficacy of deutetrabenazine in 158 pediatric patients (6-16 years) with moderate to severe Tourette Syndrome. Patients received either deutetrabenazine (low dose or high dose) or placebo using a 1:1:1 randomization over eight weeks of dosing. The primary endpoint was the change in the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) from baseline to week eight between placebo and active treatment groups.
About Tourette Syndrome
Tourette Syndrome is a neurodevelopmental disorder with onset before age 18 years, characterized by motor and phonic tics that persist for greater than one year. Symptoms of Tourette Syndrome typically occur first in early childhood, with peak severity around the age of 10 years. Most individuals with Tourette Syndrome experience improvement of symptoms in late adolescence and into adulthood.
About AUSTEDO® (deutetrabenazine)
AUSTEDO® is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved by the U.S. Food and Drug Administration for the treatment of tardive dyskinesia in adults and for the treatment of chorea associated with Huntington’s disease. Safety and effectiveness in pediatric patients have not been established.
Indications and Usage
AUSTEDO® is indicated for the treatment of chorea associated with Huntington’s disease and for the treatment of tardive dyskinesia in adults.
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: Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase in the corrected QT (QTc) interval. A clinically relevant QT prolongation may occur in some patients treated with AUSTEDO® who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor. Dose reduction may be necessary. The use of AUSTEDO® in combination with other drugs known to prolong QTc may result in clinically significant QT prolongations. For patients requiring AUSTEDO® doses greater than 24 mg per day who are using AUSTEDO® with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of AUSTEDO® or the other drugs. 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.
CYP2D6 Metabolism: In patients who are poor CYP2D6 metabolizers or are taking strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO® should not exceed 36 mg (maximum single dose of 18 mg).
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.
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.
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 regarding the results of two registration trials of deutetrabenazine in pediatric patients with Tourette Syndrome, 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. Important factors that could cause or contribute to such differences include risks relating to:
and other factors discussed in our Annual Report on Form 10-K and subsequently filed reports, including in the sections captioned "Risk Factors” and “Forward Looking Statements.” 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.
Kevin C. Mannix
972 (3) 926-7516
972 (54) 888 5898