ONTOZRY® (cenobamate) receives European Commission approval for the treatment of drug-resistant focal-onset seizures in adults
Cenobamate provides new hope in bringing patients with epilepsy a step closer to seizure freedom
Rome, 30th March 2021 – Angelini Pharma, an international pharmaceutical company part of the privately held Italian Angelini Group that has recently acquired the biopharmaceutical company Arvelle Therapeutics, announced today that the European Commission (EC) has granted marketing authorization for ONTOZRY® for the adjunctive treatment of focal-onset seizures with or without secondary generalization in adults patients who have not been adequately controlled despite an history of treatment with at least two anti-epileptic medicinal products.
The EC marketing authorization is valid in all European Union Member States plus Iceland, Norway and Liechtenstein.
“ONTOZRY® will be a welcome new treatment option in Europe for adults who have not yet been able to control their focal-onset seizures with available treatments. Treatment-resistant epilepsy has a devastating effect on patients and their families, and we are proud to help address this urgent health challenge,” said Pierluigi Antonelli, CEO Angelini Pharma “Angelini Pharma looks forward to bringing ONTOZRY® to patients across Europe and will continue to address the needs of patients with central nervous system disorders through our innovative product portfolio and pipeline.”
“This approval marks a breakthrough in the treatment of focal-onset seizures in adults with epilepsy. It is very important that patients have a new treatment option because most of them continue to have seizures that can have devastating effects on their lives” said Agnese Cattaneo, Chief Medical Officer Angelini Pharma “There are an estimated six million people in Europe with epilepsy and approximately 40% of adult patients with focal epilepsy have inadequate control of seizures after treatment with two anti-seizure medications (ASMs). The EC approval of cenobamate gives them all hope for a better life”.
“Antiseizure medications introduced during the last three decades have improved our ability to tailor treatment choice to individual needs but have had little impact on seizure outcomes in people with refractory epilepsy” commented Emilio Perucca Professor of Clinical Pharmacology, University of Pavia, and Immediate Past President, International League against Epilepsy “Cenobamate differs from these medications because its use results in unprecedented seizure freedom rates for these patients. This is important because only freedom from seizures can permit a return to a normal and fully productive life”.
The EC approval is based on three key trials involving over 1,900 patients. The pivotal trial (study 017) published in The Lancet Neurology3 is a multicentre, double-blind, randomized, placebo-controlled trial that demonstrated that cenobamate at doses of 100 mg, 200 mg, and 400 mg/day significantly improved seizure control versus placebo for adult patients with focal-onset seizures taking 1-3 ASMs.
Cenobamate demonstrated significantly higher responder rates (percentage of patients achieving ≥50% reduction in seizures) across all doses during the 12-week maintenance phase compared to placebo. The responder rates were 40% (p=0.036), 56% (p<0.001), and 64% (p<0.001), for the 100 mg, 200 mg, and 400 mg groups, respectively, compared to 25% for the placebo arm. Furthermore, 4% (not significant), 11% (p=0.002), and 21% (p<0.001), of patients treated with cenobamate 100 mg, 200 mg, and 400 mg, respectively, reported zero focal-onset seizures (100% seizure freedom) compared with only 1% of placebo treated patients during the maintenance phase.3
The global disease burden of epilepsy is high.4,5 A diagnosis of epilepsy confers significant disability on the individual, including physical, psychological and social issues that negatively impact self-esteem, family environment, relationships, leisure and working life.4,6
In addition, people with epilepsy whose seizures are poorly controlled have higher morbidity and mortality rates and often experience comorbid illnesses, social stigmatisation and an impaired quality of life.7,8
Cenobamate, which was discovered by SK Biopharmaceuticals and SK life science, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of partial-onset (focal) seizures in adults in 2019, and it is commercially available in the U.S under the brand name XCOPRI® (cenobamate tablets) CV.
“The approval by the European Commission is another major milestone in our efforts to increase access to cenobamate and to support patients with a much-needed new treatment option” said Jeong Woo Cho, PhD, President and CEO of SK Biopharmaceuticals and SK life science “As a fully-integrated global pharmaceutical company, we are committed to discovering, developing and delivering new treatment options for epilepsy and other central nervous system disorders to people around the world”
For more information, please contact:
Daniela Poggio - Executive Director Global Communications, Angelini Pharma - daniela.poggio@angelinipharma.com
Hyongki Park - Head of Communications, SK Biopharmaceuticals Co., Ltd. - h.p.comm@sk.com
About Cenobamate
Cenobamate was discovered by SK Biopharmaceuticals and SK Life Science and is an FDA-approved ASM for the treatment of partial-onset seizures in adults (also known as focal-onset seizures). Cenobamate has been approved in the U.S. where it is commercially available under the trademark XCOPRI®9.
Cenobamate is a novel small molecule that provides a unique, dual, complementary mechanism of action aimed at treatment of seizures. 10,11,12 Cenobamate is the only anti-seizure medication which, at clinically relevant concentrations, acts both as a positive allosteric modulator of GABAA receptors at a non-benzodiazepine binding site and preferentially blocks the persistent sodium current.11,12 The unique dual mechanism of action of cenobamate suggests that it has the potential to both prevent seizure initiation and limit seizure spread.13,14,15,16,17
Long-term data of cenobamate is being studied in the open-label extensions of the double-blind placebo control trials as well as the open-label safety study in adults with uncontrolled focal-onset seizures.18 Additionally, cenobamate is being assessed in an ongoing randomized, double-blind, placebo-controlled trial evaluating its safety and efficacy as adjunctive therapy in patients with primary generalized tonic-clonic seizures (NCT03678753).19
Cenobamate has recently gained recognition by healthcare regulatory bodies in the United Kingdom and Germany given its potential use in treatment resistant focal-onset seizures in epilepsy. The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has designated cenobamate as a Promising Innovative Medicine (PIM). A PIM designation is an early indication that a medicinal product is a promising candidate for the Early Access to Medicines Scheme.
In addition, as of August 2020, the German Federal Institute for Drugs and Medical Devices (BfArM) has included cenobamate for the treatment of drug-resistant focal-onset seizures in adults in its list of confirmed drugs for compassionate use (CPU) programmes for one year within the country.
IMPORTANT SAFETY INFORMATION AND INDICATION FOR ONTOZRY® IN THE EUROPEAN UNION
ONTOZRY® has been approved in the EU for the adjunctive treatment of focal-onset seizures with or without secondary generalization in adult patients with epilepsy who have not been adequately controlled despite a history of treatment with at least 2 anti-epileptic medicinal products. The recommended starting dose of cenobamate is 12.5 mg per day, titrated gradually to the recommended target dose of 200 mg per day. Based on clinical response, dose may be increased to a maximum of 400 mg per day.
Cenobamate is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, and patients with familial Short-QT syndrome.
According to the cenobamate EU Risk Management Plan, the occurrence of drug rash with eosinophilia and systemic symptoms (DRESS) has been recognized as an important identified risk of the drug. Important potential risks are hypersensitivity, suicidality (class effect), QT shortening, and reproductive / embryofoetal toxicity.
In clinical trials, the most commonly reported adverse reactions were somnolence, dizziness, fatigue and headache. The approved Product Information of ONTOZRY® includes the routine risk minimisation measures for reducing safety risks in patients treated with the medicinal product.
About Study 0173
Study 017 was a multicentre, double-blind, randomized, placebo-controlled, dose-response study to evaluate the safety and efficacy of cenobamate as an adjunctive therapy in adults (18 to 70 years old) with uncontrolled focal epilepsy despite treatment with 1-3 anti-epileptic drugs (AEDs).
Following an 8-week baseline period, the study participants were randomized to one of three doses of cenobamate (100 mg, 200 mg and 400 mg once daily) or placebo for 18 weeks (6-week titration phase and 12-week maintenance phase). The primary outcomes were median percentage seizure reduction over the entire study and ≥50% responder rate (percentage of patients achieving ≥50% reduction in seizures) during the maintenance phase. Patients who had the option to enrol in an open-label extension of the 017 study will provide additional insight into the long-term clinical efficacy and safety profile of adjunctive cenobamate.
References:
1. Epilepsy Alliance Europe. Background information. https://www.epilepsyallianceeurope.org/about/background/ Last accessed 03.12.2020.
2. Chen Z et al. JAMA Neurol. 2018 Mar 1;75(3):279-286.
3. Krauss GL et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicenter, double-blind, randomized, placebo-controlled, dose-response trial. Lancet Neurol. 2020 Apr;19(4):288-289.
4. Epilepsy: a public health imperative. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
5. ILAE/IBE/WHO. Global Campaign Against Epilepsy: Out of the Shadows. 2003.
6. Kaiser S, et al. Long-term follow-up of topiramate and lamotrigine: a perspective on quality of life. Seizure. 2002;11:356–360.
7. Engel J. Bringing epilepsy out of the shadows. Neurol. 2003;60(9):1412.
8. Engel J. Approaches to refractory epilepsy. Ann Indian Acad Neurol. 2014;17(Suppl 1):S12–7.
9. Cenobamate prescribing information. FDA. Last accessed 20 July, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212839s000lbl.pdf
10. Guignet M, Campbell A, White HS, Epilepsia. 2020 Oct 16. doi: 10.1111/epi.16718. Online ahead of print
11. Nakamura M, et al. Eur J Pharmacol 2019;855:175-182.
12. Sharma R, et al. Eur J Pharmacol 2020;879:173117.
13. Anderson LL et al., Epilepsia 2014; 55(8):1274-1283.
14. Piredda SG et al, J Pharmacol Exp Ther. 1985;232(3):741-745.
15. Stafstrom CE, Epilepsy Curr 2007; 7(1):15-22.
16. Vreugdenhil M et al., Eur J Neurosci., 2004; 19: 2769-2778.
17. White HS et al, Epilepsy Res. 1997;28(3):167-79.
18. Sperling MR, et al. Epilepsia, Feb 2020;61:1099–1108.
19. Randomized, Double-Blind Study to Evaluate Efficacy and Safety of Cenobamate Adjunctive Therapy in PGTC Seizures NCT03678753.