Results of a Randomised Study Showing that Adjunctive Cenobamate Significantly Improved Seizure control in Adults with Uncontrolled Focal Seizures Published in Neurology
ZUG, SWITZERLAND – May 21, 2020 – Arvelle Therapeutics, an emerging biopharmaceutical company focused on bringing innovative treatments to patients suffering from CNS disorders, today announced the publication of a key trial (013 Study) in Neurology, the official journal of the American Academy of Neurology (AAN). The data presented suggest that a significantly higher proportion of adults with uncontrolled focal onset seizures were able to achieve seizure-freedom (zero seizures) (28% vs 9%; p=0.0001) during the maintenance phase when treated with adjunctive cenobamate vs placebo.1 In addition, the interim results of an ongoing phase 3 safety study of cenobamate in 1339 adults with uncontrolled focal seizures (021 Study) were published in Epilepsia, the official journal of the International League Against Epilepsy (ILAE). The interim report has shown a high retention rate of 83% at six months and, in the study, cenobamate has been shown to be generally safe and well tolerated as an adjunctive treatment.
Neurology publication of 013 Study
In this double-blind, randomised, placebo-controlled trial, 222 uncontrolled focal onset seizure patients taking 1–3 anti-seizure medications (ASMs) were randomized to once daily placebo or cenobamate 200 mg to study safety and efficacy in a 12-week double-blind treatment period, which included a 6-week titration phase and a 6-week maintenance phase. On average patients enrolled in the study were having 6.5 seizures per month. Key study findings included a significantly greater reduction in median seizure frequency with cenobamate compared to placebo (56% vs 22%; p<0.0001), and significantly more cenobamate patients achieved a 50% or greater reduction in seizure frequency during the double-blind period compared to those in the placebo group (50% vs 22%; p<0.0001). Additionally, post-hoc analyses of the maintenance phase showed that significantly greater percentages of patients taking cenobamate versus placebo achieved seizure reduction rates of ≥75% (39% vs 21%; p=0.0019), ≥90% (34% vs 9%; p<0.0001), and 100% or zero seizures (28% vs 9%, p=0.0001).1
Treatment-emergent adverse events (TEAEs) reported in >10% in either group (cenobamate vs placebo) included somnolence (22% vs 12%), dizziness (22% vs 17%), headache (12% vs 13%), nausea (12% vs 5%), and fatigue (11% vs 6%). Study discontinuation rates among all randomized patients were similar in the cenobamate (n=11, 10%) and placebo (n=10, 9%) groups.1
Commenting on the study results, Ilise Lombardo MD, Co-Founder and Chief Medical Officer at Arvelle Therapeutics, said: “This trial represents an important advancement in the development of cenobamate for adult patients with focal onset seizures, and its publication in Neurology adds to the body of evidence for the efficacy and safety of cenobamate. The study results suggest that cenobamate may offer a potential treatment option for patients who continue to have seizures despite the use of available treatments.”
Epilepsia interim report of phase 3 s afety study (021 Study)
Coinciding with the Neurology publication, an interim report of an ongoing, open-label, phase 3 safety study of cenobamate in 1339 adults with uncontrolled focal seizures, was published in Epilepsia. In the report, no new safety issues were identified when cenobamate was used as an adjunctive treatment. In addition, a high retention rate of 83% was observed beyond six months, and no cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported.2
Commenting on the Epilepsia report, Ilise Lombardo, said: “Many patients with epilepsy discontinue their anti-seizure medication because of intolerable side effects or lack of efficacy, diminishing their ability to achieve seizure control. The high retention rates of 83% seen in this interim report means that more people may potentially benefit from cenobamate. Retention rates provide an indication of overall clinical outcome, serving as a combined proxy measure for efficacy and safety over time.3 It´s also reassuring to see that no cases of DRESS syndrome occurred, suggesting that initiating cenobamate at a low dose and undergoing a simple titration schedule might minimize the risk of DRESS.”
“Both study results suggest that cenobamate may play an important role in overcoming the ongoing burden for a significant number of patients with epilepsy who continue to have seizures despite the use of available treatments. These results are very encouraging for many patients with focal onset epilepsy” she added.
In March 2020, Arvelle announced the European Medicines Agency’s (EMA) acceptance of the marketing authorization application (MAA) for cenobamate for the adjunctive treatment of focal onset seizures in adults with epilepsy. This validation of the MAA confirms Arvelle’s application is complete and marks the start of the assessment process for cenobamate.
There are an estimated six million people in Europe with epilepsy3 and approximately 40% of adult patients with focal epilepsy have inadequate control of seizures after treatment with two ASMs.4
For further information on the trial published in Neurology, please click here.
For further information the trial published in Epilepsia, please click here.
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About Study 013 (NCT01397968) 1
Study 013 is a multi-centre, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of cenobamate 200 mg as an adjunctive therapy in adults (18–65 years old) with uncontrolled focal (partial) onset seizures. In the study, 222 patients were randomized (113 received cenobamate and 109 received placebo) and 90% of patients, in both the treatment and placebo groups, completed double-blind treatment. Patients must have been taking 1-3 ASMs at stable doses for at least 12 weeks prior to randomization and continued taking concomitant ASMs at stable doses during the double-blind treatment period.
The primary endpoint of the study was the percent change in median seizure frequency (from baseline) per 28 days during double-blind treatment.
About Study 021 (NCT02535091)2
Study 021 is a large, global, phase 3, multi-centre, open-label study assessing the safety of cenobamate as adjunctive therapy in adults (18-70 years old) with uncontrolled focal (partial) onset seizures, taking at least one ASM. Cenobamate was initiated at 12.5 mg/day and increased at 2-week intervals to 25, 50, 100, and 200 mg/day. Further increases to 400 mg/day using bi-weekly 50 mg/day increments were allowed. The study is currently ongoing and the results published represent only interim results. The ongoing phase 3 study as well as the open-label portions of complementary studies will provide additional data on the long-term safety profile of adjunctive cenobamate when used in patients with uncontrolled focal epilepsy.
About Arvelle Therapeutics
Arvelle Therapeutics is an emerging biopharmaceutical company focused on bringing innovative solutions to patients suffering from CNS disorders. Arvelle is responsible for the development and commercialization of cenobamate, an investigational ASM, in the European market. Arvelle is headquartered in Switzerland and received start-up financing of $207.8 million, one of the largest initial financing commitments for a European-focused biopharmaceutical company, with investments from a global syndicate including NovaQuest Capital Management, BRV Capital Management, LSP, BioHealth Partners, Andera Partners, F-Prime Capital and KB Investments. More information is available at http://Arvelletx.com
Cenobamate was discovered by SK Biopharmaceuticals and SK life science and is a new FDA-approved ASM for the treatment of partial-onset (focal) seizures in adults. Cenobamate has been approved in the US where it is commercially available under the trademark XCOPRI®. In early 2019, SK Biopharmaceuticals entered into an exclusive licensing agreement with Arvelle Therapeutics to develop and commercialize cenobamate in Europe.
Cenobamate is believed to work through a unique, dual, complementary mechanism of action: Enhancing inhibitory currents through positive modulation of GABAA receptors at a non- benzodiazepine binding site, and decreasing excitatory currents by both inhibiting the persistent sodium current and enhancing the inactivated state of voltage-gated sodium channels.
Long term data of cenobamate is being further studied in the open-label extensions of the double- blind placebo control trials as well as the open-label safety study in adults with focal-onset seizures. 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).
- Chung SS et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. Neurology 14 May 2020. https://doi.org/10.1212/WNL.0000000000009530 Last accessed 16 May 2020.
- Sperling ME et al. Cenobamate (YKP3089) as adjunctive treatment for uncontrolled focal seizures in a large, phase 3, multicenter, open-label safety study. Epilepsia 12 May 2020.https://doi.org/10.1111/epi.16525. Last accessed 13 May 2020.
- Guideline on clinical investigation of medicinal products in the treatment of epileptic disorders. CHMP Draft. 26 July 2018https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-clinical-investigation- medicinal-products-treatment-epileptic-disorders-revision-3_en.pdf Last accessed 18 May 2020
- Epilepsy Alliance Europe. Background information. https://www.epilepsyallianceeurope.org/about/background/ Last accessed 8 November 2019
- Chen Z et al. Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs: A 30-Year Longitudinal Cohort Study. JAMA Neurol.2018 Mar 1;75(3):279-286.