Arvelle Therapeutics Files for IPO to Advance Cenobamate Commercialization in Europe for Focal-Onset Seizures

Epilepsy is one of the three major central nervous system (CNS) disorders in humans, with a prevalence second only to stroke. It is a CNS disease caused by abnormal and excessive neuronal discharge in the brain. During seizures, patients experience sudden, recurrent, or transient loss of CNS function. According to data from the World Health Organization, there are approximately 50 million people with epilepsy worldwide, with 2 million new cases diagnosed each year.

In 2017, the International League Against Epilepsy (ILAE) revised the classification of epileptic seizures, categorizing seizure onset as focal, generalized, or unknown. Accordingly, epilepsy types are classified as focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy, and unknown epilepsy. Notably, many patients with epilepsy exhibit multiple seizure types.

The challenge in epilepsy treatment lies in the diversity of seizure types and significant heterogeneity. Medication is the primary therapeutic approach for epilepsy, aimed at reducing seizure frequency and controlling symptoms. Currently, there is a wide array of antiepileptic drugs on the market, which are categorized into traditional agents (such as carbamazepine, phenobarbital, and sodium valproate) and newer agents (such as levetiracetam, oxcarbazepine, and lamotrigine), with the 1980s serving as the dividing line.

Despite the wide array of available medications, approximately 30% of epilepsy patients worldwide still fail to achieve adequate symptom control. Furthermore, according to The Lancet’s report on the global burden of epilepsy from 1990 to 2016, although the incidence of epilepsy improved over this 26-year period, it remains a significant cause of mortality. Consequently, major pharmaceutical companies globally are accelerating the development of novel antiepileptic drugs that offer superior efficacy, fewer adverse reactions, and reduced drug–drug interactions.

In early 2019, neurology-focused company Axovant Gene Therapies (NASDAQ: AXON) announced the establishment of its independently operated subsidiary, Arvelle Therapeutics. On February 18, 2019, the company completed a $180 million Series A financing round, which was the largest Series A funding in the European biotechnology sector in 2019.

Arvelle Therapeutics, headquartered in Basel, Switzerland, is dedicated to advancing the development and commercialization of cenobamate (brand name: XCOPRI), a novel anti-epileptic drug, in Europe.

Cenobamate is a rising star in the global anti-epileptic drug market in recent years.

This drug, independently developed by SK Life Science, a subsidiary of the South Korean company SK Biopharmaceuticals, reduces the frequency of focal seizures. Its mechanism of action targets GABAAR (indications associated with this target primarily include anxiety, insomnia, sedation, and epilepsy; multiple drugs with the same target have already been marketed).

Currently, the exact mechanism by which cenobamate exerts its therapeutic effects remains unclear. SK Biopharmaceuticals posits that it may act through two mechanisms: enhancing inhibitory signaling by positively modulating GABAA receptor activity, and suppressing excitatory signaling by inhibiting persistent sodium currents.

Focal epilepsy refers to seizures originating from a limited area of the brain. If early signs include head or eye deviation to one side, premonitory symptoms such as palpitations and fear before the seizure, and auditory or visual hallucinations during the seizure, it is most likely focal epilepsy. Clinical trials have shown that cenobamate can significantly reduce the frequency of focal seizures, with 20% of patients achieving seizure freedom during the maintenance treatment phase.

On November 25, 2019, cenobamate received U.S. FDA approval for marketing to treat focal-onset seizures in adults. This approval was based on the results of two global, randomized, double-blind, placebo-controlled studies (Study 013 and Study 017) and one large, global, multicenter, open-label safety study.

Study 013 included a 6-week titration period and a 6-week maintenance period. The data showed that cenobamate at a dose of 200 mg/day reduced the median seizure frequency by 56%, compared with a 22% reduction in the placebo group. A post hoc analysis of the maintenance period revealed that 28% of patients in the cenobamate treatment group reported zero seizures, versus 9% in the placebo group. Study 017 included a 6-week titration period and a 12-week maintenance period, evaluating Xcopri at doses of 100 mg/day, 200 mg/day, and 400 mg/day. The data demonstrated that the three Xcopri doses reduced the median seizure frequency by 36%, 55%, and 55%, respectively, compared with a 24% reduction in the placebo group, with statistically significant differences. During the maintenance period, 4%, 11%, and 21% of patients in the respective dose groups reported zero seizures, compared with 1% in the placebo group.

It is understood that cenobamate is expected to be launched in the United States in the second quarter of 2020.

The development and commercialization rights for this drug in Europe belong to Arvelle Therapeutics.

On February 14, 2019, Arvelle Therapeutics and SK Biopharmaceuticals signed a $430 million technology export agreement to collaborate on the commercialization of cenobamate in Europe. SK Biopharmaceuticals will receive an upfront payment of $100 million, which is non-refundable. The remaining contractual payments will be made by Arvelle Therapeutics upon the achievement of specified milestones, such as obtaining marketing authorization. Additionally, SK Biopharmaceuticals will receive royalties based on sales volume once the drug is marketed.

Arvelle Therapeutics plans to apply for marketing authorization in the European Union in 2020 for the treatment of focal epilepsy in adults. Additionally, the company will conduct Phase II and Phase III clinical trials on cenobamate, enrolling a total of 1,900 patients.

Arvelle Therapeutics, an independently operated subsidiary established by Axovant Gene Therapies, is an emerging biopharmaceutical company dedicated to delivering innovative therapies for patients with central nervous system disorders. In addition to utilizing cenobamate for the treatment of epilepsy, the company is conducting Phase II clinical trials to evaluate the drug’s efficacy in treating bipolar disorder, neuropathic pain, and anxiety.

According to the company’s official website, its management team possesses extensive experience. Chief Executive Officer Mark Altmeyer has 30 years of experience in the field of central nervous system (CNS) disorders and has successfully brought multiple drugs to market, including the blockbuster drug Abilify. Chief Medical Officer Ilise Lombardo has 15 years of experience and has led clinical development programs for multiple drugs in the areas of neurological and psychiatric disorders. Chief Financial Officer and Chief Business Officer Gregory Weinhoff has over 20 years of experience in healthcare corporate financing and operations.

Notably, Axovant Gene Therapies, the parent company of Arvelle Therapeutics, is a renowned and legendary player in the Alzheimer’s drug development sector. Within less than a year of its establishment, Axovant Gene Therapies went public on the New York Stock Exchange with an initial offering price of $15 per share. On its debut trading day, the stock price surged to $29, propelling the company’s market capitalization to as high as $3 billion.

One of Axovant Gene Therapies’ strategies is to acquire investigational products from pharmaceutical companies for further development. Its sole Alzheimer’s disease candidate, RVT-101, was acquired by the company from GlaxoSmithKline for $5 million.

Axovant Gene Therapies successfully completed the preliminary studies for RVT-101; however, in September 2017, the Phase III clinical trial of RVT-101 failed, and in January 2019, the drug was again declared ineffective. These two setbacks caused Axovant Gene Therapies’ stock price to plummet, falling from around $27 per share on the U.S. stock market to $2.38.

In this context, Axovant Gene Therapies chose to establish Arvelle Therapeutics in early 2019, transferring 25% of its workforce to the new company. This included appointing Mark Altmeyer, its former Chief Commercial Officer, as CEO of the new entity, and Gregory Weinhoff, its former Chief Financial Officer, as CFO and Chief Commercial Officer. These moves undoubtedly demonstrate Axovant Gene Therapies’ high expectations for the new venture.

Turning our attention to the Chinese market, there are approximately 9 million epilepsy patients in China, with 400,000 to 500,000 new cases diagnosed each year. Currently, the majority of anti-epileptic drugs (AEDs) available in the Chinese market are imported, while domestic brands consist primarily of generic medications. However, numerous Chinese companies are actively engaged in the research and development of novel anti-epileptic drugs. VCBeat has compiled a list of some new anti-epileptic drugs currently under development in China.

Chlorcyclizine was initially discovered and synthesized as an antiepileptic drug by Peking University. Later, Disha Pharmaceutical obtained a license from Peking University to develop the drug, conducting clinical studies in China. It is currently in Phase II clinical trials for the treatment of epilepsy. Pharmacokinetic and in vitro and in vivo metabolic transformation studies in rats have shown that the in vitro metabolism of Chlorcyclizine involves multiple CYP450 subtypes. It inhibits the metabolic activity of CYP2C12 and has a certain inhibitory effect on the activities of CYP1A1/2, CYP2D1, and CYP2C13.

Painegabine overcomes the issues of chemical instability and poor metabolic properties associated with retigabine. As a next-generation anti-epileptic drug candidate targeting KCNQ potassium channels, it possesses fully independent intellectual property rights. Preclinical studies have demonstrated that, compared with retigabine, painegabine exhibits excellent chemical stability and high brain distribution. These characteristics not only reduce the risk of skin pigmentation but also significantly enhance its in vivo anti-epileptic efficacy, showing robust anti-epileptic effects in various animal models, including those for refractory epilepsy.

Pyragabine was approved for clinical trials in November 2018. In June 2019, Hainan Pharmaceutical issued an announcement stating that its controlled subsidiary, Haikou Pharmaceutical Factory, intended to acquire the technology rights for Pyragabine.

The antiepileptic mechanism of oxazepine is primarily mediated through the activation of the gamma-aminobutyric acid (GABA) neurotransmitter system, exerting GABA-like activity to achieve antiepileptic effects. Oxazepine features a novel chemical structure and holds both domestic and international patents. Pharmacodynamic studies demonstrate its efficacy against seizures induced by various etiologies, with superior therapeutic effectiveness compared to currently marketed antiepileptic drugs. Furthermore, it exhibits significantly lower neurotoxicity and favorable tolerability relative to existing medications.

WX0005 is a drug jointly developed by the Technology Center of Harbin Pharmaceutical Group and Shanghai WuXi AppTec New Drug Development Co., Ltd. It is classified as a Class 1 new chemical drug under China’s national drug registration system and possesses independent intellectual property rights worldwide. The proposed indication for this novel agent is epilepsy. Its mechanism of action involves dual targeting of sodium channels and phosphodiesterase 1 (PDE1), enabling both the prevention of epileptic seizures and the mitigation of seizure-induced brain injury.

In August 2017, WX0005 received the “Notice of Approval Opinion” and the “Drug Clinical Trial Approval” issued by the China Food and Drug Administration.