ADX71149 for epilepsy


Epilepsy is one of the most common serious neurological disorders, affecting about 65 million people globally (Thurman et al. 2011). It affects 1% of the population by age 20 and 3% of the population by age 75 (Holmes et al. 2008). Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes. Epilepsy is defined by any of the following conditions: (1) at least two unprovoked (or reflex) seizures occurring >24 hours apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome (Fisher et al. 2014). The synaptic vesicle protein 2A, or SV2A has been identified as a broad spectrum anti‑convulsant target in models of partial and generalized epilepsy, and studies in animal models and human tissue suggest that changes in the expression of SV2A are implicated in epilepsy (Mendoza‑Torreblanca et al. 2013; Kaminski et al. 2012). SV2A ligands include levetiracetam (Lynch et al. 2004), which is an anti‑epileptic drug commercialized under trademark Keppra®, is approved in Europe and the USA as a monotherapy or add‑on therapy in patients diagnosed with epilepsy.

Glutamate is the primary excitatory neurotransmitter in the brain and plays a key role in the initiation and spread of seizures. When activated, the mGlu2 receptor decreases the release of glutamate and consequently, helps to maintain neurotransmitter balance. In the presence of agonist-induced activation, positive allosteric modulation of mGlu2 receptors could result in the normalization of the excessive glutamate release seen during a seizure. Epilepsy remains a challenging unmet medical need, with a significant proportion of the patient population struggling in their day-to-day management of seizures


Under our agreement with Janssen, they are responsible for financing the development and commercialization, if any, of ADX71149. Janssen has completed Phase 1 and two Phase 2a clinical trials in schizophrenia and anxious depression, respectively. Janssen has announced that ADX71149 has been extensively profiled in preclinical models of epilepsy showing both standalone activity and in combination with SV2A ligands including Keppra. Janssen has patented the combination of mGlu2 PAM with SV2A ligands for the treatment of epilepsy.

A multi-center Phase 2 study was also conducted to assess the efficacy, safety, tolerability, and pharmacokinetics of adjunctive ADX71149 administration in patients with focal onset seizures with suboptimal response to levetiracetam or brivaracetam. The primary objective of the study was to evaluate the efficacy of ADX71149 in combination with levetiracetam or brivaracetam using a time to baseline seizure count endpoint. Part 1 of the study evaluated the acute efficacy of ADX71149 over 4 weeks. Patients who did not reach their monthly baseline seizure count in Part 1 continued double-blind treatment during Part 2 until they reached their monthly baseline seizure count or 8 weeks, deemed the maintenance efficacy phase. More information on the study can be found with identifier NCT04836559.

Data were reported from a total of 110 evaluable patients, who each received either 50 mg or 100 mg of ADX71149 twice daily (100 mg or 200mg twice daily, respectively, for patients receiving CYP3A4 inducing anti-seizure medication) in addition to their standard dose of levetiracetam or brivaracetam and up to three other anti-seizure drugs. The Phase 2 study did not achieve statistical significance for the primary endpoint of time for patients to reach baseline seizure count when ADX71149 was added to standard of care. The study demonstrated adjunctive administration of ADX71149 was safe and well tolerated and our partner Janssen announced it has discontinued development of ADX71149 (JNJ-40411813) in epilepsy. The partnership between the two companies remains ongoing while the full data set is being analyzed.