XEN1101 for Epilepsy

XEN1101, A Selective KV7 Potassium Channel Modulator for the Treatment of Epilepsy

We are developing XEN1101, a KV7 potassium channel opener, for the treatment of epilepsy including: treatment-resistant adult and pediatric focal seizures; rare pediatric forms of epilepsy, such as EIEE7, an early infantile epileptic encephalopathy associated with mutations in the KCNQ2 gene that cause loss-of-function in the KV7.2 potassium channel; as well as potentially other neurological disorders. We acquired XEN1101 from 1st Order Pharmaceuticals pursuant to an asset purchase agreement in April 2017. The KV7 potassium channel opener mechanism has been clinically validated as an effective adjunctive treatment for treatment-resistant focal seizures as demonstrated with ezogabine, an earlier generation KV7 opener. XEN1101’s unique composition is chemically designed to improve upon potency, selectivity and PK of ezogabine, and is not expected to have ezogabine’s composition-specific skin and eye pigmentary issues.

In addition to XEN1101’s strong pre-clinical data, and the clinical validation from the use of ezogabine, there is strong human genetic validation to support the use of XEN1101 as a potential treatment for epilepsy. The KCNQ2 gene encodes for the KV7.2 voltage-gated potassium channel. Loss-of-function missense mutations in KCNQ2 can cause an extremely severe epilepsy disorder characterized by multiple, daily, treatment-resistant seizures often presenting within the first week of life. This human genetic validation further underpins the important role KCNQ2 plays in limiting the hyper-excitatory state of the brain and as a target for the prevention of seizures in humans.

Clinical Development

In October 2017, following acceptance of our clinical trial application, or CTA, for XEN1101 by the Medicines & Healthcare products Regulatory Agency, or MHRA, in the United Kingdom, we initiated a randomized, double-blind, placebo-controlled Phase 1 clinical trial to evaluate the safety, tolerability and pharmacokinetics of both single ascending doses, or SAD, and multiple ascending doses, or MAD, of XEN1101 in healthy subjects. The XEN1101 Phase 1 clinical trial includes a pharmacodynamic biomarker read-out from a transcranial magnetic stimulation, or TMS, study, designed to assess XEN1101’s ability and potency to modulate cortical excitability, thereby demonstrating activity in the target CNS tissue. We have completed a Phase 1a pilot TMS study in 8 healthy subjects and have now begun a double-blind, placebo-controlled, randomized cross-over Phase 1b TMS study in approximately 15 healthy subjects. We expect to present interim Phase 1 results at the 14th EILAT Conference on New Antiepileptic Drugs and Devices to be held in Madrid, Spain on May 15, 2018. The release of the complete Phase 1 results, including the Phase 1b TMS data, is anticipated in the second half of 2018. We anticipate initiating a Phase 2 clinical trial evaluating XEN1101 as a treatment for adult focal seizures by year end. We also intend to explore a parallel plan to advance XEN1101 into rare, pediatric forms of epilepsy as soon as feasible thereafter.

About Focal Seizures

A focal seizure is localized within the brain and can either stay localized or spread to the entire brain, which is typically categorized as a secondary generalized seizure. Focal seizures are the most common type of seizure experienced by people with epilepsy. The treatment of an individual patient with focal seizures is currently focused on reduction of seizure frequency, with seizure freedom as the ultimate goal. Focal seizures (simple, complex and secondarily generalized tonic-clonic) account for approximately 60% of seizures (GlobalData Report 2017) of which approximately 33% are considered resistant to current treatments (Epilepsy Foundation). It is estimated that the addressable population in the United States could include approximately 460,000 adults and 70,000 pediatric epilepsy patients with refractory seizures.

About Early Infantile Epileptic Encephalopathy (EIEE7)

Mutations in the KCNQ2 gene result in loss-of-function in the KV7.2 potassium channel that can cause a rare, extremely severe, single-gene epilepsy disorder known as EIEE7 that typically presents with seizures within the first week of life. These seizures can occur multiple times a day and are often difficult to treat. Typically, the seizures are associated with abnormal brain wave patterns on EEG. While the seizures in EIEE7 often resolve within months to years, many children sustain some degree of permanent developmental impairment involving one or more domains (motor, social, language, cognition). This can range from mild to severe depending on a number of different factors. Some children may also have autistic features.