CLINICAL TRIALS PROFILE FOR EZOGABINE

All Clinical Trials for Ezogabine

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT01332513 ↗	An Open Label, Randomised, Repeat Dose Study to Assess the Pharmacokinetic Performance of Five Ezogabine/Retigabine Modified Release (MR) Formulations at Steady State Compared to the Immediate Release (IR) Formulation.	Completed	GlaxoSmithKline	Phase 1	2011-02-10	This is an open-label, single centre, repeat dose, up- titration study in healthy male and female subjects to assess the pharmacokinetic (PK) performance of five prototypes of ezogabine modified release tablet formulations. The study will consist of a screening period, a treatment phase (consisting of a titration phase, bioavailability phase and food effect phase) and a post-treatment follow-up visit. The study duration from screening to follow up will be approximately 7 weeks. No study procedures will start before informed consent is obtained. Subjects will remain in the clinical unit for the duration of the treatment period (35 days). Subjects will receive repeat doses of ezogabine for up to 34 days starting at a dose of 100 mg IR TID (300mg TDD) with a standard meal (to be consumed 30 min prior to dosing) for Days 1-3, on days 4-6 subjects will receive 150mg IR TID (450mg TDD). On Day 7 through to the end of the study subjects will receive ezogabine (Mr or IR) at a dose of 600mgTDD. On Day 7 subjects will enter into a 6-way cross over period to investigate the 5 MR formulations being tested (each at 300mg BID) and the single IR formulation (at 200mg TID). Subjects will receive each formulaition for 4 days and blood samples for pharmacokinetic analysis will be collected up to 24 hours post dose on each 4th day (PK days). On Day 31 subjects will enter into a food effect phase to investigate the 5 MR formulations being tested (each at 600mg QD). Subjects in this period will have a PK day on Day 33 (following a standard breakfast), and on Day 34 (following a high fat breakfast) to investigate a food effect on the PK profile of ezogabine.
NCT01462656 ↗	Risk of Urinary Retention With Retigabine	Terminated	GlaxoSmithKline		2011-02-01	A prospective cohort study of antiepileptic drug (AED) polytherapy-treated epilepsy patients within the HealthCore Integrated Research Database (HIRD) will be conducted. Following the launch of Ezogabine (EZG), patients initiating a new AED polytherapy regimen will be followed until the earliest of an episode of urinary retention (UR), change in their AED regimen, end of follow-up, or end of study (when the specified sample size of EZG AED polytherapy users has been attained). After the end of study, the incidence of UR during exposures to EZG and non-EZG AED polytherapies will be compared. Polytherapy will be defined as treatment regimen containing at least two different AEDs. A prospective cohort study of patients who receive EZG under circumstances not indicated in the product label within the HIRD will also be conducted. Following the launch of EZG, epilepsy patients initiating AED monotherapy with EZG as well as non-epilepsy patients initiating EZG for another disease will be followed until the earliest of an episode of UR, change in their AED regimen (if applicable), end of follow-up, or end of study. The incidence of UR during exposure to EZG under circumstances not indicated in the product label will be described. A descriptive analysis of the patients will also be included. To meet the other secondary objective, non-EZG AED monotherapy users will be identified in the prospective cohort and incidence of UR will be calculated to determine if there is a difference in UR risk between monotherapy and polytherapy AED use.
NCT01462669 ↗	Crossover Study to Evaluate the Pharmacokinetics of Ezogabine/Retigabine in Taiwanese Subjects	Completed	GlaxoSmithKline	Phase 1	2012-04-10	The purpose of this study is to investigate the pharmacokinetics of single oral doses of ezogabine/retigabine and the primary metabolite (NAMR) in healthy male and female Taiwanese volunteers. Subjects will receive four separate doses of ezogabine/retigabine tablets: 50 mg, 100 mg, 200 mg and 400 mg administered once orally. Blood samples will be obtained at pre-defined timepoints over the duration of the study to determine the concentration of ezogabine/retigabine and NAMR. Safety assessments will include measurements of vital signs, collection of adverse events, clinical laboratory tests and the Columbia Suicide Severity Rating Scale.
NCT01480609 ↗	Effect of Haemodialysis on the Pharmacokinetics of Ezogabine/Retigabine and Its N-acetyl Metabolite	Completed	GlaxoSmithKline	Phase 1	2011-11-30	This in an open-label, single dose, fixed sequence, two treatment period study enrolling 8 patients (to obtain 6 evaluable) with end stage renal disease (ESRD) receiving haemodialysis. Patients will remain in the unit during each treatment period from admission to the collection of the final PK sample. The doses of ezogabine/retigabine in the two treatment periods will be separated by at least 7 days.
NCT01494584 ↗	Study in Pediatric Subjects With Epilepsy	Terminated	Bausch Health Americas, Inc.	Phase 2	2012-07-25	This is an open-label study to evaluate the pharmacokinetics, safety and tolerability of ezogabine/retigabine in subjects aged 12 years to less than 18 years with uncontrolled partial onset seizures or Lennos-Gastaut syndrome.
NCT01494584 ↗	Study in Pediatric Subjects With Epilepsy	Terminated	Valeant Pharmaceuticals International, Inc.	Phase 2	2012-07-25	This is an open-label study to evaluate the pharmacokinetics, safety and tolerability of ezogabine/retigabine in subjects aged 12 years to less than 18 years with uncontrolled partial onset seizures or Lennos-Gastaut syndrome.
NCT01494584 ↗	Study in Pediatric Subjects With Epilepsy	Terminated	GlaxoSmithKline	Phase 2	2012-07-25	This is an open-label study to evaluate the pharmacokinetics, safety and tolerability of ezogabine/retigabine in subjects aged 12 years to less than 18 years with uncontrolled partial onset seizures or Lennos-Gastaut syndrome.

Clinical Trial Conditions for Ezogabine

Condition Name

Condition Name for Ezogabine
Intervention	Trials
Epilepsy	12
Epilepsy; Seizure	2
Epileptic Syndromes	2
Nervous System Diseases	2

Condition MeSH

Condition MeSH for Ezogabine
Intervention	Trials
Epilepsy	11
Seizures	4
Central Nervous System Diseases	2
Disease	2

Clinical Trial Locations for Ezogabine

Trials by Country

Trials by Country for Ezogabine
Location	Trials
United States	56
Australia	3
Greece	1
Poland	1
France	1

Trials by US State

Trials by US State for Ezogabine
Location	Trials
Maryland	6
Texas	5
Florida	5
California	5
Minnesota	4

Clinical Trial Progress for Ezogabine

Clinical Trial Phase

Clinical Trial Phase for Ezogabine
Clinical Trial Phase	Trials
Phase 4	3
Phase 3	4
Phase 2	4

Clinical Trial Status

Clinical Trial Status for Ezogabine
Clinical Trial Phase	Trials
Completed	8
Terminated	6
Recruiting	2

Clinical Trial Sponsors for Ezogabine

Sponsor Name

Sponsor Name for Ezogabine
Sponsor	Trials
GlaxoSmithKline	11
Bausch Health Americas, Inc.	3
Valeant Pharmaceuticals International, Inc.	3

Sponsor Type

Sponsor Type for Ezogabine
Sponsor	Trials
Industry	20
Other	10
NIH	1

Ezogabine: A Versatile Drug with Promising Clinical Trials and Complex Market History

Introduction

Ezogabine, known by its trade names Potiga in the U.S. and Trobalt in the EU, is a drug that has navigated a complex journey through various clinical trials and market phases. Initially approved for epilepsy, it has been repurposed and is now being explored for other neurological conditions, including Amyotrophic Lateral Sclerosis (ALS) and rare forms of pediatric epilepsy.

Initial Approval and Market History

Ezogabine was first approved by the FDA in 2011 as an add-on treatment for adults with partial-onset seizures[3][5].

• It was marketed by GlaxoSmithKline (GSK) but was withdrawn from the market in June 2017 due to commercial reasons, despite its efficacy in treating epilepsy[2][5].

Safety Concerns and Regulatory Actions

The drug's market presence was marred by safety concerns, including reports of skin discoloration, pigment changes in the eye, and potential vision loss. These issues led to a black-box warning from the FDA and recommendations for regular eye exams for patients on the medication[2][5].

Repurposing for ALS

A significant development in the use of ezogabine came from research supported by the New York Stem Cell Foundation (NYSCF). Using induced pluripotent stem cell (iPSC) models of ALS, researchers discovered that ezogabine could reduce the overactive electrical activity of motor neurons, a hallmark of ALS. This led to a phase 2 clinical trial involving 65 ALS patients.

• The trial, conducted by Dr. Brian Wainger and Dr. Kevin Eggan, showed that ezogabine effectively reduced motor neuron excitability in ALS patients. The next steps involve determining whether longer treatment can sustain these benefits and potentially slow disease progression[1][4].

Repurposing for Pediatric Epilepsy

Xenon Pharmaceuticals has taken up the mantle to repurpose ezogabine for a rare and severe form of pediatric epilepsy known as KCNQ2 epileptic encephalopathy (KCNQ2-EE).

• Studies have shown that ezogabine can improve seizure frequency and cognitive development in children with KCNQ2-EE. Xenon is developing a pediatric-specific formulation of the drug and has planned a phase 3 clinical trial to evaluate its efficacy[2][5].

Clinical Trial Outcomes

ALS Clinical Trial

• The phase 2 trial for ALS involved 65 patients who were randomized to receive either 600 mg/day or 900 mg/day of ezogabine or a placebo for 10 weeks.
• The primary outcome was the change in short-interval cortical inhibition (SICI), which reflects inhibitory cortical motor circuit dynamics. The trial showed that ezogabine reduced both cortical and spinal motor neuron excitability[4].

Pediatric Epilepsy Clinical Trials

• Previous case studies and small-scale trials have demonstrated the safety and efficacy of ezogabine in reducing seizures and improving cognitive development in children with KCNQ2-EE.
• Xenon's planned phase 3 trial aims to further establish the drug's efficacy and safety in a larger patient population[5].

Market Analysis and Projections

Current Market Status

Despite its initial withdrawal from the market, ezogabine is experiencing a resurgence due to its repurposing for other conditions. The drug's ability to modulate potassium channels makes it a valuable asset in treating neurological disorders.

Future Market Potential

• ALS Market: If the ongoing and future trials confirm the long-term benefits of ezogabine in ALS patients, it could become a significant player in the ALS treatment market, which is currently limited in effective therapies.
• Pediatric Epilepsy Market: The potential for ezogabine to treat KCNQ2-EE and other rare forms of pediatric epilepsy positions it as a valuable treatment option in a niche but critical market segment. The Orphan Drug designation by the FDA further supports its market potential[5].

Challenges and Opportunities

Regulatory Hurdles

• The drug's history of safety concerns, particularly regarding vision and skin pigmentation, will need to be carefully managed. Regular monitoring and potentially new formulations may mitigate these risks.
• Xenon's ability to reference GSK's regulatory filings and the Orphan Drug designation will expedite the regulatory process[2][5].

Competitive Landscape

• The epilepsy market is competitive, but ezogabine's unique mechanism of action and its potential in treating rare and severe forms of epilepsy could carve out a distinct niche.
• In the ALS market, any drug that shows promise in slowing disease progression will be highly valued, given the current lack of effective treatments[1][4].

Key Takeaways

• Ezogabine has shown promising results in reducing motor neuron excitability in ALS patients and improving outcomes in children with KCNQ2-EE.
• The drug's market history is complex, with initial approval and subsequent withdrawal due to commercial reasons and safety concerns.
• Ongoing and planned clinical trials are crucial for establishing the long-term efficacy and safety of ezogabine in these new indications.
• Regulatory support, such as the Orphan Drug designation, and the ability to reference previous regulatory filings, will be key in expediting its return to the market.

FAQs

What is ezogabine, and how was it initially used?

Ezogabine, known by its trade names Potiga and Trobalt, was initially approved in 2011 as an add-on treatment for adults with partial-onset seizures.

Why was ezogabine withdrawn from the market?

Ezogabine was withdrawn from the market in 2017 due to commercial reasons, despite its efficacy, and also due to safety concerns including skin discoloration and potential vision loss.

What new conditions is ezogabine being explored for?

Ezogabine is being explored for the treatment of Amyotrophic Lateral Sclerosis (ALS) and a rare form of pediatric epilepsy known as KCNQ2 epileptic encephalopathy (KCNQ2-EE).

What are the results of the ALS clinical trial for ezogabine?

The phase 2 clinical trial for ALS showed that ezogabine reduced both cortical and spinal motor neuron excitability in 65 patients.

What are the next steps for ezogabine in treating KCNQ2-EE?

Xenon Pharmaceuticals is planning a phase 3 clinical trial to evaluate the efficacy of ezogabine in treating KCNQ2-EE, with the trial expected to start in the near future.

Sources

1. Promising Results Published on a New ALS Drug Discovered with NYSCF Support - NYSCF
2. Xenon adds discontinued GlaxoSmithKline drug ezogabine to epilepsy pipeline - FierceBiotech
3. 022345Orig1s000 - accessdata.fda.gov
4. Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis - JAMA Neurology
5. XEN496 Being Developed for KCNQ2 Epileptic Encephalopathy - NeurologyLive