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Novel Prodrug Approaches Demonstrate Effective Seizure Control Through Multiple Administration Routes
At the 2022 American Epilepsy Society (AES) Annual Meeting, Xyzagen presented research from its Kv7 channel opener prodrug program, highlighting the development of XYG204, a water-soluble prodrug of Ezogabine designed to enable effective seizure control through multiple routes of administration.
The presentation demonstrated how Xyzagen’s prodrug strategy addresses key limitations of ezogabine by improving solubility, stability, and flexibility of dosing—supporting both oral and parenteral use in acute and chronic seizure settings.
Scientific Focus and Program Overview
XYG204 was developed to overcome the formulation and pharmacokinetic challenges associated with ezogabine, a first-in-class Kv7 channel opener. While ezogabine demonstrated clinical efficacy, its poor solubility, instability in water and light, and limited dosing flexibility restricted its use—particularly in acute neurological settings.
Xyzagen’s prodrug approach modifies the physicochemical properties of ezogabine to enable stable, high-concentration formulations suitable for multiple administration routes, while preserving effective Kv7 channel modulation.
Key Research Highlights
- High Solubility and Stability: XYG204 demonstrated solubility in water and alcohols at concentrations ≥200 mg/mL at physiologically acceptable pH, with stability under acidic conditions for more than 11 days at room temperature.
- Improved Acid Stability: At 5 mg/mL in 1N HCl at 37°C, XYG204 remained stable for over 11 days, while ezogabine fully degraded by Day 4.
- Multi-Route Administration: The prodrug effectively released ezogabine following oral (PO), intramuscular (IM), and subcutaneous (SC) administration.
- Robust In Vivo Efficacy: In rats, IM administration of XYG204 at 75 mg/kg provided nearly complete protection (97.6%) in the maximal electroshock (MES) seizure model at 1 hour post-dose, with full protection observed from 2 to 8 hours.
- Sustained Exposure: Plasma concentrations of ezogabine remained above 10 μM for up to 8 hours following XYG204 administration.
These findings support the potential utility of XYG204 in acute neuronal hyperexcitability scenarios, including severe seizures, status epilepticus, and related neurological emergencies.
Presentation Details
Event: American Epilepsy Society (AES) Annual Meeting
Presentation Title: Prodrugs of Kv7 Channel Opener Ezogabine Are Effective in Releasing Ezogabine and Blocking Seizures by Oral and Parenteral Routes of Administration
Presenters: Christopher Crean, MS; Sarah Thrasher, BS; Angela Dixon, BS; Imani Susu, BS; Edward Brown, PhD; Polina Danshina, PhD
Executive Quote
“Our presentation at the AES Annual Meeting represents our mission to continue to develop improved therapies for patients with epilepsy and other neurological disorders,” said Christopher Crean, Founder and CEO of Xyzagen, Inc. “The promising results from our Kv7 research program demonstrate that our prodrug approach can effectively overcome the limitations that led to the market withdrawal of ezogabine, potentially offering patients a more reliable and convenient treatment option.”
Background on Ezogabine
Ezogabine (EZG) was a first-in-class Kv7 channel opener approved in June 2011 as adjunctive therapy for partial onset seizures. Despite its efficacy, the drug was removed from the market in June 2017 due to challenges including its three-times-daily dosing regimen and concerns about bluish skin discoloration and potential retinal pigment changes.
These pigmentary changes were associated with dimers of ezogabine and its primary metabolite. The XYG204 prodrug approach aims to address these limitations while preserving the therapeutic benefits of Kv7 channel modulation and expanding the routes of administration since EZG is unstable in light and water.
Final Takeaways
Xyzagen’s AES 2022 presentation highlights the company’s ability to apply deep Kv7 biology, pharmacology, and PK expertise to advance differentiated prodrug strategies. By re-engineering the delivery and exposure profile of established mechanisms, Xyzagen continues to explore new therapeutic opportunities in epilepsy and other neurological disorders.
If you’re exploring prodrug strategies to improve PK, stability, or route of administration, contact Xyzagen to learn how our integrated expertise can support your program.
About Xyzagen, Inc.
Xyzagen augments a client’s pharmacology and pharmacokinetics drug development team. As a leading pharmacokinetics consultancy and contract research organization with wet lab and rodent vivarium facilities, Xyzagen is able to push model informed drug development into its First-in-Rat® and First-in-Mouse® discovery platforms as well as support late stage clinical noncompartmental PK, PopPK and Quantitative Medicine. Our knowledge in pharmacology and pharmacokinetics allows the client to expand their core scientific team during the critical period of candidate selection up to the PreIND meeting and through clinical development and the preNDA meeting. We’re a boutique organization which allows for small clients to work directly with experts during their critical decisions.
Media Contact:
Christopher Crean
Founder & CEO
Xyzagen, Inc.
Phone: (919)-762-2072
Email: [email protected]
