Abstracts

Rationale: XEN496 (INN: retigabine; USAN: ezogabine) is a neuronal KCNQ (Kv7) potassium channel opener under development by Xenon Pharmaceuticals as a precision medicine treatment for KCNQ2-related neonatal epileptic encephalopathy (KCNQ2-EE). Ezogabine was previously marketed as a coated immediate-release (IR) tablet formulation (Potiga/TrobaltTM, GlaxoSmithKline) for adjunctive treatment of focal seizures in patients aged 18 years and older. It was withdrawn from the global market in July 2017 for commercial reasons. While the tablet formulation was used off-label in the KCNQ2-EE pediatric population (Millichap et al. Neurol. Genet. Oct 2016, 2:1-5), a pediatric formulation was not marketed. In view of our development plans for XEN496 in KCNQ2-EE, we undertook the development of a pediatric-friendly XEN496 formulation to allow for flexible weight-based dosing without requiring extemporaneous compounding. Methods: A modified quality-by-design approach was implemented in the formulation development of this Biopharmaceutical Classification System Class 2 (low water solubility, high permeability) drug. In addition, a risk-based matrix was developed to guide the advancement of different prototypes. Excipient compatibility for XEN496 was established through an accelerated-condition (40°C, 75% relative humidity) stability study of binary mixtures of XEN496 and excipients. Lead blends within the compatibility space were then designed and their in vitro dissolution profiles determined. Blends with the most promising dissolution profiles were dry granulated through roller compaction and re-tested for dissolution prior to stability assessment. The impact of drug loading on dissolution performance was also assessed, along with the potential for non-specific binding of formulated XEN496 to common plastics such as those employed in feeding bottles and nasogastric feeding tubes. The candidate formulation was then advanced to rat pharmacokinetic (PK) studies in order to confirm its biopharmaceutical performance in vivo and placed on long-term stability studies.  Results: A lead granule pediatric formulation was identified through this screening paradigm. The lead formulation showed in vitro dissolution profiles (both pre- and post-granulation) consistent with an IR product (e.g., 91.2 +- 1.2% released after 10 minutes, 99.1 +- 1.0% released after 45 minutes). Optimal dissolution performance was observed with a 20% w/w XEN496 load. Granulation parameters were optimized to provide a product with a suitable particle size distribution. Spike-recovery experiments conducted in the presence of several common plastics showed no more than 6% relative loss of XEN496. Stability studies are ongoing and have shown no significant physical or chemical degradation or trends. The IR nature and suitable PK profile of this lead formulation were confirmed through rat PK studies. Conclusions: A pediatric formulation of XEN496 (granules suitable for dispersal in breast milk, infant formula, or soft foods, packaged in single-use sachets of varying fill weights) was identified and progressed into GMP drug product manufacturing and potential clinical development. This formulation is presently the focus of a Phase I PK study in adult healthy volunteers.  Funding: No funding