Long-term effects of adjunctive eslicarbazepine acetate in adult Asian patients with refractory focal seizures: Post hoc analysis of a phase III trial.

A post hoc analysis of data from Asian patients included in the study BIA-2093-304 was conducted to evaluate the long-term safety/tolerability and efficacy of adjunctive eslicarbazepine acetate (ESL) in adult Asian patients with refractory focal seizures. Part I was a randomized controlled trial, in which patients received ESL (800 or 1200 mg once daily [QD]) or placebo, assessed over a 12-week maintenance period. Patients completing Part I could enter two open-label extension periods (Part II, 1 year; Part III, ≥2 years), during which all received ESL (400-1600 mg QD). Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs). Efficacy assessments included responder and seizure freedom rates. The safety population included 125, 92, and 23 Asian patients in Parts I, II, and III, respectively. Incidence of ESL-related TEAEs was 61.3%, 45.7%, and 17.4% during Parts I, II, and III, respectively. ESL-related TEAEs (most commonly, dizziness, somnolence, and headache) were consistent with ESL's known safety profile. During Part I, responder rates were higher with ESL 800 (41.7%) and 1200 mg QD (44.4%) versus placebo (32.6%), although not statistically significant. Seizure freedom rates with ESL 800 (5.5%) and 1200 mg QD (11.1%) were also higher versus placebo (0%) (p < 0.05 for ESL 1200 mg QD versus placebo). At the end of Part II, responder and seizure freedom rates were 60.3% and 14.7%, respectively. In summary, adult Asian patients with refractory focal seizures were responsive to treatment with ESL as adjunctive therapy and generally showed treatment tolerance well for up to 3 years. No new/unexpected safety findings were observed.

Advances in Lead Generation.

Lead Generation represents a critical drug discovery phase where chemical starting points and their respective mechanism of action, quality, and potential liabilities are largely predefined. Recent advances such as DNA-encoded libraries or fragment-, chemical biology-, and virtual screening-based approaches are today as common as traditional High Throughput Screening. Innovations in characterizing lead quality have allowed more informed decision-making by discovery teams. The key challenge today is to individually tailor the right mix of methods for each project to facilitate data integration with the purpose of creating multiple high-quality lead series, ultimately translating to reduced chemistry-related pipeline attrition.

Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction.

Neuronal voltage-gated potassium channels, KV7s, are the molecular mediators of the M current and regulate membrane excitability in the central and peripheral neuronal systems. Herein, we report novel small molecule KV7 openers that demonstrate anti-seizure activities in electroshock and pentylenetetrazol-induced seizure models without influencing Rotarod readouts in mice. The anti-seizure activity was determined to be proportional to the unbound concentration in the brain. KV7 channels are also expressed in the bladder smooth muscle (detrusor) and activation of these channels may cause localized undesired effects. Therefore, the impact of individual KV7 isoforms was investigated in human detrusor tissue using a panel of KV7 openers with distinct activity profiles among KV7 isoforms. KCNQ4 and KCNQ5 mRNA were highly expressed in detrusor tissue, yet a compound that has significantly reduced activity on homomeric KV7.4 did not reduce detrusor contraction. This may suggest that the homomeric KV7.4 channel plays a less significant role in bladder contraction and further investigation is needed.