FV-137 candidate drug: Novel and selective ion channel modulation for epilepsy and pain

Abstract

Broad spectrum Anti-Epileptic Drugs (AED) are valued for their potential to treat refractory epilepsy and as general ‘neurostabilizers’ have been employed for a variety of neurological diseases including migrane, biopolar disorder and neuropathic pain. However, the benefits of historical AEDs have been constrained by unintended CNS side effects of these non-selective medicines. Combining proprietary breakthrough chemistry with Fluorinov Pharma and NIH’s in vivo phenotypic screening strategy identified three completely novel candidate drugs, including FV-137 with superior safety and efficacy profiles targeting selective ion channels. FV-137 is a novel, orally administered AED, structurally distinct than any known AED, displaying promising preclinical efficacy and safety. FV-137 emerged from a program whose goal was to identify broad-spectrum anti-epileptic drugs (AED) using gold standard benchmarks such as Depakote ® , Neurontin ® and Keppra ® as primary comparators. FV-137 was extensively screened across all available in vitro and rodent seizure models at ASP, and was found to display an excellent spectrum of anti-seizure activity and safety profiles superior to that produced by Depakote, Neurontin and Keppra. FV-137 has an oral ED50 of 22.7 ± 0.6 and 104.9±4.3 mg/kg in the rat MES (po), mouse PTZ (ip) assays, respectively. FV-137 also produced a dose related protection of a psychomotor seizure syndrome induced by a 6-Hz electrical stimulus with an oral ED50 of 48.5 ± 1mg/kg, and prevented seizures induced by sound in the Audiogenic Seizure (AGS)-susceptible Frings mouse model (i.p) with an ED50 value of 28.9 ± 3.0 mg/kg. In addition, FV-137 displayed significant efficacy in the electrically induced corneally kindled mouse, kindled rat amygdala, kindled rat hippocampal and lamotrigineresistant kindled rat seizures models. Additionally, FV-137 also increased seizure threshold in a dose– dependent manner, therefore, it has the potential to be effective in refractory, or pharmacoresistant, epilepsy. In-vivo pharmacokinetic studies in rat revealed that FV-137 had excellent oral bioavailability (F% = 85%), moderate oral half-life (~3h), and predicted plasma drug levels in the range 5-50μM across multiple models of epilepsy. In addition, drug exposure as measured by Cmax and AUC was shown to be linear with dose. Safety assessment of FV-137 suggests no interaction with the major CYP isoenzymes when tested up to 500 μM, except for 1A2 and 2D6 with IC50 values of 19 uM and 156 uM respectively and no functional hERG activity when tested up to 50 μM. Irwin and acute toxicity studies suggest a maximally tolerated oral dose of greater than 500 mg/kg in the mice and rats. Mechanistically, in whole-cell patch-clamp recordings FV-137 inhibited P/Q-type Ca 2+ Channels, Cav2.1/β4/α2δ1 and Cav2.2/β3/α2δ1, and voltage-gated Na + channels, Nav1.6 and Nav1.7 and no inhibition up to 100 μM in other related ion channels. Importantly, no significant affinities were observed in a CEREP broad profiling screen (10 μM) across 90 known GPCR, ion channel, transporter and enzyme targets. The anticonvulsant profile of FV-137 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. Furthermore, in models of neuropathic pain (spinal nerve injury [SNI] and spinal nerve ligation models [SNL]) and formalin inflammatory pain, administration of a single dose showed robust efficacy (SNI: 23 mg/kg ip; SNL: 60mg/kg and formalin: 41 mg/kg ip). On the basis of its pharmacology and superior drug-like properties, FV-137 was identified as a promising AED candidate.