Vixotrigine

Vixotrigine (BIIB074, CNV1014802, formerly raxatrigine) is a phenyl prolinamide derivative and broad-spectrum voltage-gated sodium channel (Nav) blocker originally synthesized at GlaxoSmithKline as part of a conformationally constrained glycinamide optimization program targeting state-dependent sodium channel inhibition for the treatment of neuropathic pain. The compound preferentially inhibits sodium channels in the inactivated state, producing voltage-dependent and use-dependent block that selectively suppresses high-frequency pathological nerve firing while sparing normal physiological conduction at resting membrane potentials. In recombinant expression systems, vixotrigine potently inhibits sodium currents across both peripheral and central nervous system Nav subtypes (Nav1.1, Nav1.2, Nav1.3, Nav1.5, Nav1.6, Nav1.7, Nav1.8) with use-dependent IC50 values ranging from 1.76 to 5.12 micromolar, demonstrating higher potency and more profound state-dependent inhibition than carbamazepine but a similarly broad spectrum of activity distinct from the Nav1.7-selective and Nav1.8-selective blockers that have failed to translate clinically.

The compound was advanced through Convergence Pharmaceuticals, a GlaxoSmithKline spinout acquired by Biogen in 2015 for up to 675 million dollars, through an extensive clinical program spanning trigeminal neuralgia, painful lumbosacral radiculopathy, erythromelalgia, and small fiber neuropathy. In a Phase 2a enriched-enrollment randomized withdrawal study in trigeminal neuralgia, vixotrigine at 150 mg in the published literature produced a 45 percent reduction in paroxysm frequency and a 50 percent reduction in daily pain scores compared with placebo. Two Phase 3 studies (NCT03070132, NCT03637387) were designed and initiated but were not completed. In the Phase 2 CONVEY study of painful small fiber neuropathy, vixotrigine at 200 mg in the published literature met the primary endpoint with a statistically significant reduction in average daily pain score versus placebo (least squares mean difference of negative 0.85, p equals 0.050), with effect concentrated in the diabetes-associated subgroup. A Phase 2b study in painful lumbosacral radiculopathy did not meet primary or secondary endpoints. Biogen discontinued further development of vixotrigine in the fourth quarter of 2022, recording an impairment charge of approximately 120 million dollars, citing regulatory, development, and commercialization challenges.

Pharmacokinetics in humans are characterized by rapid oral absorption (time to peak concentration approximately 1 to 2 hours), moderate tissue distribution (volume of distribution approximately 262 liters), an elimination half-life of approximately 11 hours supporting twice-daily or three-times-daily dosing, and primary metabolism via uridine diphosphate-glucuronosyltransferase (UGT) isoforms UGT1A3 and UGT2B7 to the principal metabolite M13 (N-carbamoyl glucuronide), with minimal cytochrome P450 involvement. The compound demonstrates high brain penetration (brain-to-blood ratio of 6.8 in rat) and favorable physicochemical properties (BCS Class I, aqueous solubility 16.3 mg/mL as the hydrochloride salt). An off-target monoamine oxidase B (MAO-B) inhibitory activity (pIC50 8.4) was identified in broad screening; this secondary activity is pharmacologically relevant at clinical exposures but has not been developed as a therapeutic mechanism.

The compound was well tolerated in Phase 1 studies at single doses up to 825 mg and repeat doses up to 450 mg in the published literature, with dizziness and headache as the most common adverse events and no serious adverse events, clinically significant electrocardiographic changes, or evidence of drug withdrawal on abrupt discontinuation. This monograph reviews the chemistry, discovery, and structure-activity relationships; the broad-spectrum sodium channel pharmacology in molecular and electrophysiological detail; the comprehensive pharmacokinetic record including metabolism and drug-drug interactions; the clinical evidence base across all studied indications; reconstitution, sourcing, and handling considerations for laboratory use; stack interactions; adverse-event signal; and a comparative assessment of five sodium channel blockers (carbamazepine, oxcarbazepine, lacosamide, PF-05089771, A-803467) against vixotrigine on five competency standards.