Mirogabalin

Mirogabalin (DS-5565) is a novel gabapentinoid analgesic that binds with high affinity and selectivity to the alpha-2-delta-1 (alpha2delta-1) subunit of voltage-gated calcium channels (VGCCs), developed by Daiichi Sankyo Company and approved in Japan in January 2019 for the treatment of peripheral neuropathic pain associated with diabetic peripheral neuropathy (DPNP) and postherpetic neuralgia (PHN). The compound is marketed as Tarlige in oral tablet formulation and has subsequently received regulatory approval in Taiwan (2020) and Thailand (2022) for peripheral neuropathic pain indications. Unlike the first-generation gabapentinoids gabapentin and pregabalin, which bind nonselectively to both alpha2delta-1 and alpha2delta-2 subunits with comparable affinity and dissociation kinetics, mirogabalin demonstrates preferential binding to the alpha2delta-1 subunit with a dissociation half-life of approximately 11.1 hours at alpha2delta-1 versus 2.4 hours at alpha2delta-2 in human recombinant systems. This kinetic selectivity is hypothesized to confer a favorable ratio of analgesic efficacy (mediated principally through alpha2delta-1 in dorsal root ganglia and spinal cord dorsal horn) to central nervous system adverse effects (mediated in part through alpha2delta-2 in cerebellar Purkinje neurons and other central structures), although this hypothesis has not been formally validated in controlled comparative clinical trials against pregabalin at equipotent analgesic doses.

The clinical development program for mirogabalin comprises two pivotal Phase 3 randomized, double-blind, placebo-controlled trials in Asian patients with DPNP (834 patients) and PHN (765 patients), both of which demonstrated statistically significant reductions in average daily pain scores at week 14 relative to placebo across multiple dose groups (15 mg once daily, 10 mg twice daily, and 15 mg twice daily). A separate Phase 3 program evaluated mirogabalin for central neuropathic pain after spinal cord injury in a multinational Asian trial. In contrast, the global Phase 3 ALDAY program for fibromyalgia pain, consisting of three large randomized trials enrolling more than 3,600 subjects in the United States and Europe, failed to meet the primary efficacy endpoint in all three studies; mirogabalin did not demonstrate statistically significant superiority over placebo for reduction in worst daily pain score at week 13 in fibromyalgia, and the fibromyalgia development program was subsequently discontinued. The compound is not approved by the United States Food and Drug Administration or the European Medicines Agency.

Pharmacokinetically, mirogabalin is rapidly and nearly completely absorbed after oral administration with a time to peak plasma concentration of approximately 1 hour. The compound undergoes limited hepatic metabolism (13 to 20 percent of administered dose) through uridine 5-prime-diphospho-glucuronosyltransferase (UGT) isoforms, with the majority of the dose (61 to 72 percent) excreted unchanged in urine. Renal clearance exceeds glomerular filtration rate, indicating active tubular secretion. Dose adjustment is required in patients with renal impairment. The principal adverse events are somnolence, dizziness, peripheral edema, and weight gain, consistent with the gabapentinoid class but reported at generally lower incidence than pregabalin at comparable analgesic doses in some observational comparisons.

This monograph reviews the chemistry and structural pharmacology of mirogabalin; the alpha2delta subunit binding characteristics and dissociation kinetics that distinguish the compound from pregabalin and gabapentin; the complete pharmacokinetic record; the preclinical analgesic pharmacology in neuropathic and inflammatory pain models; the clinical evidence base across peripheral neuropathic, central neuropathic, and fibromyalgia indications; sourcing and quality verification considerations; reconstitution and handling; stack interactions; adverse-event signal; and a comparative assessment of five alternative analgesic candidates against mirogabalin on five competency standards.