Small molecule direct-acting antivirals for treatment of mpox

In 2022 and 2024, outbreaks of mpox disease caused by two different clades of MPXV resulted in the World Health Organization (WHO) declaring two public health emergencies of international concern (PHEIC). Different clades/subclades/lineages of MPXV can have substantially different pathogenicity and transmission characteristics. The recent rapid spread of mpox disease, evidence for evolution of MPXV during sustained human-human transmission, challenges associated with MPXV vaccination, and disappointing results from two Phase 3 trials of a promising antiviral (tecovirimat) highlight an urgent unmet need for mpox treatments. This review assesses the current landscape of small molecule direct acting antivirals (DAAs) for mpox in the context of potential pandemic threats from ORPVs. Despite many reports of compounds with antiviral activity against MPXV and other ORPVs in vitro, none have proven effective so far in controlled clinical human studies. To address this gap, tecovirimat is undergoing further testing in Phase 3 trials for mpox, as is a second small molecule DAA (brincidofovir), both approved by national regulatory agencies (e.g., U.S. FDA) for the treatment of smallpox based on efficacy in animal models. Additional DAAs for treatment of mpox are in early development, highlighting a major gap in medical countermeasures. Compound characteristics are identified that should increase the probability of clinical success and durability for mpox and improve the likelihood that they will also be effective against other ORPVs.