Early treatment with tecovirimat against mpox disease in cynomolgus macaques.

BACKGROUND

Tecovirimat was developed as an antiviral countermeasure against orthopoxviruses and approved by the US Food and Drug Administration Animal Rule based on efficacy in preclinical studies and clinical pharmacokinetic and safety trials. However, recent randomised clinical trials in patients with mpox who initiated tecovirimat an average of 6-9 days after onset of symptoms did not show improvement in time to resolution of skin lesions. Here, we evaluated whether timing of tecovirimat initiation influenced antiviral efficacy following mpox infection in nonhuman primates and defined the therapeutic window for treatment initiation.

METHODS

In this randomised preclinical study, 32 cynomolgus macaques were challenged intravenously with 1 × 106 TCID50 mpox clade IIb virus. Oral tecovirimat (10 mg/kg, once daily for 14 days) treatment was initiated on Day 2 (post-exposure and pre-symptomatic), Day 5 (early symptomatic), or Day 9 (peak symptomatic) after mpox challenge, or no treatment was given as a control group. The primary study endpoint was area under the curve (AUC) and peak numbers of progressive skin lesions. The secondary endpoint was AUC and peak levels of plasma viral loads. Additional analyses included total skin lesions, adaptive immune responses, and transcriptomic signatures.

FINDINGS: Treatment adherence was 100%. All tecovirimat-treated animals survived to study completion on Day 28, whereas two untreated control animals required early euthanisation on Days 16 and 17. Tecovirimat efficacy was time-dependent. Progressive skin lesion AUC was significantly lower when treatment was initiated on Day 2 (P < 0.0001) or Day 5 (P = 0.0359) compared with untreated controls, but treatment was largely ineffective when initiated on Day 9 (P > 0.99).

INTERPRETATION: In this randomised preclinical study, tecovirimat demonstrated antiviral therapeutic efficacy but only when initiated early prior to peak viraemia. These findings emphasise the importance of early initiation of treatment and define the therapeutic window for optimal tecovirimat treatment in nonhuman primates.

FUNDING: This study was supported by SIGA Technologies.