INTREPID Alliance deep dive report focused on direct-acting antivirals for mpox

INTREPID Alliance Report on Direct-Acting Antivirals for Mpox
Based on review of public domain information as of March 2, 2025

Background on Orthopoxviruses

The genus Orthopoxvirus (ORPV) includes species that cause disease in humans (e.g., Variola virus [VARV], Cowpox virus and Monkeypox virus [MPXV]). These enveloped double-stranded DNA viruses share similar lifecycles and are genetically conserved*, especially in genes that are critical for viral replication. The conservation among ORPVs is reflected in the cross-protection and broad activity of several approved vaccines and antivirals, respectively. For example, both FDA approved antivirals developed to treat VARV infections are active in vitro and in animal models against all other ORPVs known to be pathogenic in humans. The most severe disease associated with ORPVs was smallpox, caused by VARV, which was responsible for an estimated 300 million deaths in the twentieth century alone. Although smallpox was declared eradicated in 1980, development of effective antivirals with different mechanisms of action and different resistance profiles remains a major public health goal.^1,2,3

Recent Outbreaks of International Concern

Recently, outbreaks of mpox disease caused by MPXV resulted in the World Health Organization (WHO) declaring two public health emergencies of international concern (PHEIC) for mpox disease, one in July 2022 and one in August 2024, which was reaffirmed in February 2025. The first was in response to a surge in mpox cases around the globe, driven mainly by sexual transmission of MPXV clade IIb among men who have sex with men. The second was in response to outbreaks of clade I MPXV, initially in the Democratic Republic of Congo (DRC) and neighboring countries.^4,5

Mpox typically resolves with supportive care alone and the WHO recently assessed the global public health risk of mpox as “moderate.”⁶ However, severe disease can develop in some individuals, and is typically associated with immunosuppression, young age, and infection with specific genotypes of MPXV. Clade Ib appears to spread more readily than clade II, requiring only close skin-skin contact (sexual or non-sexual), and notably, has a higher case fatality rate (<1-10%), especially in children.⁷ As of March 2, 2025, mpox clade Ib cases have been confirmed in 14 countries outside of Africa.⁶ The recent rapid spread of mpox disease, apparent evolution of MPXV during sustained human-human transmission,⁸ and disappointing results from two randomized controlled trials (RCTs) of an antiviral, highlight an urgent unmet need for mpox treatments that can be used efficiently in diverse settings.^9,10

Challenges with Available Treatments

Although there are both approved and pipeline antivirals with activity against MPXV, a deeper look identifies significant uncertainties and challenges. These include the unproven efficacy against mpox of approved ORPV antivirals and stage of development and/or probability of success for different leads in the pipeline.

In the United States, three treatments (tecovirimat, brincidofovir, vaccinia immune globulin [VIG]) that were developed to treat other ORPVs, can be accessed for patients with mpox through expanded access or emergency use Investigational New Drug protocols (IND).¹¹ Oral tecovirimat and brincidofovir are approved for treatment of smallpox in the United States and Canada. Tecovirimat is approved for treatment of smallpox, mpox, and cowpox in the European Union, United Kingdom, and Japan.

Notably, these approvals were based on efficacy studies in animal models combined with human safety data.^12,13 Two recently completed large RCTs of tecovirimat for mpox, one in Africa and one in the United States, failed to show a significant benefit for tecovirimat versus placebo against clade I or clade II.^9,10 Brincidofovir is under evaluation in a RCT for mpox in Africa, with preliminary data expected by mid-2025.¹⁴ One limitation of the tecovirimat clinical trials was the potential for treatment initiation at a relatively late stage of the symptomatic mpox disease (any duration of the disease for PALM007 and up to 14 days for STOMP). Therefore, the overall clinical utility of tecovirimat and/or brincidofovir as monotherapy or combination treatment of mpox remains to be determined for different stages of mpox disease and these oral agents might also have utility in pre- and post-exposure prophylaxis settings.

Another clinically available intravenous (IV) antiviral approved for cytomegalovirus (CMV) retinitis (cidofovir) has shown efficacy against ORPVs in animal models, including mpox, and is processed within cells to the same active antiviral as brincidofovir. However, cidofovir has several disadvantages when compared to brincidofovir, including reduced potency (>50-fold for MPXV), the requirement for IV administration¹⁵ and importantly, a challenging safety profile with significant potential for renal toxicity.^16,17 Similarly, a prodrug of tecovirimat (NIOCH-14) is approved for treatment of smallpox in Russia, but the active antiviral is identical to tecovirimat, and it is not approved in most of the world.^18,19 Two additional antivirals for mpox (ASC10 and NV-387) appear positioned for human efficacy testing, but discoverable clinical efficacy trials have not been initiated to date.^20,21

Promising Early Antiviral Research & Development

The preclinical landscape for mpox does not appear to contain compounds that are close to clinical efficacy testing (see INTREPID Antiviral Preclinical Clinical Development Pipeline). However, there is an abundance of published manuscripts suggesting (in silico modeling studies) or demonstrating (in cell-based assays and/or animal models) MPXV antiviral activity for diverse classes of small molecules with potentially complementary mechanisms of action. For example, nucleoside leads have recently been discovered which may selectively inhibit ORPV RNA polymerases.^22,23 It is noteworthy that several promising monoclonal antibodies with neutralizing activity against MPXV are in preclinical development; challenges for antibody-based therapies can include cost, cold-chain requirement, injectable formulation, and emergence of resistant strains.^24,25,26 The first three may pose high barriers to utilization in resource constrained, hard-to-access settings that have historically been points of origin for mpox outbreaks (e.g., DRC).

Together, these clinical and preclinical analyses highlight an urgent need for increased research and development (R&D) of antiviral treatments for MPXV and other ORPVs with pandemic potential. It is apparent that there is a scarcity of tractable preclinical compounds with well-characterized antiviral activity against MPXV. Ideally at least two orally delivered, well-tolerated, effective pan-ORPV antivirals with distinct mechanisms of action and different resistance profiles are needed. Multiple ORPV enzymes (e.g., cysteine protease, methyltransferase, DNA and RNA polymerases) and other conserved viral proteins could be targeted to generate promising pan-ORPV direct acting antivirals. Development pathways for novel ORPV antivirals are also well understood and relatively straightforward. Additionally, expertise relevant for mpox antiviral R&D was honed during efforts for preparedness against smallpox and remains accessible at numerous academic, government, and corporate institutions.

A Path Forward

Based on our current review of the clinical and preclinical landscape, the INTREPID Alliance recommendations for mpox/orthopoxvirus direct-acting antivirals include the following:

• Research and develop novel antivirals, emphasizing orally-delivered, pan-ORPV DAAs with different MOAs and resistance profiles
1. Evaluate combination therapies of DAAs early in development
• Avoid using DAAs with low barriers to resistance as monotherapy in treatment of active disease as high viral burden amplifies the risk for selection of resistance
1. Monotherapy use of DAAs with low resistance barriers may be acceptable for prevention/post-exposure prophylaxis due to absent/low viral burden
• Conduct rigorous randomized, controlled clinical trials for ORPVs currently causing disease in humans as early as possible.

*Conserved genes in this context have not had significant changes in their DNA sequence over time or across ORPV species.