Therapeutics

Direct-acting antivirals and other therapeutics for treatment of mpox

Therapeutics developed for smallpox have shown little or no efficacy against MPXV. Several clinical trials have found no evidence that tecovirimat provides any therapeutic benefits.

The mpox therapeutics pipeline is very sparsely populated. Multiple antivirals and monoclonal antibodies targeting MPXV are in pre-clinical development.

Therapeutics pipeline

Mpox therapeutics clinical development pipeline as of September 2026

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Therapeutics knowledge gaps

Primary knowledge gaps identified in the Mpox R&D Roadmap 2026:

Existing therapeutics

Is there a role for tecovirimat or other existing antivirals in mpox treatment?

Therapeutic development

What other antivirals in development have potential as mpox treatments?

Host-directed therapies

Do immune modulators or other host-directed therapies have potential as mpox treatments?

Biologics

What monoclonal antibodies or other biologics in development have potential as mpox treatments?

Mpox complications

Do existing or developmental therapeutics have potential in treatment of ocular or other mpox complications?

More detailed research questions can be found in the Mpox R&D Roadmap 2026.

Therapeutics background

Therapeutic options for mpox and other orthopoxvirus infections remain limited. Antiviral agents developed for smallpox, such as tecovirimat, cidofovir and brincidofovir, have shown activity against orthopoxviruses in vitro and in animal models, and some have been used during recent mpox outbreaks. However, high-quality randomised clinical trials failed to demonstrate clinical efficacy with tecovirimat[1] [2]. The ongoing MOSA trial will provide data on brincidofovir[3].

Pipeline

Only a small number of derivatives of licensed therapeutics and mpox-specific candidates are in clinical development, with others at preclinical stages[4] [5]. The activity spectrum of candidate therapeutics varies widely, from narrow-spectrum orthopoxvirus-specific agents to broad-spectrum antivirals. A variety of monoclonal antibody therapeutics are in preclinical development.

Potential targets

Poxviruses are complex double-stranded DNA viruses that replicate exclusively in the cell cytoplasm. During the virus cycle, three types of virus particles are generated, but only two – mature virus (MV) and extracellular virus (EV) – are infectious. EV particles have an extra outer envelope containing a distinct set of envelope proteins. Cell entry depends on a multicomponent viral entry-fusion complex (EFC) containing 15 viral proteins. Poxviruses replicate autonomously within the host cell, synthesising most of the proteins necessary to complete their replicative cycle.

Five main groups of proteins are potential targets: the enzyme(s) required for viral genome replication (viral DNA polymerase), components of the EFC, viral enzymes involved in gene expression (e.g. polyA polymerase, CAP enzyme, RNA polymerase subunits), proteins involved in virus morphogenesis, and those involved in EV formation and virus release from cells (e.g. F13, B5, A36, A33).

Repurposing

There is also potential to screen existing drugs for activity against MPXV to assess repurposing opportunities[6], or to assess compounds whose development has been halted. Host-directed therapies may be an alternative or complementary approach, to inhibit viral replication or to interfere with inflammatory responses driving severe disease.

WHO developed a target product profile (TPP) for mpox antiviral therapeutics in 2022[7]. This now needs to be reviewed and updated as necessary, and a complementary target compound profile developed to provide guidance to developers on the preferred biochemical and biophysical characteristics of candidate therapeutics.

Challenges

Key issues for mpox therapeutic development include:

Animal models are not fully predictive of human efficacy.
The use of antivirals as monotherapies raises the risk of accelerated resistance to newly developed therapeutics; monoclonal antibodies are also potentially vulnerable to viral evolution, highlighting the need to target highly conserved structures.
Limited access to drugs in low- and middle-income countries, regulatory uncertainties and the challenges of running high-quality clinical trials during outbreaks limit the ability to collect clinical efficacy and safety data on candidate therapeutics.
Capacity for clinical research studies is low in key geographies such as sub-Saharan Africa.
Several key populations (e.g. children, women, people living with HIV) are typically excluded from pivotal clinical trials, leading to important data gaps.

[1] Zucker J, Fischer WA 2nd, Zheng L et al. Tecovirimat for the Treatment of Mpox. N Engl J Med. 2026;394(9):884-895. doi: 10.1056/NEJMoa2506495.

[2] PALM007 Writing Group; Ali R, Alonga J, Biampata JL et al. Tecovirimat for Clade I MPXV Infection in the Democratic Republic of Congo. N Engl J Med. 2025;392(15):1484-1496. doi: 10.1056/NEJMoa2412439.

[3] McCarty J, Cassie D, Kodihalli S et al. Brincidofovir in the Era of Mpox. Expert Rev Anti Infect Ther. 2025;23(9):781-796. doi: 10.1080/14787210.2025.2532029.

[4] Lanier ER, Mackman RL, Ruggiero L, Demarest JF, Pottage JC Jr; INTREPID Alliance Scientific Working Group. Small molecule direct-acting antivirals for treatment of mpox. Antiviral Res. 2025;243:106285. doi: 10.1016/j.antiviral.2025.106285.

[5] Perez Casas C, Burry J, Strub-Wourgaft N et al. In Critical Condition: The Urgent Need to Support Mpox Therapeutic and Diagnostic Pipelines. Clin Infect Dis. 2026;82(2):e404-e408. doi: 10.1093/cid/ciaf529.

[6] Mushebenge AG-A, Mphuthi DD. Deciphering Drug Repurposing Strategies: Antiviral Properties of Candidate Agents Against the Mpox Virus. Scientia Pharmaceutica. 2025; 93(4):51. https://doi.org/10.3390/scipharm93040051

[7] WHO. Target product profile therapeutics of monkeypox cases. 2022. Geneva: WHO. Available at: https://cdn.who.int/media/docs/default-source/blue-print/who_monkeypox_therapeutic_draft-tpp_august-2022.pdf?sfvrsn=5a0a96be_3