In Critical Condition: The Urgent Need to Support Mpox Therapeutic and Diagnostic Pipelines

Abstract

Despite 2 public health emergency declarations, limited progress has been made in the development of essential medical countermeasures for mpox, including therapeutics and point-of-care (POC) diagnostics. We analyzed mpox diagnostics registered in a public database in December 2022 and January 2025. The number of tests increased; however, independent validation lagged behind. While the World Health Organization has granted emergency use listing to 2 POC molecular tests, there are no independently validated antigen rapid diagnostic tests (AgRDTs) essential for decentralized detection. The therapeutics pipeline has shown minimal progress since 2022. Of 17 clinical trials, 14 evaluated direct-acting antivirals; 86% focused solely on tecovirimat, a drug that shows safety but not efficacy with documented resistance concerns. Key vulnerable populations, including children, pregnant women, and people with human immunodeficiency virus, remain absent from studies despite higher mortality rates. Our pipeline analysis revealed a fundamental mismatch between available countermeasures and actual needs, particularly in low-resource settings.

Mpox requires a cohesive approach to the research-to-rollout continuum for therapeutics and diagnostics, together with vaccines, that is not evidenced in relevant pipelines. Public health emergency status does not automatically translate into a robust mpox pipeline and access to countermeasures.

Mpox, previously known as monkeypox, is a viral illness caused by Orthopoxvirus monkeypox (MPXV), a species of the genus that also includes variola, cowpox and vaccinia viruses. First reported in humans in 1970, mpox is endemic to Central and West Africa. There are 2 distinct clades of the virus: clade I with subclades Ia and Ib and clade II with subclades IIa and IIb. Historically associated with zoonotic outbreaks caused by animal-to-human transmission, mpox outbreaks can also start and spread through extended chains of human-to-human transmission. Despite prior evidence from West African outbreaks that mpox could start and spread through close human contact without an identifiable zoonotic event, limited global attention was paid to the pathogen until mid-2022, which saw rapid expansion of cases in Europe and North America, predominantly among gay men and other men who have sex with men [1, 2]. In July 2022, the World Health Organization (WHO) declared this global outbreak of clade IIb MPXV a public health emergency of international concern (PHEIC) [3]. This PHEIC ended in May 2023, though cases and outbreaks of IIb continue to be reported to this day. As of July 2025, 138 countries had reported laboratory-confirmed mpox cases to WHO, with a cumulative total of 158 425 cases since 2022 [4].

In August 2024, a new outbreak of clade MPXV Ib was declared a public health emergency of continental security (PHECS) by the Africa Centres for Disease Control and Prevention (CDC) and a PHEIC by WHO [5, 6]. In June 2025, WHO extended the declaration, given persistent transmission of multiple MPXV clades in different settings, increasing the incidence in some African countries, and sustained global risk due to underdetection and international spread [7]. As of July 2025, African countries have reported 26 734 laboratory-confirmed cases of mpox associated with 115 deaths, for a case fatality rate (CFR) of 0.4% [7]. However, the actual number of cases and deaths is likely much higher, as many countries involved have limited capacity and long turnaround times for DNA polymerase chain reaction–based confirmatory diagnosis [8]. Current information suggests that CFRs among people with MPXV vary depending on viral clade, affected population, and, importantly, access to appropriate supportive care. Several groups are at higher risk of severe disease and mortality, which has been reported as up to 6% mortality for children aged <5 years and 15% for people with advanced HIV-1 disease [9, 10].

Every aspect of the mpox response has lagged behind actual needs. During the global outbreak, scale-up of vaccination and testing capacity did not keep pace with the rates of new infections in the United States, where most reported cases were clade IIb infections [11]. In affected African countries, the inequities are far more severe. An estimated 18–22 million doses are needed to meet the Africa CDC's current goal of vaccinating 10 million people in 6 months, yet fewer than 5.6 million doses have been pledged for donation by high-income countries with stockpiles of effective vaccines. As of July 2025, just over half of pledged doses had been made available for countries; 698 000 people, just over 1% of the Africa CDC target, have received a single dose [12]. The African CDC/WHO Mpox Continental Preparedness and Response Plan for Africa, now entering its second phase, has not been adequately funded [13, 14].

Vaccine access can be expanded through funding and by addressing regulatory challenges to allow the supply of currently approved products. After 3 years and 2 WHO PHEICs, there are no rapid, affordable, point-of-care (POC) diagnostics or direct-acting antivirals with established efficacy. No novel antivirals have entered clinical trials. As shown in Table 1, the overwhelming majority (82%) of completed and ongoing trials have focused on a single drug, tecovirimat, with documented concerns about development of resistance, and studies have yet to show efficacy in reducing time to lesion resolution or pain. The pipeline has not kept pace with the pathogen.

Table 1.

Mpox Molecular Diagnostics Pipeline as of July 2025

Status	True POCa	Near POCb	Laboratory-Based
In research and development phase	9	31	121
Regulatory approval (excluding CE-IVDD)	0	1 (Xpert Mpox)	19
CE-IVDD	2 cartridge-based products (Pluslife, PortNAT)	5 (EasyNAT, Coyote, Merlin, Anbio, Genes2Me)	40
World Health Organization emergency use list	1 (PortNAT)	3 (EasyNAT, Xpert Mpox, Radione)	2 (Alinity, Cobas)

A CE-IVDD mark indicates a diagnostic devices' s conformity with European Union health, safety, and environmental protection directives. It is a legal requirement for many products sold within the European Economic Area (EEA).

Abbreviation: CE-IVDD: Conformité Européenne-In Vitro Diagnostic Device. POC, point of care.

^aMolecular true-POC platform: handheld or portable devices that can be operated by lay users or health workers with limited training on laboratory practices.

^bMolecular near-POC platform: medium-sized (benchtop, not portable) sample-to-answer instruments that can support rapid molecular testing in small clinics and hospitals.

EVOLUTION OF THE MPOX THERAPEUTIC AND DIAGNOSTIC PIPELINE

In 2025, WHO recommended rapid treatment initiation with antiretrovirals for people with HIV (PWH) who are diagnosed with mpox, as well as integrated HIV and syphilis testing for people with probable or suspected cases of mpox [15]. In the absence of affordable, accurate, and quality-assured diagnostics and of safe and effective treatments for people at the highest risk of mpox disease, these recommendations cannot be implemented effectively, and outbreaks are likely to continue.

With countries facing conflicting priorities and increasingly limited resources, efficiencies in the mpox response are needed now more than ever. Limited progress in the current outbreak has been, in large part, due to the lack of financial resources to adequately support the African CDC/WHO Mpox Continental Preparedness and Response Plan for Africa, now entering its second phase, with slow access to vaccines and reliable POC diagnostics and the absence of antiviral treatments for effective patient management. While there has been some progress on access to vaccines, a test-and-treat strategy with rapid diagnosis and antiviral treatment is not yet possible. Early treatment for patients, which limits disease progression and ideally transmission, could be highly impactful for both individual and community management.

An evaluation of the evolution of the diagnostics and therapeutics pipeline is disappointing. We performed an analysis based on public information to compare the current situation to the pipeline analysis we performed in 2022 [16–24]. While there are potential rapid antigen tests that could, if validated, become available to low- and middle-income countries (LMICs), there are no comparable promising candidates in the therapeutics pipeline [25]. Our critical review of the pipelines can help to prioritize the next steps in addressing existing gaps.

We analyzed the December 2022 and January 2025 composition of tests submitted by manufacturers to the DxConnect database, which is maintained by FIND, a global nonprofit that focuses on ensuring equitable access to diagnostics. While the number of diagnostic tests increased, 49% remained research-use only or had uncertain regulatory status. Laboratory-based testing still dominates. There are 2 WHO-validated POC molecular tests (see Table 2) and no independently validated antigen rapid diagnostic tests (AgRDTs), which are essential for decentralized detection [26]. In its independent evaluations, FIND identified at least 5 commercial tests that met the WHO’s target product profiles (TPPs) for mpox diagnostics and were suitable for use in LMICs based on scope of use, assay design, and price [22, 27]. However, the pace at which manufacturers are commercializing products continues to outpace crucial independent evaluations.

Table 2.

Ongoing Trials of Mpox Therapeutics as of July 2025

Compound	Phase	Design	Study Name	Location	Mpox Viral Clade	Target Sample Size	Population/ Eligibility Criteria	Status
Ongoing trials of direct-acting antivirals
Tecovirimat	4	Open-label	PALM 007 Extension—NCT06721585	Democratic Republic of the Congo	Clade I	Up to 400	Adults and children (weighing >3 kg) with laboratory-confirmed mpox and at least 1 lesion	Active, not recruiting
Tecovirimat	4	RCT, double-blind, placebo-controlled	EPOXI—NCT06156566	European Union	Clade IIb	150	Adults (aged >18 y) with laboratory-confirmed mpox	Active, planned completion date: August 2026
Tecovirimat	3	RCT, double-blind, placebo-controlled	UNITY—NCT05597735	Brazil, Argentina, Switzerland	Clade IIb	150	Adults and adolescents (aged >14 y), laboratory-confirmed or highly suspected mpox with at least 1 visible lesion, hospitalized or outpatient	Active, planned completion date: August 2026
Tecovirimat	4	Open-label, expanded access program	ISRCTN43307947	Central African Republic	Not specified	Up to 100	Adults and children weighing >13 kg treated as inpatients; immunocompromised and pregnant patients eligible for enrollment	Active
Brincidofovir (platform trial, other compounds to be evaluated in the future)	3	RCT, double-blind, placebo-controlled, platform adaptive trial	MOSA—PACTR202405860723287	Democratic Republic of the Congo, Uganda, Sierra Leone, and other African countries	Clades Ia, Ib, II	422	Adults or adolescents aged >14 y, children weighing >13 kg with laboratory-confirmed mpox and at least 1 visible lesion either hospitalized or outpatient; pregnant and immunocompromised patients eligible for enrollment	Recruiting
Other ongoing trials: ophthalmic use, immunotherapy, vaccine + drug interaction
Trifluridine eye drops	2	Open-label	−	Japan	Not specified	20	Children aged ≥6 y with mpox-induced keratoconjunctivitis, human immunodeficiency virus–positive, and immunocompromised patients eligible to enroll	Recruiting
MVA-BN vaccine + tecovirimat	2	RCT, open-label (JYNNEOS), double-blind (tecovirimat), placebo controlled	NCT04957485	United States	Not specified	100	Healthy adults (aged 18–42 y); pregnant and immunocompromised patients excluded	Active
Vaccinia immunoglobin	2	Open-label	jRCTs031240111	Japan	Not specified	20	Adults aged 18–65 y diagnosed with mpox or smallpox, treated as inpatient; pregnant and immunocompromised patients eligible	Active not recruiting

Abbreviations: MVA-BN: Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN); RCT, randomized, controlled trial.

The urgent need for reliable and affordable near-POC and true-POC tests is not new. It has been abundantly clear that simplified community-based approaches to screening and diagnosis are required for an adequate public health response to the mpox pandemic.

CONCLUSION THE MPOX PIPELINE IS IN CRIITICAL CONDITION

Unfortunately, the mpox diagnostics and therapeutics pipeline does not reflect a long-term plan to support an effective public health response where the disease is endemic and laboratory capacity is fragile. At the time of this analysis, the FIND mpox diagnostics database showed 32 commercially available antigen rapid tests, yet quality assurance remained unknown and sensitivity remained unknown or unvalidated. When available, the data strongly suggest that some of these tests either have major deficits in sensitivity, particularly for people who are tested after the acute phase of infection. WHO recently completed an evaluation of additional mpox AgRDTs. In the just-ended study, two of the five index tests achieved the expected average sensitivity (≥70%) and were very close to the expected specificity threshold, reaching 93.5% against the ≥95% benchmark. These two tests demonstrated comparatively higher sensitivity with MPXV Clade Ib, while the third test achieved 74%, meeting the expected average sensitivity threshold.Three of the five index tests achieved the expected average specificity threshold (≥95%).While the accuracy of AgRDTs in this study does not strictly meet the TPP criteria, three of the five index tests can have a role in hyperendemic remote settings with no access to DNA polymerase chain reaction ( PCR) testing.

While the potential for validated rapid mpox diagnostics is now closer than ever, there are highly limited prospects for antiviral treatments to protect the most vulnerable from severe infection and/or limit transmission to close contacts, especially among those not yet vaccinated. No treatment has yet demonstrated efficacy either in accelerating time to resolution of lesions or in reducing viral load replication.

While the use of tecovirimat is approved in the European Union and Japan, clinical trial data have shown its safety but not its efficacy, and there is also evidence that the mpox virus can become resistant to it [28, 29]. Currently, only 2 alternative therapies are being studied in clinical trials. In our analysis, we identified 17 mpox trials that involved mpox therapeutics that have been completed, halted, or launched since 2022. Of these, 15 assessed direct antiviral agents, and the others assessed trifluridine eye drops and drug–vaccine interactions. In clinical trials completed to date, 12 (80%) assessed tecovirimat. The remaining studies included injectable cidofovir and brincidofovir, 2 drugs with potential safety issues that were originally developed for smallpox and vaccinia immunoglobulin.

At the time of this writing, only 6 of those studies are ongoing. The other studies found no efficacy, were suspended due to other research developments, or failed to enroll participants. There are no ongoing therapeutic trials assessing combinations of medicines for mpox. Platform trials that use adaptive designs to evaluate multiple interventions against a common control group are powerful and provide a highly relevant framework for evaluating mpox therapeutics. There is only 1 ongoing platform trial. The primary end points of all evaluations reviewed are essentially clinical, assessing the time to resolution of skin and mucosal mpox lesions. Only studies with smaller sample sizes conducted in Japan used viral load clearance as the primary end point. Most vulnerable populations, including children, PWH, and persons who are pregnant, have not been prioritized in these ongoing studies, even though development of therapeutic options for these groups is urgent, given the increased CFRs, severity of lesions, and potential challenges with vaccination.

The preclinical pipeline includes only a few novel compounds and is largely focused on monoclonal antibodies, resulting in an unmet need for additional classes of drugs with complementary mechanisms of action [17].

Currently, this therapeutic pipeline falls far short of what is required for a robust response. An optimal MPOX Response would include A test-and-treat or test-and prevent strategy, which could be complementary to the progress in vaccination. The paucity of candidates emphasizes the limitations of current mechanisms for incentivizing the development of necessary antivirals. This is true for other pathogens of pandemic potential and should be remedied by a field-wide restructuring that is centered on incentivizing strategic and efficient product development and on accelerating efforts to fill the gap in research on current candidates [30]. Antivirals that can be adapted for use in LMICs, meet the WHO TPPs, and be promptly evaluated in combinations in factorial adaptive coordinated trials are urgently needed if mpox is to be adequately managed [31].

The 2022 PHEIC declaration on mpox was a warning and a missed opportunity to prepare for the current and inevitable future outbreaks. Vaccination rollout has yet to achieve the necessary uptake; testing rates are limited by lack of access to adequate tools; and antivirals are not yet available to support rapid and adequate care of those infected. Several rapid tests and POC molecular diagnostics could be made widely available if prompt actions are taken regarding evaluation and access. In addition, the promising antiviral candidates in preclinical stages could be adapted to the needs of LMICs and advanced through the clinical pipeline, ideally in combinations. A promising pipeline of well-performing antivirals, along with a landscape of evolving diagnostics adapted for use in LMICs, would eventually allow for a much-needed test-and-treat approach to mpox.

Even if the current level of emergency were to decrease in the near future, the threat of future mpox outbreaks remains, for which the world is still largely unprepared. The persistent potential for sustained human transmission requires a proactive, efficient, and well-resourced strategy to ensure that all necessary medical countermeasures are promptly developed and brought to market. This includes expedited regulatory evaluations before the next public health emergency is declared that are accessible to the programs and populations in greatest need in endemic areas.