The antiviral drug tecovirimat (Tpoxx) didn't accelerate lesion clearance in adults and children with clade 1 mpox participating in a randomized controlled trial in the Democratic Republic of the Congo (DRC), where a separate study found high disease severity and death rates.
Trial data on Tpoxx efficacy lacking
For the trial, published yesterday in the New England Journal of Medicine, the PALM007 Writing Group randomly assigned hospitalized mpox patients with at least one skin lesion to receive Tpoxx or a placebo for 14 days.
The goal was to determine whether the antiviral drug led to faster lesion resolution than placebo, as well as the drug's safety profile. The study was conducted from October 2022 to July 2024.
In total, 295 patients received Tpoxx, and 302 were given a placebo. Patients returned for a follow-up visit 28 days after randomization, and some also returned at 58 days. Most patients (64.3%) were children, 48.9% were female, and 65.0% had severe or grave mpox (ie, more than 100 lesions) according to World Health Organization (WHO) criteria.
Although tecovirimat was approved for the treatment of mpox by the European Medicines Agency and made available in the United States under an expanded-access investigational new drug application, the efficacy of tecovirimat in mpox remains unknown.
Mpox cases are growing in sub-Saharan Africa, particularly in the DRC. "The increasing burden of mpox is due, in part, to a growing population without cross-protective immunity after cessation of smallpox vaccination in the early 1980s," the authors wrote. "Case fatality rates and morbidity associated with clade I MPXV [mpox virus] have been high historically."
"Although tecovirimat was approved for the treatment of mpox by the European Medicines Agency and made available in the United States under an expanded-access investigational new drug application, the efficacy of tecovirimat in mpox remains unknown," they added.
No difference in time to lesion clearing
The median number of days to lesion healing was 7 with Tpoxx and 8 with placebo (competing-risks hazard ratio [HR], 1.13). The results were comparable in patients who began their trial regimen within 7 days after symptom onset (competing-risks HR, 1.16) or after 1 week (competing-risks HR, 1.00). Ten patients (1.7%) died, 5 in each trial group, within 58 days. In comparison, 4.6% of DRC mpox patients died in 2023.
The improvement in death rates might be the result of the adoption of more aggressive, standardized supportive care over time, the authors said. Of 16 pregnancies, 7 (44%) ended in miscarriage, with no differences between groups.
The proportion of patients whose blood, lesion, and nose-throat swabs tested negative for mpox via polymerase chain reaction (PCR) at 14 days was similar among Tpoxx and placebo recipients, at roughly 50%. The authors said this finding raises questions about the transmissibility of mpox after lesion resolution.
Risk factors for slower lesion healing were higher lesion count, positive PCR results for nose-throat or lesion samples, higher viral load, fever or mouth sores, and abnormally high aspartate aminotransferase levels (indicating liver, heart, or muscle damage) and high white-cell counts (indicating infection or inflammation).
Research identifying and evaluating additional treatments for clade I mpox disease is needed.
The adjudication committee identified 12 confirmed and 8 probable cases of mpox recurrence among 27 patients evaluated; 55% of patients with a recurrence had received Tpoxx, and 45% had received placebo. Seven confirmed recurrences (35%) occurred within 28 days after randomization.
The Tpoxx concentration was less than that expected on the basis of findings from trials involving healthy participants, and 35% of patients had trough concentrations below the minimum effective level. But higher drug concentrations were not linked to faster lesion healing or negative PCR results at 7 or 14 days.
Adverse events were reported in 72.9% of the Tpoxx group and 70.5% of those in the placebo group, and serious adverse events were documented in 5.1% and 5.0%, respectively. Gastrointestinal adverse events—most commonly, abdominal pain—occurred in 26.4% of Tpoxx recipients and 23.8% of the placebo group.
"Ongoing randomized, controlled trials of tecovirimat for mpox caused by clade IIb MPXV, including the STOMP and UNITY trials and EPOXI, will provide needed evidence about the efficacy of tecovirimat in other populations," the researchers concluded. "Research identifying and evaluating additional treatments for clade I mpox disease is needed."
Time to move on from Tpoxx, commentary says
In a related commentary, Timothy Wilkin, MD, MPH, of the University of California at San Diego, said researchers should investigate alternative mpox treatments that could also be effective against smallpox in case of a bioterrorist attack, such as the antiviral brincidofovir.
"Data from animal models support the use of brincidofovir with concomitant tecovirimat [meaning both drugs combined], perhaps with an improved tecovirimat dosing strategy," the study authors wrote. "Monoclonal antibodies for mpox treatment are also in development and show promise. Randomized, controlled trials of these agents should include participants at risk for severe disease, such as those with immune suppression."
The lack of Tpoxx effectiveness raises concerns about the potential use of the drug against smallpox. "It would be prudent to investigate why results from human efficacy trials were not consistent with the data from animal models," Wilkin wrote.
"Approvals under the Animal Rule may be our best option for developing drugs to defend against potential terrorist threats, but the results of PALM007 inject a note of caution into this approach and suggest that rapidly implemented field trials may be needed to establish efficacy," he added.
Disparities in regional access to healthcare
For the second study, a non–peer-reviewed paper published last week on the preprint server medRxiv, researchers from Africa performed a systematic review and meta-analysis of 22 studies on mpox severity and death rates in the DRC from 1970 to 2024 by country region and healthcare setting.
Targeted interventions, including vaccination in high-risk areas, community education, and mobile health units, are urgently needed.
Among 3,282 mpox patients, the pooled rate of severe cases was 42.8%, falling from 68.6% before 1980 to 27.6% in 2022 to 2024. Western and central DRC reported greater severity (46.8%) than eastern regions (42.7%). Case-fatality rates (CFRs) were 1.9% among patients with suspected mpox and 4.2% among those with confirmed cases. Western and central DRC had the highest CFR, at 11.4%.
CFRs were higher in community settings (6.7%) than in hospitals (0.6%), highlighting disparities in access to healthcare, the researchers said. Study year and region were significant predictors of outcomes heterogeneity, with the death rate falling over time but staying elevated in resource-limited areas.
"The observed temporal decline in severity and CFRs suggests the impact of strengthened surveillance and healthcare capacity," the authors concluded. "Targeted interventions, including vaccination in high-risk areas, community education, and mobile health units, are urgently needed. Global collaboration must address diagnostic and treatment gaps in endemic countries to prevent cross-border outbreaks."
