Small-molecule polymerase inhibitor protects non-human primates from measles and reduces shedding

Measles virus (MeV) infects via the respiratory tract, initially targeting SLAM/CD150+ immune cells in the upper respiratory mucosa, then spreading to lymph nodes and causing PBMC-associated viremia before dissemination to epithelial tissues coincident with clinical signs (fever, conjunctivitis, rash). Measles continues to cause significant morbidity and mortality, with over 200,000 deaths in 2019, and induces prolonged immunosuppression that compromises responses to unrelated pathogens. Although humans are the only reservoir and vaccination confers long-lasting immunity, setbacks in global vaccination coverage—exacerbated by the COVID-19 pandemic—have led to resurgence of outbreaks, particularly given MeV’s high R0 (13.7–18.9). To accelerate progress toward elimination and support vaccine-based eradication, the study evaluates ERDRP-0519, an orally bioavailable small-molecule inhibitor of the MeV polymerase, for prophylactic and therapeutic efficacy in a non-human primate model of human measles.

Prior studies demonstrated in vitro potency of ERDRP-0519 against MeV and other morbilliviruses and in vivo proof-of-concept in a lethal canine distemper virus ferret model, where treatment achieved complete survival and near-complete suppression of clinical signs. Resistance hotspots in the morbillivirus polymerase associated with ERDRP-0519 have been characterized, with resistant variants showing reduced fitness. Building on these data, this study advances assessment to non-human primates infected with a clinical MeV isolate.

Animal model and groups: Adult squirrel monkeys (Saimiri sciureus) were intranasally challenged with 10^6 TCID50 of MeV field isolate MV/Frankfurt/Main.DEU/171.1 (genotype D). Animals were allocated to four groups (n=6 per group unless noted): untreated; prophylactic ERDRP-0519 starting 12 h pre-infection; therapeutic day 3 (treatment start 3 days post-infection); therapeutic day 7 (treatment start 7 days post-infection). All treated animals received ERDRP-0519 b.i.d. for 14 days at 50 mg/kg orally (intragastric). One animal in the day 3 group died on day 15 post-infection; histology and parasitology found no drug-related pathology. Pharmacokinetics and ex vivo recapitulation: Single-dose oral PK (50 mg/kg) was measured by LC/MS/MS, yielding Cmax ~3.27 µM at ~2 h post-dose; in vitro EC50 values ranged 0.07–0.3 µM depending on strain. Mean plasma concentration during multi-dose treatment was ~1.6 µM, with troughs just above a conservative 1.5 µM target over a 12-day window. Ex vivo, hPBMCs infected with MeV were exposed to profiles mimicking q.d. vs b.i.d. dosing; b.i.d. was superior (p=0.0002), and constant 1.5 µM exposure was nearly sterilizing (>3-log reduction in progeny virus), informing the in vivo b.i.d. regimen. Clinical assessments: Animals were monitored for rash and other clinical signs, rectal temperature, and body weight. Virological endpoints included MeV titers in PBMCs and throat swabs over time, with limits of detection indicated, and statistical analysis by two-way ANOVA with Dunnett’s post-hoc test versus untreated controls. Immunological endpoints included total white blood cell counts and neutralizing antibody titers. On day 21 post-infection (or at death for the one animal), lymph nodes were collected for MeV N-gene RNA quantification by RT-qPCR. Safety was evaluated by gross and histopathology on day 21. Genetic analysis: Viral RNA from PBMCs and throat swabs (last viremic/positive time point) was Sanger sequenced for MeV L gene to detect resistance-associated mutations. Compliance: All procedures complied with German animal protection laws (Regierungspraesidium Darmstadt authorization).

- Pharmacokinetics: Single oral 50 mg/kg dose achieved Cmax ~3.27 µM at ~2 h, exceeding MeV EC50 (0.07–0.3 µM). Multi-dose mean plasma level ~1.6 µM; troughs slightly above 1.5 µM target. - Ex vivo potency: b.i.d. exposure was significantly more potent than q.d. (p=0.0002); constant 1.5 µM exposure reduced progeny virus by >3 logs. - Clinical efficacy: Prophylactic treatment prevented measles-typical clinical signs. Therapeutic treatment initiated at day 3 or day 7 post-infection reduced disease severity; no treated animals developed severe/generalized rash, whereas untreated controls frequently did. - Viral loads: Prophylaxis nearly ablated PBMC viremia; day 3 treatment markedly reduced viremia; day 7 treatment did not prevent PBMC viremia but significantly reduced throat swab titers. In the day 7 group, shed virus titers dropped by ~2 orders of magnitude within 72 h of treatment initiation (p=0.0199), indicating reduced potential transmission. - Hematology and immunology: Untreated animals developed typical MeV-associated leukopenia peaking around day 10, with slow recovery. Prophylactic and day 3 treatment groups showed no leukopenia; the day 7 group trended lower without significance and recovered faster than untreated, suggesting alleviated immunosuppression. Neutralizing antibody titers developed variably; some treated animals, particularly prophylaxis/day 3, had low titers by study end, possibly due to strong suppression of viral replication. - Lymph node viral RNA: MeV N-gene RNA levels at day 21 were significantly reduced versus untreated in prophylactic (p=0.0295) and day 3 therapeutic (p=0.0346) groups, indicating accelerated clearance. - Safety and resistance: Histopathology at day 21 showed only changes consistent with recent viral infection across groups, with no drug-linked toxicities. One death in the day 3 group was deemed unrelated to drug or MeV. Sequencing of the MeV L gene found no amino-acid–changing resistance mutations in known ERDRP-0519 resistance clusters.

The study addresses whether the orally bioavailable polymerase inhibitor ERDRP-0519 can prevent or ameliorate measles in a relevant primate model and reduce viral shedding that drives transmission. Achieved serum levels after b.i.d. dosing surpassed in vitro potency thresholds and translated to significant in vivo antiviral effects. Prophylaxis prevented clinical disease and largely abrogated PBMC viremia; treatment as late as day 7, aligned with epithelial spread in the MeV life cycle, still reduced throat viral loads and prevented generalized rash, indicating benefit even after onset of clinical signs. Reduced shedding supports the prospect of limiting transmission and aiding outbreak control. Trends toward reduced leukopenia suggest mitigation of MeV-associated immunosuppression, though not always statistically significant, and immune responses were variably induced, likely reflecting low antigenic stimulation under potent antiviral treatment. Safety profiles and lack of detected resistance mutations strengthen the translational potential of ERDRP-0519 to complement vaccination in eradication strategies, especially in settings with suboptimal coverage.

ERDRP-0519, an orally bioavailable MeV polymerase inhibitor, provided robust prophylactic and therapeutic efficacy in MeV-infected squirrel monkeys. Prophylaxis prevented clinical disease and viremia, and post-exposure therapy reduced disease severity and throat viral shedding, with day 7 initiation still conferring benefits. The regimen achieved serum concentrations consistent with strong antiviral activity, showed no drug-attributable toxicity, and did not select for known resistance mutations in vivo. These results support ERDRP-0519 as a promising adjunct to vaccination for measles control and potential eradication. Future work should include dose-optimization and duration studies, direct transmission studies to quantify impact on spread, comprehensive immunogenicity assessments under treatment, and clinical evaluation in humans with resistance surveillance.

- Sample size was modest (n≈6 per group), limiting power for some outcomes (e.g., leukopenia trends not always statistically significant). - One animal in the day 3 group died; although pathology suggested causes unrelated to drug or MeV, the event reduces group size and adds uncertainty. - The study duration (to day 21) may not capture longer-term outcomes, durability of immune responses, or late adverse events. - Non-human primate model, while closely mimicking human measles, may not fully recapitulate human disease and treatment responses. - Some treated animals developed low or absent neutralizing antibody titers by study end, complicating interpretation of how antiviral treatment affects long-term immunity. - OCR-like inconsistencies in some methodological descriptions suggest possible reporting typos; however, core experimental parameters are clear.