Investigational agent Zelicapavir cut time to complete RSV symptom resolution by up to a week and lowered hospitalization in high-risk adults.
Zelicapavir (EDP-938; Enanta Pharmaceuticals), an investigational once-daily oral RSV N-protein inhibitor, cut time to complete RSV symptom resolution by up to a week vs placebo in high-risk adults.¹ The phase 2b RSVHR results were presented at IDWeek 2026, held October 21-24 in Washington, DC.¹ The trial missed its primary end point, but zelicapavir also lowered all-cause hospitalization and viral load.¹
No RSV antiviral had previously shown efficacy in high-risk adults, including patients with congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), asthma, or age older than 65 years.¹ Zelicapavir targets the viral nucleoprotein to block replication.¹ According to Scott T. Rottinghaus, MD, chief medical officer of Enanta Pharmaceuticals, replication inhibitors carry a higher barrier to resistance than the fusion inhibitors studied historically.
RSVHR (NCT05568706) randomly assigned 186 symptomatic adults with RSV to zelicapavir (n = 121) or placebo (n = 65) once daily for five days.¹ Patients enrolled within three days of symptom onset. A predefined HR3 population with CHF, COPD, or age older than 75 years made up 81% of the efficacy population.¹
The primary end point measured time to resolution of lower respiratory tract disease (LRTD) symptoms to mild or absent on the RiiQ patient-reported outcome instrument.¹ Zelicapavir showed no effect on this end point or on other resolution-to-mild measures.¹ In contrast, predefined analyses of complete resolution, with all symptoms absent at two consecutive time points, and sustained resolution favored zelicapavir by up to a week.¹
Rottinghaus said complete resolution of LRTD symptoms alone showed a three-day benefit, widening to 6.7 days across all 13 RSV symptoms. He noted the investigators had no prior efficacy data to guide end point selection.
“Nobody’s actually shown a meaningful clinical benefit in this population with an antiviral before,” said Rottinghaus. “So there wasn’t pre-existing data to guide either what the primary endpoint should be or how exactly to measure it.”
He attributed the gap to measurement, since rating a symptom as moderate vs mild is subjective, while reporting whether a symptom is present is more reproducible. RSV also presents and resolves heterogeneously, with some patients starting with cough and others with rhinorrhea. Broader symptom sets therefore captured the treatment effect more fully, he said.
Zelicapavir resolved Patient Global Impression of Severity (PGI-S) scores two days faster than placebo in both the efficacy population (P = .0446) and the HR3 population (P = .0465). All-cause hospitalization occurred in 1.7% of zelicapavir recipients vs 5.0% of placebo recipients.1
At the end of treatment, 23.5% of zelicapavir recipients had undetectable viral load vs 10.0% with placebo in the efficacy population (P = .0198). Median time to undetectable viral load was four to five days faster with zelicapavir. Viral load declined an additional 0.6 log in the efficacy population and 0.7 log in the HR3 population at end of treatment vs placebo.1
Adverse events were similar between the zelicapavir and placebo arms.1 Zelicapavir reached target exposures at 55- to 57-fold multiples over the EC90.1 The investigators concluded the reductions in symptom duration, hospitalization, and viral burden support further development.1
Rottinghaus framed the symptom benefit against the regulatory benchmark set in influenza.
“We know for influenza antivirals, they were approved with about a one-day reduction in the time to symptom resolution,” said Rottinghaus. “Here we’ve seen almost a week, which is still along the lines of a 30-some percent reduction in the time to complete resolution.”
Enanta plans to initiate RESOLVE, a registrational phase 2b/3 trial in high-risk adults, in the fourth quarter of 2026.2,3 The phase 2b portion will enroll at least 200 patients, followed by a phase 3 portion of approximately 660 patients.2 Rottinghaus said RESOLVE will use complete resolution of all 13 symptoms as its primary end point, enroll the HR3 population, and extend dosing to seven days.
No antiviral is approved to treat RSV infection. Rottinghaus noted only about 20% of eligible older adults receive an RSV vaccine, leaving a substantial treatment gap despite available prevention tools.
