At the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Global 2026 conference, Chris Harris from Enanta Pharmaceuticals presented data from a Phase IIb trial that investigated zelicapavir, an oral once-daily N-protein inhibitor, for the treatment of respiratory syncytial virus (RSV) in high-risk adults.
RSV is a common respiratory virus that is often associated with mild cold-like symptoms. However, symptoms can sometimes be more severe, resulting in substantial morbidity and hospitalisation, particularly among infants, older adults, or those with underlying health conditions.
Management of RSV has undergone a dramatic transformation in recent years owing to the launch of novel prophylactic monoclonal antibodies (mAbs) and vaccines, with a range of options now available to protect the most vulnerable populations against RSV disease. However, innovation in RSV therapeutics is still lagging. For those already infected with RSV, there are still no specific approved therapies, and care is mostly supportive. Consequently, there is a strong unmet need for novel therapeutics.
Zelicapavir acts as a replication inhibitor, shutting down the production of new virions. The drug candidate has a strong preclinical profile, with nanomolar potency demonstrated against RSV-A and RSV-B. It has also demonstrated activity against all clinical isolates tested, as well as a high barrier to resistance. Zelicapavir may also act synergistically with other mechanisms of action such as fusion inhibitors or L-protein inhibitors. The drug candidate has been shown to have a favourable efficacy and safety profile in previous clinical trials and has been granted fast-track designation by the FDA.
The Phase IIb double-blind study presented at the conference enrolled 186 adults within 72 hours of the onset of RSV symptoms. Subjects were either 65 years of age or older, or had at least one of the following conditions: chronic obstructive pulmonary disease (COPD), asthma, or congestive heart failure (CHF). Approximately 80% of the subjects had either COPD, CHF, or were aged ≥75 years (known as the HR3 subpopulation) and were therefore considered to have the most severe underlying disease or risk factors. Patients received either 800mg zelicapavir or placebo (2:1 ratio) once daily for five days, followed by a 28-day follow-up period. The vast majority of patients had not previously been vaccinated against RSV, across both arms.
Analysing the Phase IIb data
The primary endpoint of the study was time to resolution of four RSV lower respiratory tract disease (LRTD) symptoms (shortness of breath, wheezing, cough, and productive cough) to mild, based on the Respiratory Infection Intensity and Impact Questionnaire (RiiQ) symptoms scale. Although the primary endpoint was not met, compelling results on multiple clinically meaningful endpoints were observed.
In both the total efficacy population and the HR3 subpopulation, zelicapavir was associated with faster symptom resolution to absent compared to placebo for the following endpoints: resolution of four RSV LRTD symptoms (improvements of 0.5 days and 3.0 days, respectively); resolution of 13 RSV symptoms including LRTD symptoms, upper respiratory tract disease (URTD) symptoms, and systemic symptoms (improvements of 2.2 days and 6.7 days, respectively); and resolution of 29 RiiQ parameters, including quality of life measures (improvements of 3.6 days and 7.2 days, respectively). Thus, the most high-risk subjects appeared to derive the greatest benefits from zelicapavir.
Symptom resolution was also measured by another patient-recorded outcome, the Patient Global Impression of Severity (PGI-S) score. Zelicapavir was associated with a statistically significant 2-day faster median time to improvement on the PGI-S compared to placebo in both the total efficacy population (p=0.0446) and the HR3 subpopulation (p=0.0465).
In addition, the RSV-associated hospitalisation rate was lower in the zelicapavir group than the placebo group (0.0% and 5.0%, respectively).
Zelicapavir was also associated with a favourable safety and tolerability profile. The percentage of subjects who experienced treatment emergent adverse events (TEAEs) was similar in both the zelicapavir and placebo groups (22.3 and 24.6%, respectively), as was the percentage of subjects who experienced study drug-related TEAEs (5.8% vs. 4.6%, respectively). However, the percentage of subjects who experienced TEAEs at grade 3 or above was notably lower in the zelicapavir group compared to the placebo group (0.8% and 7.7%, respectively) as was the percentage of subjects who experienced serious TEAEs (1.7% and 6.2%, respectively). Additionally, TEAEs leading to study drug discontinuation, TEAEs leading to study withdrawal, and TEAEs leading to death occurred in 1.5%, 3.1%, and 1.5% subjects in the placebo group, respectively, while no such events occurred in the zelicapavir group.
The next steps for zelicapavir
Despite missing the study’s primary endpoint, Enanta has announced its intention to continue the development of zelicapavir on the basis of positive secondary and subgroup efficacy data, coupled with the drug’s favourable safety/tolerability profile. A Phase III study investigating zelicapavir in high-risk adults with RSV is estimated to commence in Q4 2026, which may provide further evidence of the benefits of zelicapavir in specific subpopulations.
Zelicapavir is also being investigated in clinical trials for the paediatric population, and positive Phase II topline results have been reported in this population, which indicates that the drug candidate will be positioned as a broad-use antiviral for RSV. Furthermore, Enanta has another therapeutic candidate in Phase II development for RSV. EDP-323 is an L-protein inhibitor that has demonstrated positive data in a Phase IIa viral challenge study conducted in healthy adults.
With Enanta on the verge of progressing its lead asset to Phase III, the company is in a strong position to dominate the largely untapped RSV therapeutics market, particularly if zelicapavir and EDP-323’s mechanisms of action are shown to act synergistically, which may provide a rationale for combination therapy in certain patients.
