Abstract

ALN-RSV01 is a small interfering RNA targeting RSV replication. A Phase IIa randomized, controlled trial in 24 RSVinfected lung transplant patients administered aerosolized ALN-RSV01 or PBO daily for 3 days was previously conducted, in which ALN-RSV01 treatment led to a significant reduction in the incidence of new or progressive bronchiolitis obliterans syndrome (BOS) at Day 90 compared to PBO (p=0.027). We have now performed a Phase IIb multi-center, randomized, double-blind, PBO controlled trial in 87 RSV-infected lung transplant patients to examine the impact of ALN-RSV01 on the incidence of new or progressive BOS at Day 180. RSV positive subjects were randomized (1:1) to receive aerosolized ALN-RSV01 or PBO daily for 5 days, alongside the institution’s standard-of-care. Patient stratification to treatment was based on 2 binary factors: 1) days from symptom onset to treatment, and 2) pre-infection BOS grade. Of the 3,985 patients prescreened, 218 were RSV positive, of which 45 were randomized to receive ALN-RSV01 and 42 to receive PBO [intentto- treat (ITT) cohort]. Ten patients were without confirmed RSV infection by central laboratory, and thus a total of 77 patients (ALN-RSV01, n=44; PBO, n=33) comprised the ITTc cohort. ALN-RSV01 was found to be generally safe and well tolerated. In the ITTc cohort, there was a trend toward a decrease in new or progressive BOS at Day 180 in ALN-RSV01- treated patients compared to PBO (13.6% vs 30.3%, p=0.058), which was statistically significant in the prospectively defined Last Observation Carried Forward (p=0.028) and per-protocol (p=0.025) cohorts. Importantly, ALN-RSV01 had a treatment effect ranging from 54-65% in all of the pre-specified cohorts.