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RSV Infection
ALN-RSV: Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) is a highly contagious virus that is the most common identified cause of lower respiratory tract infections in children under one year of age. In the pediatric and adult populations, RSV accounts for more than 300,000 hospitalizations per year in the U.S. RSV infection in lung transplant patients represents an important unmet medical need. Lung transplant patients infected with RSV are at risk for both acute rejection and a bronchiolitis obliterans syndrome (BOS). BOS is a progressive inflammatory and fibrotic lesion of the small airways resulting in an irreversible loss of function in the transplanted lung, and is associated with approximately 50% mortality within five years. There is significant need for novel therapeutics to treat patients who become infected with RSV.
ALN-RSV01, is being developed for the treatment of RSV infection. Our RNAi therapeutic was designed to target the nucleocapsid "N" gene of the RSV genome, a gene that is required for the replication of the RSV. ALN-RSV01 silences the N gene, thereby reducing the virus' ability to reproduce. Our extensive pre-clinical work demonstrated potent and highly specific anti-viral efficacy with molecular proof of an RNAi mechanism of action. With these promising data in hand, we progressed toward human studies, and our Phase I studies established the safety and tolerability of ALN-RSV01 in adult human volunteers.
Results from a Phase IIb study demonstrated that inhaled ALN-RSV01 reduces the incidence of new or progressive BOS in RSV-infected lung transplant patients. Data from this study show that ALN-RSV01 is associated with a significant treatment effect, including results of a multivariate logistic regression analysis where treatment with ALN-RSV01 showed an over eight-fold reduced risk in developing day 180 BOS. Further, we showed a statistically significant effect on the secondary endpoint of day 90 BOS, and demonstrated a particularly strong effect of over 80% in patients receiving ALN-RSV01 within five days of symptom onset. In aggregate, results of secondary endpoints and additional post-hoc analyses continue to support the conclusion that treatment of RSV-infected lung transplant patients with ALN-RSV01 was generally safe and well tolerated and associated with a decreased incidence of new or progressive BOS.
We believe that these data provide important evidence that ALN-RSV01 reduces the incidence of new or progressive BOS in RSV-infected lung transplant patients, replicating the findings from our Phase IIa study of this agent in the same clinical setting.
The ALN-RSV program is partnered with Kyowa Hakko Kirin in Asia. We plan to seek a partner to continue to advance the program in other regions.
ALN-RSV01 Clinical Timeline
The Phase IIb trial was an international multi-center, randomized, double-blind, placebo-controlled study of ALN-RSV01 in RSV-infected lung transplant patients. The primary endpoint of the Phase IIb trial was the incidence of new or progressive BOS at 180 days; these data were adjudicated by an independent panel of three transplant physicians who were blinded to study drug treatment assignment. The trial enrolled 87 patients who were randomized in a one-to-one,drug-to-placebo ratio; a total of 33 sites participated from six countries. Based on local study site diagnosis of RSV infection, a total of 45 patients were randomized to receive ALN-RSV01 and 42 patients were randomized to receive placebo, defining the overall intent-to-treat study cohort (ITT). Following central laboratory testing by PCR analysis, 10 patients could not be confirmed as infected for RSV; these patients included nine patients randomized to receive placebo and one patient randomized to receive ALN-RSV01. Accordingly, a total of 77 patients (placebo, n=33; ALN-RSV01, n=44) comprised the ITTc (ITT- central lab confirmed) analysis population. Baseline characteristics were generally well balanced between treatment groups. Placebo or ALN-RSV01 (0.6 mg/kg dose) was administered by inhalation once daily for five consecutive days immediately after diagnosis with an investigational eFlow® Nebulizer System (PARI Pharma). All patients also received standard of care treatment according to the site's practices.
In the ITTc analysis, ALN-RSV01 narrowly missed the primary endpoint of new or progressive BOS at 180 days. ALN-RSV01 treatment was associated with a statistically significant reduction in the incidence of day 180 BOS in the prospectively defined LOCF and PP analyses. In all analyses, treatment with ALN-RSV01, as compared with placebo, was associated with a clinically meaningful reduction in the incidence of BOS with a treatment effect ranging from approximately 54% to 65%. ALN-RSV01 was found to be generally safe and well tolerated in the study, with a comparable incidence of reported adverse events in placebo and study drug treatment arms.
In addition, data included results from key secondary endpoints and certain post-hoc analyses, including results of a multivariate logistic regression analysis where treatment with ALN-RSV01 showed an over eight-fold reduced risk in developing day 180 BOS. Further, we showed a statistically significant effect on the secondary endpoint of day 90 BOS, and demonstrated a particularly strong effect of over 80% in patients receiving ALN-RSV01 within five days of symptom onset. In aggregate, results of secondary endpoints and additional post-hoc analyses continue to support the conclusion that treatment of RSV-infected lung transplant patients with ALN-RSV01 was generally safe and well tolerated and associated with a decreased incidence of new or progressive BOS.

