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Alnylam Announces Top-Line Results of Phase IIb Clinical Trial of ALN-RSV01, an Inhaled RNAi Therapeutic for the Treatment of Respiratory Syncytial Virus (RSV) Infection

Alnylam Completes Enrollment in Phase IIb Study of ALN-RSV01, an RNAi Therapeutic for the Treatment of Respiratory Syncytial Virus (RSV) Infection

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.

Alnylam reported that ALN-RSV01 was found to be safe and well tolerated when administered intranasally in healthy adult volunteers in two Phase I clinical studies.

Alnylam reported that all major objectives of a Phase I inhalation study in the U.S. to evaluate the human safety, tolerability and pharmacokinetics of ALN-RSV01 in healthy adult volunteers were met, including definition of a safe and well-tolerated dose and regimen for advancement of ALN-RSV01 into further Phase II development.

Alnylam presented positive results from our GEMINI study, achieving human proof-of-concept with an RNAi therapeutic, a first for the industry. The Phase II GEMINI study was designed to evaluate the safety and anti-viral activity of ALN-RSV01 in experimentally infected patients. Results from the randomized, double-blind, placebo-controlled study demonstrated that ALN-RSV01 was safe and well tolerated, and demonstrated statistically significant anti-viral efficacy with an approximately 40% reduction in RSV infection rate and 95% increase in infection-free subjects.

Alnylam and Cubist reported complete data from their Phase II study of ALN-RSV01. In the Phase II study, conducted at 11 sites in 4 countries, 24 lung transplant patients with confirmed RSV infection were randomized to receive inhaled ALN-RSV01 (N=16) or placebo (N=8) once daily for three consecutive days. Overall, the study achieved its primary objective of demonstrating safety and tolerability of ALN-RSV01. In particular, there were no drug-related serious adverse events or discontinuations, and there were no clinically significant differences in the overall adverse event profile between ALN-RSV01 and placebo. Importantly, there was no evidence of disease exacerbation related to ALN-RSV01 treatment. At the 90 day endpoint, all patients survived and the incidence of intubation, new respiratory infection, or acute rejection was comparable across ALN-RSV01 and placebo groups. In addition, new 90 day clinical data were collected, although the study was not powered for these outcomes due to the small sample size, and they were therefore considered exploratory. Related to these 90 day data, key prospectively defined clinical secondary endpoints included recovery of lung function (forced expiratory volume in the first second, or FEV1) as measured by spirometry and clinical determination of new or progressive bronchiolitis obliterans syndrome, or BOS. Baseline measurements of FEV1 were obtained from patient records prior to their RSV infection. In the study, FEV1 measurements were obtained at screening and at day 90 in order to determine the percentage of patients with FEV1 at least 20% below baseline at those time points. Thirty-eight percent of placebo patients had an FEV1 at least 20% below baseline at day 90 compared to only 14% of ALN-RSV01-treated patients (p=NS). BOS scoring was based on the decline in FEV1 during the study as well as the physicians' determination of whether there was a cause other than BOS responsible for a change in FEV1. In the study, ALN-RSV01 treatment was associated with a statistically significant decrease in the total incidence of new or progressive BOS at 90 days compared to placebo (p=0.02); 50% of placebo patients showed new or progressive BOS as compared with only 7.1% of ALN-RSV01-treated patients.

Alnylam initiated initiated a Phase IIb trial in adult lung transplant patients with ALN-RSV01. The Phase IIb trial is a multi-center, global, randomized, double-blind, placebo-controlled study in RSV-infected lung transplant patients with a primary endpoint of a reduction in incidence of new or progressive BOS. Secondary endpoints include assessments for safety and additional measurements of efficacy, including: anti-viral activity; recovery of lung function, as monitored by the proportion of patients with forced expiratory volume in the first second (FEV1), of greater than 80% of their pre-infection baseline value; and, improvement in RSV symptoms as measured by mean cumulative daily total symptom score. The trial is expected to enroll 120 patients who will be randomized in a one to one, drug to placebo ratio. All patients will receive standard of care, and those receiving ALN-RSV01 will have drug administered as a 0.6 mg/kg dose by inhalation using an investigational eFlow Nebulizer System (PARI Pharma) once daily for five days.

Phase IIb trial top-line results
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.

We reported complete results from our Phase IIb trial of ALN-RSV in adult lung transplant patients for the treatment of RSV infection. The primary endpoint of the study was the incidence of new or progressive bronchiolitis obliterans syndrome (BOS) at 180 days after RSV infection. The study missed the primary endpoint of reduced BOS in an "intent-to-treat" (ITTc) analysis of confirmed RSV infected patients (p=0.058), but achieved statistically significant reductions in prospectively defined analyses of ITTc patients with their "last observation carried forward" (LOCF) with a p-value of 0.028, and of ITTc patients treated "per protocol" (PP) with a p-value of 0.025. In all analyses, ALN-RSV01 treatment was associated with a clinically meaningful treatment effect, with a reduction of over 50% in the incidence of day 180 BOS as compared with placebo.

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.

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. The clinical manifestations of RSV infection depend on the patient's age and health status. Older children and adults often have a milder course, with cold-like symptoms, while infants and immune-compromised patients can have a more severe illness that results in bronchiolitis, pneumonia and in some instances death. 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. As a result, there is a significant need for novel therapeutics to treat patients who become infected with RSV.