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

Alnylam Publishes Results from Phase IIa Study of ALN-RSV01 in the Treatment of Respiratory Syncytial Virus Infection in Lung Transplant Patients

RSV Infection

ALN-RSV: Respiratory Syncytial Virus

We are developing a novel therapeutic that has the potential to significantly improve outcomes in patients infected with RSV. Respiratory syncytial virus infection, or RSV, is a serious respiratory infectious disease and the leading cause of pediatric hospitalizations in the U.S. (125,000 hospitalizations per year in the U.S.) RSV is also a major infectious disease in the elderly and in other adults with compromised immune systems (175,000 hospitalizations per year in the U.S.).

Alnylam's lead program, ALN-RSV01, is being developed for the treatment of RSV infection. Since initiating this program in 2005, we have made rapid progress. 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 carried out in 2006 and 2007 established the safety and tolerability of ALN-RSV01 in adult human volunteers.

In early 2008, we presented data from our Phase II GEMINI study which showed a statistically significant decrease in infection rate in adults experimentally infected with RSV, demonstrating that ALN-RSV01 has anti-viral activity in a disease setting. With these results in a randomized, double-blind, placebo-controlled study, we believe we have demonstrated human proof of concept with an RNAi therapeutic — a first for the field.

In July 2009, along with our partner Cubist, we reported the complete data from our Phase II study in adult lung transplant patients naturally infected with RSV. These results document for the first time the safety and tolerability of inhaled ALN-RSV01 in naturally infected patients, which we consider an important step forward in the advancement of our overall ALN-RSV program. In addition, while the study was not powered for efficacy and is too small to make firm conclusions, we are encouraged by the clinical endpoint data, including improvement in lung function and a statistically significant reduction in new or progressive BOS in patients receiving ALN-RSV01 as compared with placebo

Patient enrollment for our Phase IIb trial of ALN-RSV in adult lung transplant patients for the treatment RSV infection was recently completed. This study is aimed to repeat and extend the results we saw in this patient population with our recently reported Phase II study. We expect to report results in mid-2012

We are excited about the progress we have made to date, and believe the results we have demonstrated to date underscore not only the potential to treat RSV, but the broader potential for RNAi therapeutics in human disease.

The ALN-RSV program is partnered with Kyowa Hakko Kirin in Asia and Cubist Pharmaceuticals worldwide except Asia.

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.

Patient enrollment for the Phase IIb trial of ALN-RSV in adult lung transplant patients for the treatment RSV infection was completed.

RSV is highly contagious and causes infections in both the upper and lower respiratory tracts. RSV typically results in cold-like symptoms but can lead to more serious respiratory illnesses, such as croup, bronchiolitis, pneumonia, and in extreme cases, death. RSV infects nearly every child by the age of two and accounts for more than 125,000 hospitalizations annually in the U.S. pediatric population. RSV also poses a great risk to the elderly and to others with compromised immune systems. Recent studies have shown that over 170,000 elderly adults are hospitalized with RSV each year in the U.S., with more than 14,000 deaths in this patient population. There is a clear and significant need for novel therapeutics to treat patients who become infected with RSV.