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 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

Study in RSV-Infected Lung Transplant Patients Narrowly Misses Primary "Intent-to-Treat" Endpoint, but Meets Pre-Specified "Last Observation Carried Forward" and "Per Protocol" Endpoints with Clinically Meaningful Treatment Effect of over 50% for Reduction of Bronchiolitis Obliterans Syndrome

CAMBRIDGE, Mass., May 30, 2012 (BUSINESS WIRE) -- -- Alnylam to Discuss Results with U.S. and EU Regulatory Authorities and Provide Further Guidance in the Second Half of 2012 --

-- Alnylam to Host Conference Call at 8:45 a.m. ET Today to Discuss Results --

Alnylam Pharmaceuticals, Inc. ALNY -2.88%  , a leading RNAi therapeutics company, announced today top-line results from a Phase IIb trial with ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection in lung transplant patients. 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.

"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. We plan to discuss the results of this study with U.S. and European regulatory authorities later this year and, thereafter, determine appropriate next steps, if any, on our ALN-RSV program," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "In the meanwhile, we continue to execute on our 'Alnylam 5x15' product strategy with a focus on our transthyretin-mediated amyloidosis and hemophilia programs."

The Phase IIb trial was an international multi-center, randomized, double-blind, placebo-controlled study of ALN-RSV01 in RSV-infected lung transplant patients. RSV infection in lung transplant patients represents a significant unmet medical need due to the risk of developing new or progressive BOS, an irreversible loss of function in the transplanted lung associated with approximately 50% mortality within five years. 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 happened to include 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(R) Nebulizer System (PARI Pharma). All patients also received standard of care treatment according to the site's practices.

Top-line results are detailed in the table below. 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. There were three deaths in the study, two in placebo and one in ALN-RSV01, all of which were determined to be unrelated to treatment. Additional study results are expected to be presented at the European Respiratory Society Annual Congress taking place September 1-5, 2012 in Vienna.

                           ITT(2)    ITTc(3)   LOCF(4)   PP(5)
                           ======   =======   =======   =====
        N                    87        77        77       73
        ----------------   ------   -------   -------   -----
                   New or Progressive BOS at Day 180
        Placebo (n/N)       10/42     10/33     10/33    9/32
                            28.6%     30.3%     30.3%    28.1%
        ----------------   ------   -------   -------   -----
        ALN-RSV01 (n/N)     6/45      6/44      5/44     4/41
                            13.2%     13.6%     11.4%    9.8%
        ----------------   ------   -------   -------   -----
        p-value(1)          0.052     0.058     0.028    0.025
        ----------------   ------   -------   -------   -----
        Treatment Effect    53.5%     55.1%     62.4%    65.1%
        ----------------   ------   -------   -------   -----

(1)p-value determined by Cochran-Mantel-Hanzel test

(2)ITT: All randomized patients who received at least one dose of study medication. Patients with missing Day 180 BOS assessment are considered to be BOS events (i.e., regarded as "treatment failures")

(3)ITTc: All patients in the ITT population who are RSV positive by central laboratory. Patients with missing Day 180 BOS assessment are considered to be BOS events (i.e., regarded as "treatment failures")

(4)LOCF: Patients in the ITTc population with missing Day 180 BOS assessment have last observation carried forward (LOCF)

(5)PP: All patients per protocol in the ITTc population who completed five days of dosing, did not have major protocol violations and had an adjudicated Day 180 BOS assessment

"RSV represents a significant risk for lung transplant patients, as infection is associated with the development of new or progressive BOS, resulting in a significant decrease in quality of life as well as overall survival. Indeed, BOS is the leading cause of death in patients beyond the first year of transplantation," said Allan R. Glanville M.D., Medical Director Lung Transplantation, Director Thoracic Medicine, St. Vincent's Hospital, Australia. "There is clearly an unmet medical need for an effective RSV therapy for lung transplant patients, and I am encouraged by the results of ALN-RSV01 in this current study. We look forward to presenting the full results of this study at the ERS meeting in September."

Alnylam is planning to meet with U.S. and European regulatory authorities later this year to determine next steps for this program and will communicate future development plans, if any, in the second half of the year.

These new data are consistent with a previous Phase IIa, multinational, randomized, placebo-controlled study (Zamora et al., Am. J. Respir. Crit. Care Med., Feb 2011, Vol 183, No 4: pp 531-538) completed in 2009, where ALN-RSV01 was shown to significantly decrease the incidence of new or progressive BOS at day 90 in RSV-infected adult lung transplant patients. In this small study of 24 patients, inhaled ALN-RSV01 was found to be generally safe and well tolerated, which was the primary study objective. At the 90 day pre-specified endpoint, ALN-RSV01 treatment was associated with improved recovery of lung function and a statistically significant reduction in the incidence of new or progressive BOS (7.1% vs. 50%; ALN-RSV01 n=15, placebo n=8; p=0.02).

In 2008, the anti-viral activity of ALN-RSV01 was demonstrated in the company's Phase II GEMINI study (DeVincenzo et al., Proceedings of the National Academy of Sciences, May 2010, Vol 107, No. 19: 8800-8805) which was a randomized, double-blind, placebo-controlled study of intranasal ALN-RSV01 in 88 adult human volunteers experimentally infected with RSV. In this study, treatment with ALN-RSV01 showed statistically significant anti-viral activity, including a decreased RSV infection rate and an increase in the number of subjects who remained free of infection. Specifically, administration of ALN-RSV01 resulted in a 38% relative reduction in RSV infection rate (p<0.01) and a 95% increase in the number of infection-free subjects as compared with placebo (p<0.01). ALN-RSV01 was also found to be generally safe and well tolerated.

In addition, pre-clinical studies have documented the RNAi-mediated anti-viral activity of ALN-RSV01 in rodent models (Alvarez et al., Antimicrob Agents Chemother. 53(9):3952-62, 2009).

The RSV program is partnered with Cubist Pharmaceuticals in North America and the rest of the world outside of Asia, where the program is partnered with Kyowa Hakko Kirin Co., Ltd. These partners maintain certain opt-in rights for the development of ALN-RSV01.

Conference Call Information

Alnylam will host a conference call on Wednesday, May 30 at 8:45 a.m. ET to discuss the top-line Phase IIb results from its ALN-RSV01 clinical trial. To access the call, please dial 866-730-5769 (domestic) or 857-350-1593 (international) five minutes prior to the start time and provide the passcode 57541007. A replay of the call will be available beginning at 10:45 a.m. ET on May 30. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the passcode 16178252.

A live audio webcast of the call will also be available on the News & Investors page of the company's website, . An archived webcast will be available on the Alnylam website approximately two hours after the event.

About 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 1 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.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, ALN-APC for the treatment of hemophilia, and ALN-TMP for the treatment of hemoglobinopathies. As part of its "Alnylam 5x15(TM)" strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in clinical development, including programs in advanced stages, on its own or with a partner by the end of 2015. Alnylam has additional partner-based programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington's disease. The company's leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for applications in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam's VaxiRNA(TM) platform applies RNAi technology to improve the manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit .

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, statements regarding Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-RSV01, its expectations regarding the presentation of additional study results at the European Respiratory Society Annual Congress in September 2012, its plans to discuss the results of its ALN-RSV01 Phase IIb study with U.S. and European regulatory authorities later this year and thereafter, determine appropriate next steps for its ALN-RSV program, the rights of its partners to opt-in to the ALN-RSV01 study, its expectations with respect to the timing and success of its clinical trials for transthyretin-mediated amyloidosis and hemophilia, and Alnylam's expectations regarding its "Alnylam 5x15" product strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates, successfully demonstrate the efficacy and safety of its drug candidates, including ALN-RSV01, the pre-clinical and clinical results for these product candidates, which may not support further development of such product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, obtaining, maintaining and protecting intellectual property, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, and Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, as well as those risks more fully discussed in the "Risk Factors" section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam does not assume any obligation to update any forward-looking statements.

SOURCE: Alnylam Pharmaceuticals, Inc.


        Alnylam Pharmaceuticals, Inc.
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