Alnylam and Collaborators Publish New Pre-Clinical Research Demonstrating In Vivo Efficacy of Systemically Delivered RNAi Therapeutics in Ovarian Cancer

New Findings Published in the Proceedings of the National Academy of Sciences Demonstrate Suppression of Ovarian Tumor Growth in Three Different Animal Models

CAMBRIDGE, MA, USA | February 11, 2009 | Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today announced the publication of new research in the Proceedings of the National Academy of Sciences (PNAS) by Alnylam scientists and collaborators from the Lankenau Institute for Medical Research and the David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT). These new findings (Huang et al. (February 10, 2009) Proc. Natl Acad. Sci. USA, 10.1073/pnas.0813348106) demonstrate that RNAi silencing of the claudin-3 protein using lipidoid formulations of small interfering RNAs (siRNAs, the molecules that mediate RNAi) results in the suppression of ovarian tumor growth and metastases. Claudin-3 is a tight junction protein that is highly over-expressed in approximately 90% of ovarian tumors. Previous in vitro studies have shown that the over-expression of claudin-3 promotes migration, invasion, and increased survival of ovarian cancer cells.

“We are encouraged by the findings published today in PNAS, as they represent a promising therapeutic approach that could significantly slow the progression of disease in patients with advanced-stage ovarian cancer,” said David Bumcrot, Ph.D., Director, Research at Alnylam. “Clearly, these results reflect the continued progress that Alnylam and our collaborators are making in advancing systemic delivery solutions for RNAi therapeutics, as well as our commitment to scientific excellence through publication of our research data. At the same time, we are making substantial progress in advancing our therapies to patients, as evidenced by the FDA clearance of our IND filing for ALN-VSP, an RNAi therapeutic for the treatment of liver cancers.”

“I am excited by these new data as there is a very significant need for novel therapies to treat patients with ovarian cancer – a devastating disease that affects more than 20,000 women and results in more than 15,000 deaths each year in the U.S. alone,” said Janet Sawicki, Ph.D., Professor at the Lankenau Institute for Medical Research. “Advanced-stage ovarian cancer is extremely difficult to treat with today’s medicines, and these new data suggest that an RNAi therapeutic targeting claudin-3 may represent a novel treatment option in the future.”

“These data further illustrate the broad potential of RNAi therapeutics in medicine,” said Daniel Anderson, Ph.D., of the David H. Koch Institute for Integrative Cancer Research at MIT. “We are excited by the pre-clinical efficacy of these siRNA formulations, as demonstrated in multiple animal models of ovarian cancer, and I am optimistic that the delivery systems described here will provide new avenues for the treatment of cancer and other diseases.”

The published data showed that lipidoid-mediated delivery of siRNAs targeting claudin-3 in ovarian tumor tissue resulted in the dramatic silencing of the gene and a substantial reduction in tumor growth and metastases as compared to controls in three different mouse tumor models. Specifically, data with lipidoid-formulated claudin-3-specific siRNAs showed:

* in an ovarian cancer cell xenograft model with intratumoral injection, a significant silencing of claudin-3, a reduction in cell proliferation and tumor growth, and a significant increase in the number of apoptotic cells;
* in an ovarian tumor-bearing transgenic mouse model with intraperitoneal dosing, an approximately 40% suppression of tumor growth rate, including tumor regression in some mice, compared to controls, and a significant reduction of malignant ascites (fluid in the abdominal cavity that contains cancer cells), where only 22% of mice treated with the claudin-3 siRNA developed ascites compared to 75% of control-treated animals; and,
* in a mouse ovarian surface epithelial cell model with intraperitoneal dosing, a survival rate of 50% for siRNA-treated mice compared to 0% survival in control-treated animals.

In addition to ovarian tumors, claudin-3 is over-expressed in other tumor types, including breast and prostate, and therefore lipidoid-mediated delivery of siRNAs targeting this protein may also be effective in the treatment of other cancers.

‘Lipidoids’ are a new class of lipid-based molecules which are used to form novel nanoparticle formulations for systemic delivery of RNAi therapeutics. A previous study by Alnylam scientists in collaboration with scientists from MIT (Akinc et al., Nature Biotechnology 26, 561-569 (01 May 2008)), showed successful delivery of siRNAs encapsulated in lipidoid formulations when administered in multiple animal species including mice, rats, and non-human primates. Together, these data demonstrated potent, specific, and durable effects on gene expression in multiple tissues, including liver, lung, and peritoneal macrophages. Further, the Akinc et al. paper demonstrated applications of the same technology for delivery of microRNA antagonists.

About Ovarian Cancer

Ovarian cancer is the fourth most common cancer in women, and has the highest mortality rate among gynecologic malignancies in the United States. Treatment of early-stage ovarian carcinoma improves the survival rate up to 90%. However, due to the lack of effective screening tests and the asymptomatic nature of the disease in its early stages, most women are not diagnosed until the cancer has reached more advanced stages. There are currently no treatments available for those women with advanced-stage ovarian cancer who either do not respond to initial therapy or develop recurrent disease.

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. RNAi therapeutics target the cause of diseases by potently silencing specific messenger RNAs (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 applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world’s top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics; its most advanced program is in Phase II human clinical trials for the treatment of respiratory syncytial virus (RSV) infection and is partnered with Cubist and Kyowa Hakko. In addition, the company is developing RNAi therapeutics for the treatment of a wide range of disease areas, including liver cancers, hypercholesterolemia, Huntington’s disease, and TTR amyloidosis. The company’s leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko, and Cubist. To reflect its outlook for key scientific, clinical, and business initiatives, Alnylam established “RNAi 2010” in January 2008 which includes the company’s plan to significantly expand the scope of delivery solutions for RNAi therapeutics, have four or more programs in clinical development, and to form four or more new major business collaborations, all by the end of 2010. Alnylam is a joint owner of Regulus Therapeutics, a joint venture focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

About Lankenau Institute for Medical Research

Founded in 1927, the Lankenau Institute for Medical Research (LIMR) is an independent, nonprofit biomedical research center located in suburban Philadelphia on the campus of the Lankenau Hospital. As part of the Main Line Health System, LIMR is one of the few freestanding, hospital-associated medical research centers in the nation. The faculty and staff at the Institute are dedicated to advancing an understanding of the causes of cancer and heart disease. They use this information to help improve diagnosis and treatment of these diseases as well as find ways to prevent them. They are also committed to extending the boundaries of human health and well-being through technology transfer and education directed at the scientific, clinical, business and lay public communities. For more information visit:

About the Koch Institute

The MIT Center for Cancer Research (CCR) has changed its name to the David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute – pronounced “coke”) effective March 2008. This name change is linked to generous funding received in support of the creation of a new building and endeavor, to be completed by the year 2010, to house expanded and innovative cancer research at MIT. Note that all CCR facilities and faculty members have been incorporated into the Koch Institute.

SOURCE: Alnylam Pharmaceuticals, Inc.

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