Alnylam Presents Pre-clinical Data from Hypercholesterolemia, Liver Cancer, Ebola, and Progressive Multifocal Leukoencephalopathy Programs at RNAi Keystone Symposium

Business Wire,  March 31, 2008  

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Pre-clinical data presented include the following:

* potent siRNAs with in vitro anti-viral activity have been identified against all genes in the Ebola genome;

* a greater than 95 percent decrease in viral titer was seen when an RNAi therapeutic targeting one of these genes, VP35, was administered to mice infected with Ebola; and,

* the VP35 siRNA, as compared with a control non-specific siRNA, was able to protect both mice and guinea pigs from lethal Ebola infection.

Alnylam is working with the United States Army Medical Research Institute of Infectious Diseases (USAMRIID), an organization which is uniquely experienced in the handling, safety, and security requirements of specialized biological agents. Alnylam produces drug candidates which are then sent to USAMRIID for in vitro and in vivo testing against the Ebola virus. The National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), is funding this work through a federal contract (No. HHSN266200600012C).

Progressive Multifocal Leukoencephalopathy (PML)

Alnylam is developing an RNAi therapeutic for the potential treatment of PML, in collaboration with Biogen Idec. PML is caused by infection of the central nervous system with a virus called "JC virus" and can occur in certain immune-suppressed patients, including those receiving immunomodulatory therapies. In a poster titled "Developing RNAi Therapeutics Targeting JCV for Treatment of PML," Alnylam scientists presented results showing that potential JCV RNAi therapeutic candidates targeting different JCV transcripts have been identified and showed potent inhibition of secondary PML infection in vitro, both prophylactically and post-infection. Because there is no established animal model of PML, Alnylam is delivering its RNAi therapeutic to normal oligodendrocytes, the primary site of JCV infection in vivo.

Additional pre-clinical data presented from this program included the following:

* JCV siRNAs are stable in human cerebrospinal fluid (CSF) with half-lives greater than 48 hours, and do not produce unwanted cytokine responses;

* in a rodent model, siRNAs in vivo were successfully delivered and silenced an endogenous oligodendrocyte target (CNP) in a specific manner as compared with a control non-specific siRNA;

* direct central nervous system (CNS) delivery of siRNA in the rodent model silenced the CNP mRNA by approximately 75 percent, as compared with a control non-specific siRNA, and was durable for up to one week;

* CNP silencing was found to be mediated by an RNAi mechanism as measured by 5'RACE; and

* in a non-human primate model, direct infusion of an siRNA into the CNS silenced the CNP mRNA by 55 percent.

Alnylam believes these findings further support the use of RNAi as a potential therapeutic approach for the treatment of PML.

Delivery

"As we continue to develop novel delivery solutions for RNAi therapeutics, we are excited by the new data around chemical modifications for improved efficacy, safety and delivery," said Muthiah Manoharan, Ph.D., Vice President, Drug Discovery at Alnylam. "In addition, we are also encouraged by the use of simple Intralipid(TM) formulations using cholesterol-conjugated siRNAs and antagomirs which showed promising muscle delivery. Indeed, these data, with our collaborator Markus Stoffel, suggest an exciting convergence of conjugation and formulation approaches for systemic delivery of RNAi therapeutics."