Alnylam's current product focus is the development of Direct RNAi™ therapeutics. These products are designed to be administered directly to sites of diseases in various parts of the body, such as the lungs, the brain, or the eye.
Respiratory Syncytial Virus (RSV)
ASince initiating the ALN-RSV01 therapeutic program in 2005, Alnylam has made rapid progress. Our RNAi therapeutic was designed to target the nucleocapsid "N" gene of the RSV genome, a gene that is critical for the replication of the virus. ALN-RSV01 silences the N gene, thereby reducing the virus' ability to reproduce. Extensive pre-clinical work in animals demonstrated potent and highly specific anti-viral efficacy with molecular proof of an RNAi mechanism of action. We believe the results we have demonstrated to date underscore not only to the potential to treat RSV, but the broader potential for RNAi therapeutics in human disease.
ALN-RSV01 Clinical Timeline
- * In April 2008, Alnylam initiated a Phase II clinical trial to assess the safety and tolerability of aerosolized ALN-RSV01 versus placebo in adult lung transplant patients naturally infected with RSV. Those receiving ALN-RSV01 will have drug administered by inhalation via nebulizer which is the expected delivery formulation for commercialization. As a secondary objective, this trial will be the first to evaluate the anti-viral activity of ALN-RSV01 in a naturally acquired RSV lower respiratory tract infection. ALN-RSV01 is expected to advance into the pediatric patient population by the second half of 2008.
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- * In June 2007, Alnylam initiated Part 2 of the human experimental infection model (EIM) study, called "GEMINI." The GEMINI study was designed to evaluate the safety and anti-viral activity of ALN-RSV01 in infected patients. " In February 2008, Alnylam announced it had achieved human proof-of-concept with an RNAi therapeutic, a first for the industry. Results from the company's Phase II GEMINI 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.
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- * In November 2006, Alnylam initiated Part 1 the EIM study. This study was designed to establish a safe and reliable RSV infection of the upper respiratory tract in healthy adult volunteers. Results of this study, presented at the Pediatric Academic Societies' Annual Meeting in May 2007, demonstrated the establishement of a safe and reliable RSV infection of the upper respiratory tract in adult volunteers.
- * In October 2006, Alnylam initiated a Phase 1 inhalation study in the U.S. to evaluate the human safety, tolerability and pharmacokinetics of ALN-RSV01 in healthy adult volunteers. In December 2007, at the Annual Drug Delivery to the Lungs meeting, Alnylam announced that all major objectives of the trial were met, including definition of a safe and well-tolerated dose and regimen for advancement of ALN-RSV01 into further Phase II development.
- * In December 2005, Alnylam initiated Phase I intranasal studies in the U.S. and Europe to evaluate the human safety and pharmacology of ALN-RSV01 in healthy adult volunteers. In April 2006, Alnylam announced positive safety results from these studies.
Hypercholesterolemia
Hypercholesterolemia is the company's third development program. Alnylam is collaborating with researchers at UT Southwestern Medical Center to evaluate new approaches for reducing LDL-cholesterol levels using RNAi therapeutics directed to a disease target called proprotein convertase subtilisn/kexin type 9, or PCSK9. The collaboration will utilize systemic RNAi technologies developed by Alnylam such as those described in its recent Nature paper in primates (Nature 441:111-114, 2006) where systemic RNAi targeting apolipoprotein B (apoB), another protein involved in cholesterol metabolism, resulted in dramatically reduced levels of apoB mRNA and protein and resulted in a greater than 65 percent lowering of cholesterol and a greater than 85 percent lowering of LDL.
Liver Cancers
In April 2007, we advanced our second sytemic development program for the treatment of liver cancers and potentially other solid tumors. Our RNAi therapeutic, ALN-VSP01, targets two separate genes involved in the growth and development of tumors: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP). Primary liver cancer is one of the most common cancers worldwide, with more than 600,000 people diagnosed each year. Secondary liver cancer, also known as metastatic liver cancer, is cancer that spreads to the liver from another part of the body. Worldwide, more than 500,000 people are diagnosed with secondary liver cancer each year.
Our novel liposomal technology delivers ALN-VSP01 to the liver, and enables the efficient silencing of genes expressed in that organ. In pre-clinical studies, we have demonstrated the ability to silence both VEGF and KSP expression in the liver and to stop cancer cells from growing by targeting KSP. Together, our delivery technology and the specificity of siRNAs enable the advancement of ALN-VSP as an approach to treating liver cancers in a fundamentally new way.
Huntington's Disease (HD)
In January 2008, Alnylam announced that it advanced an RNAi therapeutic development program targeting the huntingtin gene for the treatment of Huntington's disease. Huntington's disease is an autosomal dominant neurodegenerative genetic disease that afflicts approximately 30,000 patients in the U.S., with an estimated 150,000 additional patients having a 50 percent risk of developing the disease. The disease is caused by mutations in the huntingtin gene leading to expression of a toxic mutated protein. This program, designated ALN-HTT, is in partnership with Medtronic, Inc. The product is expected to consist of an RNAi therapeutic targeting the Huntington's disease gene that will be delivered by Medtronic's implantable infusion pump.
Hepatitis C
Regulus Therapeutics (a joint venture between Alnylam and Isis Pharmaceuticals) most advanced program is a microRNA therapeutic that targets miR-122 for the treatment of hepatitis C virus (HCV) infection, a significant disease worldwide where emerging therapies target viral genes and are therefore more prone to resistance. Regulus is targeting miR-122, an endogenous host gene required for viral infection by HCV.Progressive Multifocal Leukoencephalopathy (PML)
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. Alnylam and Biogen Idec will initially conduct investigative research into the potential of using RNAi technology to discover and develop therapeutics to treat PML. The goal of the program is to design and optimize an RNAi therapeutic toward conserved regions of a viral genome to harness the cell's own capabilities to achieve an anti-viral therapeutic effect.
Pandemic Flu
The goal of Alnylam's influenza program is to develop Direct RNAi therapeutics effective against all flu strains including potentially highly virulent strains of flu, such as H5N1. By targeting key flu genes required for viral replication, Alnylam and its collaborator, Novartis, aim to demonstrate potent anti-viral activity for the prevention and treatment of highly pathogenic flu strains. This program has also received initial funding support from the Department of Defense's DARPA arm.
Novartis Programs
The 2005 partnership with Novartis and the Novartis Institute for BioMedical Research (NIBR), focuses on the joint discovery of new therapeutics using RNAi across multiple disease areas in Novartis' research portfolio.
Roche Programs
In July 2007, Alnylam and Roche announced an alliance initially covering four therapeutic areas: oncology, respiratory diseases, metabolic diseases and certain liver diseases. Alnylam and Roche also will collaborate on RNAi drug discovery for one or more disease targets in these therapeutic areas.Alnylam Biodefense
Alnylam Biodefense was established to build a robust platform for developing RNAi therapeutics targeting threats of bioterrorism. Funding for the company's Ebola virus, pandemic flu, and viral hemorrhagic fever programs represents an example of broad public health and federal interest in the potential of RNAi technology to treat and prevent disease from these, and other serious and life-threatening viruses.
In September 2006, Alnylam was awarded a contract to advance the development of a broad spectrum RNAi anti-viral therapeutic against hemorrhagic fever virus. With this new grant, the company is establishing Alnylam Biodefense™ – an initiative to build a robust platform for developing RNAi therapeutics targeting biological threats. Funding for this program, as with Alnylam’s pandemic flu program, represents broad public health and federal interest in the potential of RNAi technology to treat and prevent disease from these, and other serious and life-threatening viruses.
As part of a public sector-private sector partnership with its Ebola program, 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 will be producing drug candidates which will be sent to USAMRIID for in vitro and in vivo testing against the Ebola virus.
Additionally, in August 2007, has been awarded a $38.6 million contract over 33 months from the United States Defense Threat Reduction Agency (DTRA) to develop a broad spectrum RNAi anti-viral therapeutic for the treatment of viral hemorrhagic fever. Viral hemorrhagic fevers are considered by federal agencies to be high priority agents that pose a risk to national security because they can be easily disseminated from person to person, result in high mortality rates, and require special action for public health preparedness.