Alnylam Pharmaceuticals has filed a clinical trial authorization (CTA) application to the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) to start a phase 1/2 trial of ALN-AAT02 for the treatment of alpha-1 antitrypsin (AAT) deficiency-associated liver disease (alpha-1 liver disease).
ALN-AAT02 is Alnylam’s first investigational RNAi therapeutic utilizing the Company’s enhanced stabilization chemistry plus (ESC+) GalNAc-conjugate technology.
Alnylam ALN-AAT02 program lead vice president Thomas Hoock said: “We are pleased to reignite our efforts to develop a treatment for alpha-1 liver disease, where there is high unmet need with liver transplantation as the only available treatment option.
“We are also excited for ALN-AAT02 to enter the clinic as the first investigational RNAi therapeutic that will leverage the significant enhancements we have made to our GalNAc-siRNA conjugate platform.
“Pending feedback from the MHRA, we look forward to evaluating the safety, pharmacodynamics, and clinical activity of this molecule in a Phase 1/2 study in healthy volunteers and adults with alpha-1 liver disease, which we expect to initiate by year-end 2018.”
ALN-AAT02 is an investigational, subcutaneously administered RNAi therapeutic targeting alpha-1 antitrypsin (AAT) in development for the treatment of AAT deficiency-associated liver disease (alpha-1 liver disease). ALN-AAT02 utilizes Alnylam’s enhanced stabilization chemistry plus (ESC+)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of ALN-AAT02 have not been evaluated by the FDA, EMA or any other health authority.
About Alpha-1 Antitrypsin Deficiency-Associated Liver Disease
Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. About 95 percent of people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ) which expresses the Z-AAT protein. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are estimated to be approximately 120,000 individuals with the PiZZ mutation in the U.S. and major European countries, and of these, about 10 percent have an associated liver pathology (alpha-1 liver disease) caused by the aggregates of the misfolded Z-AAT protein. The only treatment options presently available for alpha-1 liver disease patients are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in people with alpha-1 liver disease may represent a promising new way to treat this rare disease.
Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugates are the Company’s next generation delivery platform utilizing the Glycol Nucleic Acid (GNA) modification which confers enhanced specificity and therapeutic index. ESC+ siRNA conjugates exhibit minimal off-target activity and sustained on-target potency. All future investigational siRNA candidates entering early-stage clinical development, starting with ALN-AAT02, are planned to employ ESC+ design.
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a major new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
Source: Company Press Release.