Primary hyperoxaluria type 1 (PH1) is an inherited disease in which the lack of a particular liver enzyme causes the body to produce excess amounts of a substance called oxalate. This leads to a buildup of insoluble calcium oxalate, causing kidney failure and further organ damage for some patients in infancy and most patients by their mid-twenties.
PH1 is an ultra-rare orphan disease, defined as a disorder that affects less than 2,000 people. This devastating disease – which is often diagnosed in early childhood – is an inborn error of metabolism resulting in excessive oxalate production. Specifically, in PH1 there is a loss of function in the alanine-glyoxylate aminotransferase enzyme that metabolizes glyoxylate into glycine in the liver, resulting in its conversion to oxalate instead. Excess oxalate in PH1 patients is unable to be fully excreted by the kidneys leading to the formation of recurrent kidney stones and the deposition of calcium oxalate crystals in the kidneys and urinary tract. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and renal obstruction by calcium oxalate stones. Compromised kidney function exacerbates the disease as oxalate is released into systemic circulation potentially resulting in subsequent accumulation and crystallization in bones, eyes, skin, heart, and the central nervous system, leading to severe illness and death. About 50 percent of patients will have kidney failure by age 15, and about 80 percent will have end stage renal disease by age 30. Current treatment options are very limited, and include frequent renal dialysis as palliative care and combined organ transplantation of liver and kidneys as the only potentially curative option.
Alnylam is developing ALN-GO1, a subcutaneously administered investigational RNAi therapeutic, for the treatment of PH1. ALN-GO1 targets the gene for glycolate oxidase (GO), an enzyme that works upstream of the defect in PH1 patients, and is designed to starve the pathway of substrate for oxalate production with the goal of preventing its associated pathology. ALN-GO1 utilizes Alnylam’s ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.
ALN-GO1 has been granted Orphan Drug Designation from the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA).
Please read the latest press releases and data presentations for ALN-GO1 here.