ALN-GO1

ALN-GO1 for Primary Hyperoxaluria Type 1 (PH1)

Small interfering RNA (siRNA) that mediates RNA interference (RNAi) and harnesses natural RNAi mechanism can prevent the production of disease-causing proteins by potently silencing specific mRNAs. ALN-GO1 (Lumasiran) is an investigational RNAi therapeutic for the effective treatment of PH1. It is specifically designed to target glycolate oxidase (GO) and reduce or prevent the overproduction of oxalate in the liver. PH1 is an ultra-rare orphan disease caused by the excessive production of endogenous oxalate and the defect of peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT) in the liver. Specifically, the overproduction of oxalate results in the formation and high deposition of insoluble oxalate crystals, further leading to renal stone formation, nephrocalcinosis, kidney failure, and ultimately severe multi-organ dysfunction (including blindness, anemia, cardiac failure, and pathologic fractures). Currently, the treatment options for PH1 are very limited, including frequent renal dialysis and combined liver-kidney transplantation, and there are no approved therapeutics for the treatment of PH1. Therefore, ALN-GO1 as a siRNA-based therapeutic is a completely potential approach to treat PH1 disease and help patients in a fundamentally new way.

Figure 1. Hepatic oxalate synthesis pathway. (Liebow, 2017)

Mechanism and Preclinical Study of ALN-GO1

ALN-GO1, which is administered as a subcutaneous injection, is designed to target GO enzyme that is an enzyme upstream of the defect in PH1 patients and also referred to as hydroxy acid oxidase 1 (HAO1). ALN-GO1 decreases the conversion of glycolate to glyoxylate and hence depletes or prevents the formation of the substrate in the pathway of oxalate production. This glyoxylate substrate is the major precursor for the overproduction of oxalate and conduces to the pathophysiology of PH1. ALN-GO1 allows the possible mechanism for increasing accumulation levels of glycolate, which is soluble and readily excreted in the urine and does not precipitate in the kidney, in order to prevent the actual pathology process that develops in PH1 potentially.

ALN-GO1 delivered by subcutaneous administration demonstrates a potent, dose-dependent, and durable silencing (up to 99 percent) of HAO1 mRNA gene encoding GO. ALN-GO1 reduces urinary oxalate concentration (up to 50% after a single dose and up to 98% after multiple doses) and increases serum glycolate concentrations in animal models of PH1. In addition, ALN-GO1 supports a once-monthly and subcutaneous dose regimen with increased potency and durability by using ESC-GalNAc conjugate technology. These preclinical results support the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 and provide a clear rationale continued development of ALN-GO1 for clinical trials.

ALN-GO1 into Clinical Trials

ALN-GO1 is in clinical trials for the treatment of PH1; these clinical research studies will evaluate its safety, tolerability of single and multiple subcutaneous doses, as well as pharmacokinetics and pharmacodynamics that effectively reduce the liver's oxalate production in people with PH1. In the phase 1/2 study, 32 healthy adult volunteers and 20 patients are treated with ALN-GO1 with an excellent safety profile. Data shows that single-dose ALN-GO1 is generally well-tolerated in patients with PH1 and is dose-dependent elevations in plasma glycolate levels after a single dose in healthy volunteers. Multiple doses of ALN-GO1 have demonstrated acceptable preliminary safety and tolerability in patients with PH1 with no drug-related serious adverse events (SAEs) or discontinuations from the study. Continued investigation of ALN-GO1 will suggest the potential of substrate reduction therapy and explore dose optimization for oxalate lowering in patients. The advancement of investigational medicines like ALN-GO1 into clinical trials provides the new pharmacological treatment option for patients with PH1.

The siRNA-based therapeutics has the potential to treat disease in a fundamentally new way. Scientists at Creative Biolabs are happy to share our experience and professional knowledge with our customers in related researches. If you are interested in more information for siRNA-based therapeutics in clinical trials, please do not hesitate to contact us.

Reference

1. Liebow, A.; et al. (2017). An investigational RNAi therapeutic targeting glycolate oxidase reduces oxalate production in models of primary hyperoxaluria. Journal of the American Society of Nephrology. 28(2): 494-503.