Hepatic Lactate Dehydrogenase A: An RNA Interference Target for the Treatment of All Known Types of Primary Hyperoxaluria

Gema Ariceta,Kelly Barrios,Bob D Brown,Bernd Hoppe,Ralf Rosskamp,Craig B Langman

doi:10.1016/j.ekir.2021.01.029

Abstract

IntroductionPrimary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage. LDHA inhibition of glyoxylate-to-oxalate conversion by RNA interference (RNAi) has emerged as a potential therapeutic option for all types of PH. LDHA is mainly expressed in the liver and muscles.MethodsNonclinical data in mice and nonhuman primates show that LDHA inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA inhibition.ResultsBased on a literature review of human LDHA deficiency, we defined the phenotype as mainly muscle-related with no liver manifestations. Healthy volunteers treated with nedosiran experienced no drug-related musculoskeletal adverse events. There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function.ConclusionPhase I clinical data on nedosiran and published nonclinical data together provide substantial evidence that LDHA inhibition is a safe therapeutic mechanism for the treatment of all known types of PH.

Highlights

Primary hyperoxaluria (PH) is a family of 3 rare genetic disorders of hepatic glyoxylate metabolism that lead to overproduction and increased renal excretion of oxalate resulting in progressive renal damage
There were no significant alterations in plasma lactate, pyruvate, or creatine kinase levels in the nedosiran group compared with the placebo group, signaling the uninterrupted interconversion of lactate and pyruvate and normal muscle function
Primary hyperoxaluria (PH) is a family of rare, autosomal recessive genetic disorders of glyoxylate metabolism resulting in overproduction of oxalate in the liver.[1,2]

Summary

Methods

Nonclinical data in mice and nonhuman primates show that LDHA inhibition by RNAi reduces urinary oxalate excretion and that its effects are liver-specific without an impact on off-target tissues, such as the muscles. To confirm the lack of unintended effects in humans, we analyzed data from the phase I randomized controlled trial of single-dose nedosiran, an RNAi therapy targeting hepatic LDHA. We conducted a review of the literature on LDHA deficiency in humans, which we used as a baseline to assess the effect of hepatic LDHA inhibition. English language articles that reported human LDHAD cases were included. Foreign language articles were included if their abstracts were in English and provided relevant patient information on LDHAD. The following types of articles were excluded from further review: articles describing other subtype deficiencies (e.g., LDHB/H) and articles reporting nonclinical data. Gov identifier NCT03392896) is a 2-part, phase I, single-ascending dose study of subcutaneous nedosiran in HVs (group A) and adult patients with PH1 or PH2 (group B) conducted between November 2017 and November 2019. The remainder of the PHYOX1 clinical trial will be described in a separate article

Results

Discussion

Conclusion