Lumasiran: expanding the treatment options for patients with primary hyperoxaluria type 1

ABSTRACT

Introduction

Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism whereby excessive endogenous oxalate production can result in kidney failure, systemic oxalosis and early death. The approval of the first therapeutic agent to alter the treatment pathway for PH1 – lumasiran, a novel RNA interference-based drug – represents a new era in the management of patients with PH1.

Areas covered

A description of PH1, its pathophysiology, clinical characteristics and available treatment strategies is provided, with a focus on substrate reduction therapy and the development of lumasiran for pediatric and adult patients with PH1.

Expert opinion

Until very recently, treatment options for patients with PH1 have been burdensome, ineffective in preventing disease progression or associated with high morbidity. Lumasiran targets hepatic glycolate oxidase, the enzyme responsible for the synthesis of the oxalate precursor, glyoxylate. Administered subcutaneously monthly initially and then quarterly, it has been found to significantly lower urinary and plasma oxalate levels, potentially reduce the development of nephrocalcinosis and halt disease progression. For the first time, patients with PH1 have a treatment that is well tolerated, effective, and administered in a way that does not adversely impact the quality of life of those affected by this devastating disease.

KEYWORDS:

• Glycolate oxidase
• lumasiran
• oxalate
• primary hyperoxaluria type 1
• renal failure
• RNA interference
• substrate reduction therapy

Article highlights

• PH1 is responsible for 1–2% of pediatric patients with kidney failure in Europe and North America, and of considerable clinical importance despite its rarity

• Conservative therapies do not prevent disease progression and liver transplantation has been the only potentially curative option

• The latest approach to the treatment of PH1 is substrate reduction therapy with the aim of reducing the production of glyoxylate, the precursor to oxalate

• Lumasiran, a subcutaneously administered RNAi therapeutic targeting glycolate oxidase, is transforming the management of patients with PH1

Acknowledgments

Writing assistance was provided by Maggie Lai of Comradis Limited, funded by Alnylam Pharmaceuticals GmBH.

Declaration of interest

S Hulton has conducted research on behalf of Dicerna and Alnylam and has received consultancy fees/honoraria from pharmaceutical companies Dicerna, Alnylam, and Chiesi within the last 3 years. She received no personal funding for this paper. The scientific team at Alnylam Pharmaceuticals GmBH were given the opportunity to check trial data factual accuracy but did not contribute to the content of the manuscript. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Alnylam Pharmaceuticals GmBH.