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Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1
Sander F Garrelfs1, Yaacov Frishberg1, Sally A Hulton1
1From the Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham (S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital (S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center for Rare Renal Diseases and INSERM Pediatric Clinical Investigation Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya (H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.), Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L., M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.).
Lumasiran significantly reduced urinary oxalate in Primary Hyperoxaluria type 1 (PH1) patients. This RNAi therapeutic offers a promising treatment for kidney failure caused by PH1.
Area of Science:
- Genetics
- Pharmacology
- Nephrology
Background:
- Primary Hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production in the liver.
- This leads to severe kidney damage, including stones, nephrocalcinosis, and kidney failure, as well as systemic oxalosis.
- Lumasiran, an RNA interference (RNAi) therapeutic, targets glycolate oxidase to decrease hepatic oxalate synthesis.
Purpose of the Study:
- To evaluate the efficacy and safety of lumasiran in patients with PH1.
- To assess the impact of lumasiran on urinary oxalate excretion and plasma oxalate levels.
- To determine the proportion of patients achieving normal or near-normal oxalate levels.
Main Methods:
- A double-blind, placebo-controlled, phase 3 trial (ILLUMINATE-A) was conducted.
- 39 PH1 patients (≥6 years) were randomized 2:1 to receive subcutaneous lumasiran or placebo for 6 months.
- Primary endpoint: percent change in 24-hour urinary oxalate excretion from baseline to month 6.
Main Results:
- Lumasiran demonstrated a significant reduction in urinary oxalate excretion (-65.4% vs. placebo, P<0.001).
- A significant decrease in plasma oxalate levels was observed (-39.5% difference vs. placebo, P<0.001).
- 84% of lumasiran-treated patients achieved normal/near-normal urinary oxalate levels at 6 months, compared to 0% in the placebo group.
Conclusions:
- Lumasiran effectively reduces urinary oxalate production in PH1 patients.
- The treatment leads to normalization of oxalate levels in the majority of patients within 6 months.
- Lumasiran represents a significant advancement in managing PH1 and preventing kidney failure.
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