Nephrotoxicity of Antisense Oligonucleotide Therapies in Duchenne Muscular Dystrophy: A Warning or a Challenge?
Author(s)
Tim ULINSKI, MD, PhD1, Lamine MAHI, MD2, Luis GARCIA, PhD3, Christian DE CHASTEIGNER, MD4, Helge AMTHOR, MD, PhD5.
1Pediatric Nephrology Department, CHU Armand Trousseau -Sorbonne-University, Paris, France, 2Clinical Research, Axelys Santé, Malakoff, France, 3END-ICAP, UMR 1179 - INSERM/Université de Versailles Saint-Quentin-en-Yvelines, Montigny le Bretonneux, France, 4Pharmacovigilance, CdC Santé, Nice, France, 5Pediatric Department, CHU Raymond Poincaré, Garches, France.
1Pediatric Nephrology Department, CHU Armand Trousseau -Sorbonne-University, Paris, France, 2Clinical Research, Axelys Santé, Malakoff, France, 3END-ICAP, UMR 1179 - INSERM/Université de Versailles Saint-Quentin-en-Yvelines, Montigny le Bretonneux, France, 4Pharmacovigilance, CdC Santé, Nice, France, 5Pediatric Department, CHU Raymond Poincaré, Garches, France.
OBJECTIVES: OBJECTIVES: Number of antisense oligonucleotide (ONA) drugs, have been approved to treat rare diseases. Safety remains one of the biggest challenges to their therapeutic utility. The aim of this review is to present the current state of knowledge on nephrotoxicity of ONA drugs in Duchenne Muscular Dystrophy (DMD).
METHODS: A literature review was conducted to analyze clinical studies and reports addressing renal side effects potentially associated with ONA therapies in DMD patients. Key findings on pathophysiological mechanisms are synthesized.
RESULTS: Renal complications, including proteinuria and microalbuminuria, are frequently observed in ONA-treated patients, likely due to tubular accumulation. In the US Golodirsen, Viltolarsen, Eteplirsen and Casimersen are approved (conditionally) to treat DMD. US FDA warnings for their use in humans due to the small number of patients included in clinical trials. To date 48 studies are listed on clintrial.gov and eudraCT, of which 24 have been completed and 6 have been interrupted with 578 and 252 patients, respectively treated. Specific cases include: i) Drisapersen, terminated due to a poor benefit-risk profile, with notable renal toxicity, ii) Vesleteplirsen, associated with severe hypomagnesemia and hypokalemia. Higher bioavailability of ONA concentrate in the liver and kidney during absorption, distribution, metabolism, and excretion. Inflammation may be closely linked to renal tubular deterioration and the occurrence of proteinuria, which may also be exacerbed by concomitant treatments. Vaccination may complicate mild nephrotoxicity through cytokine-induced activation of the immune system and a transient increase in glomerular permeability. While no direct pharmacological interactions between vaccines and ONA have been documented, post-vaccination immune responses can influence pharmacokinetics and potentiate renal effects of ONA.
CONCLUSIONS: Patients with DMD treated with ONA require vigilant renal monitoring. Recommendations include regular assessment of renal biomarkers (e.g., proteinuria, creatinine), adjustment of corticosteroids, and preference for inactivated or conjugated vaccines.
METHODS: A literature review was conducted to analyze clinical studies and reports addressing renal side effects potentially associated with ONA therapies in DMD patients. Key findings on pathophysiological mechanisms are synthesized.
RESULTS: Renal complications, including proteinuria and microalbuminuria, are frequently observed in ONA-treated patients, likely due to tubular accumulation. In the US Golodirsen, Viltolarsen, Eteplirsen and Casimersen are approved (conditionally) to treat DMD. US FDA warnings for their use in humans due to the small number of patients included in clinical trials. To date 48 studies are listed on clintrial.gov and eudraCT, of which 24 have been completed and 6 have been interrupted with 578 and 252 patients, respectively treated. Specific cases include: i) Drisapersen, terminated due to a poor benefit-risk profile, with notable renal toxicity, ii) Vesleteplirsen, associated with severe hypomagnesemia and hypokalemia. Higher bioavailability of ONA concentrate in the liver and kidney during absorption, distribution, metabolism, and excretion. Inflammation may be closely linked to renal tubular deterioration and the occurrence of proteinuria, which may also be exacerbed by concomitant treatments. Vaccination may complicate mild nephrotoxicity through cytokine-induced activation of the immune system and a transient increase in glomerular permeability. While no direct pharmacological interactions between vaccines and ONA have been documented, post-vaccination immune responses can influence pharmacokinetics and potentiate renal effects of ONA.
CONCLUSIONS: Patients with DMD treated with ONA require vigilant renal monitoring. Recommendations include regular assessment of renal biomarkers (e.g., proteinuria, creatinine), adjustment of corticosteroids, and preference for inactivated or conjugated vaccines.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
CO168
Topic
Clinical Outcomes, Epidemiology & Public Health, Real World Data & Information Systems
Topic Subcategory
Clinical Outcomes Assessment, Clinician Reported Outcomes
Disease
Genetic, Regenerative & Curative Therapies, Neurological Disorders, Rare & Orphan Diseases, Urinary/Kidney Disorders, Vaccines