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Drugs Dec 2023Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for... (Review)
Review
Nedosiran (RIVFLOZA™), a once-monthly subcutaneous small interfering RNA (siRNA) therapy, is being developed by Dicerna Pharmaceuticals, a Novo Nordisk company, for the treatment of primary hyperoxaluria (PH). It reduces oxalate overproduction by inhibiting the expression of the hepatic lactate dehydrogenase (LDH) enzyme. Nedosiran received its first approval on 29 September 2023 in the USA to lower urinary oxalate levels in children aged ≥ 9 years and adults with PH type 1 (PH1) and relatively preserved kidney function [e.g. estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m]. This article summarizes the milestones in the development of nedosiran leading to this first approval for PH1.
Topics: Child; Adult; Humans; Hyperoxaluria, Primary; Oxalates; Lactate Dehydrogenases; RNA, Small Interfering
PubMed: 38060091
DOI: 10.1007/s40265-023-01976-4 -
British Journal of Pharmacology Nov 2023Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic... (Review)
Review
Post-transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well-defined short double-stranded RNA (small interfering RNA [siRNA]), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA-induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off-target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin-mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use N-acetylgalactosamine (GalNAc) linkage for effective liver-directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non-communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.
Topics: Humans; RNA, Double-Stranded; RNA, Small Interfering; RNA Interference; RNA, Messenger; Porphyrias, Hepatic
PubMed: 36250252
DOI: 10.1111/bph.15972 -
American Journal of Kidney Diseases :... Feb 2023Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates...
RATIONALE & OBJECTIVE
Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease.
STUDY DESIGN
Phase 3, open-label, single-arm trial.
SETTING & PARTICIPANTS
Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 μmol/L at screening, including patients with or without systemic oxalosis.
INTERVENTION
Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing.
OUTCOME
Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area.
RESULTS
All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient.
LIMITATIONS
Single-arm study without placebo control.
CONCLUSIONS
Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population.
FUNDING
Alnylam Pharmaceuticals.
TRIAL REGISTRATION
Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17.
PLAIN-LANGUAGE SUMMARY
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Young Adult; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Diseases; Oxalates
PubMed: 35843439
DOI: 10.1053/j.ajkd.2022.05.012 -
The New England Journal of Medicine Mar 2022
Topics: Adult; Hand; Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Male; Nephrocalcinosis; Nephrolithiasis
PubMed: 35245013
DOI: 10.1056/NEJMicm2113369 -
Nephrologie & Therapeutique Dec 2022Small interfering RNA (siRNAs) are double-stranded RNAs of around 20 base pairs in length that trigger RNAi machinery, which promotes degradation of a target mRNA...
Small interfering RNA (siRNAs) are double-stranded RNAs of around 20 base pairs in length that trigger RNAi machinery, which promotes degradation of a target mRNA avoiding protein translation. SiRNAs are liver-targeted, using tris N-acetylgalactosamine (GalNAc) as the targeting ligand. This discovery received the Nobel Prize for medicine and physiology in 2006 and lead to substantial therapeutic advances. Application field and development of these siRNA has been very fast. Indeed, patisiran has been released in 2018 for hereditary transthyretin amyloidosis. This first treatment showed the security and efficacy of such a product. Since, treatments have been developed for acute hepatic porphyria and primary hyperoxaluria. The current pipeline for new siRNA development is ambitious; clinical trial are ongoing in nephrology, as in the IgA nephropathy. Frequent diseases are also targeted such as hypertension or hypercholesterolemia. © 2022 Published by Elsevier Masson SAS on behalf of Société francophone de néphrologie, dialyse et transplantation.
Topics: Humans; Nephrologists; RNA, Small Interfering; Amyloid Neuropathies, Familial; Hypertension; Porphyrias, Hepatic
PubMed: 36585119
DOI: 10.1016/S1769-7255(22)00646-0 -
La Tunisie Medicale Jul 2023There are three types of primary hyperoxaluria, with type 1 considered the most severe.
INTRODUCTION
There are three types of primary hyperoxaluria, with type 1 considered the most severe.
AIM
To analyze the clinical, genetic, and evolutionary characteristics of type 1 primary hyperoxaluria with pediatric onset.
METHODS
This was a retrospective, descriptive study that included Tunisian children under the age of 18 at the time of diagnosis over a period of 25 years (January 1, 1996, to December 31, 2022).
RESULTS
Thirty-five patients were included, with a mean age of 4.1 years. The most common presenting circumstances of the disease were nephrolithiasis and end-stage renal failure. The average serum creatinine level was 225.42 µmol/l. Five mutations were identified, with the p.Ile244Thr mutation being the most prevalent. Nephrocalcinosis, surgical intervention, and a creatinine level ≥57 µmol/l were predictive of progression to end-stage renal failure. The infantile form was predictive of mortality.
CONCLUSIONS
Screening for the disease would improve the prognosis of this condition.
Topics: Child; Humans; Child, Preschool; Adult; Hyperoxaluria, Primary; Retrospective Studies; Kidney Failure, Chronic; Mutation
PubMed: 38445424
DOI: No ID Found -
Clinical Journal of the American... Jul 2020
Topics: Adolescent; Adult; Anxiety; Caregivers; Child; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Calculi; Kidney Failure, Chronic; Kidney Transplantation; Quality of Life; Surveys and Questionnaires; Young Adult
PubMed: 32165441
DOI: 10.2215/CJN.13831119