Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

Garrelfs, Sander F.; Frishberg, Yaacov; Hulton, Sally‐Anne; Koren, Michael; O’Riordan, William; Cochat, Pierre; Deschênes, Georges; Shasha-Lavsky, Hadas; Saland, Jeffrey M.; Hoff, William G. van’t; Fuster, Daniel; Magen, Daniella; Moochhala, Shabbir H.; Schalk, Gesa; Šimková, Eva; Groothoff, Jaap W.; Sas, David J.; Meliambro, Kristin; Lu, Jiandong; Sweetser, Marianne T.; Garg, Pushkal; Vaishnaw, Akshay; Gansner, John M.; McGregor, Tracy L.; Lieske, John C.

doi:10.1056/nejmoa2021712

Cited by 302 publications

(285 citation statements)

References 30 publications

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“…One such RNAi therapeutic, lumasiran (Alnylam Pharmaceuticals, Inc.), depletes an enzyme (hydroxyacid oxidase 1) responsible for glyoxylate synthesis. 19 Due to its mechanism of action, lumasiran is only approved for use in patients with PH1.…”

Section: Word Count = 3587mentioning

confidence: 99%

“…Because the sample size was based on safety rather than efficacy considerations, comparison of the PD response between the PH1 and PH2 subgroups lacks statistical rigor. As 24-hour Uox excretion is an accepted surrogate endpoint for clinical outcomes (eg, progression of renal dysfunction) in studies of PH,7,31,32 the marked reduction in or normalization of 24-hour Uox excretion induced by nedosiran in PH1 and PH2 supports further development of nedosiran for the treatment of PH 19.…”

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confidence: 99%

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Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Höppe

Koch²,

Cochat

et al. 2022

Kidney International

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Word Count = 3587mentioning

confidence: 99%

mentioning

confidence: 99%

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Höppe

Koch²,

Cochat

et al. 2022

Kidney International

Self Cite

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“…Stone-specific agents can be utilized. Lumasiran, an RNAi therapy for type 1 primary hyperoxaluria, was recently approved for clinical use [ 104 ].…”

Section: Hypertension-related Ckdmentioning

confidence: 99%

Chronic Kidney Disease: Strategies to Retard Progression

Yan

Chao

Lin

2021

IJMS

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Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.

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“…Liver transplantation, by addressing the metabolic defect in PH1, can normalize oxalate levels and, if done preemptively, prevent progression to kidney failure; however, it carries substantial morbidity and mortality risk and must be paired with kidney transplantation to restore lost kidney function in patients with kidney failure. To address the limitations of current options, multiple novel PH1 therapies are in clinical testing, including RNA interference (RNAi) therapeutics that suppress expression of proteins involved in oxalate production and an enteric oxalate-degrading bacterial preparation (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Primary Hyperoxaluria Type 1 Disease Manifestations and Healthcare Utilization: A Multi-Country, Online, Chart Review Study

et al. 2021

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Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that can result in irreversible damage to the kidneys and, eventually, extrarenal organs. While kidney failure is a known consequence of PH1, few studies to date have characterized clinical consequences of PH1 prior to kidney failure, and data on healthcare resource use outcomes across different stages of disease severity in PH1 are also limited. To help fill this knowledge gap, this study characterized the clinical and healthcare resource use (HRU) burden in patients with PH1 with varying stages of kidney disease.Methods: Nephrologists in the United States, Canada, United Kingdom, France, Germany, and Italy abstracted chart data from patients with PH1 under their care via an online questionnaire. Eligible patients had confirmed PH1 and ≥2 office visits from 2016 to 2019.Results: A total of 120 patients were analyzed (median age at diagnosis, 17.4 years old, median age at index 19.5 years old, median eGFR at index 45 ml/min/1.73 m2; median follow-up 1.7 years). During follow-up, the most common PH1 manifestations were kidney stones and urinary tract infections (UTIs, both 56.8%), and the most common symptoms were fatigue/weakness (71.7%) and pain (64.6%). With regard to HRU during follow-up, 37.4% required lithotripsy, 31.3% required ureteroscopy, and 9.6% required nephrolithotomy. PH1-related hospitalizations and emergency/urgent care visits were noted for 84.0 and 81.6% of patients, respectively.Conclusions: The current study demonstrated that patients with PH1 across various stages of kidney disease exhibited a substantial clinical burden, including kidney stones, UTIs, fatigue/weakness, and pain, and required frequent HRU, including kidney stone procedures, hospitalizations, and emergency visits. These findings highlight the significant morbidity and HRU burden in patients with PH1.

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Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

Cited by 302 publications

References 30 publications

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Chronic Kidney Disease: Strategies to Retard Progression

Primary Hyperoxaluria Type 1 Disease Manifestations and Healthcare Utilization: A Multi-Country, Online, Chart Review Study

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