PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2

Baum, Michelle A.; Langman, Craig B.; Cochat, Pierre; Lieske, John C.; Moochhala, Shabbir H.; Hamamoto, Shuzo; Satoh, Hiroyuki; Mourani, Chebl; Ariceta, Gema; Torres, Armando; Wolley, Martin; Belostotsky, Vladimir; Forbes, Thomas A.; Groothoff, Jaap W.; Hayes, Wesley; Tönshoff, Burkhard; Takayama, Tatsuya; Rosskamp, R.; Russell, Kerry; Zhou, Jing; Amrite, Aniruddha; Höppe, Bernd

doi:10.1016/j.kint.2022.07.025

Cited by 42 publications

(43 citation statements)

References 38 publications

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“…A single dose of nedosiran was safe and well-tolerated in this cohort, as evidenced by a lack of treatment-related TEAEs. The AE profile of nedosiran was consistent with previously reported clinical data on nedosiran [ 15 , 18 ], with the exception of ISRs, which were not detected in PHYOX4. Only mild TEAEs were observed, and no safety risks were identified.…”

Section: Discussionsupporting

confidence: 90%

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Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4)

et al. 2023

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Nedosiran is an N-acetyl-D-galactosamine (GalNAc)–conjugated RNA interference agent targeting hepatic lactate dehydrogenase (encoded by the LDHA gene), the putative enzyme mediating the final step of oxalate production in all three genetic subtypes of primary hyperoxaluria (PH). This phase I study assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneous nedosiran in patients with PH subtype 3 (PH3) and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. Single-dose nedosiran 3 mg/kg or placebo was administered in a randomized (2:1), double-blinded manner. Safety/tolerability, 24-h urinary oxalate (Uox) concentrations, and plasma nedosiran concentrations were assessed. The main PD endpoint was the proportion of participants achieving a > 30% decrease from baseline in 24-h Uox at two consecutive visits. Six participants enrolled in and completed the study (nedosiran, n = 4; placebo, n = 2). Nedosiran was well-tolerated and lacked safety concerns. Although the PD response was not met, 24-h Uox excretion declined 24.5% in the nedosiran group and increased 10.5% in the placebo group at Day 85. Three of four nedosiran recipients had a > 30% reduction in 24-h Uox excretion during at least one visit, and one attained near‐normal (i.e., ≥ 0.46 to < 0.60 mmol/24 h; ≥ 1.0 to < 1.3 × upper limit of the normal reference range) 24-h Uox excretion from Day 29 to Day 85. Nedosiran displayed predictable plasma PK. The acceptable safety and trend toward Uox-lowering after single-dose nedosiran treatment enables further clinical development of nedosiran in patients with PH3 who currently have no viable therapeutic options. A plain language summary is available in the supplementary information.

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Section: Discussionsupporting

confidence: 90%

“…Evidence suggests this enzyme may mediate the final common step in oxalate production for all three forms of PH [ 16 , 17 ]. In clinical trials, nedosiran administration resulted in a marked reduction in 24-h urinary oxalate (Uox) and plasma oxalate (Pox) in patients with PH1 and demonstrated acceptable tolerability [ 15 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4)

et al. 2023

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“…Recent progress in the treatment of patients with PH with small interfering RNA encourages early diagnosis so that optimal medical management and patient participation in relevant clinical trials can be considered [39][40][41]. Respondents also reported difficulty covering out-of-pocket healthcare expenses associated with PH.…”

Section: Numerous Clinician Visits Indicated An Intensive Level Ofmentioning

confidence: 99%

Healthcare utilization, quality of life, and work productivity associated with primary hyperoxaluria: a cross-sectional web-based US survey

et al. 2023

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Primary hyperoxaluria (PH) is a family of ultra-rare, autosomal recessive, metabolic disorders associated with frequent kidney stones, chronic kidney disease and kidney failure, and serious complications due to systemic oxalosis, resulting in significant morbidity. We investigated the burden of PH among affected patients and caregivers. This cross-sectional, web-based survey was used to quantify the burden of PH, in terms of healthcare resource utilization, health-related quality of life, and work productivity and activity impairment among adults (≥ 18 years) with PH and caregivers of children (≤ 17 years) with PH in the US. Among the 20 respondents, there were 7 adults with PH and 13 caregivers of children with PH. Adherence to hyperhydration was noted as the most, or one of the most, difficult aspects of PH by 56% of respondents. Most patients (95%) had experienced painful kidney stone events, one-third had visited the emergency room, and 29% were hospitalized for complications due to PH. Of the 24% of patients on dialysis, all found the procedure burdensome. Adult patients’ quality of life was negatively affected across several domains. Most respondents (81%) reported that PH had a negative effect on their finances. Employed adult patients and caregivers, and children with PH, had moderate impairment in work productivity, school attendance, and activity. Anxiety about future PH-related sequelae was moderate to high. These findings highlight the need for improvements in PH medical management. A plain language summary is available in the supplementary information.

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“…111 The self-complementary double stranded sequence forming the loop in the sense strand cannot easily be loaded by the RISC, which reduces off-target toxicity and only the antisense strand will be used for RNAi. 111 GalNAc residues are attached on each of the four consecutive nucleotides of the tetraloop hairpin region ( 27 ) for recognition by the ASGP-R. Nedosiran, 112,113 which is in phase three clinical trials, was developed using GalXC technology to treat primary hyperoxaluria by inhibiting expression of hepatic lactate dehydrogenase to prevent over production of oxalate. With the use of GalXC technology, five drug candidates are in different stages of clinical trials, and more than 20 are in the early stage of development or preclinical stage.…”

Section: Introductionmentioning

confidence: 99%

Targeted delivery of oligonucleotides using multivalent protein–carbohydrate interactions

Kumar

Turnbull

2023

Chem. Soc. Rev.

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PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2

Cited by 42 publications

References 38 publications

Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4)

Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4)

Healthcare utilization, quality of life, and work productivity associated with primary hyperoxaluria: a cross-sectional web-based US survey

Targeted delivery of oligonucleotides using multivalent protein–carbohydrate interactions

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