TY - JOUR
T1 - PHYOX2
T2 - a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2
AU - PHYOX2 study investigators
AU - Baum, Michelle A.
AU - Langman, Craig
AU - Cochat, Pierre
AU - Lieske, John C.
AU - Moochhala, Shabbir H.
AU - Hamamoto, Shuzo
AU - Satoh, Hiroyuki
AU - Mourani, Chebl
AU - Ariceta, Gema
AU - Torres, Armando
AU - Wolley, Martin
AU - Belostotsky, Vladimir
AU - Forbes, Thomas A.
AU - Groothoff, Jaap
AU - Hayes, Wesley
AU - Tönshoff, Burkhard
AU - Takayama, Tatsuya
AU - Rosskamp, Ralf
AU - Russell, Kerry
AU - Zhou, Jing
AU - Amrite, Aniruddha
AU - Hoppe, Bernd
N1 - Publisher Copyright:
© 2022 International Society of Nephrology
PY - 2023/1
Y1 - 2023/1
N2 - Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90–180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs −1664 [1190], respectively; difference, 5172; 95% CI 2929–7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.
AB - Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90–180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs −1664 [1190], respectively; difference, 5172; 95% CI 2929–7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH.
KW - RNAi
KW - chronic kidney disease
KW - gene expression
KW - hyperoxaluria
KW - pediatric nephrology
KW - urology
UR - http://www.scopus.com/inward/record.url?scp=85138999405&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85138999405&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2022.07.025
DO - 10.1016/j.kint.2022.07.025
M3 - Article
C2 - 36007597
AN - SCOPUS:85138999405
SN - 0085-2538
VL - 103
SP - 207
EP - 217
JO - Kidney international
JF - Kidney international
IS - 1
ER -