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Kidney Week

Abstract: PO2538

PHYOX2: Nedosiran Reduced Urinary Oxalate Excretion in Patients with Primary Hyperoxaluria

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic


  • Baum, Michelle Amy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Langman, Craig B., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Cochat, Pierre, Hopital Femme Mere Enfant, Bron, Auvergne-Rhône-Alpes , France
  • Lieske, John C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Moochhala, Shabbir H., Royal Free Hospital, London, London, United Kingdom
  • Hamamoto, Shuzo, Nagoya Shiritsu Daigaku, Nagoya, Aichi, Japan
  • Satoh, Hiroyuki, Tokyo Toritsu Shoni Sogo Iryo Center, Fuchu, Tokyo, Japan
  • Mourani, Chebl, Hotel-Dieu de France Service d'Hematologie-Oncologie, Beirut, Beirut, Lebanon
  • Ariceta, Gema, Vall d'Hebron Hospital Universitari, Barcelona, Catalunya, Spain
  • Amrite, Aniruddha, Dicerna Pharmaceuticals Inc, Lexington, Massachusetts, United States
  • Hoppe, Bernd, Dicerna Pharmaceuticals Inc, Lexington, Massachusetts, United States

Primary hyperoxaluria (PH) is a family of 3 ultra-rare genetic disorders characterized by hepatic oxalate overproduction leading to hyperoxaluria, recurrent calcium oxalate kidney stones, nephrocalcinosis, and often, kidney failure. Nedosiran is an investigational RNA interference (RNAi) therapy that reduces overproduction of oxalate by inhibiting hepatic lactate dehydrogenase (LDH). Results from PHYOX2, the pivotal trial of nedosiran in 35 participants with PH1 or PH2 are reported here.


See Table


PHYOX2 achieved its primary and key secondary endpoints. Nedosiran resulted in a 57.5% greater daily average reduction in urinary oxalate (Uox) excretion AUC (based on D90 to D180 AUC) compared to placebo (p<0.0001). Among participants given nedosiran, 50% achieved and sustained normal or near-normal Uox at 2 or more consecutive visits after D90 compared to 0% given placebo (p=0.0025). Uox was significantly reduced in the PH1 cohort (Figure; post hoc analysis). The results in the PH2 cohort (5 nedosiran, 1 placebo) were inconsistent; only 2 out of 5 participants given nedosiran showed reduction in Uox between D90 and D180. The most common AEs were mild, self-resolving injection site reactions. There were 3 SAEs (1 in nedosiran; 2 in placebo).


Nedosiran was well-tolerated and resulted in a clinically and statistically significant sustained reduction in Uox excretion compared to placebo, with robust efficacy in the PH1 subtype. The heterogeneity of response in the smaller PH2 cohort was inconsistent with prior clinical experience and warrants further investigation.

DesignPhase 2, randomized, placebo-controlled, double-blind trial (NCT03847909)
Key inclusion criteriaGenetically confirmed PH1 or PH2; Age ≥ 6 years;
24-hr urinary oxalate (Uox) excretion ≥ 0.7 mmol (per 1.73 m2 in age < 18 years); eGFR ≥ 30 mL/1.73 m2
DemographicsSafety population: Nedosiran (n=23; PH1=18; PH2=5); Placebo (n=12; PH1=11; PH2=1)
Mean age: Nedosiran (n=23): 23.7 years; Placebo (n=12): 23.6 years
Efficacy population (mITT)*: Nedosiran (n=22; PH1=17; PH2=5); Placebo (n=12; PH1=11; PH2=1)
[*participants with at least 1 efficacy assessment after Day 90]
Nedosiran dosing (subcutaneous, once monthly X 6 months)● Ages ≥ 12 + weighing ≥ 50 kg: 170 mg
● Ages ≥ 12 + weighing < 50 kg: 136 mg
● Ages ≥ 6 to < 12: 3.5 mg/kg (not exceeding 136 mg)
Primary endpointPercent change from baseline in 24-hr Uox excretion as assessed by area under the curve (AUC) from Day 90 (D90) to Day 180 (D180)
Key secondary endpointProportion of participants reaching normalization (< 0.46 mmol; upper limit of assay normal-ULN) or near-normalization (≥ 0.46 to < 0.60 mmol; 1.3XULN) of 24-hour Uox excretion on at least 2 consecutive visits, starting from D90


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