Introduction: Primary hyperoxaluria type 1 (PH1), a rare autosomal recessive disorder associated with hepatic oxalate overproduction, leads to kidney failure, with poor historical graft survival rates after isolated kidney transplantation (iKT). A Phase 2 (NCT03350451) and 3 Phase 3 trials (ILLUMINATE-A, NCT03681184; ILLUMINATE-B, NCT03905694; ILLUMINATE-C, NCT04152200) showed sustained urinary oxalate and plasma oxalate (POx) reduction and acceptable safety with the RNA interference therapeutic lumasiran. Long-term follow-up allows for evaluation of native kidney survival and iKT outcomes in lumasiran-treated patients (pts).
Methods: Kidney function change and post-iKT outcomes were characterized.
Results: Regression-estimated mean annual rates of eGFR change (slope [SEM] mL/min/1.73m²/y) were −0.4 (1.0) over 54 months (M) in the Phase 2 trial (N=20), −0.6 (0.7) over 60 M in ILLUMINATE-A (N=39), and 0.4 (1.9) over 30 M in ILLUMINATE-B (N=18). The range of baseline (BL) eGFR values was 32–174 mL/min/1.73m² in these trials. ILLUMINATE-C enrolled PH1 pts with advanced kidney disease, assigned to Cohort A (not on hemodialysis [HD]) or Cohort B (on HD). In this study, 3 pts in Cohort A required HD before M36; the other 2 remaining Cohort A pts had mean annual rates of eGFR decline of −2.3 and −0.9 mL/min/1.73m²/y over 36 M. All 5 Cohort B pts who underwent iKT as of M36 had POx reduction from BL prior to transplantation, and further reduction post-iKT indicating improved POx clearance with functioning grafts. None experienced oxalate nephropathy after iKT. With 3–29 months of post-iKT follow-up as of M36, all 5 remained HD-free and continued lumasiran treatment.
Conclusion: Lumasiran treatment for PH1 resulted in minimal annual eGFR decline over 30 to 60 M in pts with CKD and effectively lowered POx to allow for iKT, rather than liver-kidney transplantation, in some pts with end-stage kidney disease.