End Points for Clinical Trials in Primary Hyperoxaluria

Abstract

Patients with primary hyperoxaluria experience kidney stones from a young age and can develop progressive oxalate nephropathy. Progression to kidney failure often develops over a number of years, and is associated with systemic oxalosis, intensive dialysis, and often combined kidney and liver transplantation. There are no therapies approved by the Food and Drug Association. Thus, the Kidney Health Initiative, in partnership with the Oxalosis and Hyperoxaluria Foundation, initiated a project to identify end points for clinical trials. A workgroup of physicians, scientists, patients with primary hyperoxaluria, industry, and United States regulators critically examined the published literature for clinical outcomes and potential surrogate end points that could be used to evaluate new treatments. Kidney stones, change in eGFR, urine oxalate, and plasma oxalate were the strongest candidate end points. Kidney stones affect how patients with primary hyperoxaluria feel and function, but standards for measurement and monitoring are lacking. Primary hyperoxaluria registry data suggest that eGFR decline in most patients is gradual, but can be unpredictable. Epidemiologic data show a strong relationship between urine oxalate and long-term kidney function loss. Urine oxalate is reasonably likely to predict clinical benefit, due to its causal role in stone formation and kidney damage in CKD stages 1–3a, and plasma oxalate is likely associated with risk of systemic oxalosis in CKD 3b–5. Change in slope of eGFR could be considered the equivalent of a clinically meaningful end point in support of traditional approval. A substantial change in urine oxalate as a surrogate end point could support traditional approval in patients with primary hyperoxaluria type 1 and CKD stages 1–3a. A substantial change in markedly elevated plasma oxalate could support accelerated approval in patients with primary hyperoxaluria and CKD stages 3b–5. Primary hyperoxaluria type 1 accounts for the preponderance of available data, thus heavily influences the conclusions. Addressing gaps in data will further facilitate testing of promising new treatments, accelerating improved outcomes for patients with primary hyperoxaluria.

Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

“…Though a significant reduction of urine oxalate excretion was attained after one PH1 patient received stiripentol [ 57 ], this drug failed to lower the plasma oxalate concentration in a PH patient with advanced chronic kidney disease [ 167 ]. These two independent research groups used different surrogate end points that may explain the differences in the outcome of the investigation [ 228 ]. The ongoing phase 2 clinical trial NCT03819647 [ 169 ] evaluates the efficacy of stiripentol for the treatment of PH [ 168 , 229 ].…”

Transplantation for Primary Hyperoxaluria Type 1: Designing New Strategies in the Era of Promising Therapeutic Perspectives

“…However, this POx value is very difficult to reach in daily clinical practice and also depends on systemic oxalate storage. 27 Moreover, non-PH1 patients on chronic dialysis often show a POx value > 20 μmol/L, 28 suggesting that this target value might be too low. Until now, intensive hemodialysis strategies were used (daily sessions of [high-flux] hemodialysis, nocturnal hemodialysis, or, mainly in small children, a combination of hemodialysis and nocturnal peritoneal dialysis 1 ) to maintain POx during interdialysis sessions below 30–45 μmol/L, 1 the threshold of calcium oxalate supersaturation.…”

“…Until now, intensive hemodialysis strategies were used (daily sessions of [high-flux] hemodialysis, nocturnal hemodialysis, or, mainly in small children, a combination of hemodialysis and nocturnal peritoneal dialysis 1 ) to maintain POx during interdialysis sessions below 30–45 μmol/L, 1 the threshold of calcium oxalate supersaturation. 27 , 29 , 30 After correcting the metabolic defect, some authors suggest that conventional hemodialysis could be sufficient to maintain POx values < 20 μmol/L. 1 Recurrence of oxalate nephropathy on the kidney allograft might remain a concern even after the correction of the metabolic defect.…”

“… 8 POx monitoring could also be useful because markedly increased POx values are observed in PH1 patients with advanced CKD who have systemic oxalosis. 27 …”

“…involvement 8. POx monitoring could also be useful since markedly increased POx values are observed in PH1 patients with advanced CKD who have systemic oxalosis 27. Importantly, the bone compartment is the most common organ involved in systemic oxalosis.…”