Allena Pharmaceuticals Says It Has Finalized Design with FDA for Pivotal Trial in Hyperoxaluria Using Novel Endpoint

Rare Daily Staff

Allena Pharmaceuticals said that in consultation with the U.S. Food and Drug Administration it has finalized the design of the second pivotal phase 3 trial of its experimental therapy reloxaliase in patients with enteric hyperoxaluria and will use the accelerated approval pathway to win regulatory approval.

Hyperoxaluria is a metabolic disorder characterized by elevated urinary oxalate levels that may be due to either overproduction of oxalate by the liver from a genetic defect, known as primary hyperoxaluria, or from the excess absorption of oxalate from the diet, known as secondary hyperoxaluria. Enteric hyperoxaluria is a form of secondary hyperoxaluria that is caused by either a chronic and irremediable underlying gastrointestinal disorder, or an unknown underlying cause. Kidney stones, typically the first sign of hyperoxaluria, are often painful and may require interventional procedures. Severe hyperoxaluria may also lead to kidney damage, chronic kidney disease, and end-stage renal disease, which may lead to death.

Reloxaliase is an orally-administered, recombinant oxalate-degrading enzyme that is being developed for the treatment of severe hyperoxaluria. Reloxaliase targets oxalate in the GI tract in an effort to reduce the burden of both dietary and endogenously-produced oxalate. Reloxaliase has the potential to decrease the oxalate available systemically for deposition as calcium oxalate crystals or stones in the kidneys, as well as reduce long-term kidney complications.

Allena’s URIROX program consists of two pivotal phase 3 clinical trials, URIROX-1 and URIROX-2, which are designed to evaluate the safety and efficacy of reloxaliase in patients with enteric hyperoxaluria. URIROX-1 is currently enrolling patients, and Allena initiated URIROX-2 in the fourth quarter of 2018. The primary efficacy endpoint for URIROX-2 is the percent change from baseline in 24-hour urinary oxalate (UOx) excretion measured during weeks 1-4, the same primary efficacy endpoint as URIROX-1.

“We are very pleased with the outcome of our regulatory interactions and appreciate the FDA’s guidance in finalizing the design of our URIROX Phase 3 program,” said Alexey Margolin, CEO of Allena Pharmaceuticals. “As there is no precedent for the use of UOx excretion as a surrogate endpoint for kidney stone disease progression, the FDA’s engagement and specific feedback was essential during this process. We believe alignment on URIROX-2’s innovative trial design and disease-specific endpoints represents a watershed moment in the development of therapies for severe hyperoxaluria.”

Key secondary efficacy endpoints for URIROX-2 include the proportion of subjects with a >20 percent reduction from baseline in 24-hour UOx excretion measured during weeks 1-4, which is also a secondary endpoint for URIROX-1, and data on UOx change from baseline measured during weeks 16 to 24. Twenty-four-hour UOx excretion is an established biomarker that is routinely measured in clinical practice to assess and manage patients at risk for enteric hyperoxaluria and calcium oxalate kidney stones. Data from multiple independent studies suggest that a therapeutic strategy that reduces 24-hour UOx excretion by approximately 20 percent could result in a 25 to 50 percent reduction in the incidence of kidney stone recurrence and may increase renal survival.

The FDA agreed that, if positive, biomarker data on 24-hour UOx excretion in URIROX-1 and URIROX-2 would be used for a filing for accelerated approval of reloxaliase in enteric hyperoxaluria and that patients would continue in URIROX-2 to confirm clinical benefit during the long-term follow-up phase of the trial.

January 2, 2019
Photo: Alexey Margolin, CEO of Allena Pharmaceuticals