Allena Pharmaceuticals Inc., a company negotiating a challenging path to develop an enzyme therapy for severe cases of the rare kidney disorder enteric hyperoxaluria, has started the first of two planned phase III trials in support of a potential biologic license application for the candidate, ALLN-177. The Newton, Mass-based company, which netted about $66.6 million in a November IPO, expects to report top-line data from the study, called Urirox-1, in the second half of 2019.

The design of a second larger phase III study, Urirox-2, remains subject to FDA buy-in, but is expected to begin in the second half of this year. If data from the first trial support it, Allena's team may pursue accelerated approval in the U.S. and conditional approval in the EU.

People with enteric hyperoxaluria, a subset of secondary hyperoxaluria sufferers that Allena has estimated totals about 200,000 to 250,000 people in the U.S., have an increased risk of kidney stones and kidney damage attributable to excess absorption of oxalate from the gastrointestinal (GI) tract. It's associated with bariatric surgery, Crohn's disease, ulcerative colitis, short bowel syndrome, chronic pancreatic insufficiency and cholestatic liver disease – all underlying enteric conditions that can dispose individuals to having high oxalate levels.

ALLN-177, a pill containing a recombinant crystalline formulation of the oxalate-degrading enzyme oxalate decarboxylase, is designed to address the condition with an oral biologic approach that decreases the oxalate available systemically for deposition as kidney stones and reduces long-term kidney complications as well.

"Oxalate is a knowable target that should be addressed through a variety of different drug development approaches because it's a known toxin to the kidney," Allena's president and chief operating officer, Lou Brenner, told BioWorld. "If we can limit its impact in certain high-risk patient populations, we have the potential to benefit their long-term kidney health," he said.

Brenner, a Boston-based nephrologist who noted the limitations of dietary modification in treating hyperoxaluria, joined Allena in April 2015, drawn in part by the opportunity to see oxalate "wrestled to the ground."

Allena, launched in 2011, was created by former executives and investors of Alnara Pharmaceuticals Inc. (See BioWorld Today, Nov. 16, 2011.)

The company's phase II trials of ALLN-177 enrolled a total of 113 subjects with secondary hyperoxaluria and included the largest randomized, controlled trial of a therapeutic candidate specifically targeted at oxalate, Study 713. Both Study 713 and another phase II trial, Study 649, failed to demonstrate statistically significant results in their prespecified primary endpoints – the reduction in 24-hour urinary oxalate (UOx) excretion from baseline to week four for Study 713 and a reduction in the same measure by week one for Study 649.

However, the phase II program did surface a clear trend: In the subgroup with enteric hyperoxaluria, reduction in 24-hour UOx excretion from baseline to week four was substantially greater in subjects treated with ALLN-177 (LS mean = 21.31 mg/24 hour) compared to subjects who received placebo (LS mean = -4.86 mg/24 hour), and the treatment difference was LS mean = -16.45 mg/24 hour (p = 0.184). The magnitude of the treatment effect was substantially greater than what was observed in the overall population, the company said.

For that reason, those patients are the focus of the company's first phase III trial, Urirox-1. Formerly known as Study 301, the randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of ALLN-177 in a total of 124 participants with enteric hyperoxaluria. Patients enrolled in the study will be randomized equally into two arms for a four-week treatment period. They will then self-administer either 7,500 units of ALLN-177 or a placebo with each meal or snack, up to five times per day, consistent with the eating patterns of patients with enteric hyperoxaluria, the company said. The primary endpoint of the study is percent change from baseline in 24-hour UOx excretion averaged during weeks one through four, comparing ALLN-177 to placebo. Secondary endpoints include proportion of subjects with a greater than or equal to 20 percent reduction from baseline in 24-hour UOx excretion averaged during weeks one through four.

It's the largest randomized, controlled trial of a novel therapeutic ever initiated in patients with enteric hyperoxaluria, the company said.

A lingering risk for Allena is that, while Study 713 was the largest randomized, controlled trial ever conducted in hyperoxaluria, only 18 trial participants with enteric hyperoxaluria were enrolled in the trial. Accordingly, it has limited data on the activity of ALLN-177 in that population.

Furthermore, in scientific literature and data generated in the company's own trials, Allena has said that daily UOx excretion is a biomarker that demonstrates significant variability between patients and day-to-day for the same patient. Those changes, especially in enteric hyperoxaluria patients, can be attributed to changes in diet, metabolic activity, hydration status or other factors, it noted in a recent regulatory filing. It can also be attributed to the manner in which those measurements are taken.

Despite those challenges, if all goes well, results of Urirox-1 could underpin an application for accelerated approval or conditional approval either ahead of or following the start of Urirox-2 (formerly Study 302). And, with ongoing engagement with regulators on the best design for Urirox-2, the company could find itself having a substantial voice in helping to shape the agency's view of the best endpoints for hyperoxaluria trials, an area of ongoing consideration.

Allena's shares (NASDAQ:ALNA) lost 19 cents on Tuesday to close at $6.28.

Other companies working on hyperoxaluria therapies include Dicerna Pharmaceuticals Inc. and Alnylam Pharmaceuticals Inc., both of which are advancing RNAi-based candidates for the treatment of primary hyperoxaluria, and Oxthera AB (formerly Ixion Biotechnology), with an oral lyophilized capsule containing live intestinal bacteria, Oxalobacter formigenes (strain HC-1), also for primary hyperoxaluria.