Supplementary Material for: A Double-Blind, Placebo Controlled, Randomized Phase 1 Cross-Over Study with ALLN-177, an Orally Administered Oxalate Degrading Enzyme

Background: Hyperoxaluria may result from increased endogenous production or overabsorption of dietary oxalate in the gastrointestinal tract leading to nephrolithiasis and, in some, to oxalate nephropathy and chronic kidney disease. ALLN-177 is an oral formulation of a recombinant, oxalate specific, microbial enzyme oxalate decarboxylase intended to treat secondary hyperoxaluria by degrading dietary oxalate in the gastrointestinal tract, thereby reducing its absorption and subsequent excretion in the urine. Methods: This double-blind, placebo controlled, randomized, cross-over, phase 1 study of ALLN-177 evaluated the tolerability of ALLN-177 and its effect on urinary oxalate excretion in 30 healthy volunteers with hyperoxaluria induced by ingestion of a high oxalate, low calcium (HOLC) diet. The primary end point was the difference in the mean 24-hour urinary oxalate excretion during the ALLN-177 treatment period compared with the placebo treatment period. Results: The daily urinary oxalate excretion increased in the study population from 27.2 ± 9.5 mg/day during screening to 80.8 ± 24.1 mg/day (mean ± SD) on the HOLC diet before introducing ALLN-177 or placebo therapy for 7 days. Compared to placebo, ALLN-177 treatment reduced urinary oxalate by 11.6 ± 2.7 mg/day, p = 0.0002 (least squares mean ± SD). Conclusions: In healthy volunteers, with diet-induced hyperoxaluria treatment with ALLN-177, when compared to placebo, significantly reduced urinary oxalate excretion by degrading dietary oxalate in the gastrointestinal tract and thereby reducing its absorption. ALLN-177 may represent a new approach for managing secondary hyperoxaluria and its complications.

背景：高草酸尿症（Hyperoxaluria）可因内源性草酸生成增加，或胃肠道对膳食草酸的过度吸收所致，可引发肾结石病，部分患者可进展为草酸肾病与慢性肾脏病。ALLN-177是一种重组草酸特异性微生物酶——草酸脱羧酶（oxalate decarboxylase）的口服制剂，旨在通过在胃肠道内降解膳食草酸，减少其吸收及后续尿中排泄，从而治疗继发性高草酸尿症。
方法：本项针对ALLN-177的双盲、安慰剂对照、随机交叉I期临床试验，纳入30名因摄入高草酸低钙（HOLC）饮食诱导出高草酸尿症的健康受试者，评估了ALLN-177的耐受性及其对尿草酸排泄量的影响。主要终点为ALLN-177治疗周期与安慰剂治疗周期内，平均24小时尿草酸排泄量的差值。
结果：本研究人群的每日尿草酸排泄量从筛查时的27.2±9.5mg/日，升高至启动ALLN-177或安慰剂7天治疗前的高草酸低钙（HOLC）饮食阶段的80.8±24.1mg/日（均值±标准差）。与安慰剂组相比，ALLN-177治疗可使尿草酸水平降低11.6±2.7mg/日，p=0.0002（最小二乘均值±标准差）。
结论：在饮食诱导高草酸尿症的健康受试者中，与安慰剂相比，ALLN-177治疗可通过在胃肠道降解膳食草酸、减少其吸收，显著降低尿草酸排泄量。ALLN-177或可为继发性高草酸尿症及其并发症的临床管理提供全新策略。