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

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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). <b><i>Conclusions:</i></b> 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.

<b><i>背景：</i></b> 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引发，进而导致肾结石病（nephrolithiasis），部分患者可进展为草酸肾病（oxalate nephropathy）与慢性肾脏病（chronic kidney disease）。ALLN-177是一种重组、草酸特异性微生物草酸脱羧酶（oxalate decarboxylase）的口服制剂，旨在通过降解胃肠道内的膳食草酸，减少其吸收及后续经尿液排泄，以此治疗继发性高草酸尿症。<b><i>方法：</i></b> 本研究为一项双盲、安慰剂对照、随机交叉的1期临床试验，针对ALLN-177展开，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志愿者，评估ALLN-177的耐受性及其对尿草酸排泄的影响。本研究的主要终点为对比ALLN-177治疗期与安慰剂治疗期内，24小时尿草酸平均排泄量的差值。<b><i>结果：</i></b> 研究人群的每日尿草酸排泄量从筛查时的27.2±9.5 mg/天，升高至启动为期7天的ALLN-177或安慰剂治疗前的高草酸低钙饮食阶段的80.8±24.1 mg/天（均值±标准差）。与安慰剂组相比，ALLN-177治疗使尿草酸排泄量降低11.6±2.7 mg/天，p=0.0002（最小二乘均值（least squares mean）±标准差）。<b><i>结论：</i></b> 在饮食诱导的高草酸尿症健康志愿者中，与安慰剂相比，ALLN-177通过降解胃肠道内的膳食草酸、减少其吸收，可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管理提供全新治疗策略。