Discussion
kidney failure, PH1
KIDNEY FAILURE
Recent epidemiologic data show that PH3 prevalence and burden have been underestimated [This phase I study is the first to examine targeted therapy with RNAi in patients with PH3. A single dose of nedosiran was safe and well-tolerated in this cohort, as evidenced by a lack of treatment-related TEAEs. The AE profile of nedosiran was consistent with previously reported clinical data on nedosiran [Twenty-four–hour Uox excretion is the accepted biomarker of PH disease burden, and in PH1, a higher 24-h excretion is associated with a greater likelihood of kidney failure [Firm conclusions from PHYOX4 are limited by the small sample size, which was based on safety, not efficacy, evaluations. A single-dose study of such a short duration is inadequate to draw conclusions regarding the effect on new stone formation/events, which are ubiquitous in PH3 patients. In addition, although participants were asked to avoid oxalate-rich foods, the diet was not controlled and adherence to this restriction was not measured. Therefore, we cannot speculate whether dietary variation throughout the study might have influenced Uox excretion and affected the results, although we are not certain that dietary oxalate content is an important determinant of Uox excretion in patients with PH3. Despite these limitations, our preliminary data warrant further investigation regarding the potential benefits of multiple dose nedosiran for PH3 patients in PHYOX3.In conclusion, this randomized, double‐blind, placebo‐controlled trial indicated that a single subcutaneous dose of nedosiran was safe and well-tolerated in patients with PH3, with predictable PK. The nedosiran PD data was consistent with its mechanism of action as an inhibitor of hepatic LDH predicted to reduce hepatic oxalate generation and, hence, 24-h Uox excretion. Emerging preliminary data on the effect of multi-dose nedosiran in patients with PH3 will be shared in a separate publication.
