Lumasiran may reduce urinary oxalate excretion, which causes progressive kidney failure in patients with primary hyperoxaluria type 1 (PH1), according to a study in the New England Journal of Medicine.

The multinational, randomized, double-blind, placebo-controlled trial assigned patients aged 6 years and older with PH1 in a 2:1 ratio to receive either the investigational RNA interference agent lumasiran or placebo subcutaneously for 6 months. Afterward, all patients received lumasiran for up to 54 months.

The primary end point was the percent change from baseline to 6 months in 24-hour urinary oxalate excretion corrected for body-surface area, which was estimated as the mean percent change from baseline to months 3 to 6. Secondary end points included the percent change in the plasma oxalate levels from baseline to 6 months and the percentage of patients who had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at 6 months.


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A total of 39 patients from 16 sites in 8 countries were randomly assigned to receive lumasiran (26 patients) or placebo (13 patients) from January 2019 through May 2019, and 38 completed the double-blind period. Overall, participants’ median age was 14 years (range, 6-60 years; 33% women; 77% White), and the mean baseline 24-hour urinary oxalate excretion was 1.82 mmol/24 hr/1.73 m2.

Patients who received lumasiran had a rapid and sustained decrease in 24-hour urinary oxalate excretion, with observed decreases at 1 month and steady state reached by the end of the loading-dose phase. The least-squares mean difference (lumasiran minus placebo) in the percent change in 24-hour urinary oxalate excretion from baseline to 6 months was −53.5 percentage points (95% CI, −62.3 to −44.8; P <.001). The least-squares mean percent change from baseline was −65.4% in the lumasiran group compared with −11.8% in the placebo group.

The researchers noted lumasiran treatment also led to significant improvements in all secondary end points that were tested hierarchically.

At 6 months, 84% of patients who received lumasiran had 24-hour urinary oxalate levels no higher than 1.5 times the upper limit of the normal range, compared with 0% of patients who received placebo (P <.001).

Of the 33 patients who had a baseline plasma oxalate level of at least 1.5 times the lower limit of quantitation, the least-squares mean difference in the percent change in the plasma oxalate levels from baseline to 6 months was −39.5 percentage points (95% CI, −50.1 to −28.9; P <.001).

Overall, 85% of patients who received lumasiran and 69% of those who received placebo reported adverse events, which included injection-site reactions, headache, rhinitis, and upper respiratory infection. All events were mild or moderate in severity.

The investigators noted a limitation to their findings, as patients aged less than 6 years and those with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 were excluded.

“This phase 3 trial showed that lumasiran led to substantial reductions in urinary and plasma levels of oxalate, the disease-causing metabolite in PH1, with urinary oxalate levels in most patients reaching the normal or near-normal range,” the study authors commented.

Disclosures: This research was supported by Alnylam Pharmaceuticals. Some of the study authors reported affiliations with pharmaceutical companies. Please see the original reference for a full list of disclosures.

Reference

Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med. 2021;384(13):1216-1226. doi: 10.1056/NEJMoa2021712