A Randomized Controlled Clinical Trial Testing Effects of Lademirsen on Kidney Function Decline in Adults with Alport Syndrome.

Key Points: • Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression. • There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint. • The proportions of participants with prespecified reductions in eGFR at weeks 24 and 48 were not significantly different for lademirsen versus placebo. Background: Preclinical models of disease have suggested that targeting microRNA-21 (miRNA-21) may slow the decline in kidney function in individuals with Alport syndrome (AS). The objective of this study was to investigate the effects of the anti–miRNA-21 oligonucleotide, lademirsen, on rate of eGFR decline in adults with AS at risk of rapid disease progression. Methods: This study was a phase 2 trial of lademirsen, with a randomized, double-blind, placebo-controlled period followed by an open-label period. Adults with AS, eGFR >35 to <90 ml/min per 1.73 m2, and evidence of rapidly progressive kidney dysfunction were randomized 2:1 to lademirsen 110 mg subcutaneously once weekly or placebo for 48 weeks. After a planned interim analysis (after 24 of 43 randomized participants completed the week 48 study visit or discontinued before week 48), the trial was terminated for futility. Results: Forty-three adults with AS (26 men, 17 women) participated (mean age 34 years), and 28 (lademirsen: n=19; placebo: n=9) completed 48 weeks of double-blind treatment. All participants in both groups developed treatment-emergent adverse events, mainly respiratory tract infections, headache, dizziness, metabolic/electrolyte disturbances, and anemia. Treatment was discontinued in three lademirsen-treated participants in the double-blind period and one participant in the open-label period, owing to treatment-emergent adverse events. The least squares mean eGFR slope (95% confidence interval) over 48 weeks in the lademirsen and placebo groups was −5 (−8.7 to −1.1