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

Abstract

Key Points:

1. Lademirsen, an anti–microRNA-21 therapy, was generally well-tolerated in adults with Alport syndrome at risk of rapid disease progression.

2. There were no significant differences between lademirsen-treated and placebo-treated participants in eGFR at any timepoint.

3. 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) and −5 (−10.2 to 0.8) ml/min per 1.73 m² per year, respectively. No significant differences between groups were identified in eGFR at any timepoint or in proportion of participants with prespecified reductions in eGFR at week 24 or 48.

Conclusions: While anti–miRNA-21 therapy with lademirsen was generally well-tolerated with an acceptable safety profile, no meaningful improvement in rate of kidney function decline in adults with AS at risk of rapidly progressive disease was observed.

Clinical Trial registration number:: NCT02855268.

Graphical abstract

Figure 1

Study design. ^aRandomization (R) was performed using a centralized treatment allocation system (IRT) and stratified by baseline eGFR (>35 to <60 and ≥60 ml/min per 1.73 m²). ^bAdministered by trained personnel at (or between) study visits, by a qualified health care professional or by participant or caregiver after appropriate training. ^cBlood and urine samples were collected at each visit (standard hematology and chemistry panels plus assessment for blood urea nitrogen, UACR, urine cystatin C, urine neutrophil gelatinase-associated lipocalin, UPCR, blood and urine transforming growth factor-β, and epidermal growth factor. Participants were also assessed for TEAEs and adherence to treatment (by returning used/unused medication). Pharmacokinetic samples were taken up to 4 hours predose on day 1 and weeks 4, 12, 24, 36, and 48 and 4 hours postdose on day 1 and weeks 24 and 48. ADAs were assessed at baseline and weeks 4, 12, 24, 36, and 48. ADA, anti-drug antibody; IRT, interactive response technology; SC, subcutaneous; UACR, urine albumin-to-creatinine ratio; UPCR, urine protein-to-creatinine ratio.

Figure 2

Participant disposition (randomized population, N=43). One participant experienced a TEAE that led to treatment discontinuation on the day of switching from the double-blind to the open-label period, before the participant receiving the first dose of the open-label period. However, because this participant completed the electronic case report form to enter the open-label treatment period, the participant was considered to have discontinued treatment during the open-label period. TEAE, treatment-emergent adverse event.

Figure 3

Mean (SEM) eGFR over time in participants receiving lademirsen or placebo (ITT population, N=43). ITT, intention to treat.