Interim findings from the phase III ALIGN study reveal that atrasentan, a novel drug, significantly reduces proteinuria associated with IgA nephropathy. The trial, involving 270 patients, showed that atrasentan led to a 36.1 percentage point greater reduction in urinary protein-to-creatinine ratio (UPCR) compared to placebo (95% CI -44.6 to -26.4, P <0.001). This outcome, presented at the American Society of Nephrology Kidney Week meeting, suggests a potential new treatment avenue for this rare kidney disorder.
Significant UPCR Reduction with Atrasentan
Over 36 weeks, patients receiving 0.75 mg/day of atrasentan experienced a 38.1% reduction in UPCR, compared to a 3.1% reduction in the placebo group. Notably, the atrasentan group showed a significant UPCR reduction by week 6. According to Hiddo J.L. Heerspink, PhD, of the University Medical Center Groningen in the Netherlands, and colleagues, this benefit is clinically meaningful, especially considering the high-risk trial population with a total urinary protein excretion of ≥1 g per day at baseline, despite appropriate supportive care.
The findings were simultaneously published in the New England Journal of Medicine. The researchers noted that while final results of the ALIGN trial are needed to confirm that the proteinuria reduction translates to a reduction in eGFR decline, there is growing confidence in UPCR as a surrogate biomarker in IgA nephropathy.
The Need for New Therapies
IgA nephropathy affects a significant number of individuals, with approximately half progressing to kidney failure within 20 years of diagnosis. This unmet need has spurred the development of new therapies like atrasentan, a selective inhibitor of the endothelin type A receptor. Other recently developed drugs include targeted-release budesonide (Nefecon) and iptacopan (Fabhalta).
Julie R. Ingelfinger, MD, NEJM deputy editor, commented in an accompanying editorial that both the ALIGN and APPLAUSE-IgAN trials are promising, given that trials with surrogate endpoints are widely considered predictive. However, she also noted that the continued approval of drugs approved on an accelerated pathway based on surrogate endpoints will depend on the results from planned hard endpoints.
Trial Design and Patient Population
The double-blind ALIGN study initially recruited 340 patients, with the interim results based on the first 270 patients in the main stratum (135 per trial group) who completed the week 36 visit. Participants were adults with biopsy-proven IgA nephropathy, a total urinary protein excretion of at least 1 g per day, and an eGFR of at least 30 mL/min/1.73 m2. All patients were on a maximum tolerated dose of an ACE inhibitor or a stable dose of ARB for at least 12 weeks before screening. A small percentage of patients (no more than 5%) unable to take RAS inhibitors were also eligible.
The average participant age was 45, 41% were female, 47% were from Asia, mean baseline eGFR was 58.9 mL/min/1.73 m2, and median UPCR was 1,433 mg/g.
Subgroup Analysis and Safety Profile
Subgroup analysis, stratifying patients by gender, age, race, ethnicity, continent, and Asian origin, showed that nearly all groups favored atrasentan. The only exceptions were six patients aged 65 and older, and 12 patients from Europe, where UPCR decline was not significant. All subgroups stratified by clinical characteristics, such as baseline and screening UPCR, blood pressure, eGFR, and diuretic use, favored atrasentan.
Atrasentan demonstrated a favorable safety profile, with a similar percentage of patients experiencing adverse events (AEs) in both groups. No serious treatment-emergent AEs or AEs leading to study drug discontinuation occurred. Common AEs in the atrasentan group included nasopharyngitis, peripheral edema, anemia, pyrexia, and upper respiratory tract infection. Some AEs of special interest, such as anemia, fluid retention, and vasodilatation or hypotension, were more common with atrasentan.
