Treatment with bardoxolone methyl safe and preserves kidney function in patients with Alport Syndrome: Study
USA: Treatment with bardoxolone methyl in patients with Alport syndrome receiving standard of care led to eGFR preservation compared to placebo over two years, says a study published in the Clinical Journal of the American Society of Nephrology.
Alport syndrome is an inherited disorder characterized by progressive kidney function loss. Among patients with proteinuria and Alport syndrome, current recommendations for treatment include angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors. Despite their use which slows disease progression, patients with Alport syndrome may still endure a high lifetime kidney failure risk and experience rapid disease progression.
Bardoxolone methyl activates Nrf2 (NF erythroid 2-like 2), a transcription factor that modifies the expression of genes involved in cellular energy metabolism, oxidative stress, and inflammation. Bradley A Warady from the Department of Pediatrics in Children's Mercy Kansas City, Kansas City, Missouri, and colleagues aimed to evaluate the safety and efficacy of bardoxolone methyl in Alport syndrome patients.
The study included Alport syndrome patients aged 12–70 years and eGFR 30–90 ml/min per 1.73 m2. Seventy-seven were randomly assigned to bardoxolone methyl and 80 to placebo. Safety assessment was done by monitoring for adverse events and change in vital signs from baseline, laboratory measurements (including B-type natriuretic peptide, magnesium, urinary albumin-creatinine ratio, and aminotransferase), body weight, and 12-lead electrocardiograms. Change from baseline in eGFR at weeks 100 and 48 were determined (primary efficacy endpoints). Critical secondary efficacy endpoints were eGFR change from baseline at weeks 52 and 104, following an intended four weeks off treatment.
The study led to the following findings:
· Preservation in eGFR was seen in patients randomized to bardoxolone methyl relative to placebo at 48 and 100 weeks (between-group differences: 9.2 and 7.4 ml/min per 1.73 m2, respectively).
· The corresponding mean differences in eGFR were 5.4 and 4.4 ml/min per 1.73 m2 at 52 and 104 weeks, respectively, after a 4-week off-treatment period.
· In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 ml/min per 1.73 m2).
· Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases.
· Serious adverse events were more frequent among patients randomized to placebo. In each group, three patients developed kidney failure.
Treatment with bardoxolone methyl in adolescent and adult patients with Alport syndrome
"Results from this phase 3, placebo-controlled trial in patients with Alport syndrome show that treatment with bardoxolone methyl was safe and preserved eGFR (estimated glomerular filtration rate) over two years; off-treatment results using all available data were not significantly different," the researchers conclude.
Reference:
Warady, Bradley A.1; Pergola, Pablo E.2; Agarwal, Rajiv3; Andreoli, Sharon4; Appel, Gerald B.5; Bangalore, Sripal6; Block, Geoffrey A.7; Chapman, Arlene B.8; Chin, Melanie P.9; Gibson, Keisha L.10; Goldsberry, Angie9; Iijima, Kazumoto11; Inker, Lesley A.12; Kashtan, Clifford E.13; Knebelmann, Bertrand14; Mariani, Laura H.15; Meyer, Colin J.9; Nozu, Kandai11; O'Grady, Megan9; Rheault, Michelle N.13; Silva, Arnold L.16; Stenvinkel, Peter17; Torra, Roser18; Chertow, Glenn M.19. Effects of Bardoxolone Methyl in Alport Syndrome. CJASN 17(12):p 1763-1774, December 2022. | DOI: 10.2215/CJN.02400222
