Richard Lafayette, MD

Charlotte Robinson

DocwireNews

In April 2025, the FDA granted accelerated approval to atrasentan for the reduction of proteinuria in adults with primary IgA nephropathy (IgAN). Atrasentan, marketed by Novartis under the brand name Vanrafia, is an oral selective endothelin A receptor antagonist that may be used in conjunction with supportive care, such as renin-angiotensin system (RAS) inhibitors.The approval was based on results of the phase 3 ALIGN study, which showed that atrasentan achieved a proteinuria reduction of 36.1% (P&lt;0.0001) compared with placebo and had a favorable safety profile. Nephrology Times spoke with Richard Lafayette, MD, an ALIGN study investigator and steering committee member, about ALIGN, atrasentan, and the evolving landscape of IgAN treatments. Dr. Lafayette is also a professor of medicine and director of the Glomerular Disease Center at Stanford University Medical Center.Could you explain the mechanism of action for atrasentan?Atrasentan is a classic endothelin receptor antagonist. It blocks the endothelin 1 receptor, so it can block, downstream, all of those specific effects that endothelin has on its targets.Could you briefly catch us up on the ALIGN study? What were the key results of the 36-week interim analysis?The ALIGN study was really designed to be an authoritative test of the role of endothelin blockade with atrasentan in IgA nephropathy. Blocking endothelin was purported to have multiple benefits because it acts both hemodynamically to reduce glomerular pressure, reduce proteinuria, but it also has multiple effects on other cell types including immune cells, resonant kidney endothelial cells, mesangial cells, and podocytes. It can be hemodynamically stabilizing, anti-inflammatory, and stabilizing to innate kidney cells.It is really exciting to take this study forward. This was a randomized controlled trial of adult patients with IgA nephropathy who still had more than a gram a day of proteinuria, GFR [glomerular filtration rate] over 30 [mL/min/1.73 m2], and were on maximally tolerated RAS inhibition and compared to placebo. The primary goal of the study was to show, at 9 months, that proteinuria would be statistically reduced in a clinically significant way, and then with the 2-year outcome plan, to show stabilization of kidney function compared to placebo.In this part A, 9-month analysis, we have seen the data that there was indeed a statistically significant reduction of proteinuria in a way that should be quite clinically significant because the reduction of proteinuria was 38% and about 35% relative to the placebo group. It has been suggested by prior studies and meta-analysis to be clinically significant to predict the benefit to patients&rsquo; long-term outcome.The 2-year ALIGN data will evaluate estimated GFR and whether atrasentan slows disease progression, correct? What data are still forthcoming?Correct. So again, the FDA gets to see all the data for the patients, once that 9-month interim analysis is done on a large subset of the total population. But the 2-year data will explore, as a primary outcome, changes in kidney function by estimated GFR of the atrasentan group versus placebo. It will fill in further gaps about any subgroups.It will look at sustainability of proteinuria and will also, very importantly, further comment on safety because again, at the 9-month interval, we also saw a very nice safety record. Endothelin blockade in the past had been associated with some signals towards liver toxicity, towards volume retention, even bad enough to cause heart failure. But again, there were no signals towards liver toxicity in this study. There were only very mild and reversible signs of any fluid retention with no severe adverse events such as heart failure. We&rsquo;ll be able to further evaluate both the efficacy&mdash;that proteinuria reduction&mdash;look at subgroups, look at GFR stability as the primary outcome, and further evaluate safety. It will be very exciting to see further data.The last few years have been eventful for IgAN drug development. Where does the accelerated approval of atrasentan fit into the treatment landscape?It is really a beautiful, very exciting addition because&hellip; just a little over 2 years ago, we were really relying on RAS inhibitors to be our workforce for slowing progression of chronic kidney disease in IgA nephropathy patients. The evidence was that, even though they helped, they didn&rsquo;t do enough. Others relied on corticosteroids or systemic immunosuppression, which was associated with a substantial amount of adverse events and had a mixed record of efficacy.Moving forward, now [we have] multiple agents that can target the galactose-deficient IgA production that underlies IgA nephropathy, further target potential antibodies against those galactose-deficient IgA, target the inflammation that might occur such as using complement inhibitors, use dual endothelin antagonists together with angiotensin receptor antagonism. There are so many more options now that we really can tailor our therapy better to our patients.A standalone endothelin antagonist like atrasentan is really very exciting to have in our toolbox because [for] patients who are doing well on their underlying therapy, but not quite at goal, this is really a great opportunity to get them exactly where we want in the hopes of really keeping their kidney function stable over the long run. So, it is just a very exciting, great addition.

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Accelerated Approval for Atrasentan in IgAN

IgA Nephropathy

Nephrology Times spoke with ALIGN study investigator Richard Lafayette, MD, of Stanford, upon the FDA's accelerated approval of atrasentan for IgA nephropathy (IgAN).

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