Interim ALIGN Data: Atrasentan Cuts Proteinuria in IgA Nephropathy

 Interim ALIGN Data: Atrasentan Cuts Proteinuria in IgA Nephropathy


Surrogate endpoint of urinary protein-to-creatinine ratio “broadly even handed to be predictive”

by
Kristen Monaco, Senior Workers Creator, MedPage Nowadays

October 27, 2024

SAN DIEGO — A recent drug vastly reduced IgA nephropathy-associated proteinuria, in accordance to period in-between findings of the ALIGN watch.

Within the part III trial, among 270 sufferers with the uncommon kidney disorder, these on atrasentan had a 36.1 percentage point (95% CI -44.6 to -26.4, P<0.001) elevated gash price in urinary protein-to-creatinine ratio (UPCR) relative to baseline than placebo, reported Hiddo J.L. Heerspink, PhD, of the University Scientific Center Groningen within the Netherlands, at the American Society of Nephrology Kidney Week assembly.

Over the direction of 36 weeks, sufferers on 0.75 mg/day of atrasentan had a 38.1% gash price in UPCR versus a 3.1% gash price with placebo. The on-therapy community had a critical UPCR gash price by week 6.

“This wait on is clinically meaningful, particularly within the context of a excessive-threat trial inhabitants (sufferers had a total urinary protein excretion of ≥1 g per day at baseline, despite acceptable supportive care),” Heerspink and colleagues said in a paper that became once concurrently printed within the Unique England Journal of Drugs (NEJM).

“Though the final outcomes of the ALIGN trial will likely be desired to verify that the proteinuria gash price viewed with atrasentan interprets to a gash price in eGFR decline, there is rising self assurance within the urinary protein-to-creatinine ratio as a surrogate biomarker in IgA nephropathy,” they said.

Heerspink said outcomes for eGFR trade from the predominant stratum will likely be presented at the least sufferers possess carried out the 136-week double-blind watch duration. This endpoint will expose if the drug basically preserves kidney feature.

Unique therapies are wanted for IgA nephropathy, as round half of sufferers will development to kidney failure within Two decades of diagnosis. This unmet need has led to a most up-to-date push towards growing unique therapies tackle atrasentan, which acts as a selective inhibitor of the endothelin kind A receptor.

Diverse newly developed drugs for IgA nephropathy consist of centered-launch budesonide (Nefecon) and iptacopan (Fabhalta) — an different complement pathway inhibitor — which gained accelerated FDA approval in August 2024 in accordance to sure period in-between trial findings that ancient the same surrogate endpoint of proteinuria gash price. This drug awaits outdated approval following anticipated eGFR trial outcomes with the APPLAUSE-IgAN trial.

“Both of these trials [ALIGN and APPLAUSE-IgAN] are judged to be promising, on condition that trials with surrogate pause ingredients are broadly even handed to be predictive,” Julie R. Ingelfinger, MD, NEJM deputy editor, said in an accompanying editorial.

“Yet, whether or now not and how generally drugs already or quickly-to-be licensed on an accelerated pathway on the premise of such surrogate pause ingredients will possess persevered approval once outcomes from deliberate annoying pause ingredients are evaluated is now not but positive,” she added. “No doubt, outcomes of these latter pause ingredients will have an effect on the lifetime of this unique pathway.”

Atrasentan beforehand demonstrated efficacy within the commence-designate AFFINITY basket trial, the place it reduced the 24-hour urinary protein-to-creatinine ratio by forty eight% after 12 weeks of therapy when added to most tolerated doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs).

Within the double-blind ALIGN watch, 340 sufferers were recruited, but the period in-between outcomes handiest replicate the first 270 sufferers within the predominant stratum (135 per trial community) who carried out the week 36 talk over with.

Trial participation became once extraordinary to adults with biopsy-confirmed IgA nephropathy, a total urinary protein excretion of now not now not as a lot as 1 g per day, and an eGFR of now not now not as a lot as 30 mL/min/1.73 m2. All were on a most tolerated dose of an ACE inhibitor, or a stable dose of ARB, for now not now not as a lot as 12 weeks before screening. Sufferers who were unable to take RAS inhibitors were eligible; nevertheless, the total percentage of such sufferers couldn’t exceed 5% of the total inhabitants,” the authors explained.

Common participant age became once forty five, 41% were female, 47% were from Asia, mean baseline eGFR became once 58.9 mL/min/1.73 m2, and median UPCR became once 1,433 mg/g.

In a subgroup diagnosis which stratified sufferers in accordance to gender, age, high-tail, ethnicity, continent, and whether or now not they were from Asia or now not, virtually all teams appreciated atrasentan. The excellent two subgroups that had nonsignificant UPCR decline were six sufferers, ages 65 and older, and the 12 sufferers from Europe.

All subgroups stratified by scientific traits — baseline and screening UPCR, blood stress, eGFR, and diuretic consume — appreciated atrasentan.

Sufferers taking an SGLT2 inhibitor would possibly maybe well furthermore very neatly be enrolled in an exploratory stratum. This subset of 29 sufferers had outcomes a lot like the predominant stratum, marked by a -39.6% UPCR gash price in 14 atrasentan sufferers and -3.4% (95% CI -26.3 to 26.5) within the 15 placebo sufferers at week 36 (geometric mean between-community distinction of -37.4 percentage ingredients, 95% CI -57.2 to -8.5).

Atrasentan became once furthermore neatly tolerated with a favorable safety profile, marked by a same percentage of sufferers with negative events (AEs) between the 2 teams. No serious therapy-emergent AEs or AEs main to appear at drug discontinuation occurred.

Nasopharyngitis, peripheral edema, anemia, pyrexia, and better respiratory tract an infection were more frequent AEs within the atrasentan community than within the placebo community. Also, some AEs of special curiosity — anemia, fluid retention, and vasodilatation or hypotension — were more frequent with atrasentan.

  • creator['full_name']

    Kristen Monaco is a senior team of workers creator, specializing in endocrinology, psychiatry, and nephrology news. Based out of the Unique York Metropolis advise of job, she’s worked at the firm since 2015.

Disclosures

ALIGN became once funded by Novartis. Some co-authors are firm staff.

Heerspink disclosed relationships with Alexion Prescribed drugs, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Eli Lilly and Firm, Gilead, Janssen, Novartis, Novo Nordisk, Roche, Travere Therapeutics, and Vifor Pharma. Co-authors disclosed a total lot of relationships with alternate, including Novartis.

Ingelfinger disclosed relationships with Massachusetts Scientific Society, Springer Publishing, and St. Martin’s Press.

Predominant Provide

Unique England Journal of Drugs

Provide Reference: Heerspink HJL, et al “Atrasentan in sufferers with IgA nephropathy” N Engl J Med 2024; DOI: 10.1056/NEJMoa2409415.

Secondary Provide

Unique England Journal of Drugs

Provide Reference: Ingelfinger JR “Manner stations in development — burgeoning therapy options for IgA nephropathy” N Engl J Med 2024; DOI: 10.1056/NEJMe2413288.

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