Atrasentan a new player in the IgAN treatment field?

In the prespecified interim analysis of the phase III ALIGN study, the investigational drug atrasentan shows promising signals when added to standard supportive care with a renin-angiotensin system (RAS) inhibitor in patients with IgA nephropathy (IgAN).

“Atrasentan was superior to placebo in reducing proteinuria … [There was] a statistically significant and clinically meaningful proteinuria reduction of 36.1 percent [with atrasentan] relative to placebo after 36 weeks of treatment,” said Dr Hiddo Heerspink from the University Medical Center Groningen in the Netherlands, during his presentation at ERA 2024.

The relative reductions in mean percentage change in 24-h urine protein:creatinine ratio (UPCR) from baseline to week 36 for atrasentan was 38.1 percent, whereas for placebo, it was only 3.1 percent. A comparison between arms yielded a p-value of <0.0001. [ERA 2024, abstract 109]

Similarly, in the sensitivity analysis which included all 24-hr UPCR values irrespective of restricted medication use, chronic dialysis, or kidney transplant, the relative reduction in mean percentage change in UPCR from baseline with atrasentan vs placebo was 36.7 percent.

“[Hence,] the primary endpoint was met … The sensitivity analysis of the primary endpoint demonstrated the robustness of these results,” said Heerspink, adding that the UPCR reduction with atrasentan was evident as early as week 6 and was sustained through week 36.

Favourable safety profile

Over 80 percent of participants in both arms had any treatment-emergent adverse event (TEAE). In the atrasentan arm, the most frequent TEAE was COVID-19 (20.7 percent) followed by nasopharyngitis (10.1 percent).

The atrasentan and placebo arms had similar incidences of serious TEAEs (5.9 percent vs 6.5 percent), severe TEAEs (7.1 percent vs 5.9 percent), and drug discontinuation owing to any TEAEs (3.6 percent vs 3.5 percent).

TEAEs of special interest were more prevalent in the atrasentan vs placebo arm (22.5 percent vs 14.1 percent), but none were serious. Also, most TEAEs of special interest were mild and none led to drug discontinuation. “Atrasentan was well tolerated with a favourable safety profile,” Heerspink said.

Persistent proteinuria = poor prognosis

IgAN is a heterogeneous, progressive, rare kidney disease, and about a third of individuals with persistent proteinuria progress to kidney failure within a decade. [Kidney Int 2021;100:S1-S276; Kidney Int 2012;81:833-843; JASN 2007;18:3177-3183] Endothelin A (ET_A) receptor activation drives proteinuria, inflammation, and fibrosis in IgAN. [Physiol Res 2018;67:93-105; J Am Soc Nephrol 2001;12:2321-2329; Ren Fail 2012;34:308-315; Kidney Int 2014;86:896-904]

“Endothelin 1 (ET-1) is implicated in the pathophysiology of many kidney diseases, including IgAN. Binding of ET-1 to ET_A causes mesangial cell activation, podocyte damage, and [tubular] inflammation … Together, these effects lead to progressive loss of kidney function,” Heerspink explained.

“ET_A receptor activation causes proteinuria, which is usually one of the first clinical signs of IgAN. Patients with persistent proteinuria have a poorer prognosis and are more likely to progress to kidney failure,” noted Heerspink in a press release. [https://www.novartis.com/news/media-releases/novartis-atrasentan-phase-iii-data-show-clinically-meaningful-proteinuria-reduction-further-advancing-companys-iga-nephropathy-igan-portfolio]

“The current treatment [for IgAN] consists, amongst others, of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. But clearly, these interventions are insufficient to completely halt [disease] progression,” Heerspink stressed. “That means we need additional targeted therapies that can support IgAN patients across the care pathway.”

ET_A receptor inhibition can improve kidney outcomes in IgAN patients or other causes of kidney diseases, noted Heerspink.

Atrasentan is a potent, selective ET_A receptor antagonist with the potential to be added to current supportive therapy to reduce persistent proteinuria and preserve kidney function in a broad population. In the interim analysis of the open-label AFFINITY trial, atrasentan showed clinically meaningful reductions in proteinuria and was well tolerated at 12 and 24 weeks in IgAN patients. [Kidney International Reports 2023;8:1902]

The main stratum intention-to-treat analysis set of ALIGN comprised 340 patients who had biopsy-proven IgAN with proteinuria of ≥1 g/day despite optimized RAS inhibition. They were randomized 1:1 to receive oral atrasentan 0.75 mg or placebo daily for 132 weeks, on top of their baseline supportive therapy. Of these, the first 270 patients (mean age 44.9 years, 59 percent men, 47 percent Asian) were included in the primary efficacy analysis.

May transform IgAN treatment landscape

“These data … further demonstrate the ability of atrasentan to significantly reduce proteinuria and, if approved, its potential to become a new foundational treatment for people living with IgAN that can be seamlessly added to current supportive therapy,” Heerspink said.

In the press release, Dr David Soergel, Global Head, Cardiovascular, Renal, and Metabolism Development Unit, Novartis, stated that “atrasentan has the potential to help transform how IgAN is managed for many people living with this complex illness.”

Evaluation of the key secondary endpoint (change in estimated glomerular filtration rate [eGFR] from baseline to week 136) is in progress. Participants will then have the option to enrol in the open-label extension phase. Findings from the primary eGFR analysis from the main stratum shall be presented after all participants have completed the double-blind study phase, Heerspink noted.