Atrasentan is a potent and selective, small molecule inhibitor of the endothelin A receptor for the potential treatment of IgA nephropathy (IgAN) and other proteinuric glomerular diseases.
Atrasentan in Action
Watch our video to learn more about atrasentan’s proteinuria-lowering mechanism of action as well as its anti-fibrotic and anti-inflammatory properties in proteinuric glomerular diseases.
The phase 3 ALIGN trial of atrasentan is currently enrolling patients with IgA nephropathy and the phase 2 AFFINITY trial of atrasentan is currently enrolling patients with proteinuric glomerular diseases. We identified IgAN as the lead indication for evaluation of atrasentan due to the role of endothelin activation and proteinuria in IgAN disease progression and high unmet need with the potential to submit an NDA seeking accelerated approval based on surrogate endpoints.
We in-licensed atrasentan from AbbVie in 2019. AbbVie previously developed atrasentan for diabetic kidney disease through multiple clinical trials, including >5,000 patients in their phase 3 SONAR trial. In SONAR, atrasentan showed a statistically significant p-value of 0.029 on its primary endpoint of a composite of hard kidney outcomes (i.e., first occurrence of progression to end-stage renal disease or doubling of serum creatinine). The study also demonstrated statistically significant reductions in proteinuria as well as improvements in eGFR, both of which are measures of kidney function.
IgA Nephropathy (IgAN)
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease in the developed world and a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), both of which require dialysis or kidney transplantation. IgAN is a serious progressive disease with no approved therapies, for which up to 45% of patients progress to ESRD.
IgAN is characterized by the elevated production of a galactose-deficient immunoglobulin A1, or IgA1, which is recognized as an autoantigen by circulating autoantibodies leading to the formation of immune complexes that are deposited in the glomeruli of the kidney. This process initiates an inflammatory cascade that results in protein and blood leaking into the urine, called proteinuria and hematuria, respectively.
Ultimately the filtration function of the kidney is impaired, reducing the ability to remove waste products from the blood. As the disease progresses, these waste products accumulate and can result in potentially life-threatening complications that often lead to the need for dialysis or kidney transplant.
Nature Reviews, February 2016
endothelin A receptor
Atrasentan is a selective and potent inhibitor of the endothelin A receptor, or ETA, which has the potential to provide benefit in multiple chronic kidney diseases by reducing proteinuria and having direct anti-inflammatory and anti-fibrotic effects to preserve kidney function.
Kidney Intl., November 2014
The ALIGN study, a phase 3, randomized, double-blind, placebo-controlled study of atrasentan in patients with IgAN at risk of progressive loss of kidney function, is designed to evaluate change from baseline in proteinuria and eGFR in 320 patients with IgAN. Sustained proteinuria is the most widely studied and the strongest predictor for the rate of progression to ESRD in IgAN, and may be accepted as a surrogate endpoint for regulatory approval. This global study is being conducted in approximately 20 countries across four continents at more than 120 investigative sites. For more information, visit www.alignstudy.com or contact email@example.com.
Chinook’s phase 2 basket study of atrasentan in additional populations of proteinuric glomerular disease patients with proteinuria is currently enrolling patients. Four initial cohorts will consist of patients with: IgA nephropathy with urine protein to creatinine ratio (UPCR) of 0.5 to less than 1.0 g/g, focal segmental glomerulosclerosis (FSGS), Alport Syndrome and diabetic kidney disease (DKD) in combination with an SGLT2 inhibitor. For more information, visit www.alignstudy.com or contact firstname.lastname@example.org.