Atrasentan in Patients With IgA Nephropathy

The ALIGN Study is a phase 3, double-blind, placebo-controlled study to compare the efficacy and safety of atrasentan to placebo in patients with IgA nephropathy (IgAN) at risk of progressive loss of renal function.

Inclusion Criteria: Double-Blind period: * Biopsy-proven IgA nephropathy. * Receiving a maximally tolerated dose of RAS inhibitor therapy (ACEi or ARB) that has been stable for at least 12 weeks. Exceptions from this requirement will be made for subjects who are unable to tolerate RAS inhibitor therapy. * Total urine protein ≥1 g/day as measured via 24-hour urine collection by central laboratory at Screening. * eGFR of at least 30 mL/min/1.73 m\^2 at Screening based on the CKD-EPI equation. * Willing and able to provide informed consent and comply with all study requirements. * SGLT2i Stable Stratum Only - Receiving a stable dose of an SGLT2i (per Investigator choice) in addition to a maximally tolerated and optimized dose of a RAS inhibitor that has been stable for at least 12 weeks prior to Screening. * All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month afterward. In WOCBP, use of contraceptive agents must have been started at least 1 month prior to Baseline. Open-Label Period: * Willing and able to provide informed consent and comply with all OL extension study visits and study procedures. * Completed treatment through Week 132 and completed the Week 136 visit. * All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol, throughout the study and for 1 month afterward. In WOCBP, use of contraceptive agents must have been continued after completing the double-blind portion of the study. Substudy: Subjects must meet ALL inclusion criteria to be enrolled. * Subjects who provided written informed consent prior to initiation of any substudy-specific activities/procedures and are willing to comply with all substudy visits and substudy procedures. * Completion of OL extension treatment through Week 48 visit or treated with atrasentan long enough to sufficiently determine its efficacy as per clinical judgement of the Principal Investigator. * Stable on a maximally tolerated dose of ACEi and/or ARB for at least 12 weeks prior to substudy screening visit. * All fertile men and WOCBP who engage in heterosexual intercourse must be willing to abide with highly effective forms of contraception, as specified in the protocol Exclusion Criteria: Double-blind period: * Concurrent diagnosis of another cause of chronic kidney disease including diabetic kidney disease or another primary glomerulopathy. * Clinical diagnosis of nephrotic syndrome. * BNP value of \> 200 pg/mL at Screening. * Platelet count \ 200 pg/mL at OL Screening. * Platelet count \< 80,000 per μL at OL Screening. * Hemoglobin below 9 g/dL at OL screening or prior history of blood transfusion for anemia within 3 months of OL Screening. Substudy: Subjects must meet NONE of the following exclusion criteria to be enrolled. * Participants who are not receiving atrasentan at the time of substudy screening visit in the ALIGN OL extension study phase or had atrasentan interruption for longer than 2 weeks within last 24 weeks of substudy screening visit. * ALIGN OL extension participants with insufficient compliance defined as less than 70% * Plan to receive any investigational agent (other than atrasentan or zigakibart) or approved treatment for IgAN (other than a RAS inhibitor or SGLT2i). Other ETA receptor antagonists will not be allowed during substudy extension. * eGFR \< 25 mL/min/1.73m2 or evidence of rapidly decreasing eGFR, including unrecovered acute kidney injury or expected to require renal replacement therapy within 3 months * Ongoing treatment-related SAE or ongoing related severe AESI. * Clinical suspicion of rapidly progressive glomerulonephritis (RPGN). * Received a live vaccination within 12 weeks prior to first substudy treatment administration in the substudy or plan to have a live vaccination within 6 months after the last dose of substudy treatment. * BNP value of \> 200 pg/mL at substudy Screening. * Blood pressure \>150 mmHg systolic or \>95 mmHg diastolic at screening * Known history of heart failure or conditions relating to fluid overload. * Known history of clinically significant liver disease or transaminase or bilirubin values more than twice the upper limit of normal at substudy screening. * Type 1 diabetes; for type 2 diabetes, exclusion if HbA1c \>8%, evidence of diabetic changes on kidney biopsy performed for any reason, or history of diabetic microvascular/macrovascular disease * Hemoglobin below 9 g/dL at substudy screening or prior history of blood transfusion for anemia within 3 months of substudy Screening. * Newly diagnosed or history of malignancy. * Pregnancy, breast feeding, or intent to become pregnant during the substudy period and until 24 weeks after last dose for females. * Intent to father a child or donate sperm during the substudy period and until 24 weeks after last dose for males. * History of an alcohol or illicit drug-related disorder within the past 3 years. * History or evidence of any other clinically significant medical disorder, condition, disease, or laboratory finding that, in the discretion of the Investigator, constitutes an uncertain or unfavorable benefit-risk for continued long-term therapy with zigakibart. * Use of systemic corticosteroid therapy (including budesonide) or other immunosuppressive therapy. * Current severe infection at the time of first substudy treatment in the substudy or history of recurrent, severe, infections as determined by the Investigator. * Any confirmed or suspected immunosuppressive or immune-deficient state. * Newly diagnosed positive serology for hepatitis A virus IgM antibodies (anti-HAV IgM), hepatitis B surface antigen (HBsAg), detectable hepatitis B virus (HBV) DNA, hepatitis C virus (HCV) antibodies (participants who completed treatment and are persistently antibody positive but have documentation of negative HCV polymerase chain reaction \[PCR\] will be allowed), or antibodies to HIV-1 and/or HIV-2. * Prior exposure to any therapy directed against APRIL. * History of a previous severe allergic reaction with generalized urticaria, angioedema, or anaphylaxis. * Screening weight \150 kg