Study of the Safety and Efficacy of OMS721 in Patients With Immunoglobulin A (IgA) Nephropathy

This is a Phase 3, double-blind, randomized, placebo-controlled, study in patients aged 18 years and above with a biopsy-confirmed diagnosis of IgAN and with 24-hour UPE that is > 1 g/day. The purpose of this study is to evaluate the efficacy and safety of narsoplimab (OMS721) compared to placebo on proteinuria and whether narsoplimab has the ability to slow disease progression in primary IgAN patients. The primary objective of the study is to evaluate proteinuria reduction as assessed by 24-hour UPE at 36 weeks from baseline. The trial will continue beyond 36 weeks in a blinded fashion to provide confirmatory evidence of long-term efficacy based on the annualized slope of eGFR over 24 months. The trial will enroll approximately 450 patients with 225 patients per arm, all having biopsy-proven IgAN with eGFR≥30 mL/min/1.73m\^2 and 24 hour UPE >1g/day. The study duration for each patient is expected to last approximately 112 weeks.

• OMS721 (Biological): Biological: OMS721
• Vehicle (D5W or saline) (Other): 5% Dextrose in water or normal saline solution

Primary outcomes

• Percent Change in 24-hour UPE in g/Day Compared to Baseline [36 Weeks]: The Primary Endpoint of this Study is the Percent Change from Baseline in Log-transformed 24-hour UPE in g/Day at 36 Weeks in Patients with High Baseline Proteinuria (High-risk Proteinuria Group; 24-hour UPE ≥ 2 g/day.

Secondary outcomes

• Change in Annualized eGFR Compared to Baseline. [96 Weeks]: The Rate of Change in eGFR up to 96 Weeks from Baseline in Patients with High Baseline Proteinuria (High-risk Proteinuria Group; 24-hour UPE ≥ 2 g/Day)
• Change in Annualized eGFR Compared to Baseline in All Patients. [96 Weeks]: The Rate of Change in eGFR up to 96 Weeks from Baseline in the All-patients Population (24-hour UPE > 1 g/Day)
• Change in 24-hour UPE in g/Day Compared to Baseline in All Patients [36 Weeks]: Change From Baseline in Log-transformed 24-hour UPE at Week 36 in the All-patients Population. (24-hour UPE > 1 g/Day)
• Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks. [36 weeks and 48 weeks]: Change From Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 48 Weeks in Patients With ≥ 2 g/Day UPE at Baseline (High-risk Proteinuria Group)
• Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in Patients With >= 2 g/Day UPE at Baseline (High-risk Proteinuria Group). [36 weeks and 72 weeks]: Time-averaged Change from Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 72 Weeks in Patients with ≥ 2 g/Day UPE at Baseline (High-risk Proteinuria Group)
• Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks in All Patients [36 weeks and 48 weeks]: Time-averaged Change from Baseline in the Log-transformed 24-hour UPE Between 36 Weeks and 48 Weeks in the All-patients Population
• Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in All Patients [36 weeks and 72 weeks]: Time-averaged Change from Baseline in the Log-transformed 24-hour UPE between 36 Weeks and 72 Weeks in the All-patients Population
• Safety and Tolerability of Narsoplimab for the Treatment of IgAN as Assessed by AEs, Vital Signs, Clinical Laboratory Tests, and ECGs [Week 112]: As assessed by the incidence of adverse events through study completion (Week 112) in the patient group in the all-patients population. Clinically meaningful abnormalities in vital signs, clinical laboratory tests, and ECGs were collected as AEs.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age 18 years or older at the onset of Screening
* Biopsy confirmed diagnosis of IgAN within 8 years prior to Screening or Run-in Visit 1
* Documented history of proteinuria of > 1 g/day within 6 months prior to Screening or uPCR > 0.75 by spot urine at Screening
* Mean of two proteinuria measurements > 1 g/day at baseline
* Estimated glomerular filtration rate of ≥ 30 mL/min/1.73 m² at Screening and baseline

Exclusion Criteria:

* Treatment with immunosuppressants (e.g., azathioprine or cyclophosphamide), Chinese traditional medicine with immunosuppressive function, cytotoxic drugs, or eculizumab within 8 weeks prior to Screening, unless such treatment is given for indications other than IgA.
* Treatment with systemic corticosteroids within 8 weeks prior to Screening
* Uncontrolled BP, a systolic BP of > 150 mmHg and a diastolic BP of > 100 mmHg at rest despite the combination of two or more anti-hypertensives including ACE inhibitors, ARBs, or direct renin inhibitors
* Female patients who are pregnant, breast feeding, or planning to become pregnant up through 12 weeks after the last dose of study drug, including possible retreatments. Males who are planning to father children up through 12 weeks after the last dose of study drug, including possible retreatments
* Clinical or biological evidence of Type 1 diabetes mellitus (DM), or poorly controlled DM with hemoglobin A1c > 7.5 or with evidence of diabetic nephropathy on biopsy, systemic lupus erythematosus, IgA vasculitis (Henoch-Schonlein purpura), secondary IgAN, or other renal disease during Screening and Run-In
* Presence of significant morbidity or other major illness or disease that may confound the interpretation of the clinical trial results or may result in death within 2 years of Screening
* History of renal transplantation
* Have a known hypersensitivity to any constituent of the investigational product
* Rapidly progressive glomerulonephritis, defined as a fall in eGFR of > 30 mL/min/1.73 m\^2 within 24 weeks or > 15 mL/min/1.73 m\^2 within 12 weeks prior to Screening
* Significant abnormalities in clinical laboratory values
* History of human immunodeficiency virus (HIV), evidence of immune suppression, active hepatitis C virus (HCV) infection (patients with positive anti-HCV antibody but a non-detected HCV RNA PCR can enroll), hepatitis B virus (HBV) infection (patients with positive HBsAg are excluded; for patients with isolated positive anti-HBc antibody, HBV DNA test by PCR must be non-detectable to enroll).
* Diagnosis of a malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or other cancer from which the patient has been disease-free for ≥ 5 years
* Have received any other investigational drug or device or experimental procedures within 30 days of the Screening Visit (SV) or within 5 times the plasma half-life of the administered experimental drug, whichever is longer
* Initiation or change in dosing of sodium glucose co-transporter 2 inhibitors (SGLT2i) during Screening and Run-In Periods. However, a stable dose regimen established at least 8 weeks prior to screening is acceptable
* Treatment with Tarpeyo™ (budesonide) or other approved treatments for IgAN within 6 months prior to screening. Treatment with Tarpeyo is not allowed during Screening and Run-In Periods
* Treatment with Kerendia® (finerenone) within 6 months prior to screening. Treatment with Kerendia is not allowed during Screening and Run-In Periods
* Initiation of treatment with Filspari™ (sparsentan), a dual Endothelin Angiotensin Receptor Antagonist (dEARA) or similar medication within three months prior to screening. A stable dose initiated at minimum 3 months before screening is acceptable and will take the place of ACEi/ARB as background therapy

Participant flow

Outcome results

• Percent Change in 24-hour UPE in g/Day Compared to Baseline (Primary), Least squares mean, Percent Change: OMS721 -21.3 +/- 0.0672; Placebo -16.6 +/- 0.0680
• Change in Annualized eGFR Compared to Baseline. (Secondary), Mean, mL/min/1.73 m²/year: OMS721 (High Baseline Proteinuria Group) -8.3 +/- 0.9; Placebo (High Baseline Proteinuria Group) -7.9 +/- 0.9
• Change in Annualized eGFR Compared to Baseline in All Patients. (Secondary), Mean, mL/min/1.73 m²/year: OMS721 -6.4 +/- 0.7; Placebo -7.6 +/- 0.7
• Change in 24-hour UPE in g/Day Compared to Baseline in All Patients (Secondary), Mean, g/ 24hrs: OMS721 -14.2 +/- 0.7; Placebo -10.3 +/- 0.6
• Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks. (Secondary), Mean, g/24hr: OMS721 (High-risk Proteinuria Group) 4.1 +/- 0.5; Placebo (High-risk Proteinuria Group) 4.4 +/- 0.6
• Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in Patients With >= 2 g/Day UPE at Baseline (High-risk Proteinuria Group). (Secondary), Mean, g/24hr: OMS721 (High-risk Proteinuria Group) 11.6 +/- 0.7; Placebo (High-risk Proteinuria Group) 7.5 +/- 0.8
• Change in 24-hour UPE in g/Day Between 36 Weeks and 48 Weeks in All Patients (Secondary), Mean, g/24hr: OMS721 6.2 +/- 0.5; Placebo 3.5 +/- 0.6
• Change in 24-hour UPE in g/Day Between 36 Weeks and 72 Weeks in All Patients (Secondary), Mean, g/24hr: OMS721 10.9 +/- 0.7; Placebo 14.2 +/- 0.8
• Safety and Tolerability of Narsoplimab for the Treatment of IgAN as Assessed by AEs, Vital Signs, Clinical Laboratory Tests, and ECGs (Secondary), Count of participants, Participants: OMS721 181; Placebo 179

Adverse events

Time frame: The Adverse Event period of time was from the date of Consent to up to 112 weeks (includes Screen and Run-in) or end of study visit

Serious adverse events by term

Other adverse events by term

39 more sites not listed.

• Results publication: El Karoui K, Fervenza FC, De Vriese AS. Treatment of IgA Nephropathy: A Rapidly Evolving Field. J Am Soc Nephrol. 2024 Jan 1;35(1):103-116. doi: 10.1681/ASN.0000000000000242. Epub 2023 Sep 29. PMID 37772889
• Results publication: Reich HN, Floege J. How I Treat IgA Nephropathy. Clin J Am Soc Nephrol. 2022 Aug;17(8):1243-1246. doi: 10.2215/CJN.02710322. Epub 2022 Jun 8. No abstract available. PMID 35675911

• Study Protocol (PDF, 2023-06-19)
• Statistical Analysis Plan (PDF, 2023-09-14)