ALXN2050-NEPH-201

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study of ALXN2050 (120 and 180 milligrams [mg]) in addition to background therapy consistent with the standard of care in adult participants (≥ 18 to ≤ 75 years of age) with either LN or IgAN. The study will consist of an up to 6-week Screening Period, a 26-week blinded Initial Evaluation Period, a 24-week blinded Extended Treatment Period, and an Open-label Extension (OLE) Period of up to 2 years.

Safety will be monitored throughout the study.

Key Inclusion Criteria:

Both Cohorts

• Participants on sodium-glucose cotransporter-2 (SGLT 2) inhibitors (eg, empagliflozin) must be on a stable dose for ≥ 3 months with no planned change in dose during the Blinded Treatment Periods (through Week 50).

LN Cohort

• Clinical diagnosis of SLE by 2019 American College of Rheumatology and European League Against Rheumatism criteria.

• Diagnosis of 2018 Revised International Society of Nephrology/Renal Pathology Society classification (active focal or diffuse proliferative LN Class III or IV) confirmed by biopsy obtained ≤ 6 months prior to Screening or during Screening Period. Participants may co-exhibit Class V disease. Participants with de novo or relapsing disease may be eligible.

• Clinically active LN at Screening requiring/receiving immunosuppression induction treatment in the opinion of the Investigator.

• Proteinuria with UPCR ≥ 1 g/g based on one 24 hour urine collection during the Screening Period.

IgAN Cohort

• Established diagnosis of primary IgAN based on kidney biopsy obtained any time prior to or during the Screening Period.

• Mean proteinuria ≥ 1 g/day on 2 complete and valid 24 hour urine collections during the Screening Period.

• For participants with a kidney biopsy performed > 1 year prior to Screening that was

Used for eligibility: Presence of hematuria as defined by a positive result for blood

on urine dipstick or ≥ 10 red blood cells (RBCs)/high power field (hpf) microscopy on

urine sediment (documented by the local laboratory) during Screening Period. Presence

of hematuria documented by the central laboratory may also be acceptable.

• Compliance with stable and optimal dose of RAS inhibitor treatment including maximum allowed or tolerated ACE inhibitor and/or ARB dose for ≥ 3 months prior to Screening with no expected change in dose during the Blinded Treatment Periods (through Week 50) (participants with established intolerance to RAS inhibitors may be included).

• Controlled and stable blood pressure (defined as < 140/90 millimeters of mercury [mmHg]) over the past 3 months prior to randomization.

Key Exclusion Criteria:

Both Cohorts

• eGFR ≤ 30 milliliters/minute/1.73 squared meters during Screening calculated by Chronic Kidney Disease Epidemiology Collaboration.

• For participants with eGFR < 45 mL/min/1.73 m2 at Screening, presence of any of the following in glomeruli on most recent kidney biopsy prior to or during the Screening

Period:

1. ≥ 50% interstitial fibrosis and tubular atrophy

2. ≥ 50% glomerular sclerosis

3. ≥ 50% active crescent formation

   • Concomitant significant renal disease other than LN or IgAN on the most recent biopsy prior to or during the Screening Period.

   • History of solid organ or bone marrow transplant, or planned transplant during the Blinded Extended Treatment Period (50 weeks).

   • Splenectomy or functional asplenia.

   • Known or suspected complement deficiency, unless attributable to underlying disease (that is, LN and IgAN).

   • Bone marrow insufficiency with absolute neutrophil count < 1.3 × 10^3/microliter; thrombocytopenia (platelet count < 50,000/cubic millimeter).

LN Cohort

• Participants who have initiated any of the following treatments for the current active

Ln flare:

1. Cyclophosphamide ≤ 6 months prior to Screening

2. CNIs ≤ 1 months prior to Screening

3. A cumulative dose of intravenous (IV) methylprednisolone > 3 g

4. Mycophenolate mofetil > 2 g/day (or equivalent) for ≥ 8 consecutive weeks prior to Screening

5. Prednisone or prednisone equivalent ≥ 0. 5 mg/kg/day for ≥ 8 consecutive weeks prior to Screening

• Uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 110 mmHg) on 2 or more measurements during the Screening Period.

• Prior history or clinically active SLE-related cerebritis, seizures, stroke, or stroke syndrome requiring treatment or clinically active pericarditis

• Inability to take or tolerate the standard of care background therapies

IgAN Cohort

• Diagnosis of rapid progressive glomerulonephritis as measured by eGFR loss ≥ 30% over a period of 3 months prior to or during the Screening Period.

• Secondary etiologies of IgAN.

• Prednisone or prednisone equivalent > 20 mg/day for > 14 consecutive days or any other systemic immunosuppression for the treatment of IgAN ≤ 6 months prior to Screening

• Blood pressure of ≥ 140/90 mmHg during the Screening Period confirmed on 2 measures > 30 minutes apart.