Study of ALXN2050 in Proliferative Lupus Nephritis (LN) and Immunoglobulin A Nephropathy (IgAN)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Efficacy and Safety of ALXN2050 in Adult Participants With Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN)

Conditions
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IgAN, Lupus Nephritis, Immunoglobulin A Nephropathy, LN

Intervention / Treatment
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* Drug: ALXN2050
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: ≥ 50% interstitial fibrosis and tubular atrophy ≥ 50% glomerular sclerosis ≥ 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: Cyclophosphamide ≤ 6 months prior to Screening CNIs ≤ 3 months prior to Screening A cumulative dose of intravenous (IV) methylprednisolone > 3 g Mycophenolate mofetil > 2 g/day (or equivalent) for ≥ 4 consecutive weeks prior to Screening Prednisone or prednisone equivalent ≥ 0.5 mg/kg/day for ≥ 4 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LN Cohort: ALXN2050 180 mg<br>Participants diagnosed with LN with an active flare will receive ALXN2050 in addition to standard-of-care background therapy. | Drug: ALXN2050<br>* Oral tablets<br>* Other names: ACH-0145228 (formerly);|
| Experimental: LN Cohort: ALXN2050 120 mg<br>Participants diagnosed with LN with an active flare will receive ALXN2050 in addition to standard-of-care background therapy. | Drug: ALXN2050<br>* Oral tablets<br>* Other names: ACH-0145228 (formerly);|
| Placebo Comparator: LN Cohort: Placebo<br>Participants diagnosed with LN with an active flare will receive matched placebo in addition to standard-of-care background therapy. | Drug: Placebo<br>* Oral tablets<br>|
| Experimental: IgAN Cohort: ALXN2050 180 mg<br>Participants diagnosed with IgAN will receive ALXN2050 in addition to standard-of-care background therapy. | Drug: ALXN2050<br>* Oral tablets<br>* Other names: ACH-0145228 (formerly);|
| Experimental: IgAN Cohort: ALXN2050 120 mg<br>Participants diagnosed with IgAN will receive ALXN2050 in addition to standard-of-care background therapy. | Drug: ALXN2050<br>* Oral tablets<br>* Other names: ACH-0145228 (formerly);|
| Placebo Comparator: IgAN Cohort: Placebo<br>Participants diagnosed with IgAN will receive matched placebo in addition to standard-of-care background therapy. | Drug: Placebo<br>* Oral tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Both Cohorts: Percentage Change In Proteinuria From Baseline To Week 26 | This will be based on 24-hour urine collection(s). | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Both Cohorts: Percentage Change In Proteinuria From Baseline To Week 50 | This will be based on 24-hour urine collection(s). | Baseline, Week 50 | 
| Both Cohorts: Participants Achieving > 30% And > 50% Reduction In Proteinuria At Week 26 And Week 50 Compared To Baseline | This will be based on 24-hour urine collection(s) at each time point. | Baseline, Week 26 and Week 50 | 
| Both Cohorts: Change From Baseline In Estimated Glomerular Filtration Rate (eGFR) At Week 26 And Week 50 |  | Baseline, Week 26 and Week 50 | 
| LN Cohort: Participants Meeting The Criteria For Complete Renal Response At Week 26 And Week 50 |  | Week 26 And Week 50 | 
| LN Cohort: Participants Meeting The Criteria For Partial Renal Response At Week 26 And Week 50 |  | Week 26 And Week 50 | 
| LN Cohort: Time To The First Occurrence Of Urine Protein To Creatinine Ratio (UPCR) ≤ 0.5 Gram/Gram (g/g) As Measured By Spot Urine Sample |  | Up to Week 50 | 
| LN Cohort: Participants Achieving Corticosteroid Taper To 7.5 mg/Day At Weeks 12, 26, And 50 |  | Week 12, Week 26, And Week 50 | 
| LN Cohort: Participants Experiencing A Renal Flare Through Week 50 |  | Baseline through Week 50 | 
| LN Cohort: Participants Experiencing An Extrarenal Systemic Lupus Erythematosus (SLE) Flare Through Week 50 |  | Baseline through Week 50 | 
| LN Cohort: Participants Meeting The Criteria For Treatment Failure Through Week 50 |  | Baseline through Week 50 | 
| LN Cohort: Absolute Values And Change From Baseline In Serum Albumin At Week 26 And Week 50 |  | Baseline, Week 26 and Week 50 | 
| IgAN Cohort: Participants Meeting The Criteria For Partial Remission At Week 26 And Week 50 |  | Week 26 and Week 50 | 
| Both Cohorts: Observed Plasma Concentrations Of ALXN2050 Over Time |  | Baseline through Week 50 | 
| Both Cohorts: Absolute Values And Change From Baseline In Plasma Concentration Of Bb Fragment Of Complement Factor B At Week 50 |  | Baseline, Week 50 | 
| Both Cohorts: Absolute Values And Change From Baseline In Serum Alternative Pathway Activity At Week 50 |  | Baseline, Week 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LN, ALXN2050, Complement Factor D, Complement Alternative Pathway, IgAN