Clinical trial NCT05097989: Study of ALXN2050 in Proliferative Lupus Nephritis (LN) or Immunoglobulin A Nephropathy (IgAN)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Lupus Nephritis
Immunoglobulin A Nephropathy
IgAN
LN
Keywords: ALXN2050
Complement Factor D
Complement Alternative Pathway
LN
IgAN
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-10-28
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Both Cohorts: Percentage Change In Proteinuria From Baseline To Week 26
timeFrame: Baseline, Week 26
Secondary outcomes:
measure: Both Cohorts: Percentage Change In Proteinuria From Baseline To Week 50
timeFrame: Baseline, Week 50
measure: Both Cohorts: Participants Achieving > 30% And > 50% Reduction In Proteinuria At Week 26 And Week 50 Compared To Baseline
timeFrame: Baseline, Week 26 and Week 50
measure: Both Cohorts: Change From Baseline In Estimated Glomerular Filtration Rate (eGFR) At Week 26 And Week 50
timeFrame: Baseline, Week 26 and Week 50
measure: LN Cohort: Participants Meeting The Criteria For Complete Renal Response At Week 26 And Week 50
timeFrame: Week 26 And Week 50
measure: LN Cohort: Participants Meeting The Criteria For Partial Renal Response At Week 26 And Week 50
timeFrame: Week 26 And Week 50
measure: 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
timeFrame: Up to Week 50
measure: LN Cohort: Participants Achieving Corticosteroid Taper To 7.5 mg/Day At Weeks 12, 26, And 50
timeFrame: Week 12, Week 26, And Week 50
measure: LN Cohort: Participants Experiencing A Renal Flare Through Week 50
timeFrame: Baseline through Week 50
measure: LN Cohort: Participants Experiencing An Extrarenal Systemic Lupus Erythematosus (SLE) Flare Through Week 50
timeFrame: Baseline through Week 50
measure: LN Cohort: Participants Meeting The Criteria For Treatment Failure Through Week 50
timeFrame: Baseline through Week 50
measure: LN Cohort: Absolute Values And Change From Baseline In Serum Albumin At Week 26 And Week 50
timeFrame: Baseline, Week 26 and Week 50
measure: IgAN Cohort: Participants Meeting The Criteria For Partial Remission At Week 26 And Week 50
timeFrame: Week 26 and Week 50
measure: Both Cohorts: Observed Plasma Concentrations Of ALXN2050 Over Time
timeFrame: Baseline through Week 50
measure: Both Cohorts: Absolute Values And Change From Baseline In Plasma Concentration Of Bb Fragment Of Complement Factor B At Week 50
timeFrame: Baseline, Week 50
measure: Both Cohorts: Absolute Values And Change From Baseline In Serum Alternative Pathway Activity At Week 50
timeFrame: Baseline, Week 50
Other outcomes:
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Study officials:
References: