Efficacy and Safety Evaluation of Vemircopan in Adults with Proliferative Lupus Nephritis or Immunoglobulin A Nephropathy: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-504825-38-00
Protocol: ALXN2050-NEPH-201
Sponsor: Alexion Pharmaceuticals Inc.

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Diseases & Conditions

Lupus nephritis IgA nephropathy

Objectives

The primary objective of this study is to evaluate the efficacy of **ALXN2050** in reducing proteinuria in adult participants with Proliferative **Lupus Nephritis (LN)** or **Immunoglobulin A Nephropathy (IgAN)**. Proteinuria is a critical marker of kidney damage, and its reduction is clinically significant as it may indicate improved kidney function and a potential decrease in disease progression.

Secondary objectives include:

Evaluating the efficacy of ALXN2050 to improve measures of kidney function in participants with LN or IgAN.
Characterizing the pharmacokinetics (PK) and pharmacodynamics (PD) of ALXN2050 in these participants.
Assessing the safety and tolerability of ALXN2050 in the study population.
For the LN cohort, specifically evaluating the efficacy of ALXN2050 on kidney function measures.
For the IgAN cohort, specifically evaluating the efficacy of ALXN2050 on kidney function measures.

Participants

The clinical trial involves a total of **91 participants** diagnosed with either **Lupus Nephritis (LN)** or **Immunoglobulin A Nephropathy (IgAN)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults. Participants were selected based on specific clinical diagnoses confirmed by biopsy and the presence of proteinuria, as well as compliance with stable treatment regimens. The trial includes individuals with controlled and stable blood pressure, and those who are part of a vulnerable population. Lifestyle factors such as diet and physical activity were not specified in the available data. The selection criteria ensure that participants have a clinically active form of the disease and are receiving or require immunosuppression induction treatment. The trial aims to evaluate the efficacy of ALXN2050 in reducing proteinuria among these patients.

Plans and Procedures

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, dose-finding study designed to evaluate the efficacy and safety of ALXN2050 in adult participants with **Lupus Nephritis (LN)** or **Immunoglobulin A Nephropathy (IgAN)**. The primary objective is to assess the efficacy of ALXN2050 in reducing proteinuria in these conditions. The trial is expected to run from September 2022 to July 2028, with a maximum treatment period of 154 days for each participant. Participants will be randomly assigned to receive either ALXN2050, a film-coated tablet containing the active substance **vemircopan**, or placebo tablets, both administered orally.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed based on specific inclusion criteria, such as a clinical diagnosis of LN or IgAN, confirmed by biopsy, and the presence of proteinuria. Follow-up visits will occur throughout the treatment period to monitor the participants' response to the treatment, assess safety, and collect data on primary and secondary endpoints, including changes in proteinuria and renal function. The end-of-study visit will conclude the participant's involvement, with final assessments conducted to evaluate the overall outcomes of the treatment.

Participant involvement is expected to last up to 154 days, with conditions for early termination including adverse events, non-compliance with the study protocol, or withdrawal of consent. The study will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding of ALXN2050's potential benefits in treating LN and IgAN.

Treatment

The clinical trial involves the administration of **ALXN 2050**, an experimental medication formulated as a **film-coated tablet**. The active substance in ALXN 2050 is **vemircopan**, a chemical compound. The medication is administered orally, with a maximum daily dose of 360 mg. The treatment period extends up to 154 days. The trial aims to evaluate the efficacy of ALXN 2050 in reducing proteinuria in participants with **proliferative lupus nephritis** or **immunoglobulin A nephropathy**. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, the study includes the use of **ALXN2050 Placebo Tablets** as a comparator. These placebo tablets are designed to match the appearance of the ALXN 2050 film-coated tablets but do not contain the active substance vemircopan. The placebo is administered under the same conditions as the experimental medication to maintain the double-blind nature of the trial. The inclusion of a placebo group allows for a controlled assessment of the efficacy and safety of ALXN 2050 in the target population.

Efficacy

The efficacy of ALXN2050 in the treatment of **Proliferative Lupus Nephritis (LN)** and **Immunoglobulin A Nephropathy (IgAN)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage change in proteinuria, which will be measured to evaluate the drug's effectiveness in reducing protein levels in urine. Secondary endpoints include achieving more than 30% and 50% reduction in proteinuria, changes from baseline in estimated Glomerular Filtration Rate (eGFR), and pharmacokinetic/pharmacodynamic (PK/PD) assessments such as observed plasma concentrations of ALXN2050 and changes in plasma Bb concentration and serum alternative pathway (AP) activity. Safety will also be evaluated by monitoring the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs), as well as changes from baseline in laboratory assessments.

For the LN cohort specifically, additional secondary endpoints include meeting the criteria for complete renal response (CRR) and partial renal response. The efficacy parameters will be collected and analyzed at various timepoints throughout the trial, with the treatment period extending up to 154 days. The study is designed as a Phase 2, randomized, double-blind, placebo-controlled, dose-finding trial, ensuring rigorous assessment of the drug's efficacy and safety in the target population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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

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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: a. ≥ 50% interstitial fibrosis and tubular atrophy b. ≥ 50% glomerular sclerosis c. ≥ 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). For LN Cohort: • Participants who have initiated any of the following treatments for the current active LN flare: a. Cyclophosphamide ≤ 6 months prior to Screening b. CNIs ≤ 1 month prior to Screening c. A cumulative dose of intravenous (IV) methylprednisolone > 3 g d. Mycophenolate mofetil > 2 g/day (or equivalent) for ≥ 8 consecutive weeks prior to Screening e. 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. For 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. • Clinically active Henoch-Schonlein purpura (IgA vasculitis) requiring treatment • 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. • Body mass index ≥ 38 kg/m2 during Screening