Efficacy and Safety of LNP023 Compared With Rituximab in Subjects With Idiopathic Membranous Nephropathy

Study Overview
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Brief Summary
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This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with membranous nephropathy (MN) who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria.

Detailed Description
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This is a randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with membranous nephropathy (MN) who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria. The screening period will last up to 12 weeks and the whole study will last up to 65 weeks. Approximately 52 subjects will be randomized to one of the two arms. Treatment with LNP023 or rituximab is open label. LNP023 arm have a 4-week period of initial dose treatment, followed by a 20-week period of full dose treatment to evaluate the effect of the different LNP023 doses on complement biomarkers. Efficacy will be evaluated at the end of the 24-week treatment period. The randomization ratio is 1:1; LNP023 : rituximab.

Official Title
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A Randomized, Open-label, Two Arm, Parallel Group, Proof-of-concept Clinical Trial to Investigate the Efficacy and Safety of LNP023 Compared With Rituximab in the Treatment of Subjects With Idiopathic Membranous Nephropathy

Conditions
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Glomerulonephritis, Membranous

Intervention / Treatment
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* Drug: LNP023
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female or male adult (≥18 years) subjects at screening visit with a diagnosis of idiopathic (primary) MN confirmed by renal biopsy within 36 months prior to screening. A renal biopsy may be taken at any time during the run-in period to confirm the diagnosis of MN and facilitate subject eligibility, if the most recent biopsy was performed greater than 36 months prior to the screening visit. Anti-PLA2R antibody titer of ≥ 60 RU/mL at screening visit. If sites opt to use a local laboratory, with prior agreement with sponsor, an anti-PLA2R titer performed within 4 weeks prior to screening visit can be used. Urine protein ≥ 3.5 g/24h at screening and baseline visits ≤50% reduction in both anti-PLA2R level and 24h urine protein between screening and baseline Estimated GFR (using the CKD-EPI formula) ≥ 30 mL/min per 1.73 m2 at screening Receiving stable dose at the maximum recommended dose according to local guidelines or maximum tolerated dose of ACEi and/or ARB and/or statins and/or diuretics for at least 8 weeks prior to Day 1 Vaccination against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae (in accordance with local guidelines) at least 28 days prior to Day 1 and no longer than 5 years prior to Day 1. Exclusion Criteria: Secondary causes of MN, e.g. systemic autoimmune diseases, solid or haematological malignancies, infections or chronic intake of drugs (e.g. gold salts, NSAIDs, penicillamines) Diagnostic renal biopsy showing evidence of crescent formation in glomeruli, suggestive of an alternative or additional diagnosis to primary idiopathic MN. Previous treatment with B-cell depleting or B-cell modifying agents such as, but not limited to rituximab, belimumab, daratumomab or bortezomib. Previous treatment with immunosuppressive agents such as cyclophosphamide, chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus or azathioprine within 90 days prior to Day 1. Low dose systemic corticosteroid therapy is permitted, though the subject should have been on stable dose equivalent to ≤10 mg prednisolone for at least 90 days prior to Day 1. Previous treatment with gemfibrozil or strong CYP2C8 inhibitors such as clopidogrel within 7 days prior to Day 1 Presence or suspicion (based on judgment of the investigator) of active infection within 30 days prior to Day 1, or history of severe recurrent bacterial infections Known contra-indications for the use of rituximab, including hypersensitivity to the active substance or to murine proteins, or to any of the excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections). Other contra-indications for the use of rituximab, including active, severe infection, patients in a severely immunocompromised state, severe heart failure (NYHA Class IV) or severe, uncontrolled cardiac disease.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: A randomized, open-label, two arm, parallel group, proof-of-concept, non-confirmatory study evaluating the efficacy and safety of LNP023 compared with rituximab in subjects with MN who are at high risk of disease progression defined on the basis of antibody anti-PLA2R titre and proteinuria. The screening period will last up to 12 weeks and the whole study will last up to 65 weeks. Approximately 52 subjects will be randomized to one of the two arms. Treatment with LNP023 or rituximab is open label. LNP023 arm have a 4-week period of initial dose treatment, followed by a 20-week period of full dose treatment to evaluate the effect of the different LNP023 doses on complement biomarkers. Efficacy will be evaluated at the end of the 24-week treatment period. The randomization ratio is 1:1; LNP023:rituximab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LNP023<br>LNP023 | Drug: LNP023<br>* Investigation of LNP023<br>|
| Active Comparator: Rituximab<br>Rituximab | Drug: Rituximab<br>* Comparison of rituximab dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio between baseline Urine Protein Creatinine Ratio and Urine Protein Creatinine Ratio at 24 weeks of treatment (from 24h urine collection) | To assess the efficacy of LNP023 compared with rituximab | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Meausrement of Plasma levels of Bb and sC5b-9 | Measurement of LNP023 systemic drug exposure and pharmacodynamics, mode-of-action markers and clinical efficacy | Week 24 | 
| Urine Protein Creatinine Ratio measured in first morning void | Urine Protein Creatinine Ratio (UPCR) measured in first morning void | Week 24 | 
| Proportion of subjects with a complete remission | LNP023 compared with rituximab on proteinuria remission and renal function, defined as level of proteinuria at 24 weeks, derived from 24 hour urine | Week 24 | 
| Proportion of subjects with a partial remission | LNP023 compared with rituximab on proteinuria remission and renal function defined as reduction of proteinuria from baseline at 24 weeks of treatment, derived from 24 hour urine collection | Week 24 | 
| Change in (eGFR) estimated Glomerular Filtration Rate from baseline to 24 weeks of treatment | LNP023 compared with rituximab on proteinuria remission and renal function by applying the Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation from baseline to 24 weeks of treatment | Baseline, Week 24 | 
| Pharmacokinetic parameter Tmax in plasma | Pharmacokinetics of LNP023 : Plasma concentration measured for time to maximum total concentration (Tmax) | Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) | 
| Pharmakinetic parameter Cmax in plasma | Pharmacokinetics of LNP023: Plasma concentration measured for (Cmax) maximum or peak concentration of the drug observed after its administration | Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) | 
| Pharmacokinetic parameter AUClast in plasma | Pharmacokinetics of LNP023: Plasma concentration measured for (AUClast) Area under the curve concentration calculation of AUC from time 0 to the last point | Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) | 
| Pharmacokinetic parameter AUCtau in plasma | Pharmacokinetics of LNP023 : Plasma concentration for (AUCtau) Area Under the Curve (plasma concentration-time curve for a dosing interval) | Day 29 and Day 113 (pre-dose and 0.25 hours, 0.5 hours, 1 hour 2 hours, 4 hours and 6 hours post dose) | 
| Pharmacokinetics in urine: renal plasma clearance derived from 24 hour urine sample | Pharmacokinetics of LNP023: Urine: renal plasma clearance derived from 24 hour urine sample | Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Idiopathic membranous nephropathy, MN