Study on Efficacy and Safety of LNP023 in C3 Glomerulopathy Patients Transplanted and Not Transplanted

Study Overview
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Brief Summary
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The study is an open-label, two cohort non-randomized study evaluating the efficacy, safety, and pharmacokinetics of LNP023 in patients with C3G (Cohort A) and patients who have undergone kidney transplant and have C3G recurrence (Cohort B).

Official Title
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An Open-label, Non-randomized Study on Efficacy, Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of LNP023 in Two Patient Populations With C3 Glomerulopathy

Conditions
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Glomerulonephritis

Intervention / Treatment
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* Drug: LNP023


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Cohort A and B: Written informed consent must be obtained before any assessment is performed Male and female patients between the ages of 18 to 65 (inclusive) at screening C3G patients wit proteinuria Able to communicate well with the investigator, to understand and comply with the requirements of the study At screening and baseline visits, patients must weigh at least 35 kg Supine vital signs should be within the following ranges : oral body temperature between 35.0-37.5 °C systolic blood pressure, 80-170 mm Hg diastolic blood pressure, 50-105 mm Hg pulse rate, 45 - 100 bpm . Inclusion Criteria for Cohort A: Estimated GFR (using the CKD-EPI formula) or measured GFR ≥30 mL/min per 1.73 m2 for patients on a maximum recommended or maximum tolerated dose of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) UPCR ≥ 100 mg/mmol (equivalent to ≥ 1 g/24h total urinary protein excretion) Prior to entry, all patients must have been on supportive care including a maximally tolerated dose of ACEi or ARB for at least 30 days. Inclusion Criteria for Cohort B: No histological/laboratory/clinical signs of allorejection If applicable, induction treatment after allotransplantation needs to be completed >30 days before inclusion. Transplantation of a kidney allograft >90 days before inclusion Patients need to be on a stable dose of immunsuppressive regimen prior to inclusion. Any approved treatments are allowed for this purpose. Exclusion Criteria for Cohort A and B: Use of other investigational drugs at the time of enrollment, or within 5 half-lives of randomization, or within 30 days, whichever is longer; or longer if required by local regulations A history of clinically significant ECG abnormalities, Known family history or known presence of long QT syndrome or Torsades de Pointes Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test. Women of child bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug. History of immunodeficiency diseases, or a positive HIV test result. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). Patients who cannot receive vaccinations against N. meningitidis, S. pneumoniae, or H. influenzae

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: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: The study is an open-label, two cohort non-randomized study evaluating the efficacy, safety, and pharmacokinetics of LNP023 in patients with C3G (Cohort A) and patients who have undergone kidney transplant and have C3G recurrence (Cohort B).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A - no kidney transplant<br>C3G patients who have not received a kidney transplant and have reduced C3 blood levels. | Drug: LNP023<br>* Increasing doses of LNP023 up to 200 mg.<br>|
| Experimental: Cohort B - kidney transplant<br>C3G patients who have received a kidney transplant and have C3G recurrence. | Drug: LNP023<br>* Increasing doses of LNP023 up to 200 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) | Change in proteinuria assessed by ratio to baseline of UPCR derived from 24h urine collection | Week 12 | 
| Cohort B: Change From Baseline in C3 Deposit | Histopathological changes in kidney biopsies as assessed by change from baseline in C3 Deposit Score (based on immunofluorescence microscopy) | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urine Protein Creatinine Concentration Ratio (UPCR) | Ratio to baseline UPCR derived from 24 hour urine collection | Week 12: Day 84 | 
| Change From Baseline in Urine Protein (UP) Excretion | Ratio to baseline UP excretion derived from 24 hour urine collection | Week 12: Day 84 | 
| Change From Baseline in Urine Albumin Creatinine Concentration Ratio (UACR) Excretion | Ratio to baseline UACR excretion derived from 24 hour urine collection | Week 12: Day 84 | 
| Change From Baseline Change in Urinary Albumin (UA) Excretion | Ratio to baseline UA excretion derived from 24 hour urine collection | Week 12: Day 84 | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Effect of LNP023 on estimated glomerular filtration rate (eGFR) | Day 84 | 
| Change From Baseline in Serum Creatinine | The effect of LNP023 on renal function - serum creatinine | Week 12: Day 84 | 
| Change From Baseline in Creatinine Clearance | The effect of LNP023 on renal function - creatinine clearance | Week 12: Day 84 | 
| Number of Patients With Hematuria | The effect of LNP023 on renal function - hematuria | Week 12: Day 84 | 
| Change From Baseline in Urine Protein to Creatinine Concentration Ratio (UPCR) First Morning Void | Ratio to baseline of UPCR reduction derived from total cumulative urinary excretion first morning void | Week 9: Day 64 | 
| Change From Baseline in Urine Albumin to Creatinine Concentration Ratio (UACR) First Morning Void | UACR reduction derived from total cumulative urinary excretion first morning void | Week 9: Day 64 | 
| Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUClast (AUC) | Plasma: Non-compartmental parameter analysis related to total drug for the area under the plasma-concentration-time curve calculated from time | Weeks 1, 2, 3, 4 | 
| Pharmacokinetics of LNP023 Area Under the Plasma-concentration-time Curve AUCtau (AUC) | Plasma: Non-compartmental parameter analysis related to total drug for the area under the plasma-concentration-time curve calculated to the end of the dosing interval (ngxh/mL) | Weeks 1, 2, 3, 4 | 
| Observed Maximum Concentration After Drug Administration (Cmax) | Plasma: Non-compartmental parameter analysis related to total drug, including but not limited to Cmax after the first dose. | Weeks 1, 2, 3, 4 | 
| Observed Mimum Concentration After Drug Administration (Ctrough) | Plasma: Non-compartmental parameter analysis related to total drug, including but not limited to Ctrough (Cmin) after the first dose. | Weeks 1, 2, 3, 4 | 
| Time to Reach the Maximum Plasma Concentration (Tmax) | Plasma: Non-compartmental parameter analysis related to total drug, including but not limited to Tmax after the first dose. | Weeks 1, 2, 3, 4 | 
| Summary of Change From Baseline Complement C3 Biomarker in Serum | To assess the effect of LNP023 on alternative complement pathway hyperactivity | Weeks 1, 2, 3, 4, 12 | 
| Ratio to Baseline Summary of Plasma Bb in Blood and Urine | To assess the relationship between LNP023 dose and pharmacodynamic biomarker levels of blood Bb in blood and urine | Week 1, 2, 3, 4 and 12 |