Open-Label Phase II Study to Evaluate the Efficacy and Safety of IdeS in Anti-GBM Disease

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability of IdeS in patients with severe anti-glomerular basement membrane (anti-GBM) disease receiving standard of care consisting of pulse-methylprednisolone, oral prednisolone and intravenous cyclophosphamide combined with plasma exchange (PLEX).

Detailed Description
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This is an Open-Label Phase 2 Study to Evaluate the Efficacy and Safety of IdeS in anti-GBM disease (Goodpasture's disease, i.e. GP) with Adverse Renal Prognosis. The primary efficacy objective is to evaluate the efficacy of an IdeS based regimen to salvage independent renal function measured as no need for dialysis at 6 months after IdeS treatment. The primary safety objective of this study is to evaluate the safety and tolerability of IdeS in patients with severe anti-GBM disease on background of standard care consisting of pulse-methylprednisolone, oral prednisolone and intravenous cyclophosphamide (CYC) combined with plasma exchange (PLEX). The patients will be followed during 6 months according to the study visit plan.

Official Title
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Open-Label Phase II Study in Anti-GBM Disease (Goodpasture's Disease) With Adverse Renal Prognosis to Evaluate the Efficacy and Safety of IdeS - GOOD-IDES

Conditions
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Anti-Glomerular Basement Membrane Antibody Disease

Intervention / Treatment
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* Biological: Imlifidase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Anti-GBM antibodies detected by ELISA above a level that is considered toxic by the investigator using local laboratory. Patients double-positive for anti-GBM and anti-neutrophil cytoplasmic antibodies (ANCAs) may be entered in the trial, but only if their level of anti-GBM antibodies fulfil the criteria listed above. Estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m^2 (by modification of diet in renal disease (MDRD) equation) or if the patient is non-responsive to standard treatment, and has lost >15 ml/min/1.73 m^2 after start of treatment Haematuria on dipstick and/or urinary sediment Male or female patients aged at least 18 years; Female patients of childbearing potential may participate if highly effective contraception is used during the study, according to Clinical Trials Facilitation and Coordination Group (CTFG) guidance [18], see also section 4.9 (pregnancy test should be performed before inclusion). Willing and able to give written Informed Consent and to comply with the requirements of the study protocol; and Judged to be otherwise healthy by the Investigator, based on medical history, physical examination, and clinical laboratory assessments. Patients with clinical laboratory values that are outside of normal limits (other than those specified in the Exclusion Criteria) and/or with other abnormal clinical findings that are judged by the Investigator not to be of clinical significance, may be entered into the study. Exclusion Criteria: Anuria for more than 2 days (less than 200 ml during last 48 hours); Dialysis dependency for more than 5 days (maximum 3 sessions before signing informed consent); Ongoing moderate to severe pulmonary haemorrhage (or having ceased within the last two weeks), defined as requiring assisted ventilation, oxygen or blood transfusions. Pregnancy. Symptomatic congestive heart failure (NYHA class 2-4) and requiring prescription medication or clinically evident peripheral edema of cardiac origin; Myocardial infarction, unstable angina or stroke within 3 months prior to screening; Ongoing bacterial infection requiring antibiotic therapy or viral infection with Hepatitis B, C or HIV (up to 3 months old negative test results are accepted); or active tuberculosis as indicated by chest x-ray. Patients should not have received investigational drugs within 30 days prior to screening or within 4 half-lives (whichever is longer); and History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the subject at unacceptable risk for study participation.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Open-Label, Single Arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imlifidase<br>Imlifidase 0.25 mg/kg body weight intravenous infusion | Biological: Imlifidase<br>* One dose of 0.25 mg/kg body weight imlifidase on study day 1<br>* Other names: IdeS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Independent Renal Function at 6 Months | Number of patients without need for dialysis at 6 months. A patient with independent renal function is defined as a patient without need for dialysis. | 6 months after dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Independent Renal Function at 3 Months | Number of patients without need for dialysis at 3 months. A patient with independent renal function is defined as a patient without need for dialysis. | 3 months after dosing | 
| Renal Function at 3 and 6 Months | Estimated glomerular filtration rate (eGFR) is a measure of kidney function. eGFR was calculated based on p-creatinine according to the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is above 90 mL/min/1.73m^2. Reduced kidney function is characterised by a decreased eGFR value. | 3 and 6 months after imlifidase dosing | 
| Number of Patients With Renal Function Over Time Stratified by Ranges of eGFR | eGFR is a measure of kidney function. eGFR has been calculated based on p-creatinine according to the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is above 90 mL/min/1.73m^2. Reduced kidney function is characterised by a decreased eGFR value. Number of patients per 4 different eGFR categories (0-15, 15-30, 30-60, ≥60 mL/min/1.73m^2) are presented. A shift towards a higher category during the study indicates improved renal function over time. | Pre-imlifidase, 1, 3 and 6 months after imlifidase dosing | 
| Number of Patients With Anti-GBM Antibodies Above a Toxic Level Stratified by Number of Study Visits | Anti-GBM antibodies above a toxic level defined as >20 U/mL. The level of anti-GBM antibodies was measured centrally using the Phadia ELiA(TM) anti-GBM kit. The enzyme-linked immunoassay (ELiA) is a fluorescence enzyme immunoassay. | Predose up to 6 months after dosing | 
| Number of Patients With Haematuria (Blood in Urine) | Haematuria was assessed using urine dipstick. The result was presented as: Negative/Trace/+1/+2/+3/+4. In the analysis results being +2 or above are considered as relevant. Haematuria was an inclusion criterion. All 15 patients had haematuria when included in the study. | At 6 months after dosing | 
| Change in Proteinuria During the Study | Change in proteinuria measured as u-albumin/creatinine (g/mol) in morning void during the study . | Pre-imlifidase, 3 and 6 months after imlifidase dosing | 
| Number of PLEXs Needed Over Time | Number of PLEXs needed before anti-GBM antibodies are below toxic levels. PLEX was initiated at the discretion of the investigator throughout the study. | Pre-screening and up to Day 93 after imlifidase dosing | 
| Pharmacokinetics of Imlifidase (Cmax) | Maximum observed plasma concentration of IdeS following dosing (Cmax) | Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 | 
| Pharmacokinetics of Imlifidase (AUC) | Area under the plasma concentration versus time curve (AUC) | Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 | 
| Pharmacokinetics of Imlifidase (t1/2) | Half-life during distribution phase (Alpha-t1/2) Half-life during elimination phase (Beta-t1/2) The results refers to harmonic mean. | Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 | 
| Pharmacokinetics of Imlifidase (CL) | Clearance (CL) is a measure of the ability of the body to clear imlifidase from plasma | Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 | 
| Pharmacokinetics of Imlifidase (Vz) | Vz = Volume of distribution during the elimination phase | Pre-dose, 45min, 2h, 6h, 24h, Day3, Day 7, Day 10, and Day15 | 
| Pharmacodynamics (IgG Degradation Measured as Remaining Concentration of Intact and Single Cleaved IgG) | Imlifidase specifically cleaves all subclasses of human IgG rapidly and efficiently. The cleaving process involves two steps: (i) intact IgG to single cleaved IgG followed by (ii) single cleaved IgG to completely cleaved IgG (one F(ab')2- and one homodimeric Fc-fragment) The electroluminescence analysis method used measures the sum of intact and single cleaved IgG in serum. The efficacy of imlifidase is evaluated as remaining concentration of intact and single cleaved IgG in serum after treatment. | Pre-dose up to 6 months after imlifidase administration | 
| Anti-imlifidase Antibodies (ADA) | Determination of anti-imlifidase antibody concentration | Up to 6 months after dosing | 
| Renal Histology | Kidney biopsies were classified according to the histopathologic classification for antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis developed by Berden et al. 2010. This classification has previously been applied in a study of 123 anti-GBM disease patients (von Daalen et al 2018). Histopathologic class: Focal (≤50% normal glomeruli) Crescentic (≥50% glomeruli with cellular crescents) Mixed (<50% normal, <50%crescentic, <50% globally sclerotic glomeruli) Sclerotic (≥50% globally sclerotic glomeruli) In addition information on the histological activity and kidney outcome was provided. Focal class is associated with favourable kidney outcome, whereas sclerotic carries a poor outcome. Crescentic/mixed class could have an intermediate outcome between focal and sclerotic. Immunofluorescence performed at the local hospitals was also used to assess linear IgG deposits which is a hallmark of anti-GBM antibody disease. | Before administration of imlifidase (0-33 days) and after administration of imlifidase (3-6 days) |