An Efficacy and Safety Study of Imlifidase in Treatment of Antibody-Mediated Rejection in Kidney Transplant Patients

A Randomized, Open-Label, Multi-Centre, Active Control, Efficacy and Safety Study of Imlifidase in Eliminating Donor Specific Anti-HLA Antibodies in the Treatment of Active Antibody-Mediated Rejection in Kidney Transplant Patients

The purpose of this study was to investigate how efficiently the study medication imlifidase reduces the amount of donor specific antibodies (DSA) in comparison with plasma exchange (PE) therapy, in patients who have had an active or chronic active antibody mediated rejection (AMR) after being kidney transplanted. The purpose was also to investigate and compare safety for these two treatments.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant Rejection
• Intervention / Treatment: Drug: Imlifidase; Other: Plasma Exchange

Detailed Description

Antibodies to human leukocyte antigens (HLAs) have a strong correlation with allograft injury and loss. Treatment with imlifidase, PE and immunoabsorption (IA) all aim to reduce antibody levels.

This study compared the reduction in DSA levels after treatment with imlifidase and PE in patients diagnosed with active or chronic active AMR (according to Banff 2017 or Banff 2019 criteria) having at least a 25% rise in serum creatinine compared with last measurement prior to the AMR. (Patients with delayed graft function and AMR within 10 days after kidney transplantation could be included regardless of serum creatinine level.) Eligible patients were randomized to either 1 dose of imlifidase (0.25 mg/kg) or 5-10 sessions of PEs (IA could replace PE at the discretion of the investigator).

All patients received pulse methylprednisolone Day 1 to Day 3, followed by a tapering schedule with prednisolone/prednisone. Patients randomised to imlifidase received their first dose of methylprednisolone before imlifidase was administered. The patients did also receive high dose intravenous immunoglobulin (IVIg) 3 days after imlifidase treatment or directly after the last PE. In addition a single dose of rituximab was given 5 days after completed IVIg infusion.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Sydney, Australia
    • Royal Prince Alfred Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
• Austria
  • Vienna, Austria, 1090
    • Universitätsklinik für Innere Medizin III, Klinische Abteilung für Nephrologie MUW
• France
  • Bordeaux, France, 33076
    • Hopital Pellegrin
  • Grenoble, France, 38043
    • CHU Grenoble Alpes - Néphrologie, dialyse et transplantation
  • Paris, France, 75475
    • Hôpital Saint-Louis. Service de Néphrologie et Transplantation
  • Paris, France, 75743
    • Hôpital Necker - Service de Néphrologie - Transplantation
• Germany
  • Berlin, Germany, 13353
    • Charité-Universitätsmedizin. Dept. of Nephrology and Medical Intensive Care
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10016
      • New York University Grossman School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed Informed Consent obtained before any study-related procedures
2. Willingness and ability to comply with the protocol
3. Male and/or female donor kidney recipients age ≥18 years at the time of screening
4. Presence of DSA(s)
5. Meet the Banff 2017 criteria for active or chronic active AMR
6. At least 25% rise in serum creatinine compared to last individual value taken prior to the AMR. Patients with delayed graft function and AMR within 10 days after transplant (confirmed by kidney biopsy) can be included regardless of serum creatinine level
7. Women of child-bearing potential willing or able to use at least one highly effective contraceptive method throughout the study. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly
8. Men willing to use double-barrier contraception from the first day of treatment until at least 2 months after the dose of imlifidase, if not abstinent

Exclusion Criteria:

1. Previous treatment with imlifidase
2. Previous high dose IVIg treatment (2 g/kg) within 28 days prior to inclusion
3. Lactating or pregnant females
4. Significantly abnormal general serum screening lab results judged inappropriate for inclusion in the study by the investigator
5. Intake of other investigational drugs within 5 half-lives (or similar) of the product prior to inclusion
6. Clinically relevant active infection(s) as judged by the investigator
7. Any condition that in the opinion of the investigator could increase the subject's risk by participating in the study such as severe immune deficiency and severe cardiac insufficiency [New York Heart Association (NYHA) Class IV] or severe uncontrolled heart disease
8. Known allergy/sensitivity to imlifidase, IVIg and/or rituximab and the respective excipients
9. Patient unable to tolerate treatment with plasmapheresis or immunoadsorption, as judged by the investigator
10. Unsuitable to participate in the study for any other reason as judged by the investigator
11. Positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection
12. Current diagnosis or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Imlifidase; Subjects randomized to imlifidase treatment received one intravenous dose of imlifidase, 0.25 mg/kg, administered over 15 minutes.	Drug: Imlifidase; Imlifidase is an immunoglobulin G (IgG) degrading enzyme of Streptococcus pyrogenes that cleaves all 4 human subclasses of IgG with strict specificity.; Other Names: HMED-IdeS, IdeS, IgG endopeptidase
Active Comparator: Plasma Exchange; Subjects randomized to plasma exchange (PE) treatment received 5-10 sessions of PE, as judged by the investigator. Immunoadsorption (IA) could replace PE, at the discretion of the investigator.	Other: Plasma Exchange; The subject's plasma is removed and discarded and the subject receives replacement donor plasma, albumin, or a combination of albumin and saline. IA may be used instead of PE to the discretion of the investigator. IA is achieved by passing a subject's plasma over columns that bind immunoglobulins and then the plasma is passed back to the subject.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Reduction in Donor Specific Antibodies (DSA) Level During the 5 Days Following the Start of Treatment	Maximum reduction (%) in the sum of DSA at any time point during the 5 days following the start of treatment. Only DSA with ≥1000 mean fluorescence intensity (MFI) at pre-treatment were included in the calculations. Clarification: The higher the maximum reduction percentage the lower the remaining DSA level.	Start of treatment until 5 days following start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in DSA Levels After Treatment	DSA levels were assessed at all visits throughout the study. The results are presented as reduction (%) from baseline. Clarification: The higher the reduction percentage the lower the remaining DSA level. Please observe that a negative reduction value represents an increase in DSA level from baseline.	Screening until Day 180
Estimated Glomerular Filtration Rate (eGFR) Levels	eGFR as calculated from p-creatinine is a measure of kidney function. eGFR was assessed at all visits throughout the study.	Screening until Day 180
Urine Albumine/Creatinine Ratio	The albumine/creatinine ratio in urine is a measure of kidney function.	Pre-dose until Day 180
Number of Patients With Graft Loss Within 180 Days of Treatment	Information on patients who experienced graft loss was collected throughout the study.	Screening until Day 180
Number of Patients With Signs or no Signs of Transplant Glomerulopathy at Day 180	Biopsies collected 180 days after treatment were analysed for signs of glomerulopathy.	Day 180
Number of Patients With Different Types of Kidney Histopathology Throughout the Trial	Kidney biopsies were assessed according to the Banff (2017) criteria at screening (baseline), Day 29, and Day 180. Abbreviations: AMR=Antibody mediated rejection, CMR=cell-mediated rejection	Screening, Day 29 and Day 180
Number of Patients With Resolved AMR as Assessed by Messenger Ribonucleic Acid (mRNA) Levels	Kidney biopsies were taken at screening, Day 29, and Day 180. Changes from baseline in mRNA levels were assessed as evidence of resolved AMR.	Screening, Day 29, and Day 180
Number of Administered Plasma Exchange (PE) and Immunoadsorption (IA) Sessions	Total number of administered PE and IA sessions to each treatment group are presented during the complete trial (Day 1 to Day 180) and for the time period: start of IVIg administration to Day 180.	Day 1 to Day 180
Total Serum Immunoglobulin G (IgG) Levels Until Administration of Intravenous Immunoglobulin (IVIg)	Total serum IgG levels over time following treatment until administration of IVIg. Please observe, IVIg was initiated on Day 4 (before 96 h measurement) for the imlifidase group.	Pre-dose until Day 6
Number of Patients With Intact IgG, Single-cleaved IgG (scIgG), F(ab')2 Fragments Following Treatment Until Administration of IVIg	Presence of IgG, scIgG, and F(ab')2 was analysed using sodium dodecyl-sulphate polyacrylamide gel electrophoresis (SDS-PAGE)/western blot. Of note, IVIg was administered on Day 4 (before 96 h measurement) to patients treated with imlifidase. Hence no analyses beyond this timepoint were performed for this group.	Start of treatment (Day 1) up to administration of IVIg on Day 4 (imlifidase group) and until administration of IVIg within Day 15 (PE group)
DSA Functionality Determined by C1q Analysis Pre- and Post-treatment	An MFI value above 6000 is indicative of complement fixation. Analysis of DSA functionality assessed as mean MFI levels was done before and after treatment.	Screening until Day 6
Pharmacokinetic (PK) Profile of Imlifidase: Cmax	Cmax = Maximum observed plasma concentration of imlifidase following dosing	Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: Tmax	Tmax = Time point for maximum observed plasma concentration of imlifidase following dosing	Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: t1/2	t1/2 = terminal half-life of imlifidase (refers to the time required for plasma concentration of a drug to decrease by 50%) Different mathematical models are available to describe how drugs are adsorbed, distributed, metabolised, and eliminated from the body. The time-concentration curve of imlifidase could be fitted to the so called 2-compartment model. This model divide the body into a central and an peripheral compartment. The central compartment consist of the plasma and tissues where the distribution is fast and the peripheral consists of tissues where the distribution of the drug is slower. As a result the elimination of imlifidase consists of an initial phase with a short half life (alpha-t1/2) and an elimination phase with a longer half-life (beta-t1/2).	Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: AUC	Area under the imlifidase plasma concentration vs time curve (AUC)	Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: CL	Clearance (CL) of imlifidase means the volume of blood cleared of imlifidase per unit of time.	Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
PK Profile of Imlifidase: Volume of Distribution (V)	Vss = volume of distribution associated with steady state VZ = volume of distribution associated with the elimination phase	Pre-dose, 30 min, 1 h, 2 h, 6 h, 24 h, 48 h, 72 h, 96 h, Day 6, Day 8, Day 1, and Day 15
Concentration of Anti-drug Antibodies (ADAs)	Samples were collected and analysed for presence of anti-imlifidase IgG throughout the study. Imlifidase is an IgG-degrading enzyme of Streptococcus pyogenes. Patients who have been exposed to Streptococcus prior to participating in this trial tested positive for ADA also before exposure to imlifidase.	Screening until Day 180

Collaborators and Investigators

• Sponsor: Hansa Biopharma AB
• Investigators: Study Director: Clinical Operations, Hansa Biopharma AB

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2019
• Primary Completion (Actual): May 28, 2022
• Study Completion (Actual): November 16, 2022

Study Registration Dates

• First Submitted: March 27, 2019
• First Submitted That Met QC Criteria: March 28, 2019
• First Posted (Actual): April 1, 2019

Study Record Updates

• Last Update Posted (Actual): February 28, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: 16-HMedIdeS-12; 2018-000022-66 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No