A Study to Investigate DSA Rebound in Patients Treated With Imlifidase Prior to Transplantation

An Open Label, Phase II Study to Investigate DSA Rebound in Patients With a Positive Crossmatch, Made Transplantable With Imlifidase

The purpose of this study is to assess whether imlifidase in combination with bortezomib, belatacept, rituximab and IVIg can suppress donor specific antibodies (DSA) and the occurrence of antibody-mediated rejection (AMR) in highly sensitized patients with chronic kidney disease with a positive crossmatch towards their living donor during a period of 3 months from transplantation.

Study Overview

• Status: Active, not recruiting
• Conditions: Kidney Transplantation in Highly Sensitized Patients
• Intervention / Treatment: Drug: Imlifidase

Detailed Description

Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG. The cleavage of IgG generates one F(ab')2- and one homodimeric Fc-fragment and efficiently neutralizes Fc-mediated activities of IgG. Clinical studies with imlifidase have demonstrated that the treatment enables transplantation in patients otherwise highly unlikely to be transplanted, by converting a positive crossmatch to a negative.

However, as with other desensitization methods, DSA tend to reappear within weeks after treatment and transplantation, which may cause AMR and increased risk of graft loss. In this study, treatment with imlifidase in combination with approved drugs that prevent or suppress DSA rebound by targeting antibody-producing plasma-cells and their B-cell precursors is suggested. These drugs include (i) bortezomib, a proteasome inhibitor which has activity against mature plasma cells, the source of DSA, (ii) belatacept, a fusion protein which is crucial in blocking T-cell co-stimulation and which is effective in reducing de novo DSA generation in humans, (iii) rituximab, an anti-CD20 monoclonal antibody that targets B-cells and which is an immunomodulatory agent, and (iv) intravenous immunoglobulin (IVIg) which is commonly used in desensitization regimens and for the treatment of AMR.

After being informed about the study and potential risks, all patients giving written informed consent will undergo a 2-week screening period to determine eligibility for study entry. Patients who meet the eligibility requirements will then start treatment with belatacept and bortezomib about 3 weeks prior to the imlifidase infusion and transplantation. Rituximab will be initiated 8 days after transplantation and IVIg 10 days after transplantation. Induction and maintenance immunosuppression will also be administered. The patients will be hospitalized for approximately 2 weeks following transplantation and after that 9 follow-up visits to the clinic will take place up to 6 months after transplantation.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Health Transplant Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed Informed Consent obtained before any trial-related procedures
• Male or female age 18 to 70 years at the time of screening

• Highly sensitized patients registered on the UNOS waiting list for kidney transplantation, with either of the following:

  • cPRA ≥ 99.9%
  • cPRA ≥ 98% and have been in kidney paired donation or kidney paired exchange programs for at least 1 year
• A positive crossmatch towards a living donor
• Willingness and ability to comply with the protocol

Exclusion Criteria:

• Previous treatment with imlifidase
• Previous high dose IVIg treatment (2 g/kg) within 28 days prior to imlifidase treatment
• Breast-feeding or pregnancy
• Women of child-bearing potential not willing or able to practice FDA-approved forms of contraception. Two medically acceptable methods of highly effective contraception must be used for the duration of the study (e.g. oral, transdermal, intravaginal, injectable or implantable contraceptive; intrauterine device; intrauterine hormone-releasing system; vasectomized partner; bilateral tubal occlusion; or double-barrier method). For a woman to be considered postmenopausal this ascertainment must be made according to medical records and clinical history and may be aided by measurement of elevated postmenopausal serum gonadotropin levels (FSH).
• ABO blood group incompatible transplantations (A2 and A2B kidneys will not be accepted for B recipients)
• Positive serology for HIV
• Clinical signs of HBV, HCV, CMV, or EBV infection
• EBV seronegative or with unknown EBV serostatus
• Positive SARS-CoV-2 tests at any time point from screening to transplantation
• Active tuberculosis
• Ongoing serious infections as judged by the investigator
• Severe other conditions requiring treatment and close monitoring e.g. cardiac failure ≥ grade 4 (New York Heart Association), unstable coronary disease or oxygen dependent respiratory disease
• A history of a proven hypercoagulable condition
• Present, or history of, thrombotic thrombocytopenic purpura (TTP) or known familial history of TTP
• Intake of investigational drugs (other than imlifidase) within 5 half-lives
• Contemporaneous participation in a medical device study
• Known allergy/sensitivity (except local reactions) to imlifidase or to any drug (or the excipients) specified in the protocol
• Known mental incapacity or language barriers precluding adequate understanding of the Informed Consent information and the trial activities
• Inability by the judgement of the investigator to participate in the trial for any other reason

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Imlifidase; Imlifidase is administered intravenously as one dose of 0.25 mg/kg over 15 minutes within the 24-hour period prior to transplantation. (A second dose may be given if the crossmatch test at 4 hours after the first dose remains positive.)	Drug: Imlifidase; Imlifidase is an immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that is highly specific for IgG.; Other Names: IdeS, HMED-IdeS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with DSA rebound	The recurrence of DSA may cause AMR and increased risk of graft loss. Rebound of DSA is defined as: If positive flow cytometry crossmatch test (FCXM) at screening is due to low titer, non-complement binding (C1q-negative) DSAs;Immuno-dominant DSA: a post-transplant MFI value that is ≥50% the pre-imlifidase value ORTotal DSAs: a post-transplant serum where ≥50% of the DSA prior to imlifidase have a MFI value ≥50% of the pre-transplant MFI value AND the sum MFI must be ≥50% of the pre-transplant value; If FCXM at screening is due to high titer, complement binding (C1q-positive) DSAs;Immuno-dominant DSA: a post-transplant MFI value at 1:16 dilution that is ≥8000 MFI ORTotal DSAs: a post-transplant 1:16 diluted serum where ≥50% of the DSA prior to imlifidase have an MFI value that is ≥50% of the pre-transplant MFI value AND the sum MFI must be ≥8000	Up to 3 months after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with kidney biopsy proven AMR	The standardized international Banff classification 2019 for assessment of renal allograft biopsies will be used to assess AMRs reported from the study based on for cause and protocol biopsies.	Up to 6 months after transplantation
Proportion of patient with DSA rebound	See description to primary outcome measure	Up to 6 months after transplantation
Proportion of patients with negative FCXM	Imlifidase is highly efficacious in converting a positive crossmatch to a negative	Up to 24 hours after imlifidase treatment
Levels of DSA	Analysis of DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' DSAs.	Within 4 hours before imlifidase until Day 181
Levels complement binding (C1q) DSA	Analysis of C1q DSAs before and after imlifidase will be done. The mean fluorescence intensity (MFI) will be presented for the individual patients' C1q DSAs.	Within 4 hours before imlifidase until Day 181
Graft survival	Graft survival will be summarized by end of trial.	6 months after transplantation
Patients survival	Patient survival will be summarized by end of trial.	6 months after transplantation
Safety as measured by adverse events (AEs)	Safety is assessed as type, frequency and intensity of adverse events (AEs)/Serious adverse events (SAEs) including clinically relevant changes in clinical laboratory tests, vital signs and ECG)	Up to 6 months after transplantation
Kidney function assessed by creatinine	P-creatinine is a measure of kidney function.	Up to 6 months after transplantation
Kidney function assessed by estimated glomerular filtration rate (eGFR)	Estimated glomerular filtration rate (eGFR) is a measure of kidney function. eGFR will be calculated as described by the modification of diet in renal disease (MDRD) equation. eGFR for a kidney with normal function is 90 mL/min/1.72m2. Kidney disease is characterised by a decreased eGFR. value.	Up to 6 months after transplantation
Kidney function assessed by protein/creatinine ratio in urine	The protein/creatinine ratio in urine is a measure of kidney function. Will be measured unless patients are anuric.	Up to 6 months after transplantation
Imlifidase pharmacokinetics (AUC)	AUC = Area under the imlifidase plasma concentration versus time curve	Within 4 hours before imlifidase dose until Day 15
Imlifidase pharmacokinetics (Cmax)	Cmax = Maximum observed plasma concentration of imlifidase following dosing	Within 4 hours before imlifidase dose until Day 15
Imlifidase pharmacokinetics (tmax)	tmax = Time point for maximum observed plasma concentration of imlifidase following dosing	Within 4 hours before imlifidase dose until Day 15
Imlifidase pharmacokinetics (t1/2)	t1/2 = Terminal half-life of imlifidase	Within 4 hours before imlifidase dose until Day 15
Imlifidase pharmacokinetics (CL)	CL = Clearance of imlifidase	Within 4 hours before imlifidase dose until Day 15
Imlifidase pharmacokinetics (Vz)	Vz = Apparent volume of distribution during terminal phase	Within 4 hours before imlifidase dose until Day 15
Pharmacodynamics	Concentration of IgG in patient serum will be measured. Scoring of IgG fragments will be done.	Within 4 hours before imlifidase dose until Day 10
Anti-drug antibodies (ADA) levels	Immunogenicity towards imlifidase will be assessed by the measurement of ADA levels in patient serum using a customized ImmunoCAP analysis.	Up to 6 months after imlifidase
Change in patient-reported life participation, as measured PROMIS-SF-8a	The PROMIS Social Health domain "Ability to participate in social roles & activities PROMIS-SF-8" will be used as a measure of the patients' health related quality of life.	At screening and Day 181

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2022
• Primary Completion (Estimated): March 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: September 9, 2021
• First Submitted That Met QC Criteria: September 9, 2021
• First Posted (Actual): September 20, 2021

Study Record Updates

• Last Update Posted (Estimated): December 1, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Kidney transplantation; Renal transplantation; Highly sensitized
• Other Study ID Numbers: 18-HMedIdeS-16

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