Imlifidase Desensitization in Crossmatch-positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes)

Abstract

Background: Highly HLA sensitized patients have limited access to life-saving kidney transplantation because of a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney.

Methods: This open-label, single-arm, phase 2 trial conducted at 5 transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 h. Secondary endpoints included postimlifidase donor-specific antibody levels compared with predose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile.

Results: Of the transplanted patients, 89.5% demonstrated conversion of baseline positive crossmatch to negative within 24 h after imlifidase treatment. Donor-specific antibodies most often rebounded 3-14 d postimlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 mo. With this, 38.9% had early biopsy proven antibody-mediated rejection with onset 2-19 d posttransplantation. Serum IgG levels began to normalize after ~3-7 d posttransplantation. Antidrug antibody levels were consistent with previous studies. Seven adverse events in 6 patients were classified as possibly or probably related to treatment and were mild-moderate in severity.

Conclusions: Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median calculated panel-reactive antibody of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 mo.

Trial registration: ClinicalTrials.gov NCT02790437.

Graphical abstract

FIGURE 1.

Study design. DD, deceased donor; DSA, donor-specific antibody; IVIg, intravenous immune globulin; LD, living donor.

FIGURE 2.

Patient disposition.

FIGURE 3.

Dosing and crossmatch of patients receiving >1 dose of imlifidase. CDC, complement-dependent cytotoxicity; DD, deceased donor; LD, living donor.

FIGURE 4.

Pretransplant DSAs. DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 5.

Time postimlifidase dose to reach MFI <3000 for all individual DSAs of a patient. DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 6.

DSA levels over 6 mo. DSA, donor-specific antibody; MFI, mean fluorescence intensity.

FIGURE 7.

Median eGFR for patient with and without DGF. DGF, delayed graft function; eGFR, estimated glomerular filtration rate.