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.

Current Approaches to Desensitization in Solid Organ Transplantation

“…This endopeptidase rapidly cleaves all IgG into F(ab’) and Fc fragments to impair the effector function from all circulating IgG. In both phase 1 and 2 desensitization trials, this agent led to a precipitous drop in DSA within hours, and therefore is a valuable tool for deceased donor positive crossmatch transplantation to avoid hyperacute rejection ( 44 , 52 ). The main limitation is that this drug will likely need to be part of a combination therapy regimen because it only cleaves circulating antibody and antibody levels begin to have a brisk rebound within 3-7 days ( 44 , 52 ).…”

Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients

“…Among patients completing the original 6 months of posttransplant follow‐up in the Phase 2 studies, renal function was acceptable and relatively stable. Findings on surveillance biopsies were generally favorable, with little evidence of acute or chronic active AMR beyond the early initial period 13 . Although additional protocol biopsies are not available, the eGFR in most patients remains stable up to 3 years.…”

Imlifidase for the treatment of anti-HLA antibody-mediated processes in kidney transplantation

“…8,12 Most cases of rebound DSA responded favorably to antibody reduction therapies in the Highdes trial, including plasmapheresis, IVIG, rituximab, and bortezomib. 14 Given the existing experience in kidney transplantation, current and future clinical trials of imlifidase for transplantation will administer it in combination with other therapies to inhibit repopulation of antibodies. Moving forward, the strategy will be to time these therapies in a sequence that optimizes the efficacy of each agent and avoids interactions.…”

“…Similarly, in the Highdes trial, there were no serious infections reported by the investigators as related to imlifidase and only one non-serious infection that was considered probably related (urinary tract infection). 14 There were seven treatment-emergent adverse events considered possibly or probably related to treatment in the Highdes trial. 14 These included two infusion-related reactions, one of which was considered related to the treatment where the infusion was discontinued.…”