Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Hansa Biopharma AB, P.O. Box 785, 220 07 Lund, Sweden
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants
ATC code: L04AA41
Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)-degrading enzyme of Streptococcus pyogenes that cleaves the heavy chains of all human IgG subclasses but no other immunoglobulins. The cleavage of IgG leads to elimination of Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC). By cleaving all IgG, imlifidase reduces the level of DSA, thus enabling transplantation.
Clinical studies have demonstrated that IgG was cleaved within a few hours after administration of imlifidase 0.25 mg/kg. No early increase in plasma IgG due to reflux of uncleaved IgG from the extravascular compartment has been observed, indicating that imlifidase cleaves not only the plasma IgG but the entire IgG pool, including the extravascular IgG. The return of endogenous IgG starts 1-2 weeks after imlifidase administration and continues over the next weeks.
It should be noted that turbidimetry/nephelometry methods, commonly used at hospitals for total IgG measurements, do not discriminate between different IgG fragments generated after imlifidase treatment, and can therefore not be used to evaluate treatment effect.
Three open-label, single-arm, 6-months, clinical studies evaluated the dosing regimen, efficacy, and safety of imlifidase as pre-transplant treatment to reduce donor-specific IgG and enable highly sensitised transplant candidates to be eligible for kidney transplantation. 46 patients between 20 and 73 years of age were transplanted, all diagnosed with end-stage renal disease (ESRD) and on dialysis, 21 (46%) women and 25 (54%) men. All patients were sensitised, 41 (89%) were highly sensitised (cPRA ≥80%), 33 (72%) of whom had a cPRA ≥ 95%. All patients that were crossmatch-positive before treatment with imlifidase were converted to negative within 24 hours. PKPD modelling showed that at 2 hours after administration of 0.25 mg/kg imlifidase, a crossmatch test is likely to become negative in 96% of the patients, and after 6 hours at least 99.5% of the patients are likely to become crossmatch test negative. All 46 patients were alive at 6 months with a kidney graft survival of 93%. Kidney function was restored to the expected range for kidney-transplanted patients with 90% of the patients having an estimated glomerular filtration rate (eGFR) of >30 mL/min/1.73 m² at 6 months.
Study 03 evaluated safety and efficacy of imlifidase at different dosing regimens before kidney transplantation in patients with ESRD. Ten patients were treated with a single dose of 0.25 (n=5) or 0.5 (n=5) mg/kg imlifidase and transplanted. Seven patients were DSA-positive and 6 patients had a positive crossmatch before imlifidase treatment. DSA was reduced in all 7 patients and all positive crossmatches were converted to negative after treatment. All 10 patients were successfully transplanted and had a functioning kidney at 6 months. Eight of the 10 patients had an eGFR >30 mL/min/1.73 m². Patients received immunosuppressive treatment including corticosteroids, calcineurin inhibitor, mycophenolate mofetil, and IVIg. Three patients experienced AMR during the study, none leading to graft loss.
Study 04 evaluated efficacy and safety of imlifidase in highly HLA-sensitised patients. 17 patients were included and treated with a single dose of 0.24 mg/kg. 15 (88%) patients were DSA-positive and 14 (82%) patients had a positive crossmatch before imlifidase treatment. DSA was reduced to levels acceptable for transplantation in all patients, and all patients were transplanted within few hours after imlifidase treatment. 16 of the 17 patients had a functioning kidney at 6 months with 15 (94%) patients having an eGFR >30 mL/min/1.73 m². Two patients experienced AMR, none leading to graft loss. Patients received immunosuppressive treatment including corticosteroids, calcineurin inhibitor, mycophenolate mofetil, alemtuzumab, and IVIg.
Study 06 evaluated the efficacy and safety of imlifidase in removing DSAs and converting a positive crossmatch to negative in highly sensitised patients, thus, enabling transplantation. All patients included were on the kidney transplant waiting-list and had positive crossmatch to their available donor before study inclusion (including 2 patients with a confirmed positive T-cell CDC-crossmatch test). 18 patients received the full dose of 0.25 mg/kg imlifidase, 3 of whom received 2 doses 12-13 hours apart, which resulted in cleavage of IgG and conversion of a positive crossmatch to negative in all patients. 57% of the analysed patients were crossmatch-converted within 2 hours, and 82% within 6 hours. All patients were successfully transplanted and 16 (89%) had a functioning kidney at 6-months (including the 2 patients with a confirmed positive T-cell CDC-crossmatch test). 15 (94%) patients had an eGFR >30 mL/min/1.73 m². Patients received immunosuppressive treatment including corticosteroids, calcineurin inhibitor, mycophenolate mofetil, rituximab, IVIg and alemtuzumab or equine anti-thymocyte globulin. Seven patients experienced active AMR, and another patient had subclinical AMR, none leading to graft loss.
Three patients aged 65 years and older have received imlifidase before kidney transplantation in clinical studies. The safety and efficacy outcomes for these patients were consistent with the overall study population as assessed by patient and graft survival, renal function, and acute rejection.
The European Medicines Agency has deferred the obligation to submit the results of studies with imlifidase in one or more subsets of the paediatric population in renal transplantation (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The pharmacokinetics of imlifidase were comparable in healthy subjects and patients with ESRD. The exposure to imlifidase increased proportionally after a single intravenous 15-minute infusion of 0.12 to 0.50 mg/kg body weight.
The maximum concentration (Cmax) of imlifidase was observed at or soon after the end of the infusion, with a mean of 5.8 (4.2-8.9) µg/mL after a dose of 0.25 mg/kg. The elimination of imlifidase was characterised by an initial distribution phase with a mean half-life of 1.8 (0.6-3.6) hours and a slower elimination phase with a mean half-life of 89 (60-238) hours. The mean clearance (CL) was 1.8 (0.6-7.9) mL/h/kg and the distribution volume (Vz) was 0.20 (0.06-0.55) L/kg during the elimination phase.
Non-clinical data reveal no special hazard for humans based on repeat-dose toxicity studies in rabbits and dogs, and an embryo-fetal development study in rabbits. Due to the rapid and extensive development of anti-imlifidase antibodies and associated toxicity after repeated administrations, a study on fertility and early embryonic development has not been feasible. No toxicity to the reproductive organs was observed in repeat-dose toxicity studies but the potential effect of imlifidase on male and female reproductive organs has not been fully addressed. No studies on pre- or postnatal toxicity have been conducted. No genotoxicity studies were performed since the active substance is a protein and is unlikely to interact directly with DNA or other chromosomal material.
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