FormalPara Imlifidase (Idefirix™): Key Points

A cysteine protease derived from the IgG-degrading enzyme of S. pyogenes is being developed by Hansa Biopharma AB for treatment of transplant rejection and rare IgG-mediated autoimmune conditions

Received conditional approval on 26 August 2020 in the EU

Approved for use in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor

1 Introduction

Chronic kidney disease (CKD) is a long-term, irreversible and progressive disease, and kidney transplantation is considered the treatment of choice in end-stage renal disease (ESRD) [1]. Previous exposure to human leukocyte antigen (HLA) [e.g. because of pregnancy, blood transfusion, organ transplant] causes sensitization, where patients carry antibodies to HLA; high levels of anti-HLA antibodies in highly sensitized patients is a major cause of antibody-mediated rejection (AMR) and poor graft survival [2]. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are the main pathways involved in AMR.

HLA sensitized patients express multiple alloantibodies that often result in crossmatch positivity due to the presence of donor-specific antibodies (DSAs) [3]. Because of the increased risk of AMR in highly sensitized patients, rates of transplantation in this patient population remain low; these patients remain on long-term dialysis, an option associated with complications, increased morbidity and mortality, poor quality of life and a high cost [1]. Current protocols are often associated with incomplete removal of DSAs, rebound antibody production, and an increased risk of acute and chronic AMR; these are the main causes of early graft loss and return to dialysis [1]. Therefore, an unmet medical need exists to desensitize highly sensitized patients, and convert a positive crossmatch into a negative one to allow kidney transplantation.

figure a

Key milestones in the development of imlifidase, focusing on its use in desensitization treatment of highly sensitized adult kidney transplant patients. GBM glomerular basement membrane, GBS Guillain–Barre syndrome, IND Investigational New Drug, MAA Marketing Authorization Application, US FDA Food and Drug Administration

Imlifidase (IdefirixTM) is a cysteine protease derived from the immunoglobulin G (IgG)-degrading enzyme of Streptococcus (S.) pyogenes being developed by Hansa Biopharma AB (known as Hansa Medical AB prior to December 2018) for transplant rejection and rare IgG-mediated autoimmune conditions [4]. Based on positive results from four phase II trials, imlifidase received conditional approval in the EU on 26 August 2020 for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor [4, 5]. The use of imlifidase should be reserved for patients unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized patients [5]. Imlifidase is available as a powder for concentrate for solution for infusion (11 mg). The recommended dosage is 0.25 mg/kg administered as a single dose over 15 min preferably within 24 h of transplantation; although one dose is adequate for crossmatch conversion in the majority of patients, a second dose can be administered within 24 h after the first dose if needed. After imlifidase treatment, confirmation of crossmatch conversion from positive to negative should be performed before transplantation. Imlifidase is contraindicated in patients with an ongoing serious infection or thrombotic thrombocytopenic purpura (due to the risk of developing serum sickness) [5].

Imlifidase has orphan drug designation for anti-glomerular basement membrane (GBM) disease in the EU and the USA, Guillain–Barre syndrome (GBS) in the USA, and the prevention of antibody-mediated organ rejection in solid organ transplant patients in the USA, and for the prevention of graft rejection following solid organ transplantation in the EU. Imlifidase is currently undergoing clinical evaluation for the prevention of kidney transplant rejection in the USA, Australia, France and Austria, and clinical development is underway for anti-GBM disease, and for GBS in France, the UK and the Netherlands. Clinical evaluation of imlifidase for rheumatoid arthritis, streptococcal infections and thrombotic thrombocytopenic purpura has been discontinued.

1.1 Company Agreements

In July 2020, Hansa Biopharma AB entered into an exclusive licensing agreement with Sarepta Therapeutics Inc., to develop and promote imlifidase as a pre-treatment to enable Sarepta’s gene therapy treatment in patients with Duchenne muscular dystrophy and limb-girdle muscular dystrophy with pre-existing neutralizing antibodies to adeno-associated virus (AAV), the technology for Sarepta’s gene therapy products. Under the terms of the agreement, Hansa is entitled to an upfront payment, is eligible to receive development, regulatory and sales milestone payments, as well as royalties on any gene therapy sales enabled through pre-treatment with imlifidase in patients with neutralizing antibodies [6]. In February 2015, Hansa Medical AB initiated a co-operation with Cedars-Sinai Medical Center’s Comprehensive Transplant Center and a US transplantation expert, to assist in the development of imlifidase in transplantation [7].

1.2 Patent Information

In July 2016, Hansa Medical AB filed for a patent protection for combination of imlifidase with approved anti-cancer therapies [8]. In February 2015, Hansa announced that it was developing and submitting a patent application for a second generation imlifidase molecule that allows repeated dosage, and which could potentially include chronic autoimmune disease as another therapeutic indication [9]. In March 2012, Hansa was granted a US patent (patent number 8 133 483) and a European patent (1 901 773), covering the medical use of imlifidase for the prevention and treatment of IgG-mediated indications, including transplant rejection and autoimmune diseases [10].

2 Scientific Summary

2.1 Pharmacodynamics

Imlifidase is a streptococcal protease with a unique degree of specificity for IgG (its only substrate) and cleaves IgG in two steps; the first reaction is cleavage of one of the two heavy chains to generate a single cleaved IgG molecule, followed by a second reaction to generate one F(ab’)2 and one Fc fragment; this results in elimination of Fc-dependent effector functions including CDC and ADCC [11]. The cleavage of all IgG by imlifidase reduces the levels of DSAs, and enables transplantation [5].

In vitro, imlifidase demonstrated dose-dependent inhibition of anti-HLA antibody-mediated natural killer cell activation and antibody-dependent cell-mediated cytotoxicity; the maximum therapeutic concentration of imlifidase (10 μg/ml) was associated with the greatest inhibition [2]. In the sera of treated patients, imlifidase treatment significantly decreased the levels of anti-HLA antibodies and significantly inhibited the capacity of anti-HLA antibody-mediated natural killer cell and natural killer T cell activation, post treatment.

In allosensitized recipient mice, enzymatic inactivation of DSAs using imlifidase in combination with endoglycosidase of S. pyogenes improved the survival of donor bone marrow cells and in combination with other desensitization strategies, allowed allogenic bone marrow engraftment [12].

In a mouse model of anti-GBM disease (injected with subnephritogenic doses of rabbit anti-mouse GBM, followed a week later by injection of monoclonal mouse anti-rabbit IgG antibodies), imlifidase degraded IgG bound to the GBM and prevented renal damage [13]. Imlifidase effectively removed the Fc fragments of the rabbit IgG and significantly reduced the deposition of the complement components C3 and C1q; the latter effect diminished the recruitment of leukocytes to the glomeruli. Imlifidase also prevented albuminuria in these animal models [13].

Imlifidase administration was associated with a decrease in anti-AAV antibodies and enabled efficient liver gene transfer in mice passively immunized with intravenous (IV) IgG, and enhanced liver transduction in nonhuman primates when administered before AAV vector infusion (including vector re-administration setting) [14]. In vitro, imlifidase reduced levels of anti-AAV antibodies in human plasma samples (including plasma from prospective gene therapy trial participants).

In a randomized, double-blind, dose-escalation phase I trial (NCT01802697; study 01), imlifidase (0.01–0.24 mg/kg) administered to healthy male volunteers cleaved the plasma IgG pool into single cleaved IgG within minutes of dosing; low plateau levels of IgG < 5% of the original signal were detected in blood 2–6 h after imlifidase administration and remained low until newly synthesized intact IgG appeared in plasma after 1–2 weeks [11]. The phagocytic capacity of IgG/IgG fragments was significantly reduced 2 h after imlifidase (0.24 mg/kg) administration, and remained low for at least 1 week [11].

In a single-centre, open-label, ascending-dose (0.12 mg/kg × 2, 0.25 mg/kg × 1 or 0.25 mg/kg × 2) phase II trial (NCT02224820; study 02) in highly sensitized patients with CKD (n = 8), imlifidase demonstrated IgG degradation in all patients, with < 1% of plasma IgG remaining within 48 h and remaining low for up to 1 week [15]. Imlifidase reduced mean fluorescence intensity (MFI) values of HLA class I and II in all patients and eliminated C1q binding to anti-HLA antibodies; IgG-type B cell receptors on CD19+ memory B cells were also cleaved by imlifidase [15].

Given that imlifidase specifically cleaves IgG, medicinal products based on human or rabbit IgG [e.g. rituximab, IV immunoglobulin (IVIg)] may be inactivated if coadministered with imlifidase; appropriate time intervals between administration of imlifidase and these products should be applied [5]. IVIg may contain antibodies against imlifidase; therefore, its half-life of 3–4 weeks should be considered before administration of imlifidase in these patients [5].

2.2 Pharmacokinetics

The pharmacokinetic properties of imlifidase were comparable in healthy subjects and patients with ESRD [5]. Following single 15-min IV doses of imlifidase (0.12–0.50 mg/kg), exposure increased in a dose-proportional manner. Imlifidase maximum plasma concentrations were observed at or soon after the end of infusion [5]. Elimination was characterized by an initial distribution phase with a mean half-life of 1.8 h and a slower elimination phase with a mean half-life of 89 h. During the elimination phase, the volume of distribution was 0.2 L/kg and the mean clearance was 1.8 mL/h/kg [5].

Table 2 Features and properties of imlifidase
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2.3 Therapeutic Trials

Imlifidase enabled kidney transplantation in all 10 patients in the Swedish phase II study (NCT02475551; study 03) and all 17 patients in the US phase I/II study (NCT02426684; study 04) [5], when given before kidney transplantation in highly sensitized patients to reduce or eliminate DSAs and to allow transplantation from an incompatible donor without antibody rejection [16]. DSAs were reduced in all patients who were DSA-positive at baseline in both studies, and all positive crossmatches were converted to negative after imlifidase treatment in study 03 [5]. At 6 months, 100 and 94% of transplanted patients had a functioning kidney in studies 03 and 04 and kidney function was restored to the expected range for kidney-transplanted patients with 80 and 94% of patients having an estimated glomerular filtration rate (eGFR) of > 30 mL/min/1.73 m2 [5]. Three and two patients had AMR in the Swedish and US studies, but did not lead to graft loss in any of these patients.

Studies 03 and 04 were two independently-performed open-label transplantation studies to evaluate the efficacy and safety of imlifidase given before kidney transplantation in highly sensitized patients to reduce or eliminate DSAs and to allow transplantation from an incompatible donor without early antibody rejection, conducted in Sweden [a single dose of 0.25 (n = 5) or 0.5 (n = 5) mg/kg] and in the USA (a single dose of 0.24 mg/kg; n = 17) [16]. Eligible patients (aged 18–70 years) were undergoing dialysis for ESRD and were on their regional waiting list for a transplant; all patients had extensive sensitization [median calculated panel-reactive antibody (cPRA) level of 95%] and had a clinically significant sensitization history. Patients received prophylactic antibiotic agents and continued to receive standard immunosuppression; IVIg and rituximab were also administered after transplantation in the US study [16].

Imlifidase enabled all highly sensitized patients (n = 18) to undergo kidney transplantation resulting in good kidney function and graft survival in a multinational, single-arm, 6-month, open-label phase II trial (NCT02790437; study 06) [17, 18]. Following imlifidase infusion, a positive crossmatch was converted to a negative one in 17 patients (primary endpoint) and one patient was borderline; 25% of patients had biopsy proven AMR (effectively treated using standard of care therapy and mostly attributable to DSA rebound), and there were two graft losses due to primary nonfunction. Patient survival at the end of the study was 100% and the median eGFR was 50 mL/min/1.73 m2 [18].

Study 06 enrolled patients who exhibited DSAs with a positive crossmatch test to their available live deceased donors, and had previously undergone desensitization unsuccessfully or in whom effective desensitization would have been highly unlikely [18]. Imlifidase was administered at a dose of 0.25 mg/kg on day 0, and a second dose could be given within 2 days of the first infusion if a negative crossmatch was not achieved [1]. At baseline, all patients had a positive crossmatch to their donor and half had an immunodominant DSA >12,000 MFI; the median cPRA was 99.6% and the mean MFI was > 2000 [18].

Results from an analysis of transplanted patients (n = 46) from studies 03, 04 and 06 indicate that after 6 months, 93% of these patients had a functioning graft and kidney assessments demonstrated that 87% of patients with data (n = 32) had a well-functioning kidney; 92% of patients in the crossmatch positive group (n = 39) had a functioning graft at 6 months, with a well-functioning kidney in 88% of crossmatch positive patients with data (n = 26) [19]. Up to 2 years after transplantation, there were no additional graft losses and the overall graft survival was 80% (24 of 30 patients); the 2-year death censored graft survival was 89% (24 of 27 patients).

Rebound DSAs may cause AMR, with early AMR requiring intervention being more likely amongst patients who had very high levels of DSAs prior to transplantation [5]. In clinical studies, most patients had DSA rebound that peaked 7–21 days after imlifidase treatment, with 30% of patients experiencing an AMR and all of whom were successfully treated with standard of care therapy [5].

Table 3 Key clinical trials of imlifidase
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2.4 Adverse Events

Across studies 02, 03, 04 and 06 (n = 54; 44 and 10 patients receiving 0.25 and 0.5 mg/kg of imlifidase), all patients with CKD treated with imlifidase experienced at least one treatment-emergent adverse event (TEAE) and treatment discontinuation because of a TEAE occurred in 4% of patients; 35% of patients experienced a TEAE related to imlifidase treatment [20]. Among the TEAEs considered treatment related, the most common were infections (16.7%), [including pneumonia, urinary tract infection (6% each) and sepsis (4%)], infusion site pain, infusion related reactions, increased alanine aminotransferase, increased aspartate aminotransferase, myalgia, headache and flushing (4% each) [5].

Although laboratory abnormalities were reported in a number of patients with CKD across the four clinical studies, the overall pattern was consistent with that expected in this patient population and did no fulfil the criteria for Hy’s law [20].

Severe treatment-emergent serious adverse events (SAEs) occurred in 37% of patients, and were related to imlifidase treatment in 11% of patients [20]. The most common treatment-emergent SAEs considered treatment-related in clinical studies were pneumonia (6%) and sepsis (4%) [5]. SAEs (including infections), including those considered related to treatment, were reported at a higher frequency in patients receiving a total imlifidase dosage of 0.5 mg/kg than those receiving 0.25 mg/kg [20]. There were no fatal adverse events and no deaths reported in studies 02, 03, 04 or 06 to date.

2.5 Ongoing Clinical Trials

A number of multinational clinical trials are recruiting and include a randomized, open-label, multicentre, phase II trial (NCT03897205; EudraCT 2018-000022-66), which will compare imlifidase with plasma exchange therapy in eliminating donor specific anti-HLA antibodies in the treatment of active AMR in kidney transplant patients and the prospective observational, 5 year, long-term, follow-up study (NCT03611621) of patients treated with imlifidase prior to kidney transplantation, which will include patients who have participated in the imlifidase kidney transplantation studies (studies 02, 03, 04 and 06). Also currently recruiting is an open-label, multicentre, phase II study (NCT03943589; EudraCT2018-001059-12) of imlifidase in combination with standard of care IVIg in patients with GBS. An open-label, phase II trial (NCT03157037; GOOD-IDES-01) evaluating imlifidase in patients with severe anti-GBM disease in combination with standard of care has completed recruitment and is being analysed.

3 Current Status

Imlifidase received conditional approval on 26 August 2020 in the EU for desensitization treatment of highly sensitized adult kidney transplant patients with positive crossmatch against an available deceased donor [4].