Inhibition of C3 with APL-2 Results in Normalisation of Markers of Intravascular and Extravascular Hemolysis in Patients with Autoimmune Hemolytic Anemia (AIHA)

Abstract

Background: Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease characterized by hemolysis mediated by autoantibodies directed against red blood cells (RBC). AIHA is classified as either warm (60-70%), or cold agglutinin disease (CAD, 20-25%), depending upon the temperature at which the autoantibodies show maximum binding. Warm AIHA is mediated by warm reactive autoantibodies, which are usually of the immunoglobulin G class (IgG). Almost 90% of CAD is medicated by monoclonal antibodies of IgM class. The diagnosis of wAIHA or CAD is based on the presence of hemolytic anemia, signs of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. Complement plays an important role in warm antibody AIHA. When erythrocytes are heavily coated with immunoglobulin, the amount of antigen-antibody complex can be sufficient for binding complement protein complex C1, thereby activating the classical complement pathway. CAD is almost entirely a complement-dependent disorder. Cold antibodies (IgM) temporarily bind to the RBC membrane, activate complement, and deposit complement factor C3 on the cell surface. These C3-coated RBCs are cleared slowly by the macrophages of the liver through extravascular hemolysis. Less frequently, the complete complement cascade is activated on the cell surface, resulting in the insertion of membrane attack complex C5b to C9 and intravascular hemolysis. Therefore, treatment with inhibitors of complement cascade may halt or at least attenuate acute complement mediated hemolysis in AIHA patients and improve recovery of RBC destruction. Aims: This Phase 2, open-label study is being conducted in the US and Italy to assess the safety, tolerability, efficacy, and PK of multiple subcutaneous (SC) doses of APL-2 administered daily in subjects with wAIHA or CAD. Methods: Patients with primary AIHA are eligible. Patients are required to have hemoglobin (Hb) levels <11 g/L, signs and symptoms of hemolysis, and a positive direct antiglobulin test (DAT) for IgG or IgM, and/or complement C3. The study will recruit 12 subjects with wAIHA and 12 subjects with CAD. APL-2 270 mg/d or 360 mg/d will be administered for 48 weeks. Efficacy is assessed by change from baseline in Hb, transfusion requirements, reticulocytes, lactate dehydrogenase (LDH), haptoglobin, bilirubin, and FACIT fatigue score. Endpoints will be assessed at Weeks 8, 12, 44, and 48. Results: 2 subjects with CAD (Subject 1: 270 mg/d; Subject 2: 360 mg/d) have been treated for at least 8 weeks and up to 12 weeks; 2 subjects with wAIHA (Subject 3: 270 mg/d; Subject 4: 360 mg/d) have been treated for at least 4 weeks. Subject 1 screened with Hb (NR 13.5 g/dL-17.5g/dL) of 10.0 g/dL and reported an increase to 13.0 g/dL at Week 12, with reticulocyte (NR 30-100 10^9/L) reduction from 99.6 10^9/L at Week 2 to 56.34 10^9/L at Week 8 (screening/baseline values not available). Subject 2 had baseline Hb of 7.9 g/dL and reported an increase to 13.6 g/dL at Week 8, with reticulocyte reduction from 154.34 10^9/L at baseline to 67 10^9/L at Week 8. Subject 3 had baseline Hb of 8.0 g/dL and reported an increase to 11.2 g/dL at Week 4, with reticulocyte reduction from 223.44 10^9/L at baseline to 27.12 10^9/L at Week 4. Subject 4 did not show signs of haematological improvement by Week 4, and the principal investigator decided to discontinue the subject at Day 42. Subject 1 had LDH levels within the normal range (100-200 I/U) at screening and remained normal through the study. Subjects 2 reported a baseline LDH of 339 I/U with a reduction to within NR to 107 I/U at Week 8. Subject 3 reported a baseline LDH of 235 I/U, which was also reduced to within NR at Week 4 to 123 I/U. Subject 1 had consistent indirect bilirubin (NR 0.2-0.7 mg/dL) through the study with a baseline value of 1.5 mg/dL and a Week 12 value of 1.4 mg/dL. Subject 2 had a reduction in indirect bilirubin with a baseline value of 1.3 mg/dL and a Week 8 value of 0.5 mg/dL.To date, APL-2 has generally been well-tolerated. No significant infections have been observed. Summary/Conclusions: Interim results demonstrate that systemic inhibition of C3 with APL-2 has demonstrated positive trends in haematological parameters in patients with wAIHA and CAD as early as Week 4. To date, APL-2 has been safe and well tolerated. The study is ongoing and will enroll up to 12 subjects with wAIHA and 12 subjects with CAD. Disclosures Grossi: Apellis Pharmaceuticals: Employment, Equity Ownership. Gertz:spectrum: Consultancy, Honoraria; Medscape: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Apellis: Consultancy; Teva: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; janssen: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; celgene: Consultancy; Abbvie: Consultancy; annexon: Consultancy. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Stout:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting

“…An inhibitory molecule against C1q, ANX005, blocks classical complement activation as well as haemolysis in an in vitro sheep red cell assay [171]. Pegcetacoplan (APL-2), a subcutaneously administered peptide inhibitor of C3, is assessing the preliminary efficacy in both wAIHA and CAD [16,172].…”

“…Clinical improvement by a hemoglobin median of 3.9g/dl was seen in a pivotal study [158]. Pegcetacoplan (APL-2) is a pegylated derivative of the cyclic tridecapeptide compstatin and inhibits C3 activation [172,223]. This viscous material requires a pump for subcutaneous administration and selectively binds to C3 and blocks the cleavage of C3 into C3a and C3b by C3 convertase.…”

“…This viscous material requires a pump for subcutaneous administration and selectively binds to C3 and blocks the cleavage of C3 into C3a and C3b by C3 convertase. It is being studied in PNH, macular degeneration, and AIHA with some favorable preliminary results reported, particularly in CAD [16,172,224].…”

New Insights in the Pathogenesis and Therapy of Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia

“…The C3 inhibitor, pegcetacoplan (APL-2), is a pegylated peptide designed for subcutaneous administration (150). Clinical phase 2 trials have found efficacy of pegcetacoplan in paroxysmal nocturnal hemoglobinuria as well as AIHA (151), and further studies in CAD are warranted. A high risk of infection with encapsulated bacteria might be suspected as a consequence of C3 inhibition, but thus far, clinical data have not supported this concern (150)(151)(152).…”

Targeting complement cascade: an alternative strategy for COVID-19

“…Autoimmune hemolytic anemia (AIHA) is a rare complement-dependent autoimmune disease. Systemic inhibition of C3 complement components with APL-2 has been demonstrated in phase-2 open-label study against AIHA (Grossi et al 2018 ). APL-2 is in phase 3 trial for the patients with PNH, a complement-mediated disease.…”