Inhibition of C3 with APL-2 controls haemolysis and increases haemoglobin levels in subjects with Autoimmune Haemolytic Anaemia (AIHA)

Background Autoimmune haemolytic anaemia (AIHA) is characterized by haemolysis mediated by autoantibodies directed against red blood cells (RBCs). Warm antibody (wAIHA; 60%>70%) and cold agglutinin disease (CAD; 20%>25%) subclasses are defined by the immunoglobulin (Ig) isotype involved and its thermal optimum for binding RBCs. wAIHA is mediated by IgG while 90% of CAD is mediated by IgM isotypes. CAD and wAIHA outcomes can be life-threatening, but no therapies are approved. Complement C3b deposition on RBCs plays a central role in AIHA, accelerating phagocytosis in the liver and/or spleen (extravascular haemolysis) and forming membrane attack complexes (intravascular haemolysis). By blocking formation of C3b, APL-2, a cyclic peptide, has potential as a novel therapeutic for AIHA. Aims To assess whether inhibiting complement C3 with daily subcutaneous (SC) doses of APL-2 (270 mg/day or 360 mg/day) prevents intra- and extravascular haemolysis in AIHA subjects, reducing anaemia associated signs and symptoms. Methods Subjects with primary AIHA were eligible for this Ph 2 open-label study to assess the safety, tolerability, efficacy, and pharmacokinetics of APL-2. Subjects had haemoglobin (Hb) levels <11 g/dL, signs of haemolysis, and a positive direct agglutinin test (DAT) for IgG and/or complement C3. Twenty-four subjects (13 CAD, 11 wAIHA) were recruited and will be treated with APL-2 for 48 weeks. Efficacy was assessed by change from baseline in Hb, transfusion requirements, absolute reticulocyte counts (ARC), lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin (INDBIL), and Functional Assessment of Illness Therapy (FACIT) fatigue score. Data are reported after 16 weeks (Day 112). Results Two of 13 CAD subjects withdrew; 7 of 11 remaining subjects reached Day 112. Mean Hb (standard error [SE]) increased from 8.9 (0.4) [n=13] to 11.6 (0.5) [n=7] g/dL, and mean LDH, ARC, and INDBIL returned within normal range. Mean FACIT scores (SE) increased 9.9 (3.4) points from baseline. Two subjects had pre-study and 1 had on-study transfusions (normalized to 112 days). All 13 CAD experienced ≥1 treatment-emergent adverse event (TEAE), mainly Grade 1-2 and unrelated. Four subjects reported 10 unrelated serious adverse events (SAEs) (6 SAEs in 1 subject). Three subjects experienced 3 unrelated Grade 3 TEAEs (pneumonia, dyspnoea, hypertension); 1 subject reported 2 unrelated Grade 4 TEAEs (high calcium, high creatinine) and withdrew. Eight of 11 wAIHA subjects were DATmonoC3+ and 3 were DATmonoC3-. Two of 3 DATmonoC3- withdrew for lack of response and efficacy data are reported for 8 DATmonoC3+ subjects. Six of these reached Day 112. Mean Hb (SE) increased from 9.2 (0.3) [n=8] to 10.8 (0.5) [n=6] g/dL, and mean ARC and INDBIL returned within normal. Mean FACIT scores (SE) increased 2.7 (2.8) points from baseline. One subject had pre-study and 2 had on-study transfusions (normalized to 112 days). Ten of 11 wAIHA (C3+ and C3-) experienced ≥1 TEAE, mainly Grade 1-2 and unrelated. Five subjects reported 8 unrelated SAEs. Five subjects experienced 13 unrelated Grade 3 TEAEs (oral squamous cell carcinoma, haemolytic flare, purpura, acute kidney injury, dyspnoea, chest pain); 1 subject reported 1 unrelated Grade 4 TEAE (haemolytic flare) and withdrew. Six-month data for 10 CAD and 6 wAIHA C3+ is planned for June 2019. Conclusion APL-2 increases Hb values in CAD and wAIHA C3+ within the first weeks of treatment with sustained benefit with longer exposure. APL-2 reduces intra- and extravascular haemolysis shown by reductions in LDH, INDBIL, and ARC. APL-2 appears to be safe and well-tolerated.