A Phase 2a, Randomized, Open-Label Study to Evaluate Multiple Dosing Regimens of Subcutaneous ALXN1820 in Adult Patients with Sickle Cell Disease

Background:Sickle cell disease (SCD) is a group of inherited disorders that result in chronic hemolysis/anemia and vaso-occlusive crises (VOC). Current management options for SCD do not adequately address both anemia and VOC. Hematopoietic stem cell transplant is the only curative treatment but is associated with life-threatening complications. Complement activation may play an important role in the pathophysiology of SCD since intravascular hemolysis of sickle red blood cells (RBCs) leads to release of free hemoglobin triggering activation of the complement alternative pathway (CAP). Intravascular hemolysis and CAP activation promotes anemia and VOC in patients with SCD. Properdin is an endogenous activator of the CAP (Roumenina LT, et al. Am J Hematol. 2020;95(5):456-464; Vercellotti GM, et al. Am J Hematol. 2019;94(3):327-33).

ALXN1820 is a novel, humanized, bispecific, VHH antibody that simultaneously binds human albumin and properdin. The antibody effectively and selectively inhibits CAP activation while binding to albumin, which confers an extended circulatory half-life to the molecule. Pretreatment with a mouse anti-properdin antibody significantly ameliorated signs of hemolysis and VOC in a mouse model of SCD. The safety, pharmacokinetics and pharmacodynamics of ALXN1820 are being evaluated in an ongoing study in healthy volunteers (NCT04631562).

Study design, methods, and study population: This open-label Phase 2a study will evaluate the safety, tolerability, efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple doses and dosing regimens of ALXN1820 administered subcutaneously to patients with SCD (see Figure for study schema). Key inclusion criteria are confirmed diagnosis of SCD (HbSS and HbSß⁰-thalassemia), hemoglobin levels 5.5-10g/dL at screening, 1-10 VOC episodes in the past 12 months, and vaccination requirements (meningococcal, Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae). Concomitant treatment with stable dose of hydroxyurea is permitted during the study as applicable. Key exclusion criteria are receiving voxelotor or crizanlizumab within 60 days of providing informed consent and, prior treatment with complement inhibitors within 6 months of first study dose. Key endpoints of the study are shown in the Table. Safety analyses will be performed on the Safety Population and will be reported by each cohort and treatment arm. Efficacy analyses will include absolute and percentage change from baseline to the end of the Treatment Period (12 weeks) in complement biomarkers, hemoglobin, hemolysis markers, and hemopexin for Cohort 1 and Cohort 2.

Conclusion: Complement activation may play an important role in the pathophysiology of SCD. Treatment with an anti-properdin antibody significantly ameliorated signs of hemolysis and VOC in a mouse model of SCD supporting the potential of ALXN1820 to treat SCD. Data from this Phase 2 study are anticipated to confirm the potential of ALXN1820 to treat SCD and guide the design of future studies in patients with SCD and other complement-mediated diseases.

Dai:Alexion Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company, Other: Support for attending meetings and/or travel. Hill:Takeda Pharmaceuticals: Current holder of stock options in a privately-held company; AstraZeneca: Current holder of stock options in a privately-held company. Harris:Sanofi: Current equity holder in private company. Shen:Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in private company. Gasteyger:Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in private company.