Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, potentially life-threatening disease characterized by complement-mediated hemolytic anemia. PNH arises from a somatic mutation resulting in impairment of an anchor protein responsible for the expression of numerous proteins at the cell surface of the red blood cells, including CD55 and CD59, two complement inhibitory proteins. The subsequent uncontrolled activation of the complement system leads to both intravascular hemolysis triggered by the membrane attack complex (MAC) and extravascular hemolysis, or cell opsonization, mediated by C3b accumulation at the cell surface. Eculizumab, an anti-C5 antibody, is available as a treatment for PNH, however some patients continue to be transfusion-dependent as a result of on-going activation of C3, upstream of C5. Due to the key position of C3 in the complement cascade, APL-2, a cyclic peptide inhibitor of C3, may prevent both intravascular and extravascular hemolysis and could therefore be potential treatment for PNH and beneficial for patients still requiring transfusions despite standard of care treatment.


These initial phase I studies were designed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple doses of APL-2 administered by subcutaneous injection (SC) in healthy adult volunteers.


Both studies were conducted at a single center (Australia) and were double-blind, placebo-controlled designs. Subjects were monitored for up to 43 days following single dosing and 84 days following multiple dosing. Safety was assessed by intensive clinical monitoring. Serial blood sampling was performed for the determination of APL-2 concentrations in serum. Blood samples were also obtained to determine relevant markers of complement activity (C3, CH50 and AP50). Additional relevant PD markers (intact C3, iC3b, C3a, C4a and C5a) were measured in latter Cohorts. Prior to multiple dosing subjects received Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae Type B (Hib) vaccinations.


In total 51 subjects were enrolled into the two studies. Twenty-four subjects received APL-2 as a single dose (ranging from 45 to 1,440mg) and 7 subjects received placebo. Sixteen subjects received repeated daily doses of APL-2 for 28 consecutive days (ranging from 30 to 270 mg/day) and 4 subjects received placebo. There were no serious adverse events (SAE's), treatment emergent adverse events (TEAEs) leading to study drug discontinuation, or severe adverse events reported. There were no clinically relevant changes in vital signs, ECG findings or safety laboratory tests. Following single and multiple doses APL-2 exposure increased linearly with increasing dose up to the highest doses tested and APL-2 serum concentrations were close to steady-state after 28 days of daily dosing. A reduction in AP50 was seen following a single dose of 1440mg APL-2 and following multiple daily doses of 180 and 270 mg.


The studies concluded that pharmacological doses of APL-2 were safe and well tolerated and that APL-2's PK/PD profile supports daily SC administration. In addition, daily APL-2 doses of 180mg and 270mg significantly reduced hemolytic activity as early as eight days after the start of dosing, and this inhibition was maintained through the dosing period. PK data from these studies has been used to develop a PK/PD model which has been used to aid dose selection in the subsequent studies in PNH patients.


Grossi:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Bedwell:Apellis Pharmaceuticals Inc: Consultancy. Deschatelets:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Edis:Apellis Pharmaceuticals Inc: Employment, Equity Ownership. Francois:Revon Systems Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Liberate Medical Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apellis Pharmaceuticals Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Johnson:Apellis Pharmaceuticals Inc: Consultancy. Richardson:Apellis Pharmaceuticals Inc: Consultancy. Tan:Apellis Pharmaceuticals Inc: Consultancy. Vega:Apellis Pharmaceuticals Inc: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.

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