Safety and Pharmacokinetics of the Complement Inhibitor TT30 in a Phase I Trial for Untreated PNH Patients

TT30 is a novel, recombinant human fusion protein, linking the C3d-binding domain of human complement receptor 2 (CR2) with the complement regulatory domain of human factor H (fH). TT30 is designed to inhibit the complement alternative pathway (CAP) at sites of local activation; it has been shown to be effective in preventing hemolysis and C3b-mediated opsonization in paroxysmal nocturnal hemoglobinuria (PNH) in vitro. This first in human study, TT30-PNH-002, was a multi-center open-label, single-dose, dose-escalation study of two formulations of TT30, ALXN1102 (10mg/ml) and ALXN1103 (50mg/ml). The study was conducted in patients with a diagnosis of PNH, defined as a PNH clone size of  ≥10% or a PNH clone size between 5% and 10% with evidence of intravascular hemolysis documented within the previous 12 months; patients were not receiving concurrent treatment or treatment with a complement inhibitor within 60 days prior to screening. The primary endpoint of the study was assessment of the safety and tolerability of a single dose of TT30 when administered by IV infusion or separately by SC injection; secondary endpoints included pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. The ALXN1102 formulation was administered by IV infusion to the 0.1 (n=1), 0.3 (n=1), and 1 mg/kg (n=3) dose level cohorts. The ALXN1103 formulation was administered by IV infusion to the 3 mg/kg (n=1) dose level cohort and by SC injection to the 1 (n=2) and 3 mg/kg (n=2) dose level cohorts. Patients were dosed one at a time, and each patient was evaluated before the next patient could be dosed. All 10 patients completed the study as planned; across all groups, 28 mild and 5 moderate treatment-emergent adverse event (TEAEs) were experienced. Treatment with both formulations of TT30 was considered safe, with no apparent dose-related safety risks. One patient who received ALXN1102 at 1.0 mg/kg IV experienced transient hypocalcemia associated with transient asymptomatic prolongation of the QT interval, both of which spontaneously resolved by 24 hours without intervention and may have been related to citrate in the formulation. Subsequent patients supplemented with oral calcium at the start of the infusion did not experience these events, nor were citrate-related toxicities seen in patients who received ALXN1103, which contains a lower amount of citrate. The secondary endpoints of the study were to characterize the PK of a single dose of TT30, to assess CAP, complement classical pathway (CCP) inhibition, PD effects on markers of intravascular hemolysis such as lactate dehydrogenase (LDH), and to characterize the immunogenicity of TT30. Serum TT30 total and peak (AUCs and Cmax) exposures increased with increase in IV or SC dose. Serum CAP activity declined in a dose-dependent manner following dosing in all IV dose cohorts, and approached zero % of baseline value (complete CAP inhibition) in the 1 mg/kg and 3 mg/kg IV dosing cohorts, when circulating levels of TT30 were in the range of approximately 5-10 ug/ml.  CAP activity returned to baseline by 24 hours, when circulating TT30 was below 1 ug/ml, and appeared to remain stable thereafter.  Serum CCP activity remained near baseline in all patients at all times. LDH levels dropped by 20% in the 1 mg/kg and 3 mg/kg IV dose cohorts and rose over time after CAP activity returned to baseline. Similarly, there was a decline in serum CAP activity and LDH levels in the 1 mg/kg and 3 mg/kg SC dose cohorts that returned to pre-treatment baseline over time, by 24 hours. No immunogenicity was observed in any patient, following either IV or SC dosing of a single dose of TT30. In conclusion, both TT30 formulations were safe and well tolerated; preliminary PK and PD data support the concept that treatment by targeted complement inhibitors like TT30 result in pharmacologically relevant CAP inhibition in PNH, as demonstrated by LDH decrease. Nevertheless, such therapeutic inhibition is short-lasting, and further strategies are needed to sustain pharmacological levels of TT30 for  chronic treatment in PNH.