First in Human Single-Ascending Dose Study: Safety, Biomarker, Pharmacokinetics and Exposure-Response Relationships of ALXN1210, a Humanized Monoclonal Antibody to C5, with Marked Half-Life Extension and Potential for Significantly Longer Dosing Intervals

Introduction: ALXN1210 is a humanized monoclonal antibody (mAb), with a sequence closely related to eculizumab (Soliris^®). ALXN1210 binds specifically to human complement protein C5 and was engineered to eliminate the formation of C5a and the terminal complement complex with extended duration of complete complement inhibition. The mechanism of action of ALXN1210 provides strong clinical rationale for potential therapeutic use in patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, and other complement-mediated diseases. Clinical experience with eculizumab supports the reduction of free C5 to undetectable levels for complete inhibition of hemolysis.

Methods: In this Phase 1, randomized, blinded, placebo-controlled, single-ascending dose study, healthy subjects received a single intravenous (IV) dose of 200 mg (cohort 1) or 400 mg (cohort 2) ALXN1210 or placebo (PBO), and were then followed for 150 days. Subjects were vaccinated with a tetravalent conjugate N. meningitidis vaccine and received prophylactic penicillin V. The primary objective was to evaluate the safety and tolerability of a single dose of ALXN1210. Secondary objectives were to characterize the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of ALXN1210. PD effects of ALXN1210 were assessed as the change in serum free C5 and ex vivo (cell-based) hemolytic activity.

Results: Fourteen subjects enrolled in the study: 4 received 200 mg ALXN1210, 6 received 400 mg ALXN1210, and 4 received PBO. Serum ALXN1210 concentrations were measureable for the entire 150-day follow-up period. Mean C_max and AUC_∞ increased in a dose-proportional manner, with a mean terminal half-life of approximately 32 days and low (<20%) intersubject variability in PK parameters.

Levels of free C5 were reduced by >99% from baseline in all subjects who received ALXN1210. Additionally, all subjects who received a single dose of 400 mg ALXN1210 reached or exceeded the ALXN1210 threshold level of 100 µg/ml and had >99% elimination of free C5. For subjects with ALXN1210 levels >100 µg/ml, average elimination of C5 was >99%. No reductions in free C5 concentrations were observed in subjects who received PBO. Mean chicken red blood cell (cRBC) hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210. The duration of suppression of mean cRBC hemolysis was dose dependent. No anti-drug antibody (ADA) response was observed during the 150-day follow-up period.

Seven subjects (70%) receiving ALXN1210 reported 21 treatment-emergent adverse events (TEAEs); 3 in cohort 1 (200 mg) reported 6 TEAEs, and 4 in cohort 2 (400 mg) reported 15 TEAEs. The most frequently reported event was headache in subjects receiving ALXN1210 (3 subjects [50%], 3 events) or PBO (3 subjects [75%]; 7 events). Most (17/21; 81%) TEAEs were reported as mild, and all resolved during the trial. No drug-related serious AEs or treatment discontinuations due to TEAEs were reported.

Conclusions:

• Single IV doses of 200 mg or 400 mg ALXN1210 were well tolerated in healthy subjects.

• Serum ALXN1210 concentration data exhibited a terminal half-life of 32 days-longer than eculizumab (9 days).

• Mean ALXN1210 C_max and AUC_∞ increased in a dose-proportional manner.

• 100% of subjects who received ALXN1210 had samples with >99% elimination of free C5.

• In subjects who received a single IV 400-mg dose of ALXN1210:

  • 100% reached or exceeded the ALXN1210 threshold level of 100 µg/mL;

  • 100% obtained >99% elimination of free C5;

  • Mean elimination of free C5 was >99%.

• For ALXN1210 levels >100 µg/ml, average elimination of free C5 was >99%.

• Mean cRBC hemolytic activity was completely inhibited after a single dose of 200 or 400 mg ALXN1210, and duration of suppression of mean cRBC hemolysis was dose dependent.

• No ADA response was observed after a single dose of ALXN1210 during the 150-day follow-up period.

• Data modeling supports that >99% elimination of free C5 will be achieved with doses of ALXN1210 administered at 4-week or longer dosing intervals.

A multiple ascending dose study is ongoing, and 2 studies examining the safety, tolerability, efficacy, PK, and PD of ALXN1210 administered at ≥4-week dosing intervals will be initiated in PNH patients before the end of 2015.