To report the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of subcutaneous (SC) ALXN1720 in healthy volunteers (HVs) (NCT04920370).

ALXN1720, a novel 28 kD bispecific variable domain on a heavy chain (VHH) antibody, binds complement component 5 (C5), inhibiting its cleavage into C5a and C5b. ALXN1720 also binds to albumin, which extends its half-life. The low molecular weight of ALXN1720 enables SC injection, designed for self-administration.

HVs aged 18–45 years were recruited into 12 cohorts at a single site in the UK. In each cohort, participants were randomized (3:1) to receive ALXN1720 or placebo. HVs received either SC ALXN1720 as a single dose (30–1700 mg), multiple doses (100 or 300 mg) once weekly for three weeks, or a single dose of IV ALXN1720 (300 mg). One cohort received SC 900 mg loading dose then 600 mg maintenance doses once weekly for seven weeks. Primary objective was the evaluation of ALXN1720’s safety and tolerability in healthy adults.

The study enrolled 97 HVs. ALXN1720 was well tolerated with no serious adverse events (SAEs) reported. All AEs were mild in severity. Dose proportionality was concluded across the range of single doses. ALXN1720 serum exposure increased dose dependently over 3 weekly doses of 100 mg and 300 mg. Single doses ≥100 mg and extended multiple dosing achieved complete terminal complement inhibition (serum free C5 < 0.5 ug/mL). Low-titer, treatment-emergent (TE)-anti-drug antibodies were observed in 12% (9/73) of participants who received ALXN1720 SC. There was no indication that TE-anti-drug antibodies had any impact on drug concentration (PK) or safety profiles. Mean absolute bioavailability of SC ALXN1720 was 96%.

Healthy adults tolerated ALXN1720 well. ALXN1720 exposure was dose-proportional and was associated with corresponding decreases in serum free C5 concentrations. Immunogenicity was low.