Zamerovimab/Mazorelvimab

SYN023 is a mixture of 2 humanized monoclonal antirabies antibodies (CTB011, CTB012). Two first‐in‐human studies evaluated ascending intramuscular (IM) injected doses (Study SYN023‐001; N = 15) and IM vs subcutaneous (SC) administration (Study SYN023‐003; N = 35) in healthy adults. In both studies, end points were safety, pharmacokinetics (PK), pharmacodynamics/rabies virus neutralizing activity (RVNA), and immunogenicity (anti‐SYN023 antibodies). Adverse events were mild and infrequent at all doses tested by IM injection (0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg), or by SC injection (0.3 mg/kg). There were no apparent trends in adverse event frequency or nature with increased dose or with administration route. Serum PK of SYN023 component antibodies appeared comparable to each other at each dose tested and when administered IM versus SC with serum exposure doubling over the second week after administration. At the lowest dose tested (0.3 mg/kg) by either IM or SC injection, RVNA levels exceeded the concentration generally accepted as protective against rabies (≥0.5 IU/mL) by day 1 after administration. Supra‐inhibitory levels persisted >42 days. RVNA increased with higher doses. Anti‐CTB011 and anti‐CTB012 antibodies occurred with no apparent effect on PK or safety. These data support the potential use of SYN023 in antirabies postexposure prophylaxis.

SYN023, a mixture of two anti-rabies humanized monoclonal antibodies (mAbs), namely, CTB011 and CTB012, has been developed as a safe and cost-effective alternative to RIG in the use of postexposure prophylaxis (PEP) after rabies exposure.

This phase I bridging study was designed to compare the pharmacokinetics (PK) of SYN023 (0.3 mg/kg) alone (cohort A, n = 8) or in combination with a rabies vaccine (cohort B, n = 24) in healthy Chinese subjects with those in American subjects to guide the design of further clinical trials. Their safety was assessed for the development of adverse events (AEs) by laboratory examinations. The levels of serum CTB011, CTB012 and anti-drug antibodies (ADAs) were measured longitudinally for 85 days. Serum rabies virus neutralizing antibody (RVNA) levels were measured as a pharmacodynamic (PD) surrogate.

Some subjects with injectable SYN023 at 0.3 mg/kg developed temporary AEs and adverse drug reactions (ADRs) of Grade 1 or 2, particularly in cohort B, probably due to vaccine coadministration. SYN023 injection displayed a typical and reliable PK, similar to that of human IgGs. Following injection with SYN023, Chinese subjects had slower absorption with higher exposures for CTB011 but lower exposures for CTB012 than American subjects. The SYN023 recipients achieved protective levels of RVNA (≥0.5 IU/mL) on day 3 post injection. A few subjects developed temporary ADA, which did not affect the safety and PK/PD of SYN023 in Chinese subjects.

SYN023 at 0.3 mg/kg is relatively saf e and effective and can be selected for further clinical trials in Chinese subjects. The clinical trial registration number is CTR20190281. http://www.chinadrugtrials.org.cn/eap/clinicaltrials.searchlist?a=a®_no=CTR20190281.