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Background: ZB002 is a recombinant human monoclonal antibody (mAb) that targets human TNFα with an Fv domain identical in amino acid sequence to adalimumab and was designed to have an extended half-life. Adalimumab has been approved for the treatment of a broad spectrum of autoimmune diseases but has a half-life of only approximately 2 weeks and is dosed either weekly (QW) or every 2 weeks (Q2W)[1]. The fragment crystallizable (Fc) domain of ZB002 consists of a hybrid immunoglobulin G (IgG) 1/2 constant region containing 2 amino acid substitutions, M428L and N434S, referred to as the Xtend™ Fc domain. This domain is designed to increase affinity to the neonatal Fc receptor (FcRn) and thus increase ZB002 half-life, potentially enabling reduced frequency of administration.
Objectives: The objectives of this study were to evaluate ZB002 safety and tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) in healthy volunteers (HV).
Methods: This study was a double blind, randomized, placebo-controlled, single ascending dose (SAD) study. Male and female HVs ages 18-55 were enrolled at a single center (New Zealand Research Center). Eight HVs were enrolled into each dosing cohort and randomized in a 3:1 ratio to receive subcutaneous ZB002 or placebo. Dose escalation between cohorts was approved by a Safety Review Committee (SRC). Doses tested were 20 mg, 40 mg, 80 mg, 160 mg, and 240 mg. ZB002 PK and anti-drug antibodies (ADA) were analyzed, and PD effects were assessed using ex vivo stimulated whole blood.
Results: No safety signals were identified by the SRC, with adverse events consistent with expectations in a HV population, and no serious adverse events observed. PK results showed a ZB002 half-life of approximately 6-7 weeks. Modelling and simulations indicate that potentially efficacious dosing for indications such as rheumatoid arthritis could be administered every 2 months (Q2M). Given the long dosing interval, administration of a loading dose would help to bring patients to steady state rapidly. Pharmacodynamic analysis revealed approximately 95% inhibition of ex vivo -stimulated TNFα production in samples obtained from the HVs 8 hours post dosing with ZB002.
Conclusion: This study demonstrated that ZB002 was safe and well tolerated at the doses studied. Observed ZB002 half-life and confirmation of target engagement warrants continued clinical development.
REFERENCES: [1] Humira Full Prescribing Information. US Food and Drug Administration website.
Acknowledgements: NIL.
Disclosure of Interests: Cory Sellwood: None declared, Stephen Wax Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma, Minggeng Gao Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma, Mark Matijevic Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma, Mason Yamashita Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma, Shan Yu Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma, Sujata Arora Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma, Rachel Kirk Holds stock/options in Zenas BioPharma, Employee of Zenas BioPharma.