2035: Interim Phase 1 Results for SPY002, a Novel Half-Life Extended Monoclonal Antibody Targeting TL1A, Suggest A Potential for Q3M or Q6M Maintenance Dosing for Rheumatologic Disease

Background/Purpose: TL1A is an inflammatory cytokine and a member of the TNF superfamily. Target cells that express DR3 and respond to TL1A include T cells, B cells, fibroblast-like synoviocytes (FLS), and osteoclasts, each of which is associated with inflammation and joint damage in rheumatoid arthritis (RA), ankylosing spondylarthritis (axSpA), and psoriatic arthritis (PsA). Synovial fluid and serum TL1A levels are highly elevated in RA, axSpA, and PsA, and TL1A promotes FLS activation, chemokine signaling, and MMP production by osteoclasts in vitro. Variants in the TL1A gene are associated with both TL1A levels and the diagnosis of RA, axSpA, and PsA or psoriasis, and multiple animal models demonstrate that TL1A inhibition is therapeutic in arthritis.


SPY002 is an investigational fully human IgG1 monoclonal antibody that specifically binds to TL1A and blocks the interaction of TL1A with its receptor, known as death receptor 3 (DR3). It includes a YTE modification in the Fc domain to increase the binding affinity to FcRn and thereby extend the antibody half-life. A Phase 1, first-in-human study in healthy volunteers is being conducted to characterize the safety, tolerability, PK, and PD properties of SPY002.

Methods: SPY002-101 is a randomized, double-blind, placebo-controlled single ascending dose (SAD) Phase 1 study in healthy volunteers aged 18 to 65. Study participants were randomized to either SPY002 or placebo in a 3:1 ratio as in dose cohorts as follows: 100 mg SC, 300 mg SC, 300 mg IV, 1000 mg IV, or 1500 mg IV. Blood was collected to evaluate safety, PK, PD (serum soluble TL1A levels), and ADA assessments at scheduled study visits. Interim safety and bioanalytical data with up to four months of follow-up from the first SAD cohort were analyzed.

Results: Interim PK data from all cohorts demonstrated dose-proportional pharmacokinetics for SPY002. Noncompartmental analysis and population PK modeling suggested a half-life extension of approximately 3-fold relative to typical monoclonal antibodies. PD analysis demonstrated saturating effects on soluble TL1A levels beginning with the lowest dose tested (100 mg SC) that extend to the latest time points assessed thus far. Blinded safety data from all cohorts thus far demonstrated SPY002 to be well tolerated with no serious or severe adverse events, with most adverse events being mild in severity and unrelated to study agent.

Conclusion: Interim PK analysis following single doses of SPY002 demonstrated half-life extension supporting potential maintenance dosing at a frequency of every 3 to 6 months with a single SC injection. SPY002 resulted in saturating changes in soluble TL1A levels. SPY002 was well tolerated, with all adverse events being non-serious and typical of a Phase 1 study in healthy volunteers. These results support advancement of SPY002 into clinical trials in rheumatologic disease and in other potential indications.