Background/Purpose:

In patients with rheumatoid arthritis (RA) reduced numbers and functional impairment of regulatory T cells (Tregs) have been observed. Tregalizumab is a humanized, agonistic monoclonal antibody which binds to a unique epitope of CD4, and induces Treg-specific activation and suppresses CD4 and CD8 effector cell proliferation and activity in vitro. Phase 2a randomized controlled RA trials of monotherapy (Study 962) and in combination with methotrexate (MTX) (Study 971) indicated efficacy in RA patients at SC doses of ≥25 mg with most pronounced effects on tender and swollen joint counts.

A biomarker was developed to monitor biologic response in humans.  An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was utilized to better characterize the optimal doses of tregalizumab for further investigation.

Methods:

In the Phase 2b trial 979, MTX inadequate responders (MTX-IR) were randomized to tregalizumab 25, 50, 75 mg, or placebo SC weekly (in combination with stable MTX) for 12 weeks with 12 weeks’ follow-up. The primary endpoint was ACR20 response at week 13 (1 week post treatment); SDAI, CDAI, PK-PD, and safety were also evaluated.

The integrated model utilized biomarker and clinical data from all completed RCTs and healthy volunteer studies of tregalizumab, together with interim data from the ongoing Study 979. This model was able to describe the relationship between SC tregalizumab doses and biologic responses. The model was then used to predict the dose-response relationship and to inform dose selection for the planned Phase 2b trial TREAT 2b (Study 986).

Results:

The interim clinical analysis of Study 979 in 112 patients indicated efficacy vs. placebo (ACR20/50/70 responses at Week 13). The most pronounced effects were seen for tender and swollen joint counts.  In Study 979  tregalizumab was well tolerated with no major safety findings, no CD4 cell depletion was observed

PK-PD modeling demonstrated a significant correlation between dose, biomarker data, and clinical efficacy. Moreover, the model showed that maximal biologic response had not yet been attained with weekly doses up to 75 mg, predicting greater biologic response and better clinical efficacy with higher doses exceeding 75 mg, approaching a plateau at 200 mg weekly.  

Conclusion:

Interim efficacy and safety data from the Phase 2b Study 979, combined with data from previous RCTs, indicated the feasibility and tolerability of this therapeutic approach.  The integrated PK-PD model confirmed the rationale for testing higher doses of tregalizumab up to 200 mg SC weekly in combination with MTX.  Therefore, in the Phase 2b multicenter RCT (TREAT 2b – Study 986) 304 MTX-IR patients will receive tregalizumab 25 mg, 100 mg, 200 mg, or placebo SC weekly for 24 weeks, followed by an extension phase of 24 weeks. The available data support further development of tregalizumab.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/use-of-a-biologic-marker-for-an-integrated-pharmacodynamic-and-clinical-analysis-to-inform-further-clinical-development-including-dose-selection-for-the-phase-2b-trial-treat-2b-of-tre/