A Phase I/Phase II Study of Intravenously (IV) Administered Tc 99m Tilmanocept (TCT) to Determine Safety, Tolerability, Optimal Clinical Dose Selection, and Imaging Timepoint in Patients Clinically Diagnosed with Rheumatoid Arthritis (RA)

Objectives: Activated macrophages are a critical component of the inflammatory etiology of RA due to prolonged RA joint inflammation and destruction through the release of pro-inflammatory cytokines and chemokines. At present, there are no reliable means to non-invasively monitor disease activity in these patients. TCT is a radiopharmaceutical imaging agent that binds to the macrophage mannose receptor CD206 that reside on macrophages with high affinity. Previous clinical studies demonstrated the safety and tolerability of TCT in the subcutaneous (SC) route of administration. This Phase I/Phase II study of IV administered TCT was completed in RA subjects and contrasting healthy controls (HC) presenting initial safety and tolerability findings, as well as a powered determination of an optimal clinical dose and timepoint for imaging. Methods: A total of 39 subjects (33 active RA/6 HC) divided into 11 groups received various combinations of IV Tc 99m at 1, 5 and 10 mCi with 50, 200, or 400 µg of tilmanocept (see Figure 1) and had standard gamma camera whole- body planar imaging as well as AP spot view of the hands and wrists at 1 and 3 hours post-injection. Twelve of the 39 subjects (6 RA/6 HC) underwent whole-body planar scans for radiodosimetry assessment and pharmacokinetic analysis. An independent panel of 3 blinded readers performed a visual assessment of joint-space uptake for determination of inter-reader agreement. Quantitative assessment of count activity in individual joint spaces of the hands and wrists was extracted from each subject by placing separate ROI on 1 and 3-hour planar anterior images and used to model the optimal timepoint and dose for detecting TCT uptake in involved RA joints. Results: No adverse drug reactions (ADRs) or serious adverse events (SAEs) were observed in any dose group. Planar imaging revealed that TCT localizes specifically to inflamed joints in RA subjects when compared to HC subjects (see Figure 2). Qualitative and quantitative data analysis and modeling revealed an optimal mass dose of 134 µg tilmanocept/10 mCi of Tc 99m stable over an imaging time frame of 1-3 hours post-injection. Conclusions: IV administration of TCT was well-tolerated and demonstrated joint-specific localization in RA subjects, revealing potentially significant immunodiagnostic information about CD206-expressing synovial macrophage involvement in RA patients. Additionally, increased TCT activity via IV administration may enhance localization and