1486MO - The synovial and systemic pharmacokinetics and pharmacodynamics of intra-articular administration of the CSF1 receptor antibody AMB-05X in a phase II proof-of-concept trial in tenosynovial giant cell tumor

Background

It is well established that CSF1 action at the CSF1R mediates the formation and expansion of TGCT – a benign but locally aggressive neoplasm. Indeed, oral or intravenous administration of CSF1R inhibitors may yield tumor regression over weeks to months of repeat dosing. With these systemic exposures, on-target side effects such as liver enzyme elevation and facial edema often present and may complicate the treatment paradigm. We hypothesized that administration of a potent, inhibitory anti-CSF1R antibody, AMB-05X, into the affected synovium could yield sustained, high local concentrations with low systemic exposures and thus enable tumor regression with minimal pharmacologic side effects.

Methods

8 TGCT patients with confirmed TGCT of the knee were enrolled in a Phase 2 study wherein AMB-05X was administered intra-articular (IA) at a dose of 150 mg every 2 weeks over a 12-week treatment period. The synovial and serum pharmacokinetics of AMB-05X were monitored. CSF1 levels in the joint and serum were also quantitated as a pharmacodynamic marker since inhibitor action at the CSF1R interferes with native and tumor-derived CSF1 elimination.

Results

The clearance of antibodies administered intra-articular is not well characterized and, in fact, has often been regarded as short-lived. The unique formulation of AMB-05X administered at the dose and regimen employed in this proof-of-concept study yielded high local concentrations that were sustained beyond expectations such that accumulation over the dosing period was extensive (>5-fold). Importantly, systemic exposures were consistently approximately 1/5 that of the synovial concentrations. Moreover, pharmacodynamic elevation of CSF1 levels was approximately 20-fold greater in synovial fluid vs serum. CSF1 levels in both compartments achieved a plateau, indicative of full receptor engagement, early in the treatment period.

Conclusions

The AMB-05X PK and PD results support expansion of the clinical development of AMB-05X in TGCT with IA treatment at a comfortable interval of once-monthly or less.

Clinical trial identification

AMB-051-01.

Editorial acknowledgement

Legal entity responsible for the study

AmMax Bio.

Funding

AmMax Bio.

Disclosure

M. Huang: Financial Interests, Personal, Stocks/Shares: AmMax Bio. L. Alani: Financial Interests, Personal, Full or part-time Employment: AmMax Bio. T. Huang: Financial Interests, Personal, Member: AmMax Bio. L. Hsu: Financial Interests, Personal, Member of the Board of Directors: AmMax Bio. K. Johnson: Financial Interests, Personal, Officer: AmMax Bio. All other authors have declared no conflicts of interest.