1828P - ARX517: A next generation anti-PSMA antibody drug conjugate (ADC) demonstrates notable stability and pharmacokinetic (PK) profile in the ARX517 phase I clinical trial (APEX-01)

Background

ARX517 is a next-generation, anti-PSMA, ADC conjugated to AS269 (pAF-269; a potent tubulin inhibitor), at a drug-to-antibody ratio (DAR) of two. ARX517 was designed to address the instability issues encountered by previous PSMA-targeted ADCs with three key components: a non-cleavable PEG linker, a non-cell permeable payload, and stable oxime conjugation chemistry. The site-specific conjugation of AS269 to the mAb is enabled using proprietary synthetic amino acid incorporation. This ADC design minimizes premature payload release and off-target toxicity.

Methods

21 patients received ARX517 at doses ranging from 0.32 to 2.4 mg/kg across 7 cohorts. ARX517 was administered by intravenous infusion q3w. Patient serum samples were collected at fixed time points and evaluated in validated Total Antibody (TA; sum of deconjugated antibody and conjugated antibody), ADC (conjugated antibody with a DAR of 1 or 2), and payload pAF-AS269 assays. The lower limit of quantitation for the TA, ADC, and pAF-AS269 assays were 62.5 ng/mL, 7.8 ng/mL, and 0.02 ng/mL, respectively. PK parameters were determined using noncompartmental analysis based on serum concentrations of TA, ADC, and pAF-AS269.

Results

ARX517 exhibited virtually overlapping TA and ADC PK concentration-time curves at all dose levels tested, indicating strong stability of the ADC with minimal premature payload release. A long ADC terminal half-life of ∼6–10 days was observed at doses ≥ 1.4 mg/kg, thereby maximizing drug exposure over a dosing cycle of 3 weeks. Low concentrations of pAF-AS269 (approximately 0.02–0.2 ng/mL) were observed at all dose levels and appeared slowly in the circulation, with Cmax observed approximately 7 days after administration. This is in contrast to other ADCs that typically exhibit payload Cmax hours to days after dosing.

Conclusions

ARX517 is the first anti-PSMA ADC tested in the clinic to demonstrate notable stability and a long terminal half-life. These attributes enable continuous drug delivery throughout the dosing cycle to potentially improve efficacy and minimize toxicity due to premature payload release, indicating a clear and favorable therapeutic index.

Clinical trial identification

NCT04662580.

Editorial acknowledgement

Mark English, PhD, of Cancer Communications and Consultancy Ltd, Cheshire, UK, provided editorial assistance (funded by Ambrx).

Legal entity responsible for the study

Ambrx.

Funding

Ambrx.

Disclosure

S.T. Tagawa: Financial Interests, Personal, Advisory Board: Convergent Therapeutics, AIkido Pharma; Financial Interests, Personal, Other, Consultant: EMD Serono, Telix Pharma, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, Myovant, EMD Serono; Financial Interests, Personal, Stocks/Shares: AIkido Pharma; Financial Interests, Personal, Other, Patent co-inventor: Gilead; Financial Interests, Institutional, Local PI: Medivation, Astellas, Janssen, Amgen, BMS, AstraZeneca, Bayer, Merck, Clovis, Seagen; Financial Interests, Institutional, Steering Committee Member: Gilead, Novartis, POINT Biopharma, Clarity, Ambrx, Promontory. J. Shen: Financial Interests, Personal, Advisory Board: Bayer, Kite/Gilead, Sanofi, AstraZeneca; Financial Interests, Local PI: Ambrx, Arvinas, BMS, MacroGenics, Merck, Eli Lilly, Exelixis. L. Skidmore, J. Nelson, S. Zhang: Financial Interests, Personal, Full or part-time Employment: Ambrx. R. Pachynski: Financial Interests, Institutional, Local PI: Ambrx.