Results indicated that SDX-7320 and palbociclib, when given as single agents, demonstrated significant inhibition of tumor growth. However, additional efficacy was observed when the agents were combined.

When SDX-7320 was administered as a monotherapy at a dose of 8 mg/kg, it yielded a tumor growth inhibition rate (TGI) of 49%. Single-agent palbociclib, delivered at 20 mg/kg, elicited a TGI rate of 47%, while 40 mg/kg of palbociclib resulted in a TGI rate of 65%.

When 8 mg/kg of SDX-7320 was given in combination with 20 mg/kg of palbociclib, the TGI rate was even higher, at 70%; then the agents were given at 8 mg/kg and 40 mg/kg, respectively, the TGI rate further increased to 80%.

"[Due to the fact] the tumor growth in the vehicle animals declined after day 25, the analysis focused on the day 25 data,” Peter Cornelius, PhD, senior director of Translational Research at SynDevRx, said in a presentation on the findings. “All agents had statistically significant effects on tumor growth; however, the combination showed the greatest effect on tumor growth inhibition, with the highest dose [demonstrating] the largest effect, at 80% TGI.”

In the model, the 40-mg/kg dose of palbociclib monotherapy was not well tolerated and resulted in multiple premature events, according to Cornelius. However, when the 40-mg/kg dose of palbociclib was used in combination with SDX-7320, the effect reversed and survival improved compared with the 40 mg/kg dose of palbociclib alone, Cornelius explained.

SDX-7320 is a prodrug of a fumagillin-class, small molecule MetAP2 inhibitor. The prodrug is a polymer-drug conjugate comprised of a hydroxypropylmethacrylamide – methacrylamide co-polymer carrier, a specific enzyme-cleavable peptide linker, and the pharmacologically active fumagillol derivative SDX-7539.

In vivo, enzymes cleave the polymer-drug conjugate to release the active drug. Polymer-drug conjugation has many benefits, according to Cornelius. This may help limit central nervous system penetration of the small molecule, a toxicity commonly observed with other MetAP2 inhibitors, and can also solubilize the hydrophobic small molecule. Moreover, enzyme-mediated release reduces small molecule concentrations in general circulation.

References:

https://www.onclive.com/view/addition-of-sdx-7320-to-palbociclib-inhibits-tumor-growth-in-breast-cancer-xenografts