In the preclinical studies, the combination therapy had an additive effect, inhibiting tumor growth by up to 97% in an irinotecan-resistant mouse xenograft model of colorectal cancer (HT29), which was greater than monotherapy with either NKTR-102 or bevacizumab. NKTR-102 at 46mg/kg, co-administered with bevacizumab, also resulted in eight partial tumor regressions and one complete tumor regression. This compares to no tumor regressions observed with bevacizumab monotherapy, and two partial regressions and one complete regression with NKTR-102 monotherapy. NKTR-102 alone, and in combination with bevacizumab, was well-tolerated, with minimal weight loss.
NKTR-102 also exhibited superior pharmacokinetics in a repeated dose study in dogs, with a six-fold increase in exposure and a four-fold lower peak plasma concentration of SN38, the active metabolite of irinotecan, as compared to the equivalent dosing of irinotecan. In animal models, NKTR-102 had a markedly improved safety and tolerability profile when compared to irinotecan in animal models.
Tim Riley, vice president of PEGylation Research at Nektar, said: “These data reinforce our confidence in the potential of our small molecule PEGylation technology platform to improve the therapeutic potential of oncolytics that are widely used to treat cancer.”