), (ii) induction of mild sellckchem levels of antinanoparticle (specifically, anti-Tf)

antibodies that did not affect pharmacokinetics, (iii) elevation in IL-6 at the highest (27mg/kg) dose level, and (iv) identification of relatively fast nanoparticle clearance from circulation (t1/2 < 30min). Importantly, the overall safety profile indicated good tolerability at the 3 and 9mg/kg dose levels, in the range for which antitumor effects had been observed. Additional (unpublished), more comprehensive toxicology and safety-pharmacology studies were performed in four species (mouse, Inhibitors,research,lifescience,medical rat, dog, and nonhuman primate) which provided a foundation for an initial clinical dose level and anticipated toxicities. In terms of efficacy, a twice-weekly dosing regimen of CALAA-01 yielded a significant reduction in tumor burden in mouse subcutaneous tumor models, including liver and melanoma [42], at dose levels in the range of 2.5–10mg/kg. CALAA-01 preclinical evaluation culminated in the submission of an Investigational

Inhibitors,research,lifescience,medical New Drug (IND) application which received approval in April 2008. Shortly thereafter, a first-in-humans phase I investigation of CALAA-01 in patients having solid tumors was initiated. Patients who were refractory to standard-of-care Inhibitors,research,lifescience,medical treatment received four twice-weekly infusions (days 1, 3, 8, and 10) during a 21-day cycle over which numerous safety evaluations were made. CT assessments of tumor burden were performed, and PET assessment of tumor metabolism was also Inhibitors,research,lifescience,medical made. For volunteers willing to provide biopsies, assessments of RRM2 levels and investigation of the RNAi mechanism of action were also performed. At the time of this writing, a phase Ib study remains open, but interim clinical data have been published [26, 27]. Several dose level escalations spanning an order of magnitude (3, 9, 18, 24, and 30mg/m2) have

been tolerated, and key observations of RRM2 downregulation have been made Inhibitors,research,lifescience,medical in multiple patients. Pharmacokinetics indicate relatively fast clearance, consistent with preclinical findings, and some transient elevations in cytokines (IL-6, IL-10, and TNF-α) were seen. Importantly, the first evidence of the RNAi mechanism in humans (for any siRNA) and the first evidence of dose-dependent tumor accumulation of nanoparticles administered systemically in humans (for any nanoparticles) have been observed in this Drug_discovery study (Figure 10). Taken together, these early indications of safety and efficacy suggest potential for CALAA-01 and the RONDEL platform for continued clinical investigation. Figure 10 Interim data from a first-in-man, phase I clinical evaluation of CALAA-01 reveals RRM2 down regulation via an RNAi mechanism of action. (a) Measurements of RRM2 mRNA or protein levels in tumor inhibitor Tofacitinib biopsies from three patients (A, B, and C2) obtained before … 8.