Abstract 3364: A randomized, placebo-controlled study of the tolerability, pharmacokinetics, and pharmacodynamics of the oral JAK2 inhibitor SAR302503 in healthy volunteers.
Authors: Zhang Meng , Xu Christine R. , Shamiyeh Elias , Liu Feng , Yin Jianyun , von Moltke Lisa L. , Smith William B. 
Published: August 2014

Abstract
Background: SAR302503 is a JAK2 inhibitor in clinical development as a treatment for myelofibrosis (MF). In a phase 1/2 study, SAR302503 provided durable reductions in spleen size and disease-related symptoms, with an acceptable safety profile in patients with MF (J Clin Oncol 2011;29:789).
Methods: Healthy males between 18 and 45 years of age received seven ascending single oral doses of SAR302503 (range, 10 to 680 mg) or placebo under fasted conditions. Blood was collected before the first dose and at intervals after dosing up to 72 hrs. For the 300, 500, and 680 mg doses, samples were also collected postdose at 104 hrs and 168 hrs. Dose proportionality was assessed using an empirical power model for log-transformed Cmax, AUClast, and AUC. Dose effect was analyzed using a linear fixed effect model for log-transformed t1/2z. STAT3 phosphorylation (pSTAT3) was measured at predose, and 3 and 24 hrs postdose. The relationship between pSTAT3 suppression and SAR302503 plasma concentration was explored using an inhibitory Emax model.
Results: Fifty-six subjects were treated and included in the safety assessment and 37 in the PK evaluation. Treatment-emergent adverse events (MedDRA v14.1) were all mild in intensity and reported by 20 of 42 subjects (48%) who received SAR302503 and by 3/14 (21%) who received placebo. There were no deaths or serious adverse events. The most frequently reported adverse events with SAR302503 were gastrointestinal occurring in 1 of 6 subjects at both the 80 and 150 mg doses, 3/6 at 300 mg, 4/6 at 500 mg, and 5/6 at 680 mg. Vomiting occurred in 1/6 and 4/6 subjects at 500 mg and 680 mg, respectively. SAR302503 was absorbed with a median tmax of 1.8 to 3.0 hrs. Mean t1/2z ranged from 62.1 to 78.2 hrs at the 300 to 680 mg doses with sampling to 168 hrs. SAR302503 exposure increased in a greater than dose-proportional manner, with a 68-fold increase in dose resulting in 473- and 989-fold increases in Cmax and AUClast, respectively. Dose had no effect on t1/2z. Subjects receiving a single dose of 300, 500, or 680 mg of SAR302503, demonstrated a reduction in pSTAT3 levels, indicative of JAK2 inhibition. The mean pSTAT3 levels 3 hrs postdose were 76%, 50%, and 42% of predose levels in the 300, 500, and 680 mg groups, respectively. The relationship between SAR302503 plasma concentration and pSTAT3 inhibition was described by an inhibitory effect sigmoid maximum effect Emax model, with an EC50 of 1230 ng/mL.
Conclusion: Adverse events associated with SAR302503 treatment were mild and primarily gastrointestinal. Following administration of single daily oral doses, SAR302503 exposure appeared to increase in a greater than dose-proportional manner. pSTAT3 inhibition was observed at doses of 300 mg and above.
Citation Format: Meng Zhang, Christine R. Xu, Elias Shamiyeh, Feng Liu, Jianyun Yin, Lisa L. von Moltke, William B. Smith. A randomized, placebo-controlled study of the tolerability, pharmacokinetics, and pharmacodynamics of the oral JAK2 inhibitor SAR302503 in healthy volunteers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3364. doi:10.1158/1538-7445.AM2013-3364