Single Oral Dose Pharmacokinetics and Safety of CEM-101 in Healthy Subjects (2008)

Poster # F1-3972a Study Design and Methodology Results J. Gordon Still, MD, PhD 6340 Quadrangle Dr., Suite 100 Chapel Hill, NC 27517 (919) 467-1716 gstill@cempra.com Background: CEM-101 is a potent new ketolide currently under development for treatment of respiratory tract infections CEM-101 pharmacokinetics and safety following escalating single oral doses administered under fasting Objectives Subjects F t i bj t (30 l d 19 f l ) b t 19 d 55 f ll d ll • Across the doses studied, the mean Cmax and mean AUCinf ranged . conditions were investigated in this first-in-human study. Methods: This was a Phase 1, randomized, double-blind, placebo-controlled, dose escalation study. Escalating single doses (50, 100, 200, 400, 800, 1200, and 1600 mg) were administered to seven groups of healthy adult subjects using 50, 100, or 200 mg CEM-101 or matching placebo capsules. Within each dose group, 5 subjects received CEM-101 and 2 received placebo. Dose escalation proceeded only after the safety of the previous dose was determined. Physical examinations, vital signs, ECGs, clinical laboratory tests, and adverse events (AEs) were monitored throughout the study. Blood samples for assay of CEM-101 concentrations and pharmacokinetic assessment were collected pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16, 24, 36, 48, and 72 h post-dose. Results: Over the dose range studied, the mean CEM-101 T1/2 ranged from 2.2 to 7.9 h. The median Tmax increased from 1.5 h at 50 mg to 6 h at 1600 mg. The mean Cmax and AUC0-inf ranged from 22.3 ng/mL and 81.5 ng•h/mL to 1970 ng/mL and 28900 ng•h/mL over the dose range. The Cmax and AUC0-inf increases were more than proportional across the dose range. These doses of CEM-101 were safe and generally well tolerated. AEs were reported in 12 of the 49 (24%) study subjects all mild or moderate in severity The most common AE was • To determine the safety and tolerability of single escalating doses of oral CEM-101. • To determine the pharmacokinetic (PK) profile of single escalating doses of oral CEM-101. Study Design and Selection Criteria • This was a Phase 1, randomized, double-blind, placebo-controlled, flexible dose escalation study. • Forty-nine healthy adult subjects were enrolled in 7 dosage groups. • Subjects were admitted to the clinical research unit on the day prior to dosing and remained in the unit for 72 hours post-dose. Safety follow-up was made by phone 7 days post-dose. • Key selection criteria: Healthy males and non-pregnant females 19 to 55 years of age. Body mass index (BMI) 18 to 30 kg/m2; total body weight >60 kg • or y-n ne su ec s ma es an ema es e ween an years o age were enro e ; a completed the study. • No significant differences were noted in demographics of CEM-101 and placebo groups. Safety and Tolerability • AEs were reported in 12 of the 49 study subjects (25%) following study drug administration; all AEs were of mild or moderate severity. • The most common AE was headache, occurring in 9 subjects (5 received CEM-101 and 4 received placebo). • For most of the AEs, no pharmacologic treatment was required. Five subjects received acetaminophen for headache, musculoskeletal pain, or low back pain. • Complaints of nausea and/or diarrhea were seen in 2 CEM-101 subjects in the 1200 and 1600 mg dose cohorts (associated with dizziness, palpitations, and symptoms of gastroesophageal reflux in 1 subject in the 1600 mg cohort) suggesting possible gastrointestinal intolerance beginning at these dose levels from 22.3 ng/mL and 81.5 ng•h/mL to 1960 ng/mL and 28900 ng•h/mL. • The Cmax and AUC increases were more than proportional across the range of doses studied. However, in the 1600 mg cohort, the mean Cmax was slightly lower than the mean Cmax in the 1200 mg cohort and the mean AUC values were slightly higher and displayed less than dose proportional increases compared with the 1200 mg cohort. These results are due to markedly lower plasma CEM-101 concentrations in one subject relative to the other four subjects that received active drug in the 1600 mg cohort. When the data from the subject with outlying values is excluded, the mean Cmax is 2153 ng/mL and the mean AUCinf is 34775 ng•h/mL, which represents an approximately dose-proportional increase in exposure over the 1200 Introduction , . headache, occurring in 9 subjects. Nausea and/or diarrhea were seen in 2 subjects in the 1200 and 1600 mg dose cohorts, suggesting possible gastrointestinal intolerance beginning at these doses. Conclusion: Over the 50 mg to 1600 mg dose range, CEM-101 was safe and generally well tolerated in healthy male and female subjects. Cmax and AUC0-inf increases were more than dose proportional across the dose range administered. CEM-101 (Figure 1) is a new macrolide antibiotic of the ketolide subclass under development for treatment of patients with community-acquired bacterial respiratory tract infections, in particular those caused by multi-drug resistant Streptococcus pneumoniae. CEM-101 binds to the 50S unit of bacterial ribosomes and inhibits bacterial protein synthesis. It has physicochemical and pharmacologic properties similar to other macrolides, but differs in h i h d tib t i l ti it i t tibl d i t t i i l di S i β . Negative pregnancy test and appropriate contraceptive methods for females of childbearing potential. Subjects with clinically significant organ disease excluded. Drug or alcohol abusers and tobacco users excluded. Subjects with history of hypersensitivity to macrolides excluded. Subjects with QTc >450 msec (470 msec for females) excluded.