Solithromycin, a 4th Generation Macrolide and the 1st Fluoroketolide, Does Not Prolong the QTc Interval: Results of a Definitive QT Study Borje Darpo1,, Sager Philip2, Meijian Zhou3, Brian Jamieson4, Prabhavathi Fernandes4, Kara Keedy4, David Oldach4 LBEV0081a 1Karolinska Institute- Division of Cardiovascular Medicine- Department of Clinical Sciences- Danderyd’s Hospital- Stockholm- Sweden. 2Stanford University School of Medicine, San Francisco, USA. 3iCardiac Technologies- Inc.- 150 Allens Creek Road- Rochester 14618- NY- USA. 4Cempra- Inc., Chapel Hill, USA. INTRODUCTION AND PURPOSE RESULTS

The rapid emergence of macrolide resistance over the past few years has The geometric mean solithromycin peak plasma concentration (Cmax)was Solithromycin did not have a clinically meaningful effect on the PR or become a major problem among clinicians and public health 5.7 µg/mL (mean AUCtau 23.4 µg*hr/mL. For subjects randomized to QRS interval. Mean ∆∆PR was 2.0 ms or below during the first 8 hours professionals. This has limited the therapeutic options for treatment of receive solithromycin, the mean placebo adjusted QTcF change from after the infusion and mean ∆∆QRS was within + 0.5 ms at all post- respiratory infections. Solithromycin, a 4th generation macrolide and the baseline < 3.0 ms at all timepoints. The largest solithromycin ∆∆QTcF was dosing timepoints. first fluoroketolide, is being developed as oral, intravenous, and pediatric observed at Hour 4, with an estimate of only 2.8 ms (upper bound, 90% suspension formulations for the treatment of community-acquired CI, 4.9 ms) (Figure 1).Ontheotherhand,QTcprolongationwasHowever, in this study, the 800 mg solithromycin infusion caused a peak bacterial pneumonia (CABP). Solithromycin has demonstrated potent in observed after dosing with oral moxifloxacin (also Figure 1). Specifically, effect on heart rate (HR) with a mean change from baseline of about 15 vitro activity against key respiratory pathogens, including Streptococcus the ∆∆QTcF was 9.7 ms, 9.8 ms, and 10.9 ms at 3 pre-defined timepoints bpm. After peaking at the end of the infusion, the mean change from pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, as well as (Hour 2, 3, and 4) with the lower bound of the 90% CI above 5 ms (7.6 ms, baseline for HR for solithromycin continued to decrease at all timepoints. atypical pathogens (Legionella pneumophila and Mycoplasma 7.7 ms, and 8.7 ms) at each timepoint. pneumoniae). Due to its extended spectrum of activity and In a concentration-effect analysis, a statistically significant, negative slope pharmacological properties, Solithromycin could also be used for other Figure 1: Placebo-Adjusted QTcF Change from Baseline for Solithromycin of solithromycin concentration versus QTcF change was observed (-0.862 indications, such as bacterial urethritis, tuberculosis, malaria, and and Moxifloxacin x10-3 ms per ng/mL) (Figure 3). biodefense.

Some medicinal products have been shown to have proarrhythmic Figure 3: Relationship Between the Individually Observed Solithromycin potential and may induce a potentially lethal QT-prolongation associated Plasma Concentrations and QTcF ventricular tachycardia known as torsades de pointes [1]. Antibiotics, specifically respiratory fluoroquinolones such as moxifloxacin and levofloxacin, along with older macrolides like erythromycin, clarithromycin, and even azithromycin, can cause QT prolongation [1].

Due to the fact that solithromycin is a member of the macrolide class, the primary objective of this study was to evaluate the effects of a supratherapeutic IV dose of solithromycin on cardiac repolarization (duration of QTc interval), using the method for heart rate correction (QTcF or an optimized subject-specific QTc) chosen by a prospectively defined test. Figure 2 shows that for moxifloxacin, the mean change from baseline for MATERIALS AND METHODS QTcF (for all 9 timepoints) was much greater than that observed for This was a Phase 1, single center, 3-way cross-over, placebo- and active solithromycin, peaking around 12 ms at 0.67 and 1 hr after dosing. The controlled, double-blind, randomized trial. A total of 48 subjects (33 change-from-baseline QTcF (∆QTcF) was similar after dosing with 800 mg males, 15 females) were randomly assigned to 1 of 6 different treatment IV solithromycin (peak of 2.3 ms at 0.67 hr) and placebo (IV saline). sequences. Each treatment sequence was comprised of the following 3 treatment periods: Day 1, Day 8, and Day 15, where study drugs were Figure 2: QTcF Change from Baseline for Moxifloxacin, Solithromycin, CONCLUSIONS administered in the morning (t=0) after subjects had fasted for 8 hrs. and Placebo Solithromycin was administered intravenously as an 800 mg dose over a Unlike respiratory fluoroquinolones and older macrolide antibiotics, 40 minute infusion period while Moxifloxacin was given once orally at a solithromycin does not prolong the QTc interval, even at supratherapeutic dose of 400 mg. The placebo control was intravenous 0.9% sodium doses. In addition, solithromycin had no clinically meaningful effect on the chloride. cardiac conduction parameters, PR and QRS interval. An increase in heart rate was observed. In a recent Phase 3 trial for CABP in which Continuous 12-lead ECGs were captured for 25 hours (starting 1 hour solithromycin was administered orally, the mean daily heart rate in before dosing and continuing until 24 hours after time 0) using a Holter patients decreased following dosing, suggesting that this physiologic recorder. Serial ECGs and blood samples for PK analysis were collected response will differ between patients with disease and healthy volunteers, through 24 hours after study drug administration. and is dose related. The results from this trial constitute a definitively negative TQT study (as defined by the ICH guidance [2]). Solithromycin The effect of study drugs (either solithromycin or moxifloxacin) on other does not prolong QT. important ECG parameters such as heart rate and PR and QRS intervals was also assessed. In addition, the relationship between plasma REFERENCES concentrations of Solithromycin and its effect on QTc was determined. 1. European Medicines Agency. Committee for Proprietary Medicinal Products (CPMP). Points to consider: The assessment of the potential for QT interval prolongation by noncardiovascular medicinal products. London, UK: European Medicines Agency; 1997. CPMP/986/96. 2. Food and Drug Administration, HHS. International Disclosures: This clinical trial was sponsored by Cempra, Inc. Conference on Harmonisation; guidance on E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs; availability. notice. Fed Regist. 2005;70(202):61134-5.