Pooled data from phase 2 and phase 3 studies suggest the efficacy and safety of Paratek Pharmaceuticals' investigational broad-spectrum antibiotic omadacycline is comparable to Zyvox in the treatment of complicated skin and skin structure infections in adults.
Omadacycline is the first drug in a new class of tetracyclines known as aminomethylcyclines, and is being developed as a once-daily IV and oral therapy. The drug also is being tested in a phase 3 trial for community-acquired bacterial pneumonia.
“The data from this pooled analysis give us additional confidence as we await the results of our phase 3 study of oral and IV omadacycline in acute bacterial skin and skin structure infections, for which we expect to report top-line results as early as the end of June this year,” Evan Loh, MD, president and chief medical officer of Paratek, told Infectious Disease News. “We look forward to sharing the full data from that study at a medical meeting in the fall. We are continuing to enroll patients in our phase 3 study of oral and IV omadacycline in community-acquired bacterial pneumonia. These combined studies, if successful, will pave the path forward for omadacycline to be available for the treatment of serious community-acquired infections where resistance is of concern."
Data presented at ECCMID 2016 were pooled from a phase 2 and a truncated phase 3 study in which adults with complicated skin and skin structure infections (cSSSIs) were given either 100 mg IV omadacycline once daily with the option of transitioning to a 200 mg or 300 mg oral daily dose, or 600 mg IV Zyvox (linezolid, Pfizer) twice daily with the option of stepping down to a twice-daily oral dose of 600 mg. Treatment lasted between 7 and 14 days, and the clinical success of each treatment was evaluated at a test-of-cure visit. Paratek explained that enrollment in the phase 3 trial was truncated due to an industrywide change in FDA regulatory guidance pertaining to the primary endpoint for serious skin infections — a change that went into effect during the conduct of the study. Accordingly, the study design was not anticipated to meet the contemplated change in the primary endpoint; thus, the study was terminated from further enrollment.
The pooled analysis included 377 patients with cSSSIs who were randomly assigned 1:1 to omadacycline or linezolid. In the intent-to-treat population (n = 359), 87.2% of patients taking omadacycline had clinical success compared with 81.1% of those taking linezolid (difference, 6 percentage points [95% CI, –1.8 to 13.9]). In the clinically evaluable population (n = 315), clinical success was reported in 97.5% of patients assigned omadacycline vs. 94.2% in those assigned linezolid (difference, 3.3 [95% CI, –1.4 to 8]).
According to the researchers, rates of adverse events were comparable between the two study arms (58% for omadacycline and 62.8% for linezolid), with gastrointestinal conditions being the most common (28.5% and 26.1%, respectively).
Low risk for cardiovascular toxicity
In a separate clinical study of healthy adults, researchers evaluated the effects of omadacycline on ventricular repolarization and the relationship between plasma concentrations of the drug and QTc intervals. Sixty-four participants who underwent a baseline electrocardiogram (ECG) were randomly assigned either a single dose of 100 mg or 300 mg IV omadacycline, 400 mg oral moxifloxacin, or placebo. After dosing, participants were Holter monitored continuously for 24 hours with an ECG, and omadacycline plasma concentrations were measured at set time points for 96 hours.
According to the researchers, omadacycline did not prolong QTc intervals when administered at either dose. Within 1 hour of dosing, patients who received 100 mg and 300 mg IV omadacycline experienced a mean maximal increase in heart rate of 17 bpm and 24 bpm, respectively, compared with an increase of 5 bpm in the moxifloxacin group and 3 bpm in the placebo group. The increases in heart rate lasted only for several hours and were asymptomatic, the researchers said, and both the 100 mg and 300 mg doses were well-tolerated.
Consistent with preclinical studies, these results suggest omadacycline has a low potential for cardiac arrhythmia or clinically significant cardiovascular toxicity, the researchers concluded. – by John Schoen
Tzanis E, et al. Abstract P1326. Presented at: European Congress of Clinical Microbiology and Infectious Diseases; April 9-12, 2016; Amsterdam.
Villano S, et al. Abstract P1321. Presented at: European Congress of Clinical Microbiology and Infectious Diseases; April 9-12, 2016; Amsterdam.
Disclosures: Loh, Tzanis and Villano are employed by Paratek.