Cempra, a clinical-stage pharmaceutical company developing differentiated antibiotics to meet critical medical needs in the treatment of bacterial infections, has described the steps expected for regulatory approval for solithromycin for community-acquired bacterial pneumonia (CABP). This path is a result of a dialogue and end-of-phase II meeting with the FDA.
"We were pleased with the FDA input and believe we are in a position to proceed with our second phase III study and the rest of the clinical program, subject to receipt of the necessary funding,” said Prabhavathi Fernandes, Ph.D., president and chief executive officer of Cempra. “We know the requirements for the CABP safety database and efficacy endpoints for NDA submission. In addition, we received preliminary feedback on the trial design for the uncomplicated gonococcal infection indication."
The phase III solithromycin clinical program in CABP will be planned to consist of an oral trial and an intravenous (IV)-to-oral clinical trial.
Cempra followed the CABP guidance the FDA proposed in a 2011 meeting of the Anti-Infective Drugs Advisory Committee. The FDA commented on the phase III oral CABP protocol in June, 2012, and this global study is ongoing. This study compares five days of oral solithromycin with seven days of oral moxifloxacin. FDA responses prior to and at the end-of-phase II meeting addressed the second phase III study, the planned intravenous-to-oral step-down trial.
In the IV-to-oral phase III study, approximately 800 patients with Port II to Port IV CABP will be randomized to either a 400mg IV dose of solithromycin or 400mg IV dose of moxifloxacin. The investigator will switch patients to oral administration of the assigned antibiotic (solithromycin or moxifloxacin) based on protocol-defined clinical criteria. Patients randomized to solithromycin will receive an 800mg loading dose on the first day of oral administration followed by 400mg once daily for a total of seven days of treatment, while patients randomized to moxifloxacin will receive 400mg once daily for a total of seven days of treatment.
The primary outcome analysis in both phase III trials is non-inferiority (NI) in the early clinical response rates (ECR). ECR is defined as improvement at 72 hours after the first dose of study drug, in at least two of the following four symptoms: cough, shortness of breath, chest pain and sputum production in the Intent-To-Treat (ITT) population. Each study is designed to provide 90% power to demonstrate NI in ECR rates of solithromycin versus moxifloxacin utilizing a 10% margin.
A co-primary outcome analysis will assess NI in ECR rates in the pooled microbiological ITT (mITT) population from the two studies. Secondary endpoints include the clinical success rate at the short-term follow-up visit five to 10 days following the last dose of study drug in the ITT and clinically evaluable populations and a comparison of safety and tolerability of solithromycin compared to moxifloxacin.
A single phase III study of solithromycin in uncomplicated gonococcal infection would likely be sufficient if the phase III CABP trials are successful. This study would be planned to include 250 patients who receive solithromycin, of which 150 are males. Treatment of Chlamydia may be included as a secondary endpoint. The specific protocol remains under discussion.