FDA committee says efficacy of solithromycin for CABP outweighs risks

Today, the FDA’s Antimicrobial Drugs Advisory Committee voted 7-6 in favor of two new drug applications for an oral and IV formulation of solithromycin, submitted by Cempra Pharmaceuticals, for the treatment of community-acquired bacterial pneumonia.

The committee met to discuss whether the efficacy results of solithromycin for the treatment of community-acquired bacterial pneumonia (CABP) outweigh the risks associated with the agent.

The FDA decided to review solithromycin based on favorable results from two phase 3 trials. The first of these, SOLITAIRE-Oral, demonstrated oral solithromycin’s noninferiority to moxifloxacin therapy among patients with identified Mycoplasma pneumoniae infection (early clinical response absolute difference, 0.29%; 95% CI, –5.5 to 6.1). More recently, SOLITAIRE-IV demonstrated similar outcomes between IV-to-oral solithromycin and moxifloxacin regimens (early clinical response absolute difference, –0.46; 95% CI, –6.1 to 5.2), regardless of macrolide resistance.

Despite these outcomes, the FDA cited concerns regarding the safety profile of solithromycin. According to the agency, a range of liver injury patterns was observed in patients with CABP, healthy volunteers and a small number of patients who received solithromycin for other conditions. In addition, the FDA stated that solithromycin is structurally related to FDA–approved telithromycin, which in a post-market analysis was linked to four hepatotoxicity-related deaths and one liver transplantation.

Paul Watkins, MD, professor at the University of North Carolina, director of the university’s Center for Drug Safety Sciences, and a paid consultant for Cempra, said the company would investigate the cases with the FDA.

“We are committed to the responsible use of this antibiotic and we want to have it available,” he said. “We have no desire to harm patients in any way.”

Prabhavathi Fernandes

The recommended dose for solithromycin is 400 mg IV once a day for 7 days. In patients switching from the IV to oral formulation, the company proposed a loading dose of 800 mg followed by 400 mg daily to complete the 7-day course. However, Prabhavathi Fernandes, PhD, president and CEO of Cempra, said during the deliberation that the company agreed with an FDA recommendation to withdraw the 800-mg loading dose of oral solithromycin because it was associated with an increase in alanine aminotransferase (ALT) levels.

During the voting process, all 13 members unanimously agreed that there was substantial evidence that solithromycin is effective against CABP. However, only one member said the risk for hepatotoxicity with solithromycin was adequately characterized. Most members said there were a lack of data on ALT elevations and expressed concern with the small sample size of patients in the phase 2 and 3 trials.

Among the seven members who said the benefits of solithromycin outweigh the risks, many said they were influenced by the threat of antibiotic resistance and limited treatment options for CABP.

FDA advisory committee member Michael Green, MD, MPH, who disagreed with the majority vote, said he could have been persuaded to vote in favor of the drug had Cempra offered a better plan for reporting adverse events.

“If they told me one or two cases would make them pause and withdraw, I could have voted yes with an understanding that they would try to work out some sort of an understanding with the FDA,” he said. – by Stephanie Viguers

Disclosures: Fernandes is president and CEO of Cempra. Watkins is a paid consultant for Cempra. Infectious Disease News was unable to confirm other participants’ relevant financial disclosures at the time of publication.