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FDA Staff Cites Liver Safety Issues With Pneumonia Drug Solithromycin

Semisynthetic macrolide set for regulatory review

Solithromycin (Solithera, Cempra Pharmaceuticals), an experimental drug to treat community-acquired bacterial pneumonia (CABP), causes a potentially concerning rise in liver enzymes, according to a preliminary review by FDA staff. The review comes two days ahead of a meeting of the agency’s Antimicrobial Drugs Advisory Committee, who will discuss whether solithromycin should be approved.

Solithromycin is a semisynthetic antibacterial drug of the macrolide class/ketolide subclass developed for the treatment of CABP caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, methicillin-susceptible Staphylococcus aureus, Legionella pneumophila, and Mycoplasma pneumoniae. As with other macrolides, solithromycin binds to bacterial 23S ribosomal RNA to disrupt protein synthesis. In addition, it binds to an extra site on the rRNA that has the potential to confer activity against bacteria with macrolide-resistance mechanisms. Solithromycin is similar to telithromycin (Ketek, Sanofi-Aventis), the only other approved ketolide.

Two phase 3 studies of solithromycin (CE01-300 and CE01-301) were conducted between 2013 and 2015. Each was a randomized, double-blind, multicenter noninferiority trial comparing solithromycin with moxifloxacin. CE01-300 evaluated a five-day oral solithromycin regimen, whereas CE01-301 evaluated a seven-day intravenous-to-oral solithromycin regimen. In each trial, the primary efficacy endpoint was an early clinical response (ECR). In both studies, solithromycin and moxifloxacin had almost identical response rates of slightly less than 80% for the ECR endpoint.

According to the FDA staff, however, a significant safety signal for hepatotoxicity was observed in the solithromycin development program. The rates of transaminase elevations were higher in solithromycin-treated patients than in those treated with moxifloxacin and were related to solithromycin exposure. The high rate of infusion site-related reactions associated with solithromycin (31.3%) compared with moxifloxacin (5.2%) was another safety concern.

Noting the structural similarity between solithromycin and telithromycin, the reviewers pointed out that, despite a low occurrence of hepatic events in the initial telithromycin new drug application safety database of almost 3,400 patients, the post-marketing phase was marked by the occurrence of more than 40 cases of severe telithromycin-related hepatotoxicity resulting in four deaths and a liver transplantation.

The reviewers further noted that in the phase 3 pooled safety database, overall alanine aminotransferase (ALT) elevations of more than three times the upper limit of normal (ULN), more than five times the ULN, and more than 10 times the ULN were seen in 7.2%, 2.4%, and 0.1% of patients, respectively, in the solithromycin arm compared with 3.6%, 1.0%, and 0.2% of patients in the moxifloxacin arm. This incidence was particularly marked in the intravenous-to-oral study (CE01-301) where the incidences of peak ALT elevations of greater than three times the ULN and greater than five times the ULN were 9.1% and 3.1%, respectively, in the solithromycin arm compared with 3.6% and 0.7% in the moxifloxacin arm.

“Despite the differences in chemical structure, the hepatic adverse effects seen with solithromycin during its development program exceed the pre-marketing hepatic signal seen with telithromycin,” the reviewers wrote. They added: “Significant gaps in knowledge of the hepatic toxicity profile of solithromycin exist.”

Sources: Reuters; November 2, 2016; and FDA Briefing Document; November 2, 2016.

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