FDA Review of Novel Antibiotic by Cempra Raises Concerns Over Infusion Reactions & Liver Toxicity


Recently, FDA reviewers met to discuss a new drug application submitted by Cempra Pharmaceuticals to treat community-acquired bacterial pneumonia.

On November 4, 2016, reviewers from the US Food and Drug Administration (FDA) met in a public meeting to discuss a new drug application submitted by Cempra Pharmaceuticals. If approved, the medication in question, solithromycin, would be indicated for treatment of community-acquired bacterial pneumonia.1

Solithromycin is a macrolide-type antibiotic that binds to bacterial RNA to disrupt bacterial protein synthesis. However, unlike existing macrolides, solithromycin binds to an additional ribosomal RNA site that is involved in macrolide resistance.1

Solithromycin is most similar to an existing macrolide known as telithromycin. Both solithromycin and telithromycin belong to the ketolide subclass of macrolide antibiotics. Given the potential for hepatic toxicity and heart rhythm disturbances with telithromycin, the approval has previously been described by one FDA safety reviewer—David Graham, MD, MPH—as a mistake.2

After the approval of telithromycin, Dr. Graham wrote, “It's as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned.” Regarding evidence of the safety and efficacy of telithromycin, Graham noted, “We don't really know if the drug works; no one is claiming it works better than other, safer drugs; and we're flying blind as far as safety goes, except for our own [adverse drug reaction] data that suggests telithromycin is uniquely more toxic than most other drugs.”2

Solithromycin, like telithromycin, was developed to address increasing rates of macrolide resistance in common infectious bacteria, such as Streptococcus pneumoniae. Unfortunately, like telithromycin, questions pertaining to the safety of solithromycin have raised doubt about whether or not the treatment should be approved.1,3

During the clinical development of solithromycin, several issues have been raised, including nonclinical evidence of hepatotoxicity, significant potential for drug-drug interactions, and a narrow therapeutic margin for the medication.1

Nonclinical toxicology data with solithromycin indicates substantial hepatic metabolism of the medication in rats and monkeys when administered orally. The medication is also a potent inhibitor of CYP3A4. Distribution of solithromycin favors the liver, spleen, gastrointestinal tract, and lung. Animal studies have also indicated potential safety issues related to hepatic dysfunction and infusion-site reactions.1

Phase III studies of solithromycin in humans compared the medication with moxifloxacin—a fluoroquinolone-type antibiotic commonly used to treat respiratory tract infections. Two studies were undertaken: 1) a study comparing a 5-day course of oral solithromycin versus a 7-day course of oral moxifloxacin, and 2) a study comparing intravenous use of solithromycin or moxifloxacin followed by a 7-day course of oral therapy.1

Both studies evaluated a primary efficacy end point of early clinical response (ECR) based on changes in symptoms of cough, dyspnea, chest pain, and sputum production. In both studies, ECR rates were slightly lower than 80% in patients receiving solithromycin and moxifloxacin, with no significant differences in efficacy detected in either trial.1

In the study evaluating oral therapy, 78.2% of patients receiving solithromycin and 77.9% of patients receiving moxifloxacin met criteria for ECR (margin: 0.3%; 95% CI: -5.5% to 6.1%). Similarly, in the intravenous-to-oral study, 79.3% of patients receiving solithromycin and 79.7% of patients receiving moxifloxacin met criteria for ECR (margin: 0.5%; 95% CI: -6.1% to 6.2%). Both studies confirmed the noninferiority of moxifloxacin and solithromycin on the primary outcome.1

Although treatment with moxifloxacin and solithromycin were noninferior in terms of the primary efficacy parameter, important differences in product safety were identified. Elevations in hepatic transaminases occurred more frequently in patients receiving solithromycin than in patients receiving moxifloxacin. Additionally, in patients receiving intravenous solithromycin, infusion-site reactions occurred in nearly one-third (31.3%) of patients. By contrast, infusion-site reactions occurred in just 5.2% of patients receiving intravenous moxifloxacin.1

Despite the recognized need for novel antibiotics, concerns over solithromycin and its predecessor, telithromycin, raise serious doubts as to whether this medication will be approved. Consistent with these concerns, shares of the pharmaceutical company commercializing solithromycin—Cempra Pharmaceuticals—fell by nearly 50% following the FDA meeting.1,4


1. US FDA. FDA briefing document: solithromycin oral capsules and Injection. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM527690.pdf. Published November 6, 2016. Accessed November 11, 2016.

2. Turner H. FDA official wants ketek support withdrawn. www.lawyersandsettlements.com/articles/drugs-medical/ketak_FDA_official-00245.html. Published July 26, 2006. Accessed November 11, 2016.

3. FDA. Ketek (telithromycin): briefing document. www.fda.gov/ohrms/dockets/ac/03/briefing/3919B1_01_Aventis-KETEK.pdf. Published January 2003. Accessed November 11, 2016.

4. Clarke T. FDA highlights liver safety issues in Cempra drug review. www.reuters.com/article/us-cempra-antibiotic-fda-idUSKBN12X1HW.6.Published November 2, 2016. Accessed November 11, 2016.

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