FDA Rejects Solithromycin for Bacterial Pneumonia

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) for the oral and intravenous antibiotic solithromycin (Solithera) as a treatment for patients with community-acquired bacterial pneumonia (CABP), due to concerns over hepatotoxicity and manufacturing issues.

Prior to the decision, the FDA's Antimicrobial Drugs Advisory Committee narrowly voted in favor of the benefits outweighing the risks for solithromycin (7-6). While the panel unanimously voted that the agent was effective (13-0) they felt that more evidence was needed for hepatotoxicity, which the panel felt was not adequately characterized (12-1).

In the CRL, the FDA recommended that Cempra, the company developing solithromycin, should conduct a new safety study to further characterize the liver toxicity seen with the antibiotic. This study, according to the FDA, would need to treat nearly 9,000 patients with solithromycin to effectively examine the probability of serious drug-induced liver injury.

The manufacturing plants in question were operated by Wockhardt Limited and Hospira, Inc. Cempra plans to provide an update to the FDA on activities at Uquifia, which is an alternate manufacturing facility for solithromycin.

"As the rates of antibiotic resistance continue to rise, there is an unmet medical need for new antibiotics to treat patients with CABP and Cempra is committed to working with the FDA to achieve the approval of solithromycin as quickly as possible," David Zaccardelli, Pharm.D. acting chief executive officer of Cempra, said in a statement.

Solithromycin is an oral and intravenous next-generation fluoroketolide. The agent is closely related to telithromycin, which has been associated with severe hepatotoxicity. This similarity caused the panel and the FDA to be cautious regarding the liver toxicity risks associated with solithromycin.

In the two clinical trials submitted to the FDA, solithromycin was shown to be non-inferior to moxifloxacin for the treatment of CABP. A pooled analysis from the two studies showed an early clinical response (ECR) of 77.2% with solithromycin compared with 78.9% for moxifloxacin (difference, -1.7%; 95% CI, -7.4 to 4.2). In a microbiological pooled assessment of the two studies, the ECR rates were 77.2% and 78.9%, for solithromycin and moxifloxacin, respectively (difference, -1.7; 95% CI, -7.7 to 4.2).

In the first study, known as SOLITAIRE-IV, 863 patients with CABP (PORT II-IV) were randomized 1:1 to solithromycin (n = 434) or moxifloxacin (n = 429) intravenously at 400 mg on day one with the option to step down to an oral once daily dose of each medication. The primary endpoint of ECR was assessed three days after the first dose of treatment.

The ECR in the solithromycin arm was 79.3% compared with 79.7% in the moxifloxacin group (different, -0.46%; 95% CI, -6.1 to 5.2). At short-term follow-up (SFU) visit five to 10 days post-therapy, clinical success was seen in 84.6% of those in the solithromycin arm and 88.6% in the moxifloxacin group (difference, -4.0%; -8.8 to 0.8).

In the second study, SOLITAIRE-ORAL, 860 patients with CABP (PORT II-IV) were randomized to oral solithromycin (n = 426) or oral moxifloxacin (n = 434). Solithromycin was administered for five days at a loading dose of 800 mg on day one followed by 400 mg on days two to five then a placebo for days six to seven. Moxifloxacin was given at 400 mg daily for seven days.

The ECR was 78.2% with solithromycin versus 77.9% with moxifloxacin (difference, 0.3%; 95% CI, -5.5 to 6.1). The clinical response at SFU was 84.5% with solithromycin versus 86.6% with moxifloxacin (difference, -2.1%; 95% CI, -7.1% to 2.8%).

In a pooled analysis of adverse events (AEs) from both studies, the most commonly observed AEs with solithromycin versus moxifloxacin, respectively, were diarrhea (4.3% vs 6.2%), headache (4.0% vs 3.4%), nausea (3.4% vs 2.8%), dizziness (2.3% vs 1.4%), and pneumonia (2.1% vs 1.2%). Across both studies, AEs led to treatment discontinuation for 4.2% of patients treated with solithromycin versus 3.3% with moxifloxacin.

ALT elevations of >three, >five, and >10 times the upper limit of normal (ULN) were seen in 7.2%, 2.4%, and 0.1% of patients in the solithromycin arm, as compared with 3.6%, 1%, and 0.2% of patients in the moxifloxacin group. ALT elevation was more common with IV-to-oral administration. The peak ALT elevations >three and >five times the ULN, respectively, were 9.1% and 3.1% with solithromycin versus 3.6% and 0.7% in the moxifloxacin arm.

In addition to CABP, solithromycin is also being explored in a phase 3 study for patients with uncomplicated urogenital gonorrhea (NCT02210325).