FDA News

FDA requires more safety data for approval of solithromycin for CABP

The FDA issued a complete response letter to Cempra Inc. stating that the company must provide additional safety data and resolve manufacturing facility inspection deficiencies before the agency can approve two new drug applications for the company’s investigational oral and IV formulation of solithromycin for the treatment of community-acquired bacterial pneumonia, according to a press release.

The FDA did not request additional information regarding the efficacy of solithromycin for community-acquired bacterial pneumonia (CABP).

In November, the FDA’s Antimicrobial Drugs Advisory Committee voted 7-6 in favor of the new drug applications 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). Meanwhile, the SOLITAIRE-IV trial 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. Further, the FDA reported 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.

The recent CRL stated that the size of the safety database, which was limited to 920 patients, is “too small to adequately characterize” the risk for serious hepatic adverse events. The agency recommended a comparative study involving approximately 9,000 patients to further evaluate the safety of solithromycin.

“Our immediate plan is to meet with the FDA as quickly as possible to discuss in more detail the clinical protocol design, including the definition of the safety endpoints that would satisfy the requirements of the FDA,” David Zaccardelli, PharmD, acting CEO of Cempra, said during a conference call today. “Of course, the exact timetable and costs for any future clinical study will depend on its feasibility, scope, duration and complexity.”

The CRL further noted that labeling for solithromycin must include information on the potential risk for hepatotoxicity, limiting its use to patients with limited treatment options. A comprehensive plan for post-marketing safety assessments is also needed.

In addition to insufficient safety data, the CRL stated that an FDA field investigator identified deficiencies during recent inspections of the company’s Wockhardt Limited and Hospira Inc. manufacturing facilities, the release said. However, no other details were available. According to the release, Cempra plans on updating the FDA with information on progress at Uquifia, an alternative manufacturing facility for solithromycin.

“While we certainly wanted a first-action approval of solithromycin because of increasing antibiotic resistance and the clear need that patients have for a new antibiotic to treat community-acquired pneumonia, as well as the strength of data we have accumulated through our clinical trials, we will now evaluate the path to potential approval of solithromycin,” Zaccardelli said. “We are committed to completing that evaluation and working with the FDA to achieve the approval of solithromycin as quickly as possible.

Based on the information requested in the CRL, we do not expect a product approval prior to 2018.” by Stephanie Viguers

References:

Barrera CM, et al. Lancet. 2016;doi:10.1016/S1473-3099(16)00017-7.

Sheets A, et al. Abstract Saturday-467. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Disclosure: Zaccardelli is an employee of Cempra.

The FDA issued a complete response letter to Cempra Inc. stating that the company must provide additional safety data and resolve manufacturing facility inspection deficiencies before the agency can approve two new drug applications for the company’s investigational oral and IV formulation of solithromycin for the treatment of community-acquired bacterial pneumonia, according to a press release.

The FDA did not request additional information regarding the efficacy of solithromycin for community-acquired bacterial pneumonia (CABP).

In November, the FDA’s Antimicrobial Drugs Advisory Committee voted 7-6 in favor of the new drug applications 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). Meanwhile, the SOLITAIRE-IV trial 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. Further, the FDA reported 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.

The recent CRL stated that the size of the safety database, which was limited to 920 patients, is “too small to adequately characterize” the risk for serious hepatic adverse events. The agency recommended a comparative study involving approximately 9,000 patients to further evaluate the safety of solithromycin.

“Our immediate plan is to meet with the FDA as quickly as possible to discuss in more detail the clinical protocol design, including the definition of the safety endpoints that would satisfy the requirements of the FDA,” David Zaccardelli, PharmD, acting CEO of Cempra, said during a conference call today. “Of course, the exact timetable and costs for any future clinical study will depend on its feasibility, scope, duration and complexity.”

The CRL further noted that labeling for solithromycin must include information on the potential risk for hepatotoxicity, limiting its use to patients with limited treatment options. A comprehensive plan for post-marketing safety assessments is also needed.

In addition to insufficient safety data, the CRL stated that an FDA field investigator identified deficiencies during recent inspections of the company’s Wockhardt Limited and Hospira Inc. manufacturing facilities, the release said. However, no other details were available. According to the release, Cempra plans on updating the FDA with information on progress at Uquifia, an alternative manufacturing facility for solithromycin.

“While we certainly wanted a first-action approval of solithromycin because of increasing antibiotic resistance and the clear need that patients have for a new antibiotic to treat community-acquired pneumonia, as well as the strength of data we have accumulated through our clinical trials, we will now evaluate the path to potential approval of solithromycin,” Zaccardelli said. “We are committed to completing that evaluation and working with the FDA to achieve the approval of solithromycin as quickly as possible.

Based on the information requested in the CRL, we do not expect a product approval prior to 2018.” by Stephanie Viguers

References:

Barrera CM, et al. Lancet. 2016;doi:10.1016/S1473-3099(16)00017-7.

Sheets A, et al. Abstract Saturday-467. Presented at: ASM Microbe; June 16-20, 2016; Boston.

Disclosure: Zaccardelli is an employee of Cempra.