Type of information: Withdrawal of a market application in the EU
Product name: solithromycin
Therapeutic area: Infectious diseases
Action mechanism: antibiotic/macrolide. Solithromycin is a next-generation oral and intravenous fluoroketolide now in Phase 3 clinical development for the treatment of moderate to moderately-severe community acquired bacterial pneumonia (CABP) and urethritis. In vitro and in vivo studies have shown potent activity against S. pneumoniae as well as an extended spectrum of activity against CA-MRSA, enterococci, Mycobacterium avium and in animal models of malaria. It is also active against atypical bacteria, such as Legionella, Chlamydophila, Chlamydia, Mycoplasma and Ureaplasma and against gonococci and other organisms that cause genitourinary tract infections. It is 8-16 times more potent than azithromycin and is active against azithromycin-resistant strains. Its activity against resistant strains is driven by its ability to bind to three sites on the bacterial ribosome, compared to one or two for current macrolides. The binding to three ribosomal sites is expected to limit resistance development.
Solithromycin does not contain a pyridine in the side chain of the molecule (as does telithromycin or Ketek®) that appears to interact with nicotinic acetylcholine receptors and could be associated with serious adverse events such as visual disturbances and exacerbations of myasthenia gravis that have been observed with telithromycin.
Company: Cempra (USA - NC)
Disease: community acquired bacterial pneumonia (CABP)
- • On March 28, 2017, Cempra announced that the company has withdrawn its marketing authorization application (MAA) seeking European Medicines Agency (EMA) approval of oral capsule and intravenous formulations of solithromycin for the treatment of community-acquired pneumonia in adults.
- Based on the Day 120 questions Cempra received from the EMA, the company believes additional data would be required. By withdrawing the MAA at this time, Cempra will conserve considerable financial resources, and it will allow the company to align its strategy to provide additional data to both the EMA and FDA to support potential approval.
- • On December 29, 2016, Cempra announced that the company has received a Complete Response Letter (CRL) from the FDA relating to the company's new drug applications (NDAs) for oral and intravenous solithromycin for the treatment of community-acquired bacterial pneumonia (CABP) in adults. The CRL states that the FDA cannot approve the NDAs in their present form and notes that additional clinical safety information and the satisfactory resolution of manufacturing facility inspection deficiencies are required before the NDAs may be approved. The FDA did not request any further information on solithromycin efficacy for CABP in the CRL. Based on their review of the NDAs, the CRL stated that the FDA determined the risk of hepatotoxicity had not been adequately characterized. The FDA noted the size of the safety database is limited to 920 patients who received solithromycin at the proposed dose and duration, and is too small to adequately characterize the nature and frequency of serious hepatic adverse effects.
To address this deficiency, the FDA is recommending a comparative study to evaluate the safety of solithromycin in patients with CABP . Specifically, the CRL recommends that Cempra consider a study of approximately 9,000 patients exposed to solithromycin to enable exclusion of serious drug induced liver injury (DILI) events occurring at a rate of approximately 1:3000 with a 95 percent probability.
The CRL noted that while the FDA reserves comment on the proposed labeling until the NDAs are otherwise adequate, even in the absence of a case of Hy's Law or of another form of serious DILI in future studies, labeling will need to include adequate information about the potential for hepatotoxicity, limiting use to patients who have limited therapeutic options and limitations regarding duration of therapy. A comprehensive plan for post-marketing safety assessment including an enhanced pharmacovigilance program would also be required.
The CRL also stated that during recent inspections of the Wockhardt Limited and Hospira, Inc. manufacturing facilities, the FDA field investigator conveyed deficiencies to representatives of the facilities. Satisfactory resolution of these deficiencies is required prior to approval. Details on these deficiencies were not provided in the CRL.
Cempra plans to request a meeting with the FDA as soon as possible to discuss the issues identified in the CRL, including the design of the recommended clinical safety study and the steps necessary to resolve the deficiencies noted at Wockhardt and Hospira. The company also plans to provide the FDA with an update on manufacturing progress at Uquifia, an alternate GMP manufacturing facility for solithromycin active pharmaceutical ingredient (API).
- • On November 4, 2016, Cempra announced that the majority of the FDA Antimicrobial Drugs Advisory Committee (AMDAC) voted (7-6) that efficacy results of Cempra's solithromycin outweigh the risks for the treatment of community-acquired bacterial pneumonia (CABP).
Members of AMDAC voted unanimously (13-0) that there was substantial evidence of the efficacy of solithromycin for CABP. The committee also voted (12-1) that the risk of hepatotoxicity with solithromycin had not been adequately characterized and discussed a variety of potential approaches to further characterize the existing liver safety information on solithromycin. The target date for the FDA to take action under the Prescription Drug User Fee Act (PDUFA) is December 27 and 28, 2016 for the oral and IV filings, respectively.
- • On August 23, 2016, Cempra announced that the European Medicines Agency (EMA) has validated the company's marketing authorization application (MAA) seeking approval of oral capsule and intravenous formulations of solithromycin for the treatment of community-acquired bacterial pneumonia. The EMA's validation of the MAA confirms that the submission is complete and formally starts the review process. The Committee for Medicinal Products for Human Use (CHMP) will now begin their assessment of solithromycin through the centralized review procedure.
- • On August 19, 2015, Cempra announced that the FDA has granted Fast Track designation for solithromycin intravenous (IV) and capsules for the treatment of community acquired bacterial pneumonia (CABP). Solithromycin is currently in Phase 3 development for the treatment of CABP and submission of a New Drug Application (NDA) is planned for 2016. Additional clinical studies with solithromycin include a Phase 3 trial in uncomplicated gonorrhea that is expected to complete patient enrollment by the end of 2015, a Phase 2 trial in chronic obstructive pulmonary disease (COPD), a Phase 2 trial in nonalcoholic steatohepatitis ( NASH ), and a Phase 1b trial in pediatric patients.
- The FDA has previously designated solithromycin IV and capsules for the treatment of CABP and solithromycin capsules for the treatment of gonorrhea as a Qualified Infectious Disease Product (QIDP). The QIDP designation will make solithromycin eligible to benefit from certain incentives as provided under the Generating Antibiotic Incentives Now (GAIN) program. These incentives include FDA priority review, eligibility for fast-track status and, if ultimately approved by the FDA , solithromycin would be eligible for an additional five-year extension of Hatch-Waxman new chemical entity exclusivity.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE: 2017-03-28
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: