Clinical Trials

Date: 2015-01-04

Type of information: Results

phase: 3

Announcement: results

Company: Cempra (USA - NC)

Product: solithromycin oral capsules

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.

Disease: community acquired bacterial pneumonia (CABP)

Therapeutic area: Infectious diseases

Country: Argentina, Bulgaria, Canada, Czech Republic, Dominican Republic, Ecuador, Estonia, Germany, Hungary, Puerto Rico, Romania, Russian Federation, South Africa, Spain, USA

Trial details:

• This Phase 3 study, Solitaire-Oral, was a double-blind, active-controlled global, multi-center trial that enrolled 860 adult patients with moderate to moderately severe CABP (pneumonia of PORT Class II, III and IV severity classification). Enrollment of PORT Class II pneumonia patients was limited to 50% of the study population. Patients were randomized to receive either oral solithromycin, as an 800 mg loading dose followed by 400 mg once daily for a total of five days, while oral moxifloxacin was dosed at 400 mg once daily for seven days. The primary objective was demonstration of non-inferiority of early clinical response at 72 (-12/+36) hours, as specified by FDA guidance, defined as having improvement in at least two of the following four symptoms (without worsening of any); cough, shortness of breath, chest pain and sputum production in the ITT. The study was designed to provide 90% power to demonstrate non-inferiority in early clinical response rate for solithromycin versus moxifloxacin utilizing a 10% non-inferiority margin. Secondary endpoints included the clinical success rate at the short term follow up visit 5 to 10 days following the last dose of study drug in the ITT and clinically evaluable populations, and importantly, a comparison of safety and tolerability of solithromycin compared to moxifloxacin. (NCT01756339)

Latest news:

• • On January 4, 2015, Cempra announced positive topline results from a global, pivotal Phase 3 clinical trial of solithromycin oral capsules (Solitaire-Oral) in the treatment of patients with community acquired bacterial pneumonia (CABP). In the intent-to-treat population (ITT, all randomized patients), solithromycin met the primary objective of statistical non-inferiority (10% non-inferiority margin) of the early clinical response at 72 (-12/+36) hours after initiation of therapy compared to moxifloxacin. Solithromycin also met the secondary objectives of non-inferiority in clinical success at the short term follow up (SFU) visit, 5-10 days after the end of therapy, both in the ITT and clinically evaluable populations. The point estimates for the primary endpoint of early clinical response were 78.2% for solithromycin and 77.9% for moxifloxacin. The 95% confidence interval for the treatment difference had lower and upper bounds of -5.5% and 6.1%, respectively. The results were similar in the combined total patient population, however, initial sub-groups analysis by age, indicate that the difference in point estimates became larger with increasing age and favored solithromycin in the ITT early clinical response groups. The results for the secondary efficacy endpoints supported results from the primary endpoint.
• This study was the first to be completed under the proposed FDA CABP guidance which allows for assessment of the new primary endpoint of early clinical response in the pooled mITT population (ITT population with microbial isolates) across two similar Phase 3 trials, utilizing a 12.5% non-inferiority margin. In this first study, solithromycin met the secondary objective of non-inferiority of the early clinical response in the mITT population. Although, the individual mITT was analyzed, the weighted pooled mITT from the two Phase 3 studies is the true secondary outcome for the NDA.
• In this clinical trial, serious adverse events (SAEs) occurred with equal frequency in both arms ( < 7% of patients) and no SAEs were considered study drug related. The most frequently reported adverse events for solithromycin were headache (4.5%, versus 2.5% incidence with moxifloxacin), diarrhea (4.2%, versus 6.5% with moxifloxacin), nausea (3.5%, versus 3.9% with moxifloxacin), emesis (2.4% versus 2.3% with moxifloxacin) and dizziness (2.1% versus 1.6% with moxifloxacin). No other treatment emergent adverse events occurred, in either arm, with 2.0% incidence or greater. C. difficile associated diarrhea was diagnosed in two patients, both of whom received moxifloxacin. Asymptomatic, reversible alanine transaminase (ALT) elevation was observed in both treatment arms. Grade 3 ALT elevation ( > 3-8xULN) occurred in 2.1% of moxifloxacin patients and 4.6% of solithromycin patients. Grade 4 ALT elevation ( > 8xULN) occurred in 1.2% of moxifloxacin patients and 0.5% of solithromycin patients. No patient in either arm of the study developed treatment emergent elevation of both ALT and bilirubin defined by Hy's Law criteria.
• • On September 25, 2014, Cempra announced the completion of enrollment of the global Solitaire-Oral Phase 3 clinical trial of oral solithromycin in adult patients with moderate to moderately severe community-acquired bacterial pneumonia. Top-line efficacy and safety data are expected to be announced during the first quarter of 2015. The study is the first of the two Cempra's global phase 3 trial to complete patient enrollment. The second ongoing trial, Solitaire-IV, will provide information on switching hospitalized patients from intravenous solithromycin to oral solithromycin with the goal of not only sending patients home earlier but sending them home on the same drug that they started on when they were admitted in the hospital. Top-line results of Solitaire-Oral are expected during the first quarter of 2015.

Is general: Yes