Clinical Trials

Date: 2016-08-25

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in Clinical Infectious Diseases

Company: Cempra (USA - NC)

Product: solithromycin

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, Chile, Colombia, Georgia, Germany, Guatemala, Hungary, Republic of Korea, Latvia, Malaysia, The Netherlands, Peru, Philippines, Poland, Romania, Russian Federation, Serbia, Slovakia, Slovenia, South Africa, Spain, Taiwan, Ukraine, USA

Trial details:

• Solitaire-Oral evaluates the safety and efficacy of an experimental antibiotic, solithromycin, in the treatment of adult patients with community-acquired pneumonia.
• Cempra initiated the second Phase 3 trial of solithromycin, Solitaire-IV, in December 2013 . This study was a double-blind, active-controlled, global, multi-center trial that enrolled 863 adult patients with moderate to moderately severe CABP and could include up to 25% PORT Class II and 75% PORT Class III/IV (with at least 25% PORT Class IV CABP patients). Patients initially received IV administration of either 400 mg of solithromycin or 400 mg of moxifloxacin. Patients could switch to oral dosing of their assigned drug based on investigator assessment of clinical stability. For solithromycin, the oral dose was an 800 mg loading dose followed by 400 mg once daily resulting in a total of 7 days of treatment with IV or IV and oral dosing. For moxifloxacin, the oral dose was 400 mg once daily for a total treatment duration of 7 days with IV or IV and oral dosing. (NCT01968733)

Latest news:

• • On August 25, 2016, Cempra announced the publication of its pivotal Phase 3 study, SOLITAIRE-IV, comparing the efficacy and safety of intravenous-to-oral solithromycin to intravenous-to-oral moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP) in Clinical Infectious Diseases. As previously reported, the SOLITAIRE-IV study demonstrated that solithromycin was non-inferior to moxifloxacin, a potent respiratory fluoroquinolone, for treatment of CABP , meeting its primary endpoint that was aligned with FDA guidance. Cempra's other pivotal Phase 3 study with solithromycin, SOLITAIRE-ORAL, which evaluated the efficacy and safety of oral solithromycin versus oral moxifloxacin for the treatment of CABP , also met its primary non-inferiority endpoint and was published in Lancet Infectious Diseases in February 2016 (See below).
• • On February 5, 2016, Cempra announced the publication of positive results from its pivotal Phase 3 clinical trial of solithromycin oral capsules in the treatment of patients with community-acquired bacterial pneumonia (CABP) in The Lancet Infectious Diseases. The article, titled, "Efficacy and safety of oral solithromycin versus oral moxifloxacin for the treatment of community-acquired bacterial pneumonia: a global, double-blind, multi-centre, randomized, active-controlled, non-inferiority trial (SOLITAIRE-ORAL )" appears in the February 4th online issue and will be published in a future print issue of the journal.
• In the intent-to-treat population of this study (ITT, all randomized patients), solithromycin met the primary objective of statistical non-inferiority to oral moxifloxacin for the treatment of CABP with a treatment success rate at the early clinical response (ECR, 72 hours after the first dose of study drug) of 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. Treatment emergent adverse events were comparable for the two patient groups with 155 (36.6%) reported for solithromycin and 154 (35.6%) for moxifloxacin. There were no serious adverse events attributed to solithromycin. In addition, there were two cases of Clostridium difficile infection, both of which occurred in the moxifloxacin group. In October, Cempra announced successful results of the second Phase 3 pivotal trial of solithromycin that used an intravenous formulation (Solitaire-IV), and has begun and is planning to complete a rolling New Drug Application (NDA) submission to the FDA for the oral and intravenous formulations for the treatment of CABP during the first half of 2016. The FDA has granted fast track designation for solithromycin IV and capsules for the treatment of CABP. The Agency has also designated solithromycin IV and capsules for the treatment of CABP as a Qualified Infectious Disease Product (QIDP).
• • On October 16, 2015, Cempra announced positive topline results from a global, pivotal Phase 3 clinical trial of intravenous (IV) to oral solithromycin (Solitaire-IV) in the treatment of patients with community-acquired bacterial pneumonia. In the intent-to-treat population (ITT, all randomized patients), solithromycin met the FDA primary objective of statistical non-inferiority (NI, 10% non-inferiority margin) compared to moxifloxacin at the early clinical response (ECR, 72 [-12/+36] hours after initiation of therapy). The point estimates for the primary endpoint of early clinical response were 79.3% for solithromycin and 79.7% for moxifloxacin. The 95% confidence interval for the treatment difference had lower and upper bounds of -6.1% and 5.2%, respectively.
• Solithromycin also met the co-primary objective of statistical NI compared to moxifloxacin at the ECR in the microbiological ITT (mITT) population (those patients with an etiologic diagnosis of the cause of CABP ) from the pooled data from both Phase 3 studies. The point estimates were 77.2% for solithromycin and 78.9% for moxifloxacin with lower and upper bounds of the 95% confidence interval for the treatment difference of -7.4% and 4.2%. Solithromycin also met the secondary endpoint of NI compared to moxifloxacin in the mITT population at the ECR time point from Solitaire-IV alone. The point estimates for this endpoint were 80.3% for solithromycin and 79.1% for moxifloxacin with lower and upper bounds of the 95% confidence interval for the treatment difference of -8.1% and 10.6%.
• Additional secondary endpoints evaluated solithromycin at the short term follow up visit (SFU) 5-10 days after therapy in both the ITT and clinically evaluable (CE) populations. Clinical success rates as determined by investigators at the SFU visit were high for both the solithromycin and moxifloxacin groups in the ITT population with point estimates of 84.6% and 88.7%, respectively. Clinical success rates were also high in the CE-SFU population for both the solithromycin and moxifloxacin groups, with point estimates of 86.4% and 92.8%, respectively. This CE outcome was skewed in favor of moxifloxacin by a blinded drug supply shortage which led to discontinuation of study drug in solithromycin patients only. Censoring these 5 patients, all of which fell on the solithromycin side, results in point estimates for CE population success at the SFU visit of 87.6% for solithromycin patients.
• The primary endpoint for the European Medicines Agency (EMA) was NI in the ITT and the CE-SFU populations limited to patients with PORT III/IV CABP at the SFU time point. Solithromycin was non-inferior to moxifloxacin in the ITT-SFU population. As well, solithromycin would be NI to moxifloxacin in the CE-SFU population after censoring those patients from the CE population who had early discontinuation of blinded study drug due to supply issues.
• The FDA has granted Fast Track designation for solithromycin IV and capsules for the treatment of CABP . The agency has also 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).
• In this Solitaire-IV Phase 3 clinical trial, fatalities occurred with similar frequency in both arms, with 5 patients on the solithromycin arm (1.2%) and 7 patients on the moxifloxacin arm (1.6%) dying due to pneumonia or its complications during the study period. More treatment-related adverse events were observed with solithromycin (34.3%) than with moxifloxacin (13.1%), a difference largely due to the occurrence of infusion site reactions (primarily of mild or moderate severity) in solithromycin patients. Infusion site pain is a known side effect of IV macrolides as a class and is not typically noted with fluoroquinolones. In this trial, 2.1% of IV solithromycin patients (9 of 432 patients) discontinued study drug dosing due to these adverse infusion related events. Serious adverse events (SAEs) occurred in 6.9% of solithromycin patients and 5.4% of moxifloxacin patients. Among all SAEs, only 3 were considered related to the study drug, all of which were allergic reactions (2 patients receiving solithromycin and 1 patient receiving moxifloxacin). The most frequently reported non-serious, non-infusion related adverse events for solithromycin were diarrhea (4.4%, versus 5.9% with moxifloxacin), headache (3.5%, versus 4.2% with moxifloxacin), nausea (3.3%, versus 1.6% with moxifloxacin), hypokalemia (2.5%, versus 2.1% with moxifloxacin), dizziness (2.5%, versus 1.2% with moxifloxacin), insomnia (2.1%, versus 1.1% with moxifloxacin) and hypertension (1.2%, versus 2.1% for moxifloxacin). Study drug discontinuation due to non-infusion related adverse events was comparable between study arms (3.5% of solithromycin patients, 3.8% of moxifloxacin patients). No other non-serious treatment emergent specific adverse event was reported with 2.0% incidence or greater in either treatment arm. C. difficile associated diarrhea was diagnosed in 1 patient in this study, a moxifloxacin patient. Alanine transaminase (ALT) elevation was observed in both treatment arms. Grade 3 ALT elevations ( > 3-8×ULN) occurred in 8.2% of solithromycin patients and 3.4% of moxifloxacin patients and Grade 4 ALT elevations ( > 8×ULN) occurred in 0.7% of solithromycin patients and 0.5% of moxifloxacin patients. Treatment emergent ALT elevations were generally asymptomatic, reversible, and not associated with increased bilirubin. No solithromycin patient met Hy's Law criteria of concurrent ALT and bilirubin elevations post-baseline.
• No long QT associated arrhythmias were observed in this study. Mean QTcF at all time points was lower among solithromycin patients compared to moxifloxacin patients. Mean heart rates decreased in both treatment arms with Day 4 decreases of -11.5 bpm in solithromycin patients versus -13.3 bpm in moxifloxacin patients and End-of-Therapy decreases of -12.7 bpm in solithromycin patients versus -14.5 bpm in moxifloxacin patients. In patients who have tachycardia in the setting of pneumonia, the central tendency with solithromycin therapy is a reduction in heart rate that differs little (1-2 beats) from that observed with moxifloxacin.
• Analyses of the results are ongoing and Cempra will present additional data from the Solitaire-IV clinical trial as well as pooled data from the two Phase 3 trials at upcoming scientific meetings.
• An additional Phase 3 clinical trial, Solitaire-U, began in August 2014 in patients with uncomplicated gonorrhea and chlamydia infections. The trial is being conducted in Australia and the U.S. and will enroll approximately 300 patients in a randomized 2-arm study with a single oral dose of 1000 mg of solithromycin compared with the standard of care, 500 mg of ceftriaxone administered intramuscularly and 1000 mg of oral azithromycin.

Is general: Yes