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Paratekpharma.comA Pooled Analysis of Two Randomized Multicenter, Evaluator-Blind Studies Comparing the Safety and
Efficacy of Omadacycline and Linezolid for the Treatment of Complicated Skin and Skin Structure Infections
S. Ken Tanaka, PhD; Surya Chitra, PhD; Lynne Garrity-Ryan, PhD; Evan Tzanis; Evan Loh, MD Paratek Pharmaceuticals, King of Prussia, Pennsylvania, USA Table 1. Study Populations
Table 4. Summary of Adverse Events
• ≥18 years of age with wound infection, major abscess, infected ulcers in the lower • For the ITT population at the test of cure visit, 156 (87.2%) patients on omadacycline Background: Omadacycline is the first of a new class of antibiotics, the
extremity or cellulitis. Number (% of Patients)
had clinical success compared to 146 (81.1%) patients on linezolid (Figure 1).
Number (% of Patients)
aminomethylcyclines, currently in clinical development as a once daily oral and • Major abscesses were any abscess which involved subcutaneous or deeper tissues • In the CE population, clinical success occurred in 156 (97.5%) patients on Linezolid
intravenous (IV) formulation for community-acquired bacterial pneumonia (CABP) and that either had spontaneously ruptured and were draining or required surgical omadacycline compared to 146 (94.2%) on linezolid.
acute bacterial skin and skin structure infections (ABSSSI). A phase 2 and a truncated incision and drainage. Disposition populationa Any treatment-emergent AE phase 3 study in patients with complicated skin and skin structure infections (cSSSI) Intent-to-treat (ITT) Figure 1. Clinical Success Across Different Patient Populations
were conducted. Both studies compared the safety and efficacy of omadacycline, • Patients with diabetes mellitus or documented vascular insufficiency with infected a broad-spectrum agent with activity against methicillin-resistant Staphylococcus ulcers of the lower extremity were eligible if the lesion was acutely infected and the Modified intent-to-treat (mITT) aureus (MRSA). Results from these two studies were pooled to evaluate the effect of ulcer was not present for >3 months. TEAEs by System Organ Class Clinically evaluable (CE) omadacycline on safety, tolerability, and efficacy.
• Patients with cellulitis alone were eligible if they had diabetes mellitus or vascular Microbiologically evaluable (ME) Nervous system disorders Material/Methods: Patients were randomized 1:1 to omadacycline 100 mg IV once a
insufficiency or if they received immunosuppressive therapy within 3 months prior General disorders and administrative site conditions day (QD) with an option to transition to 200 mg or 300 mg orally QD or linezolid 600 to developing cellulitis. mg IV twice daily (BID) with an option to transition to 600 mg orally BID and treated • Patients were eligible if they had received <48 h of antibiotic therapy prior to aFor purposes of this pooled analysis, this population excludes patients who were randomized and not treated. for 7-14 days. Patients in both studies were evaluated at the test of cure visit. enrollment or if they had received Skin and subcutaneous tissue disorders ≥48 h of therapy and a resistant pathogen was identified.
• 93.9% of patients in both treatment groups completed the study (Table 2).
Psychiatric disorders Results: A total of 377 patients randomized to either omadacycline or linezolid,
• 11 patients in each group discontinued the study early. Metabolism and nutrition disorders with 359 patients in the intent-to-treat population (ITT), 179, and 180, respectively. • Patients with infections that could be controlled by surgical intervention Infections and infestations Mean age was 43.7 years with omadacycline and 41.9 years with linezolid. For (e.g., amputation, incision, and drainage) alone were not eligible. Table 2. Patient Disposition
the ITT population at the test of cure visit, 156 (87.2%) patients on omadacycline Clinical Success (%)
Musculoskeletal and connective tissue disorders had clinical success compared to 146 (81.1%) patients on linezolid. In the clinically • Overall, the incidence of adverse event for both omadacycline and linezolid was evaluable (CE) population, clinical success occurred in 156 (97.5%) patients on Number (% of Patients)
• Patients were randomized 1:1 to comparable (Table 5).
omadacycline compared to 146 (94.2%) on linezolid. In the microbiologically evaluable (ME) population, microbiological success occurred in 123 (97.6%) patients with – Omadacycline 100 mg IV once a day (QD) with an option to transition to oral QD – A higher incidence of headache and creatine phosphokinase increased was omadacycline compared with 112 (97.4%) patients with linezolid. Adverse event rates dosing of 200 mg (phase 2 study) or 300 mg (truncated phase 3 study). [After reported with omadacycline.
for both omadacycline and linezolid were comparable; 58% in the omadacycline conduct of the phase 2 study, it was determined that the 300 mg oral dose was – A higher incidence of diarrhea and alanine aminotransferase increased was group and 62.8% in the linezolid group experienced an adverse event. Gastrointestinal most appropriate to provide exposure equivalent to the 100 mg IV dose] reported with linezolid.
adverse events were the most frequent for omadacycline (28.5%) and linezolid (26.1%). Diff. 95% CI: 6.0 (-1.8, 13.9)
– Linezolid 600 mg IV twice daily (BID) with an option to transition to 600 mg Withdrawal of consent Table 5. Treatment-Emergent Adverse Events Occurring in at Least 3% of Patients
Conclusions: In this analysis, the success rates for omadacycline and linezolid in the
• Microbiological success rates are shown in Figure 2.
Lost to follow-up in Either Treatment Group
treatment of cSSSI were comparable in the ITT, ME, and CE populations at the test • Phase 2: aztreonam 2 g IV every 12 h could be added for a suspected or of cure visit. Pooled analyses support a favorable and comparable tolerability profile documented Gram-negative infection.
Figure 2. Microbiological Success in MITT and Microbiologically
Number (% of Patients)
for both omadacycline and linezolid. These data further support the development • Phase 3: moxifloxacin 400 mg IV or oral could be added for suspected or Excluded condition of omadacycline as a broad spectrum, once a day, oral and IV treatment for serious Linezolid
documented Gram-negative infection. community-acquired infections. – Total treatment duration was up to 14 days, at the discretion of the investigator based on clinical response • Patients in both studies were evaluated at the test of cure (TOC) visit, which • Treatment groups were generally comparable at baseline (Table 3).
occurred 10 to 17 days after the last dose of study medication.
• Mean age was 43.7 years with omadacycline and 41.9 years with linezolid; the • Omadacycline, a first-in-class aminomethylcycline antibiotic, is undergoing omadacycline group had a higher proportion of female patients.
evaluation in phase 3 studies as oral and intravenous (IV) monotherapy for – Intent-to-treat (ITT) and Safety – patients receiving ≥1 dose of study medication • In the phase 2 study, 145 of 219 (66.2%) of patients were diagnosed with major Alanine aminotransferase increased the treatment of acute bacterial skin and skin structure infections (ABSSSI) – Modified ITT (mITT) – ITT population with a baseline pathogen and community-acquired bacterial pneumona (CABP). In vitro, omadacycline Creatine phosphokinase increased demonstrates activity against Gram-positive and Gram-negative aerobes including – Clinically evaluable (CE) – all patients in the ITT population who had a protocol- • In the truncated phase 3 study, 92 of 140 (65.7%) of patients were diagnosed with multi-drug resistant strains of Staphylococcus spp. and Streptococcus spp., as well defined qualifying infection, received study medication for ≥5 days, had all as anaerobes and atypical bacteria including Legionella spp. and Clostridium difficile protocol-defined clinical evaluations, and had not received non-study antibiotics Clinical Success (%)
(Macone et al, 2014). In phase 1 studies, omadacycline has an elimination half-life of Table 3. Baseline Demographics (ITT Population)
– Microbiologically evaluable (ME) – CE population with a baseline pathogen Aspartate aminotransferase increased approximately 17 hours, peak plasma concentrations of 0.6 and 1.8 mg/L after 300 Decreased appetite mg oral and 100 mg IV doses, respectively, and low protein binding (21%)(Sun et al, 2011; Ting et al, 2010). • Primary hypothesis: safety and tolerability of omadacycline and linezolid were SUMMARY AND CONCLUSIONS
• A phase 2 study and a truncated phase 3 study in patients with complicated skin and skin structure infections (cSSSI) were conducted (Noel et al, 2012; Noel et al, 2012a). • Secondary hypothesis: rate of clinical response at the TOC for omadacycline was • Clinical success rates for omadacycline and linezolid in the treatment of cSSSI Diff. 95% CI:
Enrollment in the phase 3 study was stopped early due to changing regulations non-inferior to linezolid (the Phase 3 study was originally planned to enroll a total of were comparable in all evaluated populations at the TOC visit. regarding the primary efficacy endpoint. Both studies compared the safety and Age >64 years, n (%) 790 patients and utilize a 10% non-inferiority margin; there was no a priori plan to Safety and Tolerability
• Pooled analyses support a favorable and comparable tolerability profile for both efficacy of omadacycline versus linezolid. Results from these two studies were pool the results across studies) • Gastrointestinal adverse events were the most frequent for both omadacycline oral and IV formulations of omadacycline and linezolid. pooled for these analyses. • Clinical success = study treatment was completed and infection resolved (28.5%) and linezolid (26.1%) (Table 4).
• These data further support the development of omadacycline as a broad spectrum, once daily, oral and IV treatment for serious community-acquired • 5 patients discontinued the study because of AE • Microbiological success = all infecting pathogens were eradicated and no superinfecting pathogens were isolated – 3 Omadacycline: gas in soft tissues, small bowel obstruction, elevated liver • 2-sided 95% confidence intervals (CI) were calculated for the difference in success – 2 Linezolid: heart burn, erythematous generalized rash/pruritus • Macone AB, Caruso BK, Leahy RG, et al. In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents rates between treatments Chemother. 2014;58:1127-35. Hispanic or Latino, n (%) • 7 patients experienced serious AEs, none of which were considered related to study • Noel GJ, Draper MP, Hait H, et al. A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of Phase 2 Study
Phase 3 Study
linezolid for treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother. 2012;56:5650–5654.
• Noel GJ, Draper MP, Hait H, Tanaka SK. Safety and efficacy of PTK 0796 (Omadacycline) as treatment of complicated skin and soft tissue infection (cSSTI). Poster presented at 22nd European Congress on Clinical Microbiology and Infectious Diseases, March 31-April 3, 2012a, London, UK.
– 4 Omadacycline: worsening confusion, small bowel obstruction/ acute • Sun H, Maietta R, Machineni S, et al. A single-dose study to evaluate the pharmacokinetics, safety, and tolerability of multiple formulations of PTK 0796 in healthy subjects. Poster presented at 21st European Congress on Clinical Microbiology and Infectious Diseases, May 7-11, 2011, Milan, Italy.
Duration of treatment gastroenteritis, depression, left pleural effusion (patient subsequently diagnosed • Ting L, Sun H, Kovacs SJ, et al. Pharmacokinetics of intravenous and oral PTK796, a new aminomethylcycline antibiotic. Abstract K-124, presented at • 377 patients were randomized to either omadacycline or linezolid.
with metastatic lung cancer which resulted in death) the 50th ICAAC, September 12-15, 2010, Boston, MA.
July 2007 to January 2008 April 2009 to April 2010 – 3 Linezolid: recurrent wound infection, worsening infection (right Achilles), • 359 patients were included in the ITT and Safety populations (Table 1).
worsening right hand cellulitis aMean ± standard deviation.
Dr. Stephan Madaus Vertreter des Lehrstuhls für Bürgerliches Recht, Deutsches, Europäisches und Internationales Unternehmensrecht (Prof. Dr. Horst Eidenmüller, LL.M.) Übung im Bürgerlichen Recht für Fortgeschrittene Übungsfall Biologieprofessor P. hat von einer Reise nach Südkorea Ginseng-Wurzeln mitge- bracht, die er einem befreundeten Pharmakologen zu Forschungszwecken zur Ver-