Clinical Trials

Date: 2017-10-06

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at IDWeek 2017

Company: Paratek Pharmaceuticals (USA - MA)

Product: omadaycline

Action mechanism:

• antibiotic. Omadacycline is a once-daily oral and IV, well-tolerated broad spectrum investigational antibiotic being developed for use as empiric monotherapy for patients suffering from serious community-acquired bacterial infections, such as acute bacterial skin and skin structure infections, community-acquired bacterial pneumonia, urinary tract infections and other community-acquired bacterial infections, particularly when antibiotic resistance is of concern to prescribing physicians.
• Omadacycline has been granted Qualified Infectious Disease Product designation and Fast Track status by the U.S. Food and Drug Administration for the target indications.

Disease: acute bacterial skin and skin structure infections (ABSSSI)

Therapeutic area: Infectious diseases

Country:

Trial details:

• OASIS-1 (Omadacycline in Acute Skin Structure Infections Study) evaluated the efficacy and safety of IV-to-oral once-daily omadacycline against twice-daily linezolid over a 7 to 14-day course of therapy in 645 treated patients. The primary efficacy endpoint for the FDA was early clinical response (ECR) at 48 to 72 hours after the first dose of study drug in the modified intent-to-treat (mITT) population (patients without a potentially causative monomicrobial gram-negative infection).

Latest news:

• • On October 6, 2017, Paratek Pharmaceuticals announced the results of three sub-analyses from the Phase 3 OASIS-1 study that show a consistent safety and efficacy profile of omadacycline, when treating Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in patients with comorbid conditions, which could be associated with reduced treatment efficacy and increased safety-related adverse events. These data have been presented at IDWeek 2017 in San Diego.
• The analyses compared omadacycline to linezolid in subsets of ABSSSI patients enrolled in the global Phase 3 registration study with: chronic kidney disease; high body mass index; diabetes, and a history of intravenous drug users with or without hepatitis C infection. In addition to omadacycline demonstrating a consistent efficacy and safety profile compared to linezolid, these data suggest that no dose adjustments for omadacycline are required in patients with these comorbid conditions.
• OASIS-1 (Omadacycline in Acute Skin Structure Infections Study) evaluated the efficacy and safety of IV-to-oral once-daily omadacycline against twice-daily linezolid over a 7 to 14-day course of therapy in 645 treated patients. In the mITT analysis population, omadacycline achieved the primary efficacy endpoint of statistical non-inferiority (10% margin) compared to linezolid. The ECR for the omadacycline and linezolid treatment arms was 84.8% compared to 85.5%, respectively.
• Additionally, the FDA-specified secondary endpoint was the investigator assessment of response at the post treatment evaluation (PTE) visit (7-14 days after the completion of therapy) in both the mITT population (86.1% for omadacycline vs. 83.6% for linezolid) and in the clinically evaluable (CE) population (96.3% for omadacycline vs. 93.5% for linezolid).
• Omadacycline in Chronic Kidney Disease with ABSSSI: In this safety analysis, 522 patients had stage 0/1 chronic kidney disease (CKD-0/1), 119 had stage 2/3 chronic kidney disease (CKD-2/3). Response rates at ECR assessment were slightly higher in patients with CKD-0/1 in the omadacycline group (87.4%) compared to patients with CKD-2/3 (82.3%). Similarly, for patients treated with linezolid, ECR rates were 87.1% and 83.7% for CKD-0/1 and CKD-2/3, respectively.
• PTE responses in the mITT population were 87.0% for omadacycline vs. 84.8% for linezolid in CKD-0/1 patients. In patients with CKD-2/3, rates were 90.3% vs. 85.7% for omadacycline and linezolid, respectively. PTE responses in the CE population were 96.7% for omadacycline vs. 94.4% for linezolid in CKD-0/1 patients, and 94.7% for omadacycline vs. 91.1% for linezolid in patients with CKD-2/3.
• Overall, omadacycline was safe and generally well tolerated in patients with CKD, with similar AEs to subjects without CKD. Overall, the safety and efficacy of omadacycline in patients with CKD-0/1 and CKD-2/3 was similar to that observed in the general population. TEAEs were comparable between omadacycline and linezolid treatment.
• Omadacycline in Diabetic and Obese Patients with ABSSSI: In the sub-analyses comparing omadacycline to linezolid in patients with high BMI, evaluable patients had elevated BMI of ?25 (n=417). Of those, 225 were overweight (25 < BMI <30) and 192 were obese (BMI > 30); irrespective of BMI, 59 patients had a medical history of diabetes.
• Omadacycline outcomes were comparable at ECR assessments in patients with normal (BMI <25) and high BMI. Outcomes in the high-BMI omadacycline treatment group were comparable to outcomes in the linezolid treatment group for the primary endpoint in the mITT (84.8% vs. 85.9%). At PTE, high BMI omadacycline-treated patients showed higher clinical success than linezolid-treated patients (85.9% vs. 83.4%) in the mITT population. PTE response in the high BMI CE population were 95.8% for omadacycline vs. 93.1% for linezolid.
• At PTE, in both the mITT and CE populations, omadacycline-treated diabetic patients showed higher clinical success compared to linezolid-treated diabetic patients. Overall, the safety and efficacy of omadacycline was consistent regardless of BMI or diabetes diagnosis.
• Omadacycline in ABSSSI Patients with a History of IV Drug Use (IVDU) and Hepatitis C (HCV+): In this analysis, 322 patients were IVDU and 168 were IVDU/HCV+. ECR rates were comparable for both omadacycline and linezolid in both IVDU and non-IVDU patients, regardless of HCV diagnosis. PTE responses with omadacycline were higher than linezolid in non-IVDU patients in both the mITT and clinically evaluable (CE) populations. For both omadacycline and linezolid, clinical success at PTE tended to be lower among IVDU and IVDU/HCV+ patients, compared with the non-IVDU and non-IVDU/HCV- patients in the mITT populations. The lower clinical success observed among IVDU and IVDU/HCV+ patients was due to the greater number of indeterminate responses (e.g. lost to follow-up, withdrew consent). Tolerability was similar across all patient groups, with no major differences in liver function.
• • On April 24, 2017, Paratek Pharmaceuticals announced  that an analysis of microbiology data from its Phase 3 study of omadacycline in acute skin infections found that once-daily treatment with IV-to-oral omadacycline is effective in treating the most frequently isolated bacterial pathogens associated with skin infections, including methicillin-resistant Staphylococcus aureus (MRSA). These findings were presented for the first time at the annual meeting of the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2017) in Vienna, Austria.
• Paratek also presented full clinical efficacy, safety and tolerability results from the OASIS study. The full results demonstrate the efficacy and safety of omadacycline compared to linezolid in acute bacterial skin and skin structure infections (ABSSSI).
• Analyses by Infection Type and Pathogen in the OASIS Study: OASIS was a global Phase 3 randomized, double-blind, multi-center study comparing the safety and efficacy of IV-to-oral once-daily omadacycline with twice-daily linezolid over a 7-to-14-day course of therapy in 645 treated adult patients with ABSSSI. To analyze clinical success per infection type, the modified intent-to-treat (mITT) population included randomized subjects without a sole Gram-negative pathogen at screening (n=627). Among this population, infection type broke down as follows: 33% wound infection; 38% cellulitis/erysipelas; and 29% major abscess. At Post Therapy Evaluation (PTE, 7 – 14 days after the last day of treatment), once-daily omadacycline was effective across all infection types studied. Compared to twice-daily linezolid, efficacy for once-daily omadacycline was comparable in wound infection (81% vs 81%), cellulitis/erysipelas (91% vs 85%), and major abscess (85% vs 85%). Further analysis of the micro-mITT population, which included patients with at least one Gram-positive pathogen at screening (n=455), showed that the most common pathogen was Staphylococcus aureus (68% overall, 61% MSSA and 39% MRSA) followed by Streptococcus anginosus (19%) with mixed Gram-positive and Gram-negative infections in 15% of the patients. Overall clinical success at PTE in this group was 83% for omadacycline vs 83% for linezolid (MSSA 84% vs 82%; MRSA 83% vs 86%, S. anginosus 75% vs 70%, mixed infections 81% vs 76%).
• The full results of OASIS presented  at ECCMID expanded on the positive topline results first announced in June 2016. Omadacycline met the U.S. Food and Drug Administration-specified primary efficacy endpoint of early clinical response (ECR) and the two European Medicines Agency-specified co-primary efficacy endpoints for post-treatment evaluation (PTE). In the study, the ECR in the modified Intent to Treat (mITT) population for the omadacycline and linezolid treatment arms was 84.8% compared to 85.5%, respectively.
• At PTE in the mITT and the clinically evaluable (CE) populations, omadacycline achieved the primary efficacy endpoint of statistical non-inferiority (10% margin) compared to linezolid. In the mITT population at PTE, clinical success rates for the omadacycline and linezolid treatment arms were 86.1% and 83.6%, respectively. In the CE population at PTE, clinical success rates for the omadacycline and linezolid treatment arms were 96.3% and 93.5%, respectively.
• Additional presentations at ECCMID highlighted the efficacy of omadacycline in ABSSSI across geographic regions and demonstrated that omadacycline reduces skin lesion size and local signs of ABSSSI.
• Regional distribution of infection type remained consistent across OASIS study locations in North America, Latin America, Eastern Europe and Western Europe, with aureus emerging as the most prevalent. Clinical success at PTE among the mITT population (n=627) for omadacycline vs linezolid was 80.7% vs 80.2% in North America; 100% vs 94% in Eastern Europe and 82.6% vs 76.2% in Western Europe; Latin America was not included in the evaluation because of a limited sample size (< 5 subjects per treatment group).
• Further analysis of OASIS demonstrated treatment of ABSSSI with omadacycline or linezolid led to similar and rapid reductions in lesion size and local signs of infection. In the mITT population, median baseline lesion area was 299.5 cm2 (OMC) and 315.0 cm2 (LZD) at initial evaluation. Infection presence and severity was similar for both treatment groups at baseline. Reduction in lesion area of > 50% was seen on day two for both omadacycline and linezolid-treated patients (14% vs 11%). A 99% reduction was reported for both therapies at PTE.

Is general: Yes