Background Analysis: US FDA Advisory Committee to Review Paratek’s Omadacycline for Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections – AUG 8, 2018 (AMDAC)

Announcement

The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Wednesday, August 8, 2018 to discuss new drug applications (NDAs) for omadacycline tablets and injection, sponsored by Paratek Pharmaceuticals, Inc. (Paratek), for the proposed indications for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections.

Indication Background

Description of Indication

Community-acquired bacterial pneumonia (CABP) is a bacterial infection of lung tissue that is associated with chest pain, cough, sputum production, difficulty breathing, chills, rigors, fever, or hypotension. It differs from hospital-acquired pneumonia in that CABP patients have had little or no contact with medical institutions.

Acute bacterial skin and skin structure infection (ABSSSI) is a bacterial skin infection that involves deep tissue, requires surgical intervention (e.g. cellulitis, major cutaneous abscesses, and infected wounds, or is associated with a significant underlying disease (e.g., diabetes or systemic immunosuppression) that complicates response to therapy.

As more and more bacteria become resistant to currently available antibiotics, there is a need for better antibiotic stewardship and for new antibiotic treatments.

Product Background

Description of Product

Omadacycline is an aminomethylcycline subtype of tetracycline antibiotic. The molecule was designed to overcome tetracycline resistance mechanisms by substituting at the 7- and 9-positions on the tetracycline chemical structure. 

Paratek’s clinical development program (CDP) for omadacycline has investigated once-daily oral and intravenous (IV) formulations.

Clinical Trials of Proposed Indication

The NDAs are supported by three pivotal, phase 3 clinical trials: two studies in ABSSSI (named OASIS-1 and OASIS-2) and one study in CABP (named OPTIC). OASIS-1 (ClinicalTrials.Gov ID: NCT02531438) evaluated the safety and efficacy of once-daily, IV-to-oral omadacycline against twice daily linezolid. OASIS-2 (ClinicalTrials.Gov ID NCT02877927) evaluated the safety and efficacy of once-daily, oral-only omadacycline compared to twice-daily, oral-only linezolid. OPTIC (ClinicalTrials.Gov ID NCT02531438) compared the safety and efficacy of once-daily, IV-to-oral omadacycline to IV-to-oral moxifloxacin for treating adults with CABP.

Paratek has reported that omadacycline met all FDA and European Medicines Agency (EMA) primary endpoints in each study and demonstrated a generally safe and well-tolerated profile. Comprehensive data from the CDP, including detailed analyses by the company and by the FDA, will be presented in briefing materials that will be posted ahead of the meeting. The briefing materials for the meeting will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. Presented below is information from the omadacycline CDP based on press releases made by Paratek.

OASIS-1 Primary Analyses

OASIS-1 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). 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).

OASIS-1 Subgroup Analyses

Chronic Kidney Disease

In a safety analysis of patients with chronic kidney disease (CKD), 522 patients had stage 0/1 chronic kidney disease (CKD-0/1) and 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 adverse events (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. Treatment-emergent adverse events (TEAEs) were comparable between omadacycline and linezolid treatment.

Diabetic and Obese Patients

In sub-analyses comparing omadacycline to linezolid in patients with high body mass index (BMI), evaluable patients had elevated BMIs 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.

History of IV Drug Use and Hepatitis C

In this analysis, 322 patients with a history of IV Drug Use (IVDU) and 168 were IVDU and Hepatitis C positive (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.

OASIS-2 Primary Analyses

OASIS-2 evaluated the efficacy and safety of once-daily, oral-only omadacycline compared to twice-daily, oral-only linezolid in 735 adults with ABSSSI. Omadacycline met the FDA-specified primary endpoint of statistical non-inferiority (NI) in the mITT population (10% NI margin, 95% confidence interval) compared to linezolid at the ECR, 48 to 72 hours after the first dose of study drug. The ECR rate for omadacycline was 87.5% compared to 82.5% for linezolid.

Additionally, omadacycline met statistical NI compared to linezolid for the EMA-specified co-primary endpoints at the PTE, 7 to 14 days after completion of therapy in the mITT and the CE populations. Clinical success rates at PTE in the mITT population for the omadacycline and linezolid arms were 84.2% vs. 80.8%, respectively; and in the CE population were 97.9% vs. 95.5%, respectively.

Omadacycline demonstrated high clinical success rates for infections caused by the most common ABSSSI pathogens, including methicillin-resistant Staphylococcus aureus (MRSA).

In the OASIS-2 study, there was a low rate of study treatment discontinuation for both omadacycline and linezolid patients at 10.9% vs. 14.2%, respectively. Less than 2% of patients discontinued treatment due to adverse events in both treatment groups. No deaths occurred in the omadacycline treatment arm. The most common TEAEs in omadacycline and linezolid treated patients were nausea (30.2% vs. 7.6%, respectively) and vomiting (16.8% vs. 3.0%, respectively). Seventy-five percent of the nausea was classified as mild, with none reported as severe, and only one omadacycline patient discontinued treatment for gastrointestinal events. The vast majority of the onset of the nausea or vomiting in omadacycline patients occurred during the loading-dose phase on day 1 or day 2, and the median duration of these episodes was two days. Additional TEAEs, occurring in ≥ 3% of omadacycline patients were increased alanine aminotransferase (ALT; 5.2%), increased aspartate aminotransferase (AST; 4.6%), diarrhea (4.1%), and headache (3.5%), which were generally comparable between treatment arms. No subject in either treatment group developed Clostridium difficile infection.

Evan Loh, MD, President, Chief Operating Officer and Chief Medical Officer of Paratek has stated, “The gastrointestinal adverse event rates were higher in this study than in OASIS-1; however, these events were generally mild and transient. The completion and efficacy rates were very high in this study, confirming the utility of the oral-only omadacycline regimen and our confidence in the approvability of omadacycline for ABSSSI and CABP.”

OASIS-1 and OASIS-2 Pooled Analyses

The combined OASIS-1 and OASIS-2 analysis showed that antibiotic resistance was common, occurring in 61.3% of S. aureus isolates identified at baseline with more than one-third identified as multidrug resistant (MDR) (≥3 antibiotic classes). The rate of clinical success at post-treatment evaluation (PTE) with omadacycline was 81.0% when multidrug resistant Staphylococcus aureus (MDR SA) was present and was comparable to SA overall at 83.0%. Clinical success at PTE with linezolid occurred in 82.3% of patients when MDR SA was present and 81.3% with SA overall.

Methicillin-resistant Staphylococcus aureus (MRSA) was identified in 32.4% of patients. Clinical success rates at PTE for patients with MRSA were high in each treatment arm (84.4% for omadacycline; 81.5% for linezolid). Panton Valentine Leukocidin (PVL) presence correlates with community-acquired MRSA and was identified in 89.3% of the characterized MRSA isolates. Clinical success rates at PTE for treatment of patients with PVL+ MRSA were high (84.5% for omadacycline; 83.0% for linezolid).

OPTIC

The OPTIC study compared the safety and efficacy of once-daily, IV-to-oral omadacycline to IV-to-oral moxifloxacin for treating adults with CABP. In the study, 774 patients were randomized. Omadacycline met the FDA-specified primary endpoint of statistical NI in the ITT population (10% NI margin, 95% confidence interval) compared to moxifloxacin at the early clinical response (ECR) 72-120 hours after initiation of therapy. The ECR rates for the omadacycline and moxifloxacin treatment arms were 81.1 % and 82.7%, respectively.

Additionally, the FDA-specified secondary endpoints evaluated omadacycline at PTE visit 5-10 days after the completion of therapy in both the ITT population (87.6% for omadacycline vs. 85.1% for moxifloxacin) and in the CE population (92.9% for omadacycline vs. 90.4% for moxifloxacin) as determined by investigators. The secondary endpoints also achieved statistical NI. The co-primary endpoints for the EMA were NI in the ITT and CE CABP populations in those patients with Pneumonia Severity Index (PORT) III and IV at the PTE time point. Omadacycline demonstrated a high response rate and met statistical NI to moxifloxacin for both populations using a prespecified 97.5% confidence interval. High success rates were observed with response rates of 88.4% (omadacycline) vs. 85.2% (moxifloxacin) and 92.5% (omadacycline) vs. 90.5% (moxifloxacin), respectively.

Regulatory Background

US Regulatory Background

Early October 2018 – PDUFA date

February 2, 2018 – Paratek announced the completion of submissions of NDA 209816 (omadacycline tablets) and NDA 209817 (omadacycline injection)

Priority Review, Qualified Infectious Disease Product, Fast Track

Under a research agreement with the US Department of Defense, omadacycline is also being studied against pathogenic agents causing infectious diseases of public health and biodefense importance, including plague and anthrax.

EU Regulatory Background

2H 2018 – A Marketing Authorization Application (MAA) to EMA is planned. In a press release dated April 23, 2018, the company stated that they are on track to file an MAA in the second half of 2018.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: Paratek Pharmaceuticals, Inc. Drug Name: omadacycline Drug Class: antibiotic Indication: community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.