Paratek Successfully Tackles Patient Challenges in Phase 3 Trial

By Ed Miseta, Chief Editor, Clinical Leader

Paratek bills itself as a pharmaceutical company developing innovative medicines based on tetracycline chemistry. The company’s main focus is on drugs targeting infectious diseases—an area of great need, as current antibiotics will ultimately lose their effectiveness as bacteria inevitably develop resistance.

Paratek’s lead candidate, omadacycline, is the first in a new class of tetracyclines known as aminomethylcyclines. In 2015, Paratek initiated a Phase 3 registration study in acute bacterial skin and skin structure infections, or ABSSSI, to determine the efficacy and safety of intravenous to oral dosing regimen of omadacycline compared to linezolid (an antibiotic used for the treatment of infections caused by Gram-positive bacteria that are resistant to other antibiotics). That study reported positive safety and efficacy data in June of 2016.

The company is currently conducting two additional Phase 3 studies with omadacycline, including a trial of the intravenous to oral dosing regimen in patients with community acquired bacterial pneumonia, or CABP, and a trial using just the oral formulation in patients with ABSSSI.

In this Q&A, Dr. Evan Loh, president and COO for Paratek, discusses some of the clinical challenges faced when enrolling patients for the ongoing Phase 3 studies. In addition, he notes how completing these studies will position the company for a new drug application as early as the first half of 2018.

Ed Miseta:  What can you tell us about the additional Phase 3 trials for omadacycline?

Dr. Evan Loh: The pneumonia trial is a randomized, double-blind multi-center study designed to compare the safety and efficacy of omadacycline to moxifloxacin for adults with Community Acquired Bacterial Pneumonia (CABP). The study planned to enroll approximately 750 adult subjects at 120 centers worldwide, and was designed to satisfy both FDA and EMA requirements.

The second skin trial is very similar to our successful Phase 3 trial of intravenous to oral omadacycline that we completed in the middle of 2016. This study will enroll approximately 650 adult subjects and will again use linezolid as the comparator. But this study will use only the once-daily oral formulation of omadacycline. We’re excited about this trial because we’ve heard from physicians that they want an equivalent oral formulation that will help them get patients out of the hospital quickly and, potentially, give them an option to keep patients from ever having to be admitted. 

Miseta: What were the end points you hoped to achieve?

Loh: For our skin studies, the primary efficacy endpoint for FDA is Early Clinical Response. That is, a greater than 20 percent reduction in lesion size 48 to 72 hours after first dose of study drug in the modified Intent to Treat, or mITT, population. There are co-primary endpoints for Europe: Clinical response at post treatment evaluation in the mITT population and clinical response at post treatment evaluation in the clinically evaluable population.

For the pneumonia study, the primary efficacy endpoint for FDA evaluation, as defined in the protocol, is the number of subjects with clinical success at the early clinical response assessment visit, which is 72 to 120 hours after the first dose of study drug. The EMA Co-Primary Endpoints are the Investigator’s Assessment of Clinical Response five to ten days after the completion of treatment for the Intent to Treat (ITT) and Clinically Evaluable (CE) populations.

In both studies, other efficacy outcome measurements include overall survival and resolution or improvement of signs and symptoms at the post treatment evaluation visit. Safety and tolerability are also being assessed by treatment-emergent adverse events, vital sign measurements, electrocardiograms, and laboratory values.

Miseta: Were there any new or creative methods used to recruit patients for this trial?

Loh: Across all studies, we performed extensive country and site feasibility globally to ensure there was a past history of performance and quality. That is something that was very important to us going into the study. We also felt that extensive vendor and site engagement with Paratek would be critical factors to a successful enrollment process. Personnel from Paratek conducted numerous site visits and we sent regular communications to sites. The primary purpose of those communications was to share best practices with all sites, which we also felt would be a key factor to conducting a successful study.

Miseta: Was all of that done at the start of the studies?

Loh: A lot of it was. But in the case of the pneumonia study, the indication is largely seasonal. For that reason, we also conducted a mid-study meeting in order to re-engage with sites. During that meeting, site personnel participated in a workshop we designed to share lessons learned along the way and to share best practices on identifying and recruiting subjects. The lessons learned will also help us in identifying and recruiting patients for future trials.   

I would also add that community acquired bacterial pneumonia is a disease where it helps to be in the right place at the right time. Past performance isn’t always the best predictor of future results. To be successful in patient identification and recruitment, you have to cast a wide net and understand the patient pathway in order to ensure success. There were also tools that we provided to sites to help with study awareness and potential referral networks, which generally included access and outreach materials to attract potential patients.

Miseta: Did you go directly to sites, or were you able to use patient groups or social media to help with the recruitment process?

Loh: We always look for innovative ways of reaching out to patients, but given the indication and protocol entry requirements for this study, patient advocacy groups and media were not utilized. Often, patients’ first see a doctor because of their symptoms (Chest pain, shortness of breath, cough and/or productive cough) in the emergency room or clinic, so understanding that process and working with sites to establish patient referral networks was the key focus of our recruitment efforts.

Miseta: Was Paratek able to incorporate anything into these trials to make them more patient centric?

Loh: Making trials more patient centric is obviously a topic of concern for all pharma companies today. One of our goals was to make participation in this trial as easy as possible for patients. For this study, our protocol was designed to allow flexibility when possible in order to avoid any additional burden on patients. There is always extra patient data that you would like to have, but we opted to not collect any unnecessary or “nice to have” data. This was done to minimize patient procedures and their time requirements at the site. 

In addition, patient facing materials were developed by Paratek to explain the indication, the study requirements, and procedures. In conjunction with the informed consent, this helped potential patients and their families understand the study so they could make an informed decision about participation.

Miseta: Were there any additional challenges you faced?

Loh: When we submit our NDA one of the challenges will be integrating data from multiple studies that span 10 years of clinical trial work. With any world-wide trial, global regulatory challenges are always expected. We never know exactly how a reviewer will react to a clinical trial application. Geographic standards for treatment can also be an issue, as well as sourcing of comparator drugs.