Entasis Therapeutics CEO: 'Our Antibiotics Work Differently'

Benzinga spoke with Entasis Therapeutics Holdings Inc ETTX CEO Manos Perros, Ph.D. for the latest news and updates in the company's pathogen-targeted antimicrobial pipeline.

Benzinga: In late June, Entasis announced that David Meek was appointed as chairman of the board. With over 25 years' experience, and as the current CEO of Ipsen, what does the addition of Meek mean for the company?

Perros: David brings extensive industry experience to our board and a strong commercial background across several therapeutic areas, but in particular in oncology and rare diseases, providing a valuable strategic perspective as we work to successfully develop and commercialize our innovative pathogen-targeted treatments.

David is also the CEO of a multinational company and has deep experience in dealmaking.

Interestingly, David's specialty is not in infectious diseases; however, our antibiotics work differently from the way that typical antibiotics have been prescribed and commercialized in the past, so we are closer to a rare disease model.

We are currently approximately 18 months away from a data readout for our lead program, sulbactam-durlobactam (ETX2514SUL) for multidrug-resistant Acinetobacter infections followed by what we hope will be FDA approval.

BZ: What are some of the ways in which Entasis Therapeutics operates differently from other companies in the space?

Perros: There has been a profound evolution that has led to many companies including large pharma deciding to exit the space in a transition that has left the rest of the industry struggling.

By "struggling," I mean that this is a relatively tight market. The vast majority of the antibiotics market refers to generic broad-spectrum antibiotics that are widely used and inexpensive.

Very often, the doctors that prescribe these do not know what pathogens cause the infection. Therefore, they instill empiric therapy as treatment. Physicians pick an antibiotic or two, and sometimes even more, that is likely to kill that type of bacteria based on the context. So they choose multiple antibiotics to try and kill all the pathogens that they believe have caused the infection. This is what we call "empiric therapy."

This has worked for the most part, but unfortunately, the approach is widely used and has had the unintended consequence of antimicrobial resistance. This means the bugs and bacteria develop resistance to the drugs that are used to kill them.

So they adapt in real-time evolution: from the population of drug-sensitive bacteria that do not die from the drug emerges a new type of pathogen that is even more resistant to the drug.

The more the drug is used for treatment, the more resistant the bacteria will become. You see why empiric therapy is a necessary evil: physicians use multiple antibiotics, often unnecessarily, to cure the patient, but this drives emergence of AMR, which ultimately harms the community.

The consequence is that, today in the U.S., up to an estimated 200,000 antimicrobial-resistant deaths are reported each year.

These are patients that a decade ago could be treated by mainstream antibiotics, but now these drugs do not affect the bacteria. It is even worse elsewhere in the world, such as in Eastern Europe and Southeast Asia, where those numbers are even higher.

BZ: Before we get into the programs, can you give us an overview of what is meant by pathogen-targeted? What does this mean?

Perros: Rather than trying to treat a disease such as pneumonia, where antibiotics work the same as generic drugs for the majority of patients, we select a single pathogen like hospital-acquired Acinetobacter and develop a drug. In our case, our lead product sulbactam-durlobactam is specifically targeted to destroy that pathogen.

This pathogen-targeted approach is what differentiates Entasis. For example, Acinetobacter is a species of bacteria that is widely found in hospitals and infects fragile patients who have depressed immune systems, such as from chemotherapy, a hip replacement or severe burn. That is when Acinetobacter infects patients, and it can be very deadly.

If the patient has an Acinetobacter infection today in the U.S., there is a 50% chance the patient will die.

In places like Eastern Europe and Southeast Asia, those numbers can be as high as 90%. Those patients have very limited options. If a doctor diagnoses a patient with an Acinetobacter infection, then the doctor will often combine multiple drugs.

These combinations can become toxic, and many of the involved patients are diagnosed with dialysis and/or placed on the kidney transfer list.

A more targeted drug is needed to combat this pathogen for these seriously sick and drug-resistant patients. Our drug combination sulbactam-durlobactam would only be given to these very sick fragile patients who are resistant to the more generic broad- spectrum antibiotics.

BZ: Can you go a bit deeper to give us some insight into the company’s unique pathogen targeted approach to antibiotic development?

Perros: Each of our products is targeting a pathogen or a group of pathogens. For example, the sulbactam-durlobactam combination is enrolling patients who have lung infections as well as similar infections in other areas of their body.

So instead of looking at a single body site, we are looking at patients that are suffering from the same pathogen at different body sites.

Entasis’ programs target specific bacteria — much like cancer drugs today in oncology target specific mechanisms that cause cancer — which allows us to develop a unique drug that specifically targets the pathogen causing the infection.

We aim to optimize the drugs to kill the bacteria that are directly causing the infection.

BZ: What are the lead products that the company has in its pipeline? Can you provide an update on the current stage of development for each?

Perros: We currently have a pipeline of pathogen-targeted products. Our lead program is sulbactam-durlobactam (ETX2514SUL), which is being evaluated in our ongoing pivotal Phase 3 trial for the treatment of patients with pneumonia and bloodstream infections caused by carbapenem-resistant Acinetobacter baumannii.

This Phase 3 is called ATTACK, and its goal is to enroll patients in the U.S., Europe, and Asia to evaluate the fixed-dose combination of broad-spectrum β-lactamase inhibitor durlobactam with sulbactam. The data from the sulbactam-durlobactam ATTACK trial is expected in the second half of 2020.

If we are successful, this will likely be the first antibiotic product that will have an indication on its label for the treatment of Acinetobacter.

Our second lead program is zoliflodacin, which targets uncomplicated gonorrhea. It is a novel single-dose oral antibiotic that is first in its class to be developed for this indication. This program is planned to enter a Phase 3 trial in the second half of this year.

We have a partnership with the not-for-profit organization Global Antibiotic Research and Development Partnership based in Geneva, Switzerland, which is fully funding and initiating the Phase 3 trial shortly.

The trial will examine the efficacy and safety of zoliflodacin in patients who are affected by gonorrhea, including drug-resistant gonorrhea. We anticipate data in early 2021.

Our third product ETX0282CPDP is an orally-available, broad spectrum inhibitor of Class A and C beta-lactamases. It is currently in Phase I development and is aimed at treating complicated urinary tract infections, which develop as a result of infection with the drug-resistant Enterobacteriaceae pathogens.

BZ: Entasis presented on its innovative programs, including the sulbactam-durlobactam and zoliflodacin programs, at the American Society for Microbiology Microbe Conference 2019. What were some key takeaways from that conference?

Perros: At the recent ASM Microbe conference this summer, we provided data from studies on each of our unique pathogen-targeted antimicrobial programs.

These were largely updates on ongoing preclinical work, supporting the continued advancement of each of our clinical candidates. A particular highlight was the oral presentation by Ruben Tommasi, our chief scientific officer, who provided an overview of our preclinical and clinical pipeline and pathogen-directed drug design platform.

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