Creating a ‘new world’ to bring about next-gen antibiotics
Antibiotic resistance has been named one of the biggest threats to global health by the World Health Organization (WHO), with even ‘last-line’ antibiotics, those used as a last defence against resistance, not being effective in certain cases.
The demand for new treatments is high, with national regulators, such as the US Food and Drug Administration (FDA), encouraging the development of treatments. The FDA even stepped into the debate about reimbursement of the antibiotic products to suggest that a new model would have to be found to incentivise R&D efforts from the pharmaceutical industry.
Several large pharma companies recently exited the space, including Novartis and AstraZeneca, making the development of new antibiotics dependent upon smaller companies.
One such company is Entasis Therapeutics, which spun-out from AstraZeneca in 2015, and is entering Phase III trials for its lead candidate, ETX2514SUL, this year. In-PharmaTechnologist (IPT) spoke to the company’s CEO, Manos Perros (MP), about the future of antibiotic development will unfold and what could entice the big pharma companies back into the space.
IPT: How are current antibiotics used?
MP: You treat an infection by organ and by body size, without often knowing what is the pathogen that you're actually trying to kill. This has worked this has worked for a little while because we've had successive waves of antibiotics, which would be effective against bugs that develop resistance to the previous line.
IPT: How does this encourage the development of antibiotic resistance?
MP: Resistance happens when you use antibiotics widely, the pathogens develop resistance pretty quickly – the more you use it, the more rapidly resistance develops. We've been in a world where antibiotics are prescribed to millions of patients – you'd invent one drug and you could use it to treat an ear infection, or urinary tract infection, or foot infection, with the same drug. That gives you a very wide use but also the rapid emergence of resistance. The other thing it gives you is a low margin, high volume business model, which is really how antibiotics have always been sold. There are downsides to this model, particularly when you run out of new drugs, after you pick the low hanging fruit, as we have done, and you get to the point where it's becoming harder to find new effective, safe drugs. That's where we are today.
IPT: What happens when resistance develops?
Today, you have a number of patients, and we estimate approximately 200,000 infections per year in the US, which are multi-drug resistant. This means that multiple lines of antibiotics do not work in patients today who are treated with what we describe as salvage therapy – these are drugs that have been around for decades, which are toxic and fully tolerated but are really the only option for many patients. Sometimes you can save a patient's life, but sometimes you don't. Often patients walk out of the hospital, for those who make it, with lifelong side effects.
IPT: How is Entasis looking to interrupt growing antibiotic resistance?
MP: The way we built Entasis is actually slightly different and looks to operate in a world where the majority of patients will be treated with inexpensive, generic drugs. For those few patients for whom these drugs no longer work, they will be treated with new antibiotics, which are going to be pathogen-targeted and are going to be designed to treat drug-resistant infections with good effectiveness and toleration. That is the kind of molecule that we work on at Entasis.
IPT: Entasis is effectively working on creating a next-generation of antibiotic reserves?
MP: That's right. Reserves is one of the ways to describe it and stewardship is another. Many of our peers will complain that they discovered drugs, which are then put on the shelf. That's the third way of saying the same thing. We embrace that, I think this is the right way of using such drugs because you want to use them only when you need to use them – for the patients who cannot be treated with inexpensive, generic drugs. When the safe, generic antibiotics, which save 95% of patients, don’t work then you reach out and you use the new drug that is tailored to target the resistant pathogens. That's the way to do it.
IPT: How does Entasis discover and develop its pipeline?
MP: First of all, you need to invent those drugs and rather than going after screening campaigns and looking for substances in soil, for instance, we actually identify the pathogen and design molecules that target that specific resistance. As an example, our lead program is ETX2514SUL, which is a program that targets Acinetobacter infection. For us, step one is to identify if Acinetobacter has a medical need, understand the resistance, in that case, resistance is due to a class of β-lactamases, and then design a molecule that is going to address this resistance issue. For ETX2514SUL, the molecule is a β-lactamase inhibitor. So, that's step one, identify the pathogens and step two is to design the molecule very specifically.
Step three is to develop it in a way that's targeted, and that's where things become interesting because if you wanted to develop a drug for pneumonia or for a skin infection, very often, you need to run large clinical trials. The patients who are not very well typed, they are the pneumonia patients that can be infected by any one of a dozen or so pathogens and so you need large numbers. The FDA will ask you to do two Phase III trials because the data is not very homogenous. However, what we do is we target patients – we are looking for patients who only have drug-resistant infections. So, you can now design a much more targeted trial with patients who are much more homogeneous in the way in which the infection impacts them and you get a clear signal with smaller numbers. We are about to start a Phase III in a much smaller patient population, that means you're getting to the patients faster, and at a lesser cost.
IPT: What’s the model when the molecule is approved?
MP: That's where you're looking at a different model – rather than a low margin, high volume, it becomes a high margin, low value model because you use the antibiotic in a much smaller number of patients, almost disease-like, in terms of numbers. It's not unlike oncology, where you had chemotherapy for every patient for breast cancer and, nowadays, you actually type the cancer and you adapt the treatment to the patient. So, that's our vision for the antibiotic market of the future: generics for the majority of patients and for those where this would not work, you reach for the premium price, targeted antibiotics.
IPT: Are these types of conversations escalating to payers?
MP: I'm a chemist and where we are now, as a clinical stage company, we're going into Phase III this year – so, we have some way to go. We are starting to engage with payers and have discussions with individuals with key stakeholders. I do think for health care and, in terms of cost, it is actually a better approach than having patients spend weeks in the hospital. In the case of Acinetobacter infections, the drug resistance rates in the US, which is one of the lowest in the world, are about 50% and, of those patients, 50% will die in today's standards of care. Of those who don't die, they can stay in the hospital for three or four weeks in an intensive care unit, so not only would a treatment save the patients' lives but you save the healthcare system money.
IPT: A lot of larger companies have backed away from the space, how do you see that changing?
MP: I think when we have a changing environment, from high volume, low margin to low volume, high margin, that smaller companies will drive change. I think as we go into this new world, and we have a few treatments that are working in this new way and are actually profitable, I think big pharma will return. It's a business decision that has driven bigger companies out of the space, for the most part. I think showing that the business model is viable that will bring big pharma back.
Manos Perros has served as Entasis Therapeutics’ CEO, co-founder, and director since May 2015. Prior to this, Perros worked for AstraZeneca as VP and head of infection research and early development from 2010 to 2015.