Overcoming The Hurdles of Starting up a Biopharmaceutical Company

Every emerging biopharmaceutical company has an interesting story that describes how they overcame major startup challenges, including study design, funding, and drug targeting strategies. eXIthera is developing a small molecule, EP-7041, to control the blood-clotting pathway and enable healthy blood flow without the concerns of adverse clotting or major bleeding via selective inhibition of Factor XIa. In this interview, Moe Alsumidaie speaks with Neil Hayward, PhD, CEO of eXIthera, to advise on his experience overcoming the challenges of starting up an emerging biopharmaceutical company. 

Moe Alsumidaie: What factors influenced the design of your early phase trials with EP-7041? 

Neil Hayward: Heparin has been approved as an anticoagulant for a long time. We did our research by

Neil Hayward, PhD

engaging surgeons, and they are looking for a therapeutic that stops clot formation and protects the patients from stroke, without the marked bleeding they observe with heparin. Additionally, they don’t want their machines-the heart-lung machines, bypass machines, or ECMO machines-to clog. This led us to target our compound for these two purposes. 

In our discussions with the agency, we are presenting EP-7041 as an alternative to heparin. We see the potential for EP-7041 to become the procedural anticoagulant of choice. Our goal is to have an open and honest conversation with the FDA. We really want to know what type of study the FDA would like to see first. As a small biotech company, we cannot afford a failure.

We have had extensive conversations with regulatory consultants who have listened to potential Principal Investigators (PIs) for the Phase II study, and we learned that it is essential that we identify critical study endpoints, and ensure the study is powered by sufficient enrollment numbers to ensure the statistics work. 

Our goal is to have a definitive proof of concept study that we can apply broadly. That could mean additional Phase II studies or, perhaps, a large Phase III study. Most importantly, we want the study to be successful. So, we are taking our time with the regulators and our PIs to address this significant unmet need.

MA: It is well known that the highest failure rate in pharma is in the preclinical phase. How have you overcome the challenges of preclinical and early-stage development? 

NH: I'm a pharmacologist by training, so I think preclinical studies are critical. The question is, are they really predictive of what happens in humans? 

Early on, preclinical work demonstrated that EP-7041 could make clots smaller with a decreased bleeding liability. With that data, we were confident to move into the clinic. My opinion is, as soon as you have that sort of information, you really need to bite the bullet, demonstrate the compound is safe and get into humans as quickly as possible. That was the reason we moved swiftly into Phase 1.

MA: How is eXIthera differentiating its strategies from other pharma companies? 

NH: A big difference between eXIthera and big pharma, such as BMS, Novartis, Bayer and J&J for example, is that we have a simple small molecule that is both a potent and selective inhibitor of Factor XIa. Although big pharma is targeting Factor XI, most of them are using antibodies or antisense approaches. 

The advantage is that we understand the critical sites on the enzyme. The difficulty has been to find a compound with not just high potency, but also the selectivity to inhibit only Factor XI, not Factor X or thrombin. If you inhibit Factor X or thrombin, you're going to get unwanted bleeding.

We also understand the PK (pharmacokinetics) of EP-7041. We want a compound that has a short half-life. We hope to use EP-7041 in numerous acute hospital settings, so the physician should be able to administer the drug, measure aPTT and promptly begin treatment. When the procedure is complete, there is no need for a reversal agent (for example with heparin, protamine is used to reverse its activity, and it, like heparin, has potential safety issues to the patient), just simply stop administering EP-7041, and the drug will clear quickly. 

We feel these are the significant advantages of a small molecule like EP-7041.

MA:How do you plan to design your Phase II trial?

NH: We are focused on addressing the bleeding complications in high-risk patients undergoing extracorporeal circulation, such as patients in the ICU that require extracorporeal life support or patients requiring cardiac surgery that are placed on a cardiac bypass machine during the surgical procedure. Both situations require the patient and the machine are protected from clot formation, which is why we believe EP-7041 will be successful. We are in discussions with various specialists, such as cardiothoracic surgeons, perfusionists, anesthesiologists, hematologists and ECMO specialists. Once we are in a hospital setting and demonstrate EP-7041 is effective, we believe these groups will talk. We just want to have a successful initial Phase II trial.

MA: How did you acquire the licenses for EP-7041? How does license ownership influence investors?

NH: It’s an exciting story. Our asset came from Daiichi Sankyo, where I previously worked. When Daiichi Sankyo shut down U.S. operations, years of negotiations resulted in eXIthera acquiring the rights to key patents of the chemicals I had worked on. Because there was a clear plan to execution, impressive early drug-like compounds from Daiichi, and we owned the patents with no reach through, the investors came in!

Our Series A was $4 million, which enabled us to identify, synthesize, and test EP-7041. The Series B was $14 million, which has taken us to where we are now. We are in the process of raising our Series C, which will enable us to initiate and execute proof-of-concept/Phase II in patients where there is a tremendous unmet medical need.

MA: What advice would you give to other emerging biopharmaceutical companies?

NH: When I founded the company in 2012, I was adamant that I wanted to work with people with whom I had worked before, either in-house or at CROs. This was important because it’s easy to spend money when you’re designing and executing studies but, if something goes wrong, you've got to be able to speak freely to one another, tell the truth, hide nothing, work together and, importantly, have fun and move forward. I've been very particular with the people with whom I’ve chosen to work with. People are the most critical thing. Luckily, we have a beautiful, simple story. The drug has performed exceedingly well. But one of the reasons, I think, is because I’m surrounded by good people who aren't shy to tell me I'm wrong and to give me good advice.