From Invention to Market: The Drug Process With Colin Meyer, MD

Colin Meyer, MD, is Reata Pharmaceutical’s Chief Medical Officer and leads product development and strategy, clinical trial design and analysis, and medical affairs. Colin received a BS degree in chemistry with specialization in biochemistry and a BA degree in biology from the University of Virginia. He received an MD degree from the University of Texas Southwestern Medical School and an MBA degree from Southern Methodist University Cox School of Business. In this episode he discusses the process of how a drug goes from invention to market.

I’m Colin Meyer. I’m the Chief Medical Officer at Reata Pharmaceuticals. I’ve been at the company for 15 years, the second employee after Warren Huff, the CEO, and based here in Dallas, Texas.

When Reata was started, our CEO, Warren Huff, had the idea of aggregating a bunch of novel drugs together in a portfolio knowing that most drugs in development fail for one of many different reasons. Since we were a very small company at the time, we didn’t want to have to compete with much larger pharmaceutical companies. We decided to in-license projects primarily from academic labs. The projects were very interesting. The biology was cutting edge, and there were no other drugs that had the same mechanism as those that we in-licensed.

The lead drug was actually initially invented at Dartmouth by a famous scientist, Dr. Michael Sporn, who discovered a really important pathway that’s fundamental to the progression of many diseases in fibrosis. He discovered that pathway at his time at the National Cancer Institute. He was there for about 35 years. When he retired from there and went to Dartmouth, his goal was to develop novel drugs that could suppress inflammation that was important in the body’s response the injury.

In the lab, he optimized our drug from a natural product starting material and found that it was just as potent as steroids, but worked through a completely different set of pathways, and identified that it had activity in many different disease settings. At that time, the profile, while very interesting, wasn’t clear. We in-licensed the molecules from Dartmouth and MD Anderson as well, who had also been working on the project. We’ve now been developing the drug and in many different diseases.

There are many reasons why drugs are never able to safely make it to patients and demonstrate efficacy, the first of which is that it’s oftentimes difficult to know what causes the disease. In the setting of pulmonary hypertension, as you very well know, most patients have idiopathic disease. By definition, it’s unknown what causes it. It’s very hard then for researchers in a lab to model the disease.

Even though there have been a few models developed for pulmonary hypertension, it’s unclear if a specific model, whether in cells or animals, actual recapitulates what’s happening in humans. You could develop a drug that shows activity in those models, but then shows no activity in humans because that model simply wasn’t relevant. Alternatively, you could be fortunate and find a drug that does have activity and that pathway is applicable to humans. That’s one major challenge.

A second is that drugs may not be safe. A drug, for instance, may have activity in animals or people, but it may have significant toxicities that make the risk benefit profile not favorable. I guess lastly, the process is extremely long and time-intensive. It takes a lot of effort from people, time, and dollars to get drugs to the market. It’s just a very extensive and large effort.

Oftentimes, because of the very long timelines, it often takes a decade or a decade and a half to get a drug approved and go through all the clinical trials. It takes literally hundreds to thousands of people to work on the process and participate in the trials, and then drugs need to be able to demonstrate appropriate safety. Most drugs cannot make it through all those hurdles, and therefore, most drugs never get approved.

It rarely goes smoothly. There’s always challenges. Even with a drug that looks like it’s extremely promising and should work or has worked previously, you’ll never know what you may encounter. It just depends upon the specific setting.

It could be that you get the drug into people, and in clinical testing, you run into some unexpected safety issue that’s never been seen before. Then the question is can you figure out what that safety finding was and how it happened. Is it specific to the drug or part of the drug, or is it perhaps due to the specific type of patient who you’re treating? Not all patients are good subjects for clinical research, because you want a very homogenous group of patients.

You could have patients in there who don’t represent the rest or who have a very severe manifestation in the disease and very fragile and something could happen to them. Hopefully, in that setting, if there’s an unexpected safety finding, you can figure it out and then circumvent it by either adjusting the properties of the drug or the population that you’re studying.

From an efficacy perspective, there’s been many drugs that have shown promising activity and then failed to reproduce it in subsequent trials, in part, because early trials are either small or not representative of the later stage trial, or there’s a different patient population who’s tested. The drug may work in one type of patient but may not work in another type.

I think it depends upon the specific type of drug that’s being developed. Some drugs that are used and approved in pulmonary hypertension were initially studied elsewhere. Someone had a hypothesis that perhaps this drug, the mechanism of action could apply and be used safely. That’s been a major path for several of the drugs that are used. Some of them have to be used at higher doses in patients with pulmonary hypertension. Others have to be managed closely for their side effects. Making sure you find the right dose for the individual patient is very important.

With new drugs that have different mechanisms of action, then it’s just either a specific hypothesis about an aspect of the disease that’s not being effected by the current therapies, or perhaps there’s, once again, activity in other types of patients that may apply to PH patients.

I think the initial trials in people with PH, most companies cast a broad net and look to determine if there is activity across all patients or in some of the patients. Does it work better in patients who are on no background therapies, or does it also work in patients who are on background therapies? Does their disease duration affect treatment, the stage of the disease or other parameters?

I think the focus first is trying to look for a signal of activity and then, as you move on in development, especially towards a registrational trial or Phase 3 trial, it’s making sure that you can enhance that signal and show a very clear effect for efficacy and, hopefully, show appropriate safety.

A major consideration and challenge is making sure that you can enroll a set of patients who are fairly homogenous and then watch them carefully for the duration of the trial. A big challenge that everyone has in the setting of rare diseases, including pulmonary hypertension, is that, fortunately, it’s not extremely common, and most patients are on active therapy. It can be hard to find a patient who meets the certain eligibility criteria for a trial and where the physician feels like that patient would be appropriate for the trial.

Many of the patients are doing well on available therapies. Oftentimes, the physicians don’t want to rock the boat and try something new. They wait for those patients to be in need of additional therapies. Oftentimes, trials in PH they’re enrolling have to wait for those patients who would be suitable for the trial, and may not be doing well on their background therapies.

I think there’s two key aspects of all of the efforts in rare diseases. Number one, the acknowledgement by regulatory authorities like the FDA that rare diseases are extremely important and that there should be tractable paths to approval. There needs to be trials that can be conducted in a reasonable period of time to allow new therapies to get to patients. The FDA and other regulators globally have been much more open to facilitate more efficient development paths for new drugs. That’s been extremely helpful for probably all companies working in rare diseases.

The second is recognition by the community of patients who have rare diseases in formation of patient advocacy groups. They’ve been extremely helpful with us in multiple of our programs to connect the community together so that there is support amongst patients, so there’s recognition of efforts within the space. That can be to helping the patients who are newly diagnosed understand their disease and how to cope with it, how to connect to people who also have it, and also, obviously for companies like us, it allows there to be an identifiable pool of patients who could potentially contribute in our clinical trials.

It’s really important for patients to know that clinical trials are an option, and that it’s extremely important in order to make progress in their particular disease. If there were no clinical trials, there would be no new treatments for any disease. I think it’s really helpful in the setting of PH that there’s groups like yours [www.phaware.global], who are getting the word out to patients that it is important to participate in clinical trials if you’re an appropriate patient, because it really helps further research and, hopefully, progress in the patients.

We’re executing our Phase 3 registrational trial with our lead drug in connective tissue disease associated PH patients. It’s a global trial. We hope to make a lot of progress and get closer and hopefully have an answer to the CATSLYST trial. Additionally, we’re studying an expanded set of patients in our LARIAT Phase 2 trial, which is studying the drug in settings of pulmonary hypertension caused by interstitial lung disease.

We’re making a lot of progress and, hopefully, we’ll have a lot of opportunity with the drug, as it works differently than others and should complement their activities.

My name is Colin Meyer, and I’m aware that I’m rare.

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Learn more about the Phase 3 CATALYST trial: www.catalysttrial.com