A Passion to Solve the IBD Enigma

Dr. Andres Yarur is on a mission that’s taken him from his Chilean homeland to Miami, Chicago, Wisconsin and most recently to Los Angeles, in search of better outcomes for patients by optimizing the tools currently available and further developing novel approaches to manage IBD.

“If I only have limited therapeutics in my clinic and my patient is still not doing well,” said Dr. Yarur, “what can I do with what I have? How can I make the same drug work better?”

His medical career began in Chile. He was always interested in pharmacology and as a medical student was involved in pharmacogenomic studies and investigating the effects of anti-rejection drugs in patients with a liver transplant under Roberto Segovia. At the time, he was struck by the potential impact he could make by advancing the science.

“I saw people that were very sick, they would get a liver transplant and it would really change their lives. But that was just the beginning… the next step was to avoid organ rejection while minimizing adverse effects.”

During medical school, he experienced the plight of the underserved up close, and it imprinted on him an urge to help people. “As a medical student, I worked in a lab studying genetic variations of the cytochrome P450 system and how they affect response and safety among people of different racial backgrounds.” Dr. Yarur has a gift for human interaction; he enjoys developing relationships and he began to see a medical career as a way to help people while combining it with his love of science.

Access to care has also been an interest of his. “It makes you wake up and realize that unfortunately there are a lot of disparities in how people receive healthcare,” said Dr. Yarur. “And it inspires you to try and do your part.”

And Dr. Yarur has done his part, wherever his journeys have taken him. From Chile, he did his residency at Jackson Memorial Hospital and University of Miami in Florida. His program director suggested he meet Dr. Maria Abreu, who had been a student of his and had recently come to Miami as the new Chair. Dr. Abreu insisted he shadow her in her clinic and that is when he was introduced to the world of inflammatory bowel disease.  He was particularly interested in the long-term relationships between patients and physicians and on the immunopharmacology-based therapies.

He realized therapies were quite limited and he saw this as a challenge.  “It was very inspiring to see patients with life-long debilitating diseases fighting through. Despite the limited available therapies, an overwhelming number of people were simply not doing well. IBDs are complex conditions not only from the biological and clinical standpoints, but also emotionally,” he said. He was determined to better understand why therapy failure was so common and what we could do to improve that therapeutic ceiling. While at the University of Miami, he conducted several studies looking into the pharmacokinetics of biologic therapies and how they could explain non-response to the available biologics.

“Why aren’t these biologic medicines reaching the tissue like they should? Does it even matter?”

Those clinical observations led to the ATLAS study, which looked at how drug levels in different tissues were correlated with efficacy and found that some patients with active disease, despite having detectable levels of anti-TNF in their blood and healthy tissue, had really low drug levels in the intestinal tissue that was severely inflamed. The ATLAS study became a proof-of-concept for Dr. Yarur’s hypothesis and encouraged further investigation.

At the time, he also performed one of the first studies looking into the clinical implications of adalimumab pharmacokinetics. Despite adalimumab having a different structure than infliximab, the study found that the rate of anti-drug antibody formation was still quite significant and that even though the clinical pharmacokinetic properties overlapped with infliximab, they were not the same.

He also investigated how to combine therapeutic drug monitoring of anti-TNF and thiopurines. “We knew combination therapy of both drugs is more effective than each drug alone and we also knew therapeutic drug monitoring could be useful when optimizing monotherapies of infliximab and azathioprine independently. But how about if we combine both?” he said.

After finishing his Gastroenterology fellowship, he moved to Illinois and completed an advanced IBD Fellowship at the University of Chicago, one of the top IBD centers in the country.  “I really enjoyed my time at the University of Chicago. It was such an extraordinary experience, and I was very fortunate to work closely with and learn from many world-renown IBD experts including David Rubin and Russell Cohen in a truly outstanding environment.”

After accepting a joint position with the Medical College of Milwaukee (MCW) and the Milwaukee VA, he was given the task of improving the VA’s IBD care, while building a research structure at MCW. He also continued his work to try to understand non-response to newer therapies and to develop clinical trials. “My role was to integrate the clinicians and researchers and build a top-quality team focused on IBD,” said Dr. Yarur. “We began collaborating with other centers and put MCW on the map in terms of IBD research.”

Simultaneously at the VA, Dr. Yarur established an IBD clinic, ensuring that veterans with these diseases received the specialized support they needed. “Working with the VA was a very good opportunity to help a lot of IBD patients benefit from specialized care,” he said.

“We got them access to the right medications and established a system of IBD care. It was an extremely rewarding experience.”

In 2022, Dr. Yarur was offered an Associate Professor of Medicine position at Cedars-Sinai in Los Angeles. He arrived energized by observations that while today’s therapeutics are wonder drugs for some patients, they can be frustratingly ineffective for others. His most recent research has attempted to answer some of these questions.

“The use of therapeutic drug monitoring had been widely used for anti-TNF but it was poorly understood for novel drugs with different mechanisms of action. The assumption was that the same strategies that helped optimize anti-TNF were valid with other biologics, but this was not really true. It was important to understand if and how therapeutic drug monitoring and drug optimization as we knew it was applicable to other biologics.”

The COMBO IBD study found that even though higher thiopurine metabolite levels did correlate with high infliximab levels, this was not true for vedolizumab or ustekinumab. He also participated in the ENTERPRET study, showing that applying early therapeutic drug monitoring in patients with UC not responding to vedolizumab does not improve outcomes – even in patients with a high drug clearance.

His research in the CONSTELLATION study on visceral fat found clues as to why some patients with higher amounts of visceral adipose tissue poorly respond to certain biologic medicines. He is trying to better understand how metabolically active fat can affect drug pharmacokinetics and pharmacodynamics. “As obesity in general becomes more and more prevalent, it’s going to be a very important topic. Even with all the options that we now have available, we still see a huge unmet need for more efficacious treatments,” Dr. Yarur said. “As the disease and our environment evolve, therapies must also evolve.

“We need to continue raising the therapeutic ceiling. This will involve creating more personalized treatment regimens that must incorporate non-pharmacologic approaches such as diet, exercise, and other lifestyle modifications.”

Dr. Yarur said he looks forward to a future of new therapies and wants to stay on the cutting edge of optimizing new treatments as they become available.

“A lot of bench studies have made valuable progress aiming to improve and tailor treatment targets.  However, these new discoveries need to be trialed and put into place the right way before we can safely assume they can be applied in practice,” said Dr. Andres. “Integrating molecular discoveries and learning how they can be useful to help our patients will be challenging but a pivotal step in the process,” he continued. “Being part of that process and moving the needle forward in how we test these new molecular pathways and therapeutic targets is going to be extremely important, and it’s a big passion of mine.”

Dr. Yarur’s advice to young physician-scientists derives from his own experiences: “Seek for inspiration in your patients. How can you improve their lives? Don’t be hesitant to “think outside of the box” and persist on what you want to do without losing perspective.  The rest will come along.”

“I took the initiative to go and explore,” he said. “I encourage everyone to do the same. Get out of your comfort zone and do work that inspires others.

“For the future of our field and our patients, it matters that you push yourself to be more than just a practitioner. Be an inspiration.”