Bench to Bedside to Market and Back Again: Revolutionizing the Microbiome

Twenty years ago, when Mark Pimentel, MD, FRCP(C), released some of the first papers showing an impact on irritable bowel syndrome by eradication of bacterial overgrowth in the small intestine, he was met with disregard, disbelief and controversy.

“In 1999, when our first papers came out, we were ridiculed publicly at the big meetings,” he told Healio during a visit to Cedars-Sinai. “People did not believe what we were doing. Only when the word ‘microbiome’ emerged in 2003 and everyone was starting to study the microbiome, we began turning heads. Suddenly, maybe our work was interesting. Maybe it was important.”

Despite the de novo interest in an area Pimentel saw as the missing piece to a diagnostic and treatment puzzle in IBS and other diseases, the funding failed to follow. After 15 years of chasing funding and seeing little to none, Pimentel and his colleagues Ruchi Mathur, MD, FRCP(C), and Ali Rezaie, MD, FRCP(C), took matters into their own hands and ultimately created the Medically Assisted Science and Technology – or MAST – group at Cedars-Sinai.

MAST’s goals are many, but the roots remain in the microbiome and bringing diagnostics and treatment from an academic center to the clinic and eventually to the market so they can make the biggest impact on patient care.

“MAST has a lot of mandates, but these mandates are always in the context of our background as physicians. Let’s figure out treatments and diagnostics and devices that we see as a need in the clinic and try to develop them and get them to a place where they would really help patients and fill in the gaps we see daily,” Pimentel said.

Rezaie added: “It’s more than knowledge gaps; it’s filling clinically relevant knowledge gaps.”

‘Blockbuster’ Status

Mathur said it was the culmination of 15 years of research on rifaximin – now Xifaxan (Salix Pharmaceuticals) – that caught the attention of Cedars-Sinai’s Technology Transfer division.

“Not only was it a success as far as a blockbuster drug goes – it hit blockbuster status in 2018 – but it was also a success in the fact that it changed the way that people practiced medicine,” Mathur said. “Referrals to gastroenterologists for IBS-D have dropped by almost 25%. This is a significant decrease and it has an impact on health care costs and on the IBS population and their burden of suffering.”

She explained that Tech Transfer saw this success and also saw the research and possible products that the team had in its pipeline while the team was coming to the same realizations.

“We seem to have good collective ideas. Maybe we should be doing things we think are right for patients. Maybe instead of another laxative for a constipated patient, maybe we figure out what’s causing their constipation and try to solve it,” Pimentel said.

With this collaboration with Tech Transfer, along with generous philanthropy, interested foundations and other means, MAST is able to leverage their success and bridge the funding deficit in IBS and other areas.

“If you think about IBS affecting a billion people worldwide and 40 million in the U.S. and being the most expensive disease, you’d think there would be more interest in funding something that could help economically in the U.S. and help patients more broadly. But there was almost nothing,” Pimentel said. “As a result of this funding deficit, there are very few people researching IBS. There are even fewer people doing meaningful mechanistic work.”

And as a result, even less scientists bringing new innovative products to market.

Refocusing from the Bench

While research in the microbiome arena has exploded since 2003, Pimentel, Mathur and Rezaie took aim at the endpoints being used – shifting their focus from stool to the small bowel.

“Everybody looks at stool. Everyone has stool. It’s easy to get stool,” Mathur said. “A lot of the science, including the Microbiome Project, have been based on taking this incredibly long organ and condensing it down to an ounce or two of stool, which is kind of weird. If you think about the GI tract, you have completely different ecological systems throughout the GI tract. The Ph status changes. The oxygen conditions change. Where you digest food (the small bowel) is very different from where you start to make stool. You have this big linear tube and we have said all of this is represented by results from stool.”

“But, there’s a whole area of the small bowel that they missed,” Pimentel added. “Using stool as a surrogate for disease or for measuring or understanding disease was not something we believed.”

Rezaie said stool easily masks those diseases that may start in the small bowel.

“At the end of the day, the most nutritiously and metabolically active part in the gut is the small bowel: 20 feet of active segment. That’s where almost all the nutrients get absorbed, digestive enzyme-associated chemical reactions occur, and all the action happens,” Rezaie said. “That’s why we are going directly inside the small bowel and aspirating what we want to examine.”

MAST is looking at the small bowel via endoscopy and Rezaie explained that even this technology – a capillary double-lumen catheter inspired based on a lotus roots design – has moved into licensing with a device company. Currently, MAST has samples from 350 patients with a short-term goal of 1,000 patients sequenced and a long-term goal of 10,000. Mathur explained that once more patients are sequenced, they will look at specific diseases and the small bowel microbiomes associated with the patients who have that disease.

“Are we seeing a plethora of a certain organism? Is something missing?” Mathur said. “We can start to see those patterns and then maybe we can start to specifically intervene. It’s a form of personalized medicine. We are noticing patterns already. We’ve seen it in some rheumatologic diseases in just 300 subjects.”

Pimentel, Mathur and Rezaie were buzzing about the data they are set to present at DDW 2019, mostly from the REIMAGINE study.

“We are going to be presenting the first slices of deep sequencing of the small bowel. ... We are already finding bugs linked to disease. That’s huge. Despite 10 years of microbiome work in stool, few smoking guns so far, so I’m excited to be studying this final frontier,” Pimentel said.

The MAST directors credit their full team for the progress made so far.

“When you have really smart PhDs and patient-driven MDs that are scientists, that’s a really good combination. At our research meeting, I proposed separating the research and the clinical stuff and they all said, ‘No!’” Pimentel said. “Our lab feels like everything they do connects. They’re super motivated. ... Every single research meeting is an open forum. ... Everybody has an impact.”

“We never know where the next great idea is going to come from,” Mathur added. “When we have lab meetings and discussions, the med student, the resident rotating through, the newest lab member along with the PhDs – everybody gets a say. That’s a democracy. We value young eyes. We value new eyes. We value the opinions of everyone who is part of our dynamic and innovative team.”

To – and From – the Bedside

“We are very lucky in our group here at MAST because we have really good basic science going on and we are able to take that basic science and put it quickly into the clinical realm. Then, because of our affiliation with Tech Transfer, we often are able to take that directly to those who can then take it to the public. Bench to bedside to market,” Mathur said. “However, sometimes it doesn’t go in that particular direction. Sometimes it is an observation we see in clinic that triggers us to go back to the bench and explore. This can actually result in more excitement and innovation.”

With more than 6,000 patients seen each year just in the GI motility program, Rezaie said physicians at Cedars-Sinai are plugged into what most affects the patients’ quality of life.

“We see all these patients who are struggling, and they tell us what are the shortfalls in their care, what are they suffering from and what is affecting their quality of life more than anything else. Then we take those ideas – a lot of ideas in our research come from patients,” he said. “We have this cycle that I haven’t seen in any other center. We get it, we push it to the basic science lab. We prove the concept. We bring it in as translational research. We make it to the clinic and if it’s clinically successful, we even find industry partners to push it forward. If any of these steps are missing, you’re stuck for years.”

Rezaie discussed a technology that can prove to be an alternative to current antimicrobial agents that is now ready for first-in-human clinical studies. While not ready to reveal yet, he said it will be extraordinary.

“This started with one patient 3 years ago. This went all the way to the basic lab, the translational lab, we did the safety studies and now it’s ready for clinical trials. If we didn’t have this setup, this would not have happened,” Rezaie said. “That’s what is special about this program. The ultimate goal is listening to the patient and trying to come up with something that will help them eventually.”

It was a common theme among the directors.

“We often hear ‘bench to bedside’ but it’s never like that. It’s going back and forth. We will see something in clinic, and it will be bedside to bench. Then we will do the bench research for a year or 2 or 3 or however long is necessary. We will see what fails or works. Then we will make it back to the bedside. Then it might go back to the bench,” Pimentel said.

In the Market

“Believe it or not, the biggest step is from having clinical data and going to industry and finding industry partners that are appropriate,” Rezaie said. “Coming from other centers, and I have done research on three different continents, this process usually takes 10 to 20 years. On average, I would say 15 years. Here? This process can take 3 years.”

The end goal, though, is always to impact patient care and the best way to do that is to bring effective tools and treatments to market.

“This stems from my frustrating experiences with biotechnology” and the focus of one company on one product, Pimentel said. “We have more than a dozen products that we think are interesting. I want to do a lot for people, not just one thing.”

MAST’s track record – from rifaximin to the recently released IBS blood test IBS Smart (Gemelli) – laid the path for ongoing studies and interest from industry.

In his previous research, Pimentel showed methane was one of the gasses produced by the microbiome in IBS that could be measured for diagnosis and then linked it to IBS-C. Research pointed to lovastatin lactone (SYN-010, Synthetic Biologics) as a possible inhibitor of methane.

“We block methane and constipation disappears,” Pimentel said. The product now is in a phase 2 study with Pimentel and his colleagues.

“We aren’t a drug company. We can’t get it to the patients in the world. We get it to a certain point and then partner with others to get it approved and get it to market,” Pimentel said. “We have patients here. We can get the technology to a point where we can show it works in humans, that it’s safe and effective. We can de-risk products for drug companies. We can get things to a stage faster because we have direct access to patients and are able to apply these things in a responsible way.”

The secondary philosophy at MAST is that these diagnostics and treatments should not only be effective, but they should be accessible to all patients.

“Drugs and health care cost too much. When we get to the end, we are looking for partners that have the same philosophy, like Gemelli,” Pimentel said.

MAST and Gemelli conducted a consulting analysis to determine the value of IBS Smart. They determined a price tag of $500 would save the health industry about $500, but further analysis determined that only 50% of patients were willing to pay $290 out of pocket, 80% were willing to pay $220.

“So why not make it $220? Why not allow the majority of people to have this test?” Pimentel asked. “We want to make it available to everybody. Make it economic so that everybody can get it. That’s what we want ... to have a bigger impact. I want everybody who wants to get it, to be able to get it. That’s how we want to partner and help. I’ve seen the wrong side of this. ... It’s all about the patient. If it’s not about the patient, then we’re in the wrong business.”

What the Future Holds

The MAST portfolio has over a dozen products in development and nearly 20 active clinical protocols. The pipeline for devices, drugs and therapeutics is deep, with corporate partnerships and licenses to match, so Pimentel, Rezaie and Mathur are looking to the future quite often.

“I like the story that’s evolving. Am I right? Is IBS-D disappearing? Because that’s real success. Is IBS costing less ... also success. If IBS-C could also be less burdensome, that would be our next goal. Then we move on to other diseases with the microbiome. I’m not done. Not even close. I’m excited about the next thing and the next thing,” Pimentel said.

And those next things may be a global impact. Perhaps obesity, Pimentel ponders.

“The other way to help people is globally and I think sometimes as physicians we don’t know how to do that. How do we broaden our ability to help communities? How do we broaden our ability to help the global community we are in? I think this program gives us the opportunity to do that,” Mathur said. Though obesity and diabetes have reached pandemic proportions, Mathur tends to consider malnutrition as an area where they could have a significant impact.

“Imagine if we can impact that. Imagine if we can develop a slurry – probiotic or prebiotic slurry – that could help [malnourished children] digest and normalize their gut function. When WHO refeeding formulas are given, they could actually be absorbed. Imagine if these children could get the nutrition needed. That would be phenomenal,” she said. “Or perhaps we could vaccinate these children in some way that we know is going to make a difference in how they see diseases that are foodborne and waterborne in the future. That’s where we want to go.” – by Katrina Altersitz

For more information:

Mark Pimentel, MD, FRCP(C), can be reached at mark.pimentel@cshs.org.

Ruchi Mathur, MD, FRCP(C), can be reached at ruchi.mathur@cshs.org.

Ali Rezaie, MD, FRCP(C), can be reached at ali.rezaie@cshs.org.

References:

Chatterjee S, et al. Am J Gastroenterol. 2007 Apr;102(4):837-841.

Muskal SM, et al. Version 3. F1000Res. 2016;doi:10.12688/f1000research.8406.3.

Pimentel M, et al. Am J Gastroenterol. 2000 Dec;95(12):3503-3506.

Pimentel M, et al. Am J Gastroenterol. 2003 Feb;98(2):412-419.

Pimentel M, et al. Dig Dis Sci. 2003 Jan;48(1):86-92.

Disclosure: Mathur reports being a shareholder of Gemelli Biotech. Pimentel reports being on the advisory committee or board member for Salix Pharmaceuticals, Synthetic Biologics; acting as a consultant for Salix Pharmaceuticals, Synthetic Biologics; receiving grant or research support from Salix Pharmaceuticals, Synthetic Biologics; holding patents for Salix Pharmaceuticals, Synthetic Biologics; being a stockholder or having ownership Interest in Synthetic Biologics; being a shareholder of Gemelli Biotech. Rezaie reports receiving research grants and serving on a speakers bureau for Bausch Health, as well as being a shareholder of Gemelli Biotech. Cedars-Sinai has a licensing agreement with Salix Pharmaceuticals and Synthetic Biologics.