Restoring Balance In The Gut To Prevent Drug-Resistant Infection

Silvia Caballero, one of In Vivo’s 2020 Rising Leaders, is heading up Vedanta’s efforts to prevent potentially lethal infections stemming from colonization of the gut microbiome with a novel bacterial cocktail that is nearing clinical development.

A number of biotechs and academic researchers are investigating ways to fight drug-resistant pathogens, but Vedanta Biosciences Inc. is working to advance a novel approach toward clinical development – bringing balance back to a patient’s microbiome and using “good” gut bacteria to neutralize bad bacteria and stave off infections in at-risk patients.

SILVIA CABALLERO

Heading up this effort at the Cambridge, MA-headquartered firm is Silvia Caballero, leader of a five-person team focused on multi-drug-resistant organisms (MDROs) and decolonization of gut bacteria that can cause the spread of these pathogens out of the gut where they can cause life-threatening infections. The team’s VE707 – a bacterial cocktail derived from human gut flora that has shown activity against two types of bacteria (carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum beta lactamase producers (ESBL) and vancomycin-resistant Enterococci (VRE)), with a goal of demonstrating activity against a third – is slated to begin clinical development in 2022. Originally, Vedanta hoped to bring ‘707 into the clinic next year, but like many goals in the biopharmaceutical industry, the novel coronavirus had slowed progress on the candidate, Caballero said in an interview with In Vivo.

A graduate of Hunter College with a degree in biological sciences, Caballero has been finding her way onto lists of young innovators in the life sciences in recent years, including those compiled by Time Magazine and the Massachusetts Institute of Technology. She completed a doctorate from Weill Cornell Medical College, doing her PhD research in an affiliated program at New York’s Memorial Sloan Kettering Cancer Center, where she gradually turned from an initial focus on cancer to research on how the microbiome plays a role in therapeutic areas such as autoimmune, metabolic and infectious disease.

Caballero joined Vedanta as a research scientist in 2016 and has worked her way up to an associate director position, leading the team working to advance ‘707 and also investigate the possibility of addressing pediatric malnutrition with a similar bacterial cocktail. Her interest in the life sciences took hold prior to college, but she said the biggest challenge was deciding between becoming a physician or a medical researcher.

“Really, what did it for me was understanding the difference between the two and how much of an impact I could make by doing research as opposed to just seeing patients,” Caballero explained. “Unfortunately, I was unable to do both because otherwise I would have done it. But I really liked the idea of being in the lab and discovering something that could help millions of people as opposed to just a few patients.”

Working with Memorial Sloan Kettering researcher Eric Pamer introduced her to the emerging research efforts into the microbiome and its connections to other disease states, she said. Pamer was a practicing physician in addition to his oncology research and he would tell his graduate students about cases, including some that went wrong due to emergent infections. Caballero particularly was impacted by the vulnerability of patients who underwent bone marrow transplants, one of the target populations for ‘707.

“What changed my interest from cancer to infectious diseases was knowing how detrimental these organisms can be,” she said. “My mentor, Eric Pamer, would see patients and then come to the lab and tell us about a patient that he had seen during the day. I remember him telling stories and presenting data about patients undergoing bone marrow transplants. Everything would go great, they would survive the transplant, they would go home healthy and all of a sudden they would catch an infection and die.”

The issue, oftentimes in such patients, was that their microbiomes were colonized with pathogenic bacteria. Caballero realized that work was needed not just to fight off infections from these pathogens but to prevent them in the first place because of a lack of therapeutic options when an infection took hold, especially in immunocompromised patients. After earning her PhD, Caballero joined Vedanta specifically to continue working in this field of research.

VE707 is intended to address the root source of some of the most common hospital-based infections. Being developed as an oral therapy, it consists of a rationally defined bacterial consortium that decolonizes gut-dwelling MDROs in patients at high risk for developing infections, the company says. The drug is produced from pure, clonal bacterial cell banks, yielding a product of uniform composition that is free of any pathogenic strains, which can bypass the safety issues pertaining to using donor fecal material.

Funding Development

Work on ‘707 is backed by a $5.8m grant awarded to Vedanta by the non-profit CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator) last December. Vedanta also can earn up to $3.5m in milestones from CARB-X, which has also provided funding support for Vedanta’s lead program, VE303, an oral bacterial consortium candidate in Phase II for patients at high risk for Clostridioides difficile (CDI) infections.

Privately held Vedanta has raised $71.1m, as of June 2020, in series C financing, with participation from the Bill and Melinda Gates Foundation, Bristol-Myers Squibb and more recently JSR Corporation. Its clinical pipeline includes Phase I cancer immunotherapy VE800, partnered with BMS, and two wholly owned Phase I candidates, VE202 for inflammatory bowel disease and VE416 for food allergies.  (Also see "Vedanta Receives Cash Injection To Proceed With Microbiome-Derived Pipeline" - Scrip, 27 Dec, 2018.)

Caballero explained that ‘707 potentially offers a novel method for countering potentially lethal infections. What we’re trying to do is essentially eliminate the reservoir of these drug-resistant organisms that exists in the gut,” she noted. “A lot of patients that have infections like pneumonia or bacteremia … have their intestines colonized with the bacteria causing the infection. Those organisms reside in the intestine and what happens is that when the intestinal barrier is breached, they can escape and cause infections. While they’re in the intestine, they’re kind of silent, not really doing much: it’s really once they go outside of the intestine that they can become life-threatening.”The product is targeted to patients whose microbiomes are imbalanced, often as a side result of therapy they have received for other conditions. This includes cancer chemotherapy and radiation treatments, as well as antibiotics. Although otherwise well-intentioned, such therapy can “impact the microbiome in a way where it can no longer protect the host against invading organisms,” the researcher noted. “In the absence of a healthy microbial community, these drug-resistant bacteria can grow and thrive. Our goal is to basically replenish this community by reintroducing the microbes responsible for protecting against these invaders while at the same time restoring the natural ecosystem of these patients.”

Bone marrow transplant patients, she explained, have had their innate immunes bombarded and eroded by each of those types of therapy, creating a state where an MDRO is more likely to escape the intestinal tract and enter the bloodstream. Once that happens, doctors have little time to try to determine which antibiotic might be effective against the patient’s specific pathogen. “If the organism is resistant, there is not much that can be done and then the patient can get bacteremia or septicemia,” Caballero said.

She describes the work on ‘707 as a team effort, with a group that includes specialists in microbiology, immunology, pharmacology and bioinformatics. “It’s really been a great example of how people with different scientific backgrounds can come together to make something big happen,” Caballero said. “Guiding them as a group to make sure that we are able to come up with a drug candidate for this program has been an amazing experience.”

New Timelines, Same Goals

The COVID-19 pandemic has pushed back the timeline for bringing ‘707 into Phase I studies by at least a year, but Vedanta’s also has investigated whether any of its pipeline candidates could help address the pandemic, she said. The gastrointestinal distress seen in many COVID-19 patients stems from an insult to the microbiome, she added. These efforts are still at the discussion stage, but the company is exploring whether C. difficile candidate VE303 or cancer candidate VE800 could have some utility.

Asked about the best advice she has been given during her career, Caballero said it comes down to recognizing and accepting the high attrition rate that comes with life sciences research. “My mentor really instilled in me to not let failures get in the way of my success,” she pointed out. “This might sound a little cliché, but especially in science, this carried a lot of value for me because you do experience way more failures than successes in science.”

“Just hearing that from people who trusted my abilities and also that knew about my passion for science really made sure that I understood that in science, there are going to be more failures than successes and that I should not let that get in the way of achieving my goals,” she continued. “That’s the same mentality that I have now at Vedanta, it’s something I tell my team. If we don’t get an experiment to work, we just have to try again.”

[Editor's note: This article was updated on 16 July to clarify that Vedanta has raised $71.1m in series C rounds as of June 2020.]