From Conventional Modalities to Precision Medicine

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testWe sat down with Dr. Bruce Roberts, Chief Scientific Officer of Vedanta Biosciences, at The Microbiome Movement—Drug Development Summit in Boston this June and asked him to tell us his story:

Molecular virologist turned autoimmunity expert Bruce Roberts says he learned immunology on the job. Prior to becoming Chief Scientific Officer at Vedanta, Roberts was responsible for Multiple Sclerosis and Immune-Mediated Disease R&D activities at Sanofi.

“Sanofi was focused on what I would call conventional modalities, which would be small molecules and therapeutic antibodies for modulation of autoimmune conditions,” said Roberts. “As a consequence of that, I was interested in the enhancement of regulatory T cells (Tregs) because we considered this to be an important aspect for controlling autoimmune conditions.”

Regulatory T cells are so named because they are a cell type that is responsible for regulating the immune system by suppressing unwarranted immune reactions and thus preventing autoimmune disorders. It was at that point that Vedanta caught his eye. The founders showed that this was an effective means of providing benefit in preclinical studies of Inflammatory Bowel Disease (IBD); they demonstrated that a rationally designed consortia consisting of 17 commensal bacteria can suppress inflammation in four animal models of IBD. This work had been published previously (Atarashi et al. Nature 2013). Intrigued, Roberts left Sanofi to become the Chief Scientific Officer at Vedanta.

“What struck me about Vedanta was that the scientific founders had identified a way to condition the immune response in the host via the provision of specific commensal organisms to induce regulatory T cells,” said Roberts. In other words, they had figured out a way for how to control the immune response through the microbiome. For Roberts, the benefits of what Vedanta was doing were clear: using a commensal organism to condition the immune response of a patient meant that potential toxicity effects should be minimal, it could be given orally on a repeat basis if necessary, and there would be none of the side effects associated with systemic small molecule and therapeutic antibody administration.

“The mentality is entirely different,” said Roberts. “Most conventional immune-modulatory drugs suppress inflammatory immune responses, but they do not alter the nature of the disease. This means that following cessation of drug treatment, the disease is likely to rebound. Vedanta pioneered this new  type of modality, which to me represented an exciting new treatment option.”

According to Roberts, the key to clinical success is tailoring microbiome modification approaches to the specific indication. “Most people would agree that there’s been a lot of success around modulating the microbiome for clinical treatment of Clostridium difficile infection (CDI),” said Roberts.

Stool transplants are used on a regular basis and approved by the FDA to treat CDI, a bacterial infection in the colon that can cause diarrhea and inflammation. They involve the restoration of the gut microbiota by introducing healthy bacterial flora through infusion of stool obtained from a healthy donor by colonoscopy, enema, orogastric tube or by mouth in the form of a capsule containing freeze-dried material. The procedure has also been used experimentally to treat other gastrointestinal diseases. Roberts offers a word of caution: “As we start to look to the microbiome for treatment of Inflammatory Bowel Disease (IBD), we can’t just extrapolate the results of studies done on CDI. It’s a much tougher disease—a chronic condition—and it requires a different approach.” Roberts thinks it will get there. “There’s data that indicates that if you repeat stool transplants to someone with IBD, you can, over time, provide relief,” said Roberts. “But the response rates are not the same—30 percent response rates for FMT treatment of inflammatory bowel disease versus 80 percent for FMT of C. difficile. So, there’s some reason to be hopeful, but we have a long way to go.”

The next frontier? Precision medicine, says Roberts. “There is a multitude of rationally designed live bacterial consortia that could be generated to potentially treat patients with cancer, food allergies and infections with multidrug-resistant organism,” said Roberts. “Where we’re going at Vedanta is targeted manipulation of the microbiome—selecting specific organisms because they have particular biological properties and adding them back into the mix to correct for deficiencies.”

In terms of developments, Vedanta has made the following progress:

  • Vedanta’s rationally-defined consortia for treatment of CDI is planned to enter a Phase II clinical trial at the end of the year.
  • Johnson & Johnson licensed a cocktail (rationally designed consortia of commensal bacteria) from Vedanta for the treatment of IBD, and it is planned to enter the clinic by the end of the year.
  • The company has defined a commensal bacterial cocktail for the treatment of peanut allergies.
  • Vedanta has identified commensal organisms that induce Interferon-gamma-producing T cells—a brand new observation that they plan to develop for the treatment of cancer patients in combination with immunotherapy.

Success, he says, requires that the consortia of organisms is assembled using data-driven decisions that are based upon knowledge of the disease and strains most likely to provide a benefit to the affected individuals. Roberts notes that there will be fringe benefits that emerge related to understanding the nature of the microbiome in individuals with human disease. For example, preclinical data suggests that the microbiome plays a role in Multiple Sclerosis. The question is, what is the nature of the imbalance and how do you correct for it? This is the critical question for translational medicine studies, he says.

“The field is accelerating at a rapid pace, largely due to the fact that we have new insights into the nature of the commensal organisms which leads to an understanding of how they might be utilized,” said Roberts. “At the same time, we’re gaining new insights about what’s going on inpatients and what needs to be modified in order to confer benefit.”

While we could’ve talked with Bruce for days, we let him get back to the science at this point.

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