Academic collaborations have been central to the development of new immuno-oncology drugs. And now the microbiome startup Vedanta Biosciences is following the same scientific trail in advancing a new set of therapies that could one day play a role in the hot checkpoint inhibitor field.
Building on the work of Vedanta scientific cofounder Kenya Honda at Keio University, the biotech will work with a team of investigators headed by Jeffrey S. Weber, M.D., Ph.D., deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center. They’ll focus on bacterial strains that have shown signs of activating immune cells in the gut to amp up the efficacy of checkpoints like Opdivo and Keytruda, which have roiled the oncology drug market.
“Dr. Weber is a pioneer in translational research, particularly in immunotherapy and the development of checkpoint inhibitors,” said Dr. Bruce Roberts, the CSO of Vedanta.
Vedanta is one of a group of biotech upstarts looking to make drugs from bugs, so to speak. Inspired by the ability of fecal transplants to reboot the balance of healthy microbes needed in the gut to restore health, Vedanta has been developing treatments out of tailored packages of bacterial strains designed to spur specific therapeutic responses. I asked Vedanta CEO Bernat Olle a couple of questions by email. Here’s the exchange:
JC: Given the complexity of microbiome work, is this something you see as painstaking, nitty gritty requiring years of preclinical work, or are we closer to the clinic than that?
BO: The approach we are interested in exploring first is combining orally administered consortia of live bacteria with checkpoint inhibitors. The goal is to enhance the anti-tumor activity of checkpoint inhibitors by administration of bacteria that can colonize the gut and activate effector cells. (So not CAR-T as part of this collaboration but I recognize this is a potential future avenue). I would prefer not to venture a timeline to the clinic. I’d like to point out though, a distinct advantage of working with commensal bacteria that have not been recombinantly modified is that we know they can safely colonize humans in large doses, for life, so the likelihood that we are surprised by a completely unexpected safety signal is relatively low, in my view, compared to other therapeutic modalities that entail introducing new chemical entities that the human body has never seen before. And that is the primary concern when you are going into the clinic for the first time. Multiple fecal transplantation trials have moved forward in the microbiome field quite quickly, in both C. diff and IBD, despite the fact that the complexity of this approach is not well understood. In my opinion that is an acknowledgement that modifying the microbiota with native species is an approach with an attractive safety profile (of course risk/benefit considerations are different for each indication). That doesn’t mean what we’re doing is easy and linear – it’s not. There’s a lot to learn around mechanisms involved in how the microbiota interacts with the host. We’re focusing a lot of our efforts there, making sure there is a rational criteria behind the decisions of what microbes we pick to include in our drug candidates. Data from collaborations like the one we are starting with our NYU colleagues is a valuable input to our development process because it can help us determine if the effects we see in preclinical models are relevant to the human populations that we want to target.
JC: Given the recent setback at Seres (where a Phase II effort recently failed), I was struck again how a setback in a new technology at one company can be automatically attributed to everyone else (doesn’t really play out, though, as we’re seeing in gene therapy, where companies distinguish themselves in one way or another.) What are your thoughts on that?
BO: The scientifically honest thing to say is that until they have completed their root cause analysis and determine what caused the failure, it’s hard to make any conclusion on what that means to the field.
That being said, our approach is quite different from SER109. They used a procedure involving a modified form of fecal transplantation, getting fecal material directly from a donor, processing the samples and then giving the processed fraction to the patient. We have been focused on rationally selecting pure strains based on mechanistic insights, and growing them starting from cell banks via fermentation, so we can control exactly the composition of the product.
And I think the context of the accumulated clinical data in the field is useful too: there have been multiple successful randomized controlled trials with fecal microbiota transplantation (FMT), with reported cure rates in C diff. in the 80-90% range (Van Nood et al, NEJM, 2013; Youngster et al, 2014; others) and the utility of microbiome modulation is expanding to other clinical applications including IBD, with two recent placebo-controlled trials showing successful induction of remission (Moayyedi et al, 2016; Paramsothy et al, 2015). This positive clinical data is reinforced by a robust body of basic research in the field that is both identifying new potential applications of microbiome modulation and increasingly moving towards a more detailed understanding of the mechanisms involved in host-microbiome interactions that was missing from FMT approaches. So I remain optimistic of the potential of the field.
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