AbbVie Invests in Synthetic Microbes for Treatment of Intestinal Disorders

By Aaron Krol

February 10, 2016 | This morning, AbbVie announced a partnership with Synlogic of Cambridge, Mass., to create microbiome-based therapies for the treatment of inflammatory bowel disease (IBD). The two companies have sketched out a suggested three-year timeline for preclinical research and development, after which AbbVie will take over advancing any drug candidates into clinical trials.

Drugs inspired by the microbes that live in the human gut are a hot topic in biotech. Companies like Seres Health and Vedanta Biosciences are pursuing the idea from a variety of angles, from making traditional small molecule drugs that interact with the microbiome, to creating probiotics or microbial cocktails that restore a healthy balance to the gut ecosystem. IBD, including Crohn’s disease and ulcerative colitis, is an especially popular target for these companies, thanks to strong suggestions that bacterial populations can affect the course of the disease. Already, Second Genome and Coronado Biosciences have taken prospective treatments into the clinic (though the latter has been dealt serious setbacks in Phase II trials).

But even among this peculiar batch of startups, Synlogic’s approach to drug design is exquisitely odd. The company calls its products “synthetic biotics”―in fact, they’re genetically engineered bacteria whose DNA contains intricately designed “gene circuits,” built to start producing therapeutic molecules when and only when the patient needs them.

“We are not looking at correcting the dysregulation of microbes in the gut, like other microbiome companies,” CEO José-Carlos Gutiérrez-Ramos tells Bio-IT World. “We have one bacterium, and it’s engineered to do different functions.”

Synlogic was founded in 2013 by two synthetic biologists at MIT, Timothy Lu and Jim Collins. (Bio-IT World has previously spoken with Lu about his academic work on bacterial gene circuits.) Gutiérrez-Ramos joined almost two years later, leaving a position as the head of Pfizer’s BioTherapeutics R&D group, where he had plenty of opportunity to turn emerging biotechnology ideas into drug candidates ready for submission to the FDA.

Still, synthetic biotics are a good deal more unusual than the biologic drugs he worked on at Pfizer.

His new company doesn’t quite spin functions for its microbes out of whole cloth. All the genes the company uses are copied either from the human genome, or from the bacteria living inside us. But by recombining those genes into circuits, Gutiérrez-Ramos believes Synlogic can finely control whether and when genes are expressed, giving its synthetic biotics the same dosage control as a traditional drug. Meanwhile, choosing the right bacterium to engineer―the current favorite is a strain called E. coli Nissle―ensures the biotics do not form stable colonies in the gut, but can be cleared out as soon as a patient stops treatment.

“We’re pharma guys,” he says. “What we want is to have pharmacologically well-defined products.”

The Molecular Circuit Board

Even before the partnership with AbbVie, Synlogic had a pipeline of drug candidates in development, all meant to treat rare genetic disorders caused by single mutations that shut down the activity of a crucial gene. In principle, there seems to be no reason that bacteria carrying the right genes couldn’t pick up the slack. “We know the patient is missing a function that is typically performed by the liver, or the kidney, or the pancreas,” says Gutiérrez-Ramos. “What we do is shift that function from an organ to a stable fraction of the microbiome.”

The approach is in some ways analogous to gene therapy, where a corrected version of a broken gene is inserted into a patient’s own DNA. “We don’t use that word, but the fact is it’s a non-somatic gene therapy,” Gutiérrez-Ramos says. “And if something goes wrong, you can control it just by stopping treatment.” The most advanced synthetic biotic in Synlogic’s pipeline targets urea cycle disorder, exactly the sort of disease that might otherwise be addressed by gene therapy: patients are missing a single enzyme that helps remove nitrogen from the body and prevent it from forming ammonia in the bloodstream. Synlogic will meet with the FDA this March to discuss whether and how this first product can be tested in humans.

The new IBD program with AbbVie, however, adds a whole new level of complexity. Executives from the two companies have been in discussions for around six months, and both agree that no single mechanism will be enough to provide significant relief for patients. Crohn’s and ulcerative colitis are painful autoimmune diseases that involve both a weakening of the epithelial lining in the stomach, and a buildup of inflammatory molecules. The development plan that AbbVie and Synlogic have agreed on includes three separate methods of attack to relieve these symptoms.

“One approach AbbVie is very interested in is for our synthetic biotics to produce substances that could tighten the epithelial barrier,” says Gutiérrez-Ramos. “Another approach is to degrade pro-inflammatory molecules”―the same tack taken by AbbVie’s current leading IBD drug, Humira, which targets the inflammatory protein TNFα. “Finally, we can produce anti-inflammatory molecules.”

Uniquely, synthetic biotics can perform all three functions at once; it’s just a matter of inserting the right genes. But that alone might not be a decisive advantage over some sort of combination therapy. The biggest selling point of Synlogic’s microbes is not the genes they can be engineered to express―what you might call the “output” of their gene circuits―but the input, the DNA elements called “inducible promoters” that decide when those genes should be activated.

The core idea is that patients will have a constant population of synthetic biotics in their bodies, taken daily―but those microbes will only generate their therapeutic payloads when needed. In IBD, Gutiérrez-Ramos explains, “it’s not that the patient is always inflamed, but they have flares. Our vision, and AbbVie’s vision, is that the bacteria that you take every day sense when the flare is coming, and then trigger the genetic output.”

This would be a major improvement over a drug like Humira, which after all is constantly inhibiting a part of the immune system. Patients taking Humira, or one of the many other immunosuppressant drugs for IBD, are at a constantly heightened risk of infection; tuberculosis is a particular specter for these patients. If Synlogic can find a genetic “on-switch” that responds to a reliable indicator of IBD flares, it could potentially create a much more precisely administered treatment, while still giving patients the simple dosing schedule of one pill every day.

The company has leads on two inducible promoters that might do the trick: one that reacts to nitric oxide, and another tied to reactive oxygen species. Of course, there’s no guarantee that either will respond sensitively to IBD flares in a real clinical setting. “This is an early time for the technology,” says Gutiérrez-Ramos. “We have demonstrated this in animals, but we have to demonstrate it in humans.”

Although it’s far too early to say if synthetic biotics will become an ordinary part of the pharma toolkit, AbbVie’s decision to invest in the technology offers the means to test this approach on a large scale. Synlogic expects to raise its own funding for trials of its rare disease products, which the FDA does not expect to enroll huge numbers of patients, but IBD is a problem of a very different order.

“We are very honored to work with truly the leader in treatment of inflammatory bowel disease,” says Gutiérrez-Ramos. With the backing of big pharma, it will be possible to trial microbiome-based therapies for the kinds of common, chronic diseases that are the biggest drain on our healthcare system. What’s more, the AbbVie partnership is an important signal of the industry’s faith in synthetic biology as an approach to treating disease.