The microbiome is moving forward. Second Genome of South San Francisco, CA, said Monday that it has begun its first human trial, and what could be the first in the field, of a drug based upon the emerging field of research around the trillions of microbes that live in our guts.
Second Genome began life with aspirations to help with environmental clean-up, but it is now fully devoted to pharmaceuticals. Unlike Seres Health, Vendanta Biosciences, and other startups using microbes themselves as the medicine, Second Genome is using conventional small molecule drugs to change the way microbes interact with their hosts—that is, us.
That host-microbe interaction is a new way of thinking about human biology, helped in part by sequencing technology that is teasing apart the identities and characteristics of our microbiomes. “Once you have that understanding, you’ll have [disease] targets you can address in a whole range of ways,” said Second Genome CEO Peter DiLaura (pictured). “In some cases it’ll be a bacterial strain as a therapeutic, in some cases it’ll be a synthetic biology approach. Our first approach is to use inhibitory small molecules,” he said, referring to chemical-based drugs that block disease-causing biological interactions.
Second Genome quietly began testing its first drug months ago in a Phase 1 trial, with the goal of making sure there are no safety problems in healthy volunteers, said DiLaura. That trial continues this year in another round of safety tests. If all goes well, the next step would be a trial in people with Crohn’s disease, a debilitating condition that causes the body’s own immune system to mainly attack the lining of the intestine, although it can affect the entire gastrointestinal tract.
DiLaura said Second Genome researchers have pinpointed a protein secreted by an undisclosed bacterium that interacts with human tissue and plays a key role in Crohn’s. The company’s drug, SGM-1019, is designed to block the bacterial protein’s interaction with the gut and reduce the inflammation it causes. He declined to reveal the identity of the microbe, the protein, or the “host target”—the molecular niche in the gut that the microbes are irritating.
The theory behind this work—and behind a lot of microbiome research—is that disease emerges when the delicate balance of microorganisms we host goes askew. For example, the deadly Clostridium difficile infection occurs when the gut microbes that normally keep C. difficile in check are wiped out—often by a big dose of antibiotics in a hospital. The trick to beating C. difficile is restoring a healthy mix of microbes, which it turns out are easily accessible by ingesting the healthy stool of someone else. (This is called fecal microbiota transplantation, or FMT.) Seres Health is going a step further, using a mix of bacterial spores—which bloom into bacteria once in the gut—in a more sophisticated version of FMT.
Although it’s suspected a dysbiotic—unhealthy—microbiome contributes to Crohn’s (as well as many other diseases), there’s no proof that simply rebooting a Crohn’s patient’s microbiome would do the trick. The intestine is being attacked by proteins called cytokines, unleashed by the body’s own immune cells. How a patient’s out-of-whack microbe mix triggers that reaction is something Second Genome is keeping under its hat for now, but the company obviously thinks SGM-1019 will block it.
Will that approach work if the underlying problem—a dysbiotic microbiome—isn’t addressed? Second Genome will have to wait until Phase 2 trials to find out. But DiLaura said reducing inflammation should help break a negative feedback loop and create a better environment for a healthier microbiome. “That’s the hypothesis,” said DiLaura. “If successful it should spark the ability to have a sustained and disease-modifying affect.”