Second Genome Inc. (SG) CEO Karim Dabbagh said his firm’s deal with Gilead Sciences Inc. is “pretty significant, given some of the other deals in the microbiome and inflammatory bowel disease [IBD] space,” telling BioWorld the potential $1.5 billion-plus agreement involves “biomarkers in multiple disease areas on five of Gilead’s portfolio programs in inflammation, fibrosis and oncology. Associated with that is a drug discovery collaboration around five targets in the context of IBD.” He said he “wouldn’t really put more weight on one or the other. It’s a completely integrated deal.”

Gilead, of Foster City, Calif., is paying $38 million up front. South San Francisco-based SG will deploy its Microbiome Analytics Platform – designed to harness microbiome-related scientific insights to boost treatment effects by stratifying patients – plus other discovery and development tools. The contract calls for the tie-up to last four years, though it could be stretched to six, noted Anu Hoey, chief business officer. “As we all know, research is on its own time,” she said. “If Gilead is really excited about what we’re doing, then we have the option to extend,” as determined by the progress made.

Karim Dabbagh, CEO, Second Genome

Gilead has pledged as much as about $300 million if preclinical, clinical, regulatory and commercial milestones are met in each of the five target discovery programs, as well as low double-digit royalties for any approved products. More milestone-related payments are tied to each validated biomarker delivered. Gilead owns the option to worldwide rights for up to five programs for all diseases and exclusive rights to all biomarkers.

In SG’s pipeline for IBD is SG-2-0776, a therapeutic protein derived from the microbiome that promotes mucosal healing of damaged epithelial surfaces. Clinical development is expected to start next year. Although debate continues about the triggers for IBD, one idea is that the painful condition advances by way of a breakdown of intestinal barrier function that allows bacteria or bacterial components to translocate into mucosal tissue, which activates inflammatory signaling. That could lead to more barrier disruption, kicking off a cyclic amplification loop. “We’ve been mining these genomes [in the gut] for molecules of biological importance,” Dabbagh said. “We’ve identified a protein from one of the microbes of healthy guts that restores the intestinal barrier functionality, and we’ve engineered it to be gut-delivered and have mucosal healing ability.” At earlier stages are other efforts in IBD as well as immuno-oncology.

The company has research ongoing in the central nervous system (CNS) space, too. A project with the Stanford University School of Medicine and Oregon State University in March 2019 gained a two-year, $2.1 million phase II SBIR grant to develop a platform that would discover and validate key metabolites produced by microbes in autism spectrum disorders. “There is ample evidence out there of association” between the microbiome and CNS, Dabbagh noted. The parties collected samples longitudinally from about 250 families with children affected by autism and those not affected, and then “integrated this with a large amount of other data that have been published,” he said. “We are testing the molecules that we’ve identified to be differentially present in the patients vs. unaffected individuals to show and verify that they have this brain-modulating, behavior-influencing activity.”

Anu Hoey, chief business officer, Second Genome

A recent paper in Science Advances pointed out that lab work has shown the microbiome is “fundamentally changed in many neurological conditions, including multiple sclerosis, Parkinson’s disease, autism spectrum disorders, Alzheimer’s disease, and chronic fatigue syndrome.” Cited was research published in the Journal of Neuroscience regarding the paradigm shift brought about by microbiome studies, as well as Cellular and Molecular Gastroenterology and Hepatology’s article on the brain-gut-microbiome axis. 

SG once was among the many players in nonalcoholic steatohepatitis, too. The oral small molecule SGM-2019 in January 2019 entered a phase II trial. Rationale for the approach seemed solid, since SGM-2019 targeted the P2X7 receptor, known to be involved in inflammasome activation, but the study was terminated because of a liver safety event. SGM-2019 was in-licensed from Hamburg, Germany-based Evotec AG, with which SG collaborated in March 2015.

Dabbagh worked on his second post-doctorate in the 1990s at Stanford, when the microbiome was referred to as “microflora and how it influenced the immune system.” He has watched the space evolve over the past 25 years, “transformed by the fact that we can now sequence and analyze the microflora with a variety of informatic tools and databases,” he said, as new technologies such as SG’s arose and costs went down. “Overall, the space has been tremendously influenced by the fact that there have been a lot of microbial surveys in many different disease areas, with the original datasets being associative, meaning there is a difference in the microflora in a patient population compared to another one,” so that only functionality remained to be determined.

Microbiome findings continue to roll out. In November 2019, researchers presented data at The Liver Meeting 2019 in Boston and in Nature demonstrating that bacteriophages targeted to specific members of the microbiome could be useful in fighting two different liver diseases. During the liver meeting, Biomx Inc., of Ness Ziona, Israel reported effects of targeting Klebsiella pneumoniae to fight primary sclerosing cholangitis. In Nature, a team from the University of California at San Diego reported using the bacteriophage cocktail approach to destroy cytolysin-producing Enterococcus faecalis, which abolished the occurrence of alcoholic hepatitis in humanized mice.