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7 Startups Treating Disease Using the Microbiome

We’re big fans of yogurt here at Nanalyze. It’s one of those Americanized breakfast foods that can also double as dessert while masquerading as a health food. Yogurt gets its reputation as a pseudo health snack partly because it contains various strains of probiotic bacteria that are thought to be beneficial to health by helping rebalance the gut microbiome. The problem is that most of the live “bugs” found in fermented foods like yogurt and kimchi, not to mention probiotic supplements, aren’t really effective at changing the composition of the microbiome, a community of microorganisms linked to immunity and all sorts of human health conditions.

For instance, the microbiome may be involved in chronic diseases such as Alzheimer’s, diabetes and irritable bowel syndrome when things are out of balance. There’s also research out there connecting the microbiome to mental health, depression and anxiety, with some calling the collection of bacteria and other tiny beasties in the gut a “second brain”.

We previously introduced you to the microbiome and the exciting efforts to map the genomes of the thousands of species that inhabit our guts and other parts of the body such as the skin. Those efforts will help scientists and startups alike investigate possible therapies that target the microbiome. We recently came across one such company in Evelo Biosciences when it raised $47.5 million in a Series C this month, bringing total disclosed investments to $132.5 million. Previous investors include Google and the Mayo Clinic.

Bugging Cancer

Founded in 2015, the Massachusetts startup hopes to turn naturally occurring gut microbes into a new type of medicine called monoclonal microbials. It’s a concept that’s a bit similar to monoclonal antibodies that we talked about involving cancer immunotherapy treatments. But instead of cloning proteins to help the immune system to fight cancer, monoclonal microbes would help the body’s immune and other biological systems after initial interaction with human cells in the gut. The big brains at Evelo believe these probiotic-based drugs can be used to treat all sorts of diseases including cancer:

Credit: Evelo Biosciences

Earlier this year, Evelo announced plans to begin its first oncology clinical trials using monoclonal microbials developed from strains of Bifidobacteria to treat cancer in combination with checkpoint inhibitors, molecules involved in an immune response that are increasingly being used in cancer immunotherapy treatments. The work is being done with the University of Chicago, whose researchers have recently shown that bacteria combined with a checkpoint blockade inhibitor nearly eradicated tumors in mice.

Evelo is only one of several biotechnology companies leveraging the microbiome to fight disease:

Credit: CB Insights

The market map above from the bright minds at CB Insights helped us identify six more well-funded startups developing microbiome treatments. We’ve only included mostly later stage startups that are developing drug candidates focused on the microbiome with total disclosed funding of at least $50 million.

Microbes as Drugs

Founded in 2012, Paris-based Enterome Biosciences has taken in €101.5 milion (about $124 million) in total funding. It closed a €32 million (about $39 million) in Series D financing last month, with notable investors such as Nestlé, which is a significant player in the probiotics space. Enterome also lined up an additional €40 million (about $49 million) in debt financing. The new funds will primarily help back two clinical trials focused on microbiome-associated diseases: a Phase 2 study of an oral treatment for Crohn’s disease and a Phase 1b study of a drug candidate to treat patients with aggressive brain cancer. The latter is a cancer vaccine, which are normally made from dead cancer cells, proteins or pieces of proteins from cancer cells, or immune system cells. Enterome, on the other hand, is developing bacterial-derived cancer antigens to produce an immune response. The company has a bunch of drugs in the pipeline:

Credit: Enterome Biosciences

It also established partnerships with some heavy hitters such as Johnson & Johnson and Bristol-Myers Squibb in immuno-oncology. In addition, it has established a 50-50 joint venture with Nestlé Health Science called Microbiome Diagnostics Partners, which is working on  microbiome-based diagnostics for irritable bowel disease and liver diseases.

Gut-Brain Axis

While technically an early-stage venture, New York-based Kallyope took in $66 million in a Series B this month, boosting total investments to $110 million. Founded in 2015, Kallyope has taken on the Herculean task of mapping out the so-called gut-brain axis, whereby scientists believe the microbiome and the human brain mutually affect each other through a complex web of neural circuits. Defects in those circuits have been linked to metabolic and gastrointestinal diseases, as well as central nervous systems disorders such as autism and Parkinson’s disease. The company’s technology platform combines single-cell sequencing, computational biology, opto- and chemogenetics to map the gut-brain axis, with the long-term goal of developing specific treatments to target defective circuits.

Discriminating Targets

Founded in 2005, Los Angeles-based C3J Therapeutics has raised $105 million to date. The microbiome is host to both “good” and “bad” bacteria, but when things are out of balance or awry—for example, a bad case of Delhi belly—the answer is usually to carpet bomb the gut with antibiotics, which eliminates both friend and foe. C3J Therapeutics uses the extracellular signaling molecules that the bacteria use to grow and thrive to hone in on the bad bacteria and develop therapies that kill just the bacteria of interest. C3J refers to its platform as STAMP, for Specifically Targeted Antimicrobial Peptides. You can learn a bit more about the technology here:

C3J says STAMP not only leaves the good bacterial communities alone but actually leaves them healthier after treatment. The therapy targets not just gastrointestinal infections but other areas of the body that harbor pathogens, including the respiratory tract, mouth and sinuses.

Bovine Colostrum: It Does the Body Good

Founded in 2007, PanTheryx out of hippy Boulder, Colorado, is taking a more natural approach to improving microbiome health. The company has taken in a healthy $77.3 million, with a recent round last September of about $9 million. It uses a “nutrition-based” solution to hit global health epidemics in the gut, such as infectious diarrhea, which its says is the second leading cause of death among children under five years of age. A clinical trial in Guatemala of its PTM202 seem to have mixed results. The treatment didn’t affect the duration of diarrhea but did knock out one targeted pathogen and left kids with better overall nutritional health. The main ingredient in PTM202 is bovine colostrum, a milky fluid that comes from mammal milk in the first few days after giving birth, before true milk appears. It contains proteins, carbohydrates, fats, vitamins, minerals, and proteins that fight disease-causing agents such as bacteria and viruses, according to WebMD. We wonder if it comes in a chocolate flavor.

Mining the Microbiome

Founded in 2009, San Francisco-based Second Genome straddles that line between early and late stage venture, having raised about $63 million to date. Investors include Pfizer and the Mayo Clinic. Like some of the other players in this space, such as Enterome, Second Genome is developing microbiome therapies from the bacteria themselves, using a drug discovery platform powered by machine learning. (Be sure to check out our previous article on machine learning and drug discovery.) Its leading candidate, SGM-1019, is in clinical trials for treating both nonalcoholic steatohepatitis (fatty liver disease) and irritable bowel disease.

Credit: Second Genome

The company just announced—as in today—that it would collaborate with four different academic institutions, including Stanford, to evaluate the effect of gut microbes on individual responses to cancer immunotherapies, similar to what Evelo Biosciences is doing.

Restoring the Balance

Founded in 2010, Vedanta out of Cambridge, Massachusetts has raised $55.4 million and is an affiliate of PureTech Health, a company traded on the London Stock Exchange that focuses on developing therapies caused by dysfunctions in the gut-brain axis. Vedanta isolates specific bacterial strains that have a specific biological effect on the microbiome that would restore balance to this internal ecosystem. The company has about a dozen patents related to its bacterial-based therapies. Its leading candidate is VE303, which is orally-administered and consists of live bacteria designed to restore gut balance and provide resistance against gut pathogens, including a type of bacteria called clostridium difficile. C. diff can cause serious inflammation of the colon, killing about 15,000 people per year. Right now, the best treatment for C. diff is a fecal transplant, which is as disgusting as it sounds.

Conclusion

Biotechnology health startups continue to pull in serious venture capital dollars for obvious reasons. The microbiome is a particularly hot area of research, but like any area of high-risk science, failure outpaces success by a wide margin. The reality is that most of these companies probably won’t last long term. Even those that IPO on respectable stock exchanges can struggle. Seres Therapeutics (NASDAQ:MCRB), something of a more mature version of Vedanta, is one case in point: The company went public in June 2015 with a market cap near $2 billion with shares priced around $18. Today it’s market cap is about a fifth of that and is trading below $10 a share. We also went into gory details about a synthetic biology stock called Synlogic (NASDAQ:SYBX) that is also trying to leverage bacteria for treating a number of different diseases while also trying to survive a competitive market. The only cure for that is success.

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