The Brave New World of Microbiome-based Therapies

Body Surrounded by Microorganisms

The microbiome is the trillions of microorganisms—bacteria, fungi, and viruses—that live in and on the body. Although it makes complete sense that these would play a factor in gastrointestinal diseases, such as Crohn’s and colitis, it’s less obvious that it would play a role in anything ranging from lung diseases to neurodegenerative diseases. But increasingly, evidence is suggesting it is, and a lot of investors are throwing money into the field in hopes it will come up with the next big blockbuster.

Examples of work in the field include recent research that discovered that the lungs and placentas of fetuses in the womb, as young as 11 weeks after conception, have bacterial microbiome signatures, suggesting bacteria colonize the lungs before birth. The fetal lung microbiome also appeared to change in diversity during fetal development.

“We speculate that maternal-fetal microbial DNA transfer—and perhaps of other microbial products and whole live or dead bacteria—is a realistic possibility,” said Charitharth Vivek Lai, researcher at the University of Alabama at Birmingham. “This may serve to ‘prime’ the developing innate immune system of the fetus and help in establishment of a normal host-commensal relationship.”

A study out of Washington University School of Medicine in St. Louis found a connection between the bacteria that inhabit the upper airway and the severity of childhood asthma. They found that children who had early warnings signs that their asthma was flaring up were more likely to have bacteria associated with the disease in their upper airways. Those bacteria included Staphylococcus, Streptococcus and Moraxella. In comparison, Corynebacterium and Dolosigranulum were linked to periods of good health and well-controlled asthma.

Recently, researchers found that the gut microbiome appears to play a role in the course of ALS. Scientists with the Weizmann Institute of Science worked with mice with an ALS-like disease. They found that the course of the disease slowed after the mice received specific strains of gut microbes or substances that were secreted by the microbes. The results suggest that the microbiome may play a regulatory role in people with ALS. The research was published in the journal Nature.

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And in October 2019, 4D Pharma, based in Leeds, UK, partnered with U.S.-based Merck & Co. to develop Live Biotherapeutics vaccines. Live Biotherapeutics are a new class of medicines made up of strains of gut long-term bacteria originally isolated from healthy human donors. They are then encapsulated and administered orally, where they are selectively delivered to the gut where they can interact with the patient to exert therapeutic effects.

Under the terms of the deal, 4D will use its proprietary MicroRx platform with Merck’s expertise in novel vaccine development and commercialization to discover and develop Live Biotherapeutics (LBPs) as vaccines in up to three currently undisclosed indications. Merck, under specific conditions, will acquire $5 million in 4D shares in the first year of the collaboration.

There is an undisclosed upfront cash payment. In addition, 4D is eligible for up to $347.5 million for each indication for various milestones, as well as tiered royalties on annual net sales of any product that comes out of the collaboration. Merck will cover development, manufacturing and commercialization.

“This research collaboration agreement brings together 4D’s innovation in the microbiome space and [Merck’s] track record of developing cutting-edge vaccines,” said Duncan Peyton, 4D’s chief executive officer. “[Merck] and 4D have worked closely combining world-leading science to develop a workplan to advance the understanding of this field, with the aim of generating a new class of vaccines in areas of high unmet need.”

4D currently has four clinical trials in progress: a Phase II study of Blautix in Irritable Bowel Syndrome; a Phase I/II trial of MRx0518 in combination with Merck’s Keytruda (pembrolizumab) in solid tumors; a Phase I trial of MRx0518 in a neoadjuvant setting for solid tumors; and a Phase I/II study of MRx-4DP0004 in asthma.

And those are just a few examples. Or, as Susan Adams and Will Yakowicz write in a recent Forbes articles, “Welcome to the most promising new frontier in medicine: poop. By focusing on what’s coming out of patients’ rear ends, a growing body of scientific research over the last 15 years has highlighted the crucial role the microbiome plays in human health.”

The microbiome isn’t restricted to the gut, however, as some of the examples above suggest. But some of the work is focused on that, and a 2013 New England Journal of Medicine paper showed in a clinical trial that 94% of recurrent C. diff patients recovered after receiving a microbiome-derived therapy, basically a live fecal transplant of C. diff.

Gbola Amusa, a physician and partner at Chardan, a healthcare-focused, New York-based investment bank, estimates the total amount of investment in microbiome research companies exceed $5 billion since 2014. And some of these investors are marquee names, like Bill Gates, Marc Benioff, founder of Salesforce, and Vinod Khosla, a Silicon Valley venture capitalist. Mark Zuckerberg, of Facebook, has also donated, as have Gates and Benioff, into microbiome research at Stanford, Washington University in St. Louis, and the University of California, San Francisco.

Mark Breidenbach, with Oppenheimer, told Forbes some of the investor enthusiasm has dropped because “there is no consensus about what the microbiome can do.”

Amusa, however, told Forbes, “The science is turning. When it comes through with proof, these biotech companies will be worth not hundreds of millions of dollars, but billions.”

One company that shows promise in the field is Somerville, Massachusetts-based Finch Therapeutics. In 2018, it closed on an oversubscribed Series B financing worth $36 million. At that time, it had raised $77 million. In August 2019, it completed a $53 million Series C financing, which it plans to use to advance its pipeline of microbial therapies, including CP101, a Full-Spectrum Microbiota (FSM) therapy in an oral capsule.

On January 8, 2020, Finch completed enrollment in PRISM 3, its Phase II trial of CP101 for prevention of recurrent C. difficile infections (CDI). It has received Fast Track and Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA). It enrolled a total of 206 patients randomized at 51 sites across the U.S. and Canada. The company expects to report topline preliminary data in the second quarter of this year.

Finch also has a partnership with Tokyo-based Takeda Pharmaceutical to develop drugs for ulcerative colitis and Crohn’s disease. It is also working on an autism drug.

Another company is Vedanta Biosciences, in Cambridge, Massachusetts, which has $112 million in funding, including $10 million from the Bill & Melinda Gates Foundation. On December 10, 2019, the company announced the launch of a first-in-patient trial of VE800 in combination with Bristol-Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab) in advanced or metastatic cancer. VE800 is made up of 11 commensal bacterial strains that act together to activate cytotoxic CD8+ T-cells. The therapy has been shown to improve the ability of T-cells to infiltrate tumors, suppress tumor growth and potentially improve patient survival. Preclinical work has suggested VE800 can improve the effects of checkpoint inhibitors.

Will any of this work? Particularly outside the more obvious gastrointestinal disease area? It’s possible. And for the right investor, with a little luck, it could mean millions, maybe billions, of dollars.

Chris Howerton, a Jefferies biotechnology analyst, told Forbes, “If every single microbiome paper turns into a proven therapy, it could impact the drug markets for most major categories of disease, which together were worth $350 billion in 2018 in the U.S. alone. The breadth of the microbiome’s potential application is really tantalizing.”

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