Greater understanding of the human microbiota is paving the way for future therapies across a broad array of diseases.
The past half dozen years have seen an explosion in the attention and research directed at the human microbiota and its relationship to a broad swath of human diseases. In this time, researchers have shown that nearly every therapeutic area—autoimmune diseases, infectious diseases, CNS, metabolic diseases, and even cancer—is connected in one way or another with alterations in the microbial flora. While much research focused initially on the microbial ecosystem of the gut, researchers are now also studying the microbiomes of the mouth, nasal cavity, vaginal tract, and skin.
Naturally, scientists have been exploring different modalities that can best be used to create new therapies and diagnostics from the ever-increasing data and findings of microbiome studies.
“These cover a broad range of options including complex approaches like fecal transplants that could include early uncharacterized strains of bacteria and other microorganisms, all the way to reductionist approaches,” noted Bernat Olle, a partner in the venture capital firm Puretech Ventures, who moderated a panel “Microbiome modulators: Opportunities and Challenges to Creating a New Drug Class” Thursday at BIO 2014.
As researchers seek to better understand the microbiome, one simple fact is abundantly clear: Traditional antibiotics that have been prescribed for a range of bacterial infections for decades can wreak havoc on a person’s microbiome. That’s because these antibiotics weren’t designed to selectively target the specific bacteria causing the infection and, as a result, also attack all kinds of other bacteria.
But that approach is rapidly changing, as evidenced by the drug Dificid (fidaxomicin) from Cubist Pharmaceuticals. Fidaxomicin is the first in a new class of antibiotics, which target specific bacteria, in this case C. difficile. Acquired by Cubist in its acquisition of Optimer Pharmaceuticals, fidaxomicin significantly lowers the rate of patient relapse of C. difficile versus vancomycin, another antibiotic often prescribed to treat the bacteria.
Steven Gilman, executive vice president of research and development at Cubist, said scientists at Optimer, who were looking into why fidaxomicin was effective, discovered that unlike vancomycin, it spared many of the bacteria in the gut microbiome. And because of this lighter touch and preservation of the microbiome, patients respond better and recover sooner.
Cubist has since used this knowledge to help guide the development of other of its drugs in its pipeline, including one that also targets C. difficile—surotomycin. “We actually did a Phase I and Phase II reaction study with our drug surotomycin on the impact of flora and saw essentially the same thing: that this drug doesn’t impact like vancomycin and, from a practical perspective, if that wasn’t observed we wouldn’t have taken that drug to a Phase III,” Gilman said. “So we are using microbiome data right now to make decisions in researching antibiotics.”
As the benefits of preserving an individual patient’s microbiome become more clear, this also points to the benefit of applying antibacterials as therapeutic agents. The hope is to be able to develop antibacterial medications that can make a pinpoint strike on bacteria responsible for an infection while leaving others intact. AvidBiotics CEO David Martin likens this to the therapeutic being a laser or of targeting the bacteria like a sniper.
These highly targeted agents in attacking bacteria also have the advantage of not creating resistance as frequently occurs with antibiotics. “These will not have an impact on selecting for antibiotic resistance because the bugs are already off target,” said Martin. “So there is no selective pressure of organisms to retain any antibody-resistant genes they may have acquired from their neighbors because, as you know, bacteria are exchanging genes—particularly genes that have an advantage for survival—among themselves constantly.”
The second advantage of the laser-like antibacterial approach is that whether it be gut microbiota or skin, or oral, or vaginal, the bacteria that are off target are insensitive, so one is not going to damage the rest of that microbiota. Protecting the diversity of the microbiota is also important in helping preserve colonization resistance—the mechanism by which the intestinal microflora protects itself against harmful microorganisms.
“Therefore, a very narrow spectrum agent reduces both the pressure for the spread of antibiotic resistance and reduces the unintended collateral damage to microbial ecosystem that we need for good health,” said Martin, who added that even in cases where resistance to an antibiotic doesn’t occur, there will still be damage to the microbiota.
With the microbiome playing a role in a broad array of diseases, creating diagnostic tools can provide both a census of the microbiome as well as characterizing a patient’s metagenome. That is exactly the path that Paris-based Enterome Bioscience is taking. The company currently develops personal medical tests and companion diagnostics with the goal of aiding in both the development of drugs for, and the treatment of, metabolic, gastrointestinal, and autoimmune diseases.
According to Pierre Belichard, Enterome CEO, the gut microbiome consists of around 600 species of bacteria. One of the interesting early findings by the two-year-old company was that people suffering from obesity showed a microbiome that is shrunk by around 30 percent. “For diagnostics, we can look at the number of genes and say to people that you had a problem in the early days of your life and you have a shrunken microbiome; then we will define this and start something that is like a stratification tool for people having the same disease, but the disease does not behave the same,” said Belichard.
A second potential diagnostic would be used for monitoring the microbiome and how it is responding to medication for an infectious disease. With an infectious disease the microbiome is constantly changing, Belichard noted, and these changes can eventually help guide clinicians in how they approach treatment.
In addition, via its research and focus on the gut biome, Enterome has identified potential targets that will aid in drug discovery research and development. According to Martin, this focus could serve Enterome well in the long run as research has shown that antibiotics given early in life has a major impact on the gut microbiota, and a healthy microbiome is known to be a major player in immunity.
“I think there are associations (with diseases) based on the absence or presence of certain organisms in the gut and various disorders, but very few of those have been proven,” said Martin. “That’s an opportunity for very targeted bactericidal agents that we happen to be building and many are based on the immunity system. So I think that may be the biggest opportunity—to influence the immunity system by manipulating the gut microbiome.”
Chris Anderson ([email protected]) is the former chief editor of Drug Discovery News, which he helped launch in 2005.