February 1, 2018 (Vol. 38, No. 3)
Company Pursues an Informed Approach to Drug Discovery
With some 100 trillion bacteria in the gut, the microbiome is becoming as valuable as the rainforest as a source of new therapeutic compounds. While the rainforest is exotic, the gut microbiome is equally unusual, and, is perhaps as prolific in terms of being a potential source of new drugs.
As Glenn Nedwin, Ph.D., president and CEO of Second Genome, explains, “the microbiomes of individuals are mostly dissimilar. They contain different strains, based upon birth conditions and genetics, as well as differences in diet and environment.” The commonality of microbiomes is that, regardless of the specific bacteria they contain, those bacteria functions keep us alive. They produce hormones, vitamins, amino acids, regulate the immune system, gastrointestinal system, metabolic pathways, the central nervous system, kill off “bad” bacteria, and modulate disease.
Second Genome and its strategic partners are using this information to harness the microbiome, using the bacteria therapeutically. One example is to use specific strains to increase drug response rates in patients who respond poorly to certain drugs.
“Our job at Second Genome,” Dr. Nedwin says, “is to figure out what specific strains do, go after the proteins, peptides, or metabolites they make, and use them therapeutically. Think of this as informed drug discovery.” The company is developing its own drug pipeline and has performed numerous microbiome analyses for other companies, academics, institutions, and government labs in non-competing areas.
LBNL Technology Origins
Second Genome’s core technology, PhyloChip, was exclusively licensed from Lawrence Berkeley National Laboratory in 2009.
“We have an exclusive license to a chip-hybridization technology for testing bacterial DNA sequences for environmental sampling of water quality. The problem was that not many people wanted to analyze their environmental samples,” notes Dr. Nedwin. After a year or two, the company transitioned to diagnosis and bioanalytics.
“At first, we analyzed the microbiome, but the analytics of the time weren’t sufficiently advanced to deliver the level of specificity needed for actionable insights.” To increase specificity, he continues, “we used a combination of sequencing and metagenomics for functional transcriptome analysis.” Second Genome also uses the PhyloChip, now it is fourth-generation, to identify low-abundance, rare, and important bacterial strains in a sample.
The turning point for Second Genome came in 2013 when the company realized its microbiome analytics platform could be used in the pharmaceutical industry as a drug-discovery engine. It pivoted and discovered more than 30 proteins, peptides, or metabolites derived from the gut bacteria that are influential in gastrointestinal disease, metabolic disease, and immuno-oncology.
“Animal models suggest our approach, which uses bioactive molecules derived from the microbiome-derived bacteria, can modulate all the biological systems mentioned [previously],” according to Dr. Nedwin. “In addition, we now have a government grant to apply the approach to autism.”
In the past decade, some 30,000 papers have been published correlating gut bacteria to health and disease states. “The industry didn’t pay enough attention to it,” Dr. Nedwin tells GEN. Early approaches in the industry focused on using fecal bacterial transplants to modulate disease. “Second Genome’s approach is more precise, going after bioactives with known FDA regulatory paths.”
Dr. Nedwin says the company’s microbiome-modulating discovery platform can detect both rare and abundant bacteria. He believes this approach helps the firm better identify the genus, species, and variant of the strain. “People think all bacteria are created equal, even in the same genus and species. Each bacterium can be unique from even its close cousins. For example, Bacillus anthrax is very different from Bacillus cereus,” explains Dr. Nedwin, and strains of the latter may be probiotic, while others are caustic. From the perspective of health, the challenge is to feed the beneficial bacteria and keep them alive in a hostile environment without also feeding the harmful bacteria. “It’s not clear that people understand that relationship,” Dr. Nedwin says.
To be more effective in the microbiome space, he advises strategic partners to “pick a disease where the microbiome is relevant. There are many areas. Then design a well-characterized study that compares and contrasts the presence of particular bacteria in healthy and diseased states. Get as much metadata as you can.” That metadata should include other medications the patient is taking, the presence of other diseases or conditions, as well as diet and environmental factors. “At the end of the day, bacteria are present in a situation because they are being fed, so you need to understand the bacteria correlated to the metadata.”
It’s Not Personalized
The drugs that may result from Second Genome’s approach aren’t personalized. Nor are they probiotics. What makes these drugs unique is mainly where they discovered.
To become useful as a therapeutic, researchers sequence all or part of a bacteria’s genome in various samples and make a statistical correlation between the bacteria and certain healthy or disease states. Understanding which bacteria are present and how they differ in each state may have implications for drug development.
Second Genome’s R&D team has sequenced the genomes of thousands of bacteria to identify, clone, and test the secreted, unknown, and unique proteins they produced. “We found 14 proteins that emanate from healthy gut bacteria that modulate the epithelial layer in the GI tract,” he says. “The proteins of interest may be made into a pill, an injectable, or a topical product.”
Business Model in Transition
Second Genome is transitioning from its analytics business to focus on drug development, both internally and with strategic partners. “We see ourselves as a drug discovery company with unique expertise,” points out Dr. Nedwin.
The 350 studies Second Genome has conducted for strategic partners, combined with internal findings and published studies, have yielded an abundance of data with virtually endless applications, he emphasizes. Narrowing one’s focus can be challenging but, Dr. Nedwin says, “by looking inside our bodies for bioactives that we have evolved with to keep us healthy is likely to improve the chances that the resulting drugs will work.”
The gut microbiome is a unique place to look for drugs. “We know the molecules are there, because we see their effects, and they should have a semblance of safety, as they are already inside our bodies,” he says. Therefore, “Our success rate should be quite high,” and drug development should be faster and less expensive.
Currently, Second Genome has one drug entering Phase II clinical trials in 2018 for NASH for liver disease and several in Phase I for inflammatory bowel disease and other conditions. Additionally, the company has identified many hits in metabolic disease, oncology, and inflammation. “Our goal is to be an independent, fully integrated pharmaceutical company,” Dr. Nedwin says.
Like the rainforest, the gut microbiome has the potential to yield many novel therapeutics. Second Genome, as one of the first companies in this burgeoning area, is positioned to bring those new compounds to light.