By Rich Soll, Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and WuXi AppTec Content Team

What if the gut, widely regarded as the body’s second brain, could offer a much more impactful means to effect broad systemic pharmacological actions of orally administered drugs based on the confluence of the enteric nervous system, immune system, and microbiome within it?

Scientists at Kintai Therapeutics, based in Cambridge, Massachusetts, have been investigating the nuanced interconnections of a wide variety of systems in the gut. Their explorations have led to fruitful insights and data that have inspired a transformational view that the gut could serve as a way to effectively promote health and to treat disease.

Kintai was founded in 2016 by Flagship Pioneering and operated in stealth mode until its CEO, Paul-Peter Tak, was appointed to the organization in October 2018. Tak, who has deep experiences in experimental medicine and specializes in immunology, recognized that leveraging the natural environment of the gut could pave the way for a new class of transformative medicines – and create a new modality of drug treatment. With an eye towards commercialization, Kintai is building a lean workforce, using the flexibility of its partners instead of building vertically with fixed costs.

Tak’s vast experiences include being the founding chair of what became one of the world’s largest experimental medicine centers in immunology at the Academic Medical Center of the University of Amsterdam, starting a gene therapy company, and leading GSK’s immuno-inflammatory, oncology and infectious disease R&D as Senior Vice President and later as Chief Immunology Officer. His pioneering work on the role of the vagus nerve in chronic inflammation set the foundation for bioelectronics as a therapeutic approach in autoimmune disease and served, in many ways, as partial validation of Kintai’s platform.

In a recent interview with Rich Soll and the WuXi AppTec Content Team, Tak shared the company’s deep gut-related expertise and how it is searching for innovative therapies by exploring the enteric signaling network. Tak believes their approach can drive revolutions in the field of oncology and neuroscience, as well as areas like longevity and healthy aging.

“The gut is a very interesting and unique part of the body that forms what is known as the enteric signaling network,” Tak noted.

“First, it contains 70-80 percent of our immune cells which then circulate throughout the whole body. Second, there are five hundred million neurons in the gut serving as a second brain and sending signals throughout the body, and third, 95 percent of the microbiome, weighing about three pounds, is found in the gut, producing metabolites and mediators that serve as signaling molecules,” he continued.

“Collectively, this constellation serves as a hub of communication to the rest of the body to maintain health. Its dysfunction is implicated in a host of diseases and it can have a profound impact on a drug’s efficacy and toxicity profile.”

Kintai has assimilated this knowledge to use as an opportunity for targeting potent therapeutics, exploiting the properties of the gut to activate specific pathways exactly where they need to be activated. For example, in the colon for cases of ulcerative colitis or the liver for cases of non-alcoholic steatohepatitis (NASH).

Kintai has utilized this knowledge of the gut to make pioneering discoveries, including the identification of over 44,000 new genes, 19,000 protein families, and hundreds of new metabolites that were not previously known.

The knowledge gained from this system has formed Kintai’s proprietary Precision Enteric Medicine™ (PEM™) discovery platform to seek out new druggable targets implicated in disease and has allowed a mapping of the entire enteric system for which Kintai has assembled multi-omics data. 

Through technology development, Kintai has actually doubled its knowledge of biodiversity of the gut.  When integrated alongside next generation sequencing, metabolomics, and machine learning, a powerful and deep understanding of the relationship of these cells to health and disease can then be achieved.

Leveraging these insights, Kintai has rapidly built a highly actionable pipeline, which now has 10+ programs across multiple therapeutic areas, including oncology, neurology, and immunology. 

The company is “in the race to the clinic” and at the time of the interview just got its first IND number for its first program which is in ulcerative colitis. According to Tak, this program is expected to enter the clinic in the first half of next year, taking less than three years from idea to clinic, which he called “remarkable by any standard.”

Tak expects the ulcerative colitis product to be a major drug and is confident that it can validate different aspects of their platform. This new chemical entity is inspired by the effects of natural metabolites in the colon, and has the potential to improve the efficacy of clinical treatment by at least 50 percent for patients with abdominal pain, bloody diarrhea, fatigue and other important signs and symptoms.

The second program, driven by unmet needs in metabolic syndrome, which is characterized by obesity and other symptoms, is expected to move into the clinic at the end of next year.

Two additional programs will go into the clinic in two years from now, and in the short to medium term, Kintai is building a pipeline in neurology and cancer, while increasingly exploring longevity and healthy aging. Projecting into next few years, Tak expects the company to feed its pipeline with at least two candidates per year.

While all of the company’s programs were developed in-house, Tak stressed the importance of peer review, partnership, and collaboration, including working with external partners like WuXi AppTec.

One form of peer review comes from the company’s esteemed scientific advisory board and another from specific program advisory boards.

The company has also established strong ties to academia. It recently established new collaborations with a few leading academic institutions, such as Moffitt Cancer Center, Rhode Island Hospital and the University of Cambridge, to identify novel molecules that play a fundamental role in microbiome to human signaling in different forms of cancer.

“A lot of our work is supported by external collaborations. If you imagine what we are doing, you’ll realize it’s a very big effort with many disease programs – and we have only 70 people,” Tak said.

“I think working with partners like WuXi is key because it gives much more flexibility and capability at high quality without having to build everything ourselves,” he said.

Kintai uses WuXi in two ways.

“For flexibility, we use FTE-based chemistry to complement our internal abilities and to expand our footprint without having to invest in fixed cost and capital assets. This has been critical to the success of our programs. We also use the fee for service chemistry for scale-up to support in vivo animal work,” Tak explained.

“We also use WuXi to access capabilities we do not have in-house, for example in vivo proof-of-principle studies. We have used WuXi AppTec’s New Jersey group for pharmacology models which entailed compound dosing, formulation animal husbandry, and bioanalytics. The project saw acceleration through WuXi’s contributions,” he said.

“For me it’s a natural thing to be part of larger ecosystems and to create real synergy and to be open to partnerships,” said Tak, citing his own experiences of successful collaborations during his previous work at GSK (GlaxoSmithKline), where he founded its Immunology Network.

Looking into the future of the industry, Tak suggests that there needs to be a new classification of diseases, a molecular classification rather than the current one.

“I’m an immunologist and a rheumatologist. I found that most of the immune-mediated inflammatory diseases as we call them are not real diseases, but syndromes based on a collection of clinical signs and symptoms. They may actually represent completely different pathogenic entities,” Tak said.

“A deeper understanding of the disease mechanisms will open up the opportunity of precision medicine. Collaboration is key to accelerate this,” he added.

Tak closed by adding that patients should be more involved in driving the research agenda.

“Very often in my experience, patients are more open to innovation than prescribers, regulators or companies, because patients know what it means to suffer from a disease, and they know which benefit/risk profile might be acceptable,” he said. “They also may help us understand relevant signs and symptoms that scientists and physicians may not have thought of. The patients’ voice will change the way we do clinical trials.”