Safe and Intriguing ‘Nature’s Drugs’ Taking on Complex Diseases

By Deborah Borfitz

August 13, 2024 | The cost of bringing a drug to market has, by some estimates, ballooned to $3 billion and the central problem could be the “misapplication of technology,” according to Alex Martinez, CEO of Intrinsic Medicine, a privately held biotechnology research startup he cofounded in 2018. “The industry seems to not be drawing boundaries around a product profile, informed by [drug] class data.” 

Since completion of the Human Genome Project, the focus had shifted heavily toward orphan drugs with a single genetic target, suitable only to highly targeted genetic technology platforms. There has consequently been a dwindling number of projects in the development pipeline for non-genetic, multifactorial diseases including Parkinson’s disease and irritable bowel syndrome (IBS) that are afflicting the masses, he says. 

Intrinsic Medicine aims to change all that with a focus on inherently safe compounds capable of treating chronic diseases where immune dysregulation and dysbiosis of the microbiome play central roles. Specifically, the company is creating an entire library of pharmaceutical-grade human milk oligosaccharides (HMOs) levering the properties of human milk biology to treat what it terms disorders of the “gut immune brain axis [GIBA]”—a list that includes Parkinson’s and IBS, inflammatory bowel disease (IBD) such as Crohn’s disease, and autism spectrum disorder (ASD).     

“These are intriguing compounds [that] occur in the context of breast milk, but they are not nutritional...  data suggest they may be nature’s drugs,” says Martinez. Intrinsic Medicine now has two of them under active development and is building a research platform anchored by its clinical pipeline. 

Its lead compound is a synthetic-biology-produced drug that is identical to 2’ Fucosyllactose (2’FL), the single most abundant HMO that constitutes nearly 30% of the total HMO proportion in human milk. It has already received regulatory approval in Australia to jump directly from the preclinical stage to a phase 2 clinical trial as a treatment for Parkinson’s disease and IBS, he adds. 

This HMO is known to be critical in setting homeostasis of the immune system in the gut and body in early human development. Next in line indications for 2’FL are IBD, ASD, and immune oncology.  

Pregnancy’s Positive Effect

Intrinsic Medicine believes it is the first drug developer on the planet to look at the therapeutic application of HMOs and their prescription drug path at doses far higher than what is currently found in some infant formulas, says Martinez. Previous work has been focused more on infant health with some limited supplementation studies. HMOs fall into the realm of glycobiology and, while glycans including oligosaccharides are one of the four building blocks common to all life on earth, they have not been broadly translated as a therapeutic modality like the more commonly used nucleic acids, lipids, and proteins.  

Only a few medicines fall in the glycobiology category at present, the notable exceptions being the blood thinner heparin and some antibiotics, he says. But by “evolutionary proxy,” vast numbers of drugs could be synthesized that leverage what is known about the biological activity of HMOs. From what’s been learned to date, “the right applications are as disease-modifying therapies for select disorders where the GIBA is implicated as a primary cause.” 

One very big hint emerged from data out of an infant nutrition lab at the University of California, San Diego (UCSD) about an HMO known as 3’ Sialyllactose (3’SL) that was tested in a mouse model of rheumatoid arthritis. Around the same time as the preclinical work was being produced, it was discovered that HMOs start circulating in the blood of expectant mothers in their first trimester, coinciding with these observations of remission, says Martinez.  

This was intriguing, as human epidemiology has long shown that women with autoimmune disease would often go into remission starting in the first trimester. As a backdrop to the story, he shares, the same observation of remission during pregnancy led to the 1950 Nobel-Prize-winning discovery of cortisol to become a mainstay of treatment, as cortisone, for rheumatoid arthritis. “The laureates themselves said they didn’t believe cortisol was the substance they had been originally seeking.”  

To further strengthen these findings, the UCSD preclinical rheumatoid arthritis work was confirmed by another group in South Korea that published a paper comparing the effects of 3’SL versus methotrexate (a mainstay treatment) in another rheumatoid arthritis animal model and demonstrated it worked equivalently to a high human dose of methotrexate (British Journal of Pharmacology, DOI: 10.1111/bph.14486). 

Intrinsic Medicine is now investigating a version of 3’SL that is structurally identical to that found in nature as a disease-modifying drug for oligoarticular juvenile idiopathic arthritis and atopic dermatitis. The HMO has been found in prior experiments in animals and human in vitro studies to have a strong, direct anti-inflammatory effect. 

‘Sherpa for Innovation’

Martinez is, by his own admission, a “pharma outsider.” He briefly flirted with the idea of becoming a medical doctor as an undergrad. “I have always been a healthcare-focused person,” he says, noting that his first job as a teenager was an instructional assistant for children with autism. “I just always had a passion for helping people, first one person at a time and now the goal is to do it at scale.” 

He took up a unique major known as “health and societies” at the University of Pennsylvania, which enabled him to focus on public health yet explore a gamut of synergistic courses ranging from complementary and alternative medicines and medical anthropology to health economics and healthcare management at its famous Wharton School. In the summers between terms, his work with autistic children continued.  

During this time, Martinez recalls, he became excited about a waiver project as an intern at the Centers for Medicare & Medicaid Services (CMS) that was to combine healthcare and education for children with autism, but it didn’t move forward because of legal issues. It was then he decided that to make a difference he was going to have to learn the legal system himself. 

While working his way through University of Michigan law school, he served as a clerk in the health system. “That was when I realized how reactive the practice of health law was, that we were actually perpetuating dysfunction,” says Martinez. He then became interested in entrepreneurship as a vehicle to make changes in healthcare. A business school professor enabled Martinez to lead a practicum whereby consulting groups of graduate students would spin out companies based on academic research at the university.  

Entrepreneurship and “being a Sherpa for innovation” quickly became his passion. Martinez moved to Silicon Valley to work for one of the top law firms for early-stage companies, putting him “close to the action... [but] not quite in it.” 

A year later, Martinez says, he cofounded an early digital health company “well before it was a major industry” to commercialize technology for reengineering the patient discharge experience. The technology was “health literacy operationalized through a virtual patient advocate avatar” and was designed to reduce hospital readmissions, which at the time was estimated to be costing CMS over $50 billion per year. 

Everyone loved the concept except hospital CFOs, he says, which provided a major obstacle to the business case. Hospitals were getting significant revenue from readmissions coming back through the emergency department. 

The “perverse incentive" for hospitals to not seek to reduce preventable readmissions was “just unacceptable,” says Martinez. “My parting gift from that experience was that I took part in a roundtable of experts in preventing readmissions... and we worked together on section 3025 of the Affordable Care Act” that established the Hospital Readmissions Reduction Program linking hospital payment to the quality of care. 

Postgenomic Era

As Martinez was debating his next move, a unique opportunity emerged in 2011 to build a competitive intelligence and market research function for Ionis Pharmaceuticals. Ionis was pioneering antisense technology with a focus on rare, monogenic diseases.  

His work with Ionis Pharmaceuticals helping to take a novel technology platform through multiple regulatory and commercialization paces inspired Martinez and cofounder Jason Ferrone (formerly handling regulatory affairs, corporate development, and patent issues at Ionis) to launch Intrinsic Medicine. The lens for their search and evaluation process for potential therapeutics were compounds with a high safety margin that could target prevalent if perplexing conditions related to immune dysregulation and the gut microbiome, he says. 

Human evolutionary biology was to point the way forward. This, Martinez says, is where his legal background came in. “I’m a pattern recognition guy, a logic guy...  [who is good at] connecting the dots,” and doing so without modality bias. Intrinsic Medicine (formerly known as Lupa Bio) started evaluating molecules, including HMOs that occur in the body during early human development to assess the potential to develop drugs around those biological pathways. Around this time, the company added a third cofounder—Samantha Murphy, Ph.D., who currently serves as vice president of corporate development at Aspen Neuroscience and also leads her own consulting firm.  

Initial academic experiments on HMOs clearly showed disease-modifying effects, warranting their advancement to the clinic, he says. As compounds initially developed as ingredients for infant formula, they are “generally recognized as safe,” he notes.    

Regulatory Experiment

Putting on his lawyer hat once again, Martinez knew the next best step was to talk to the U.S. Food and Drug Administration (FDA). So, Intrinsic Medicine went to IndieBio, a 16-week startup accelerator program that helps early-stage companies develop synthetic biology ideas. “I think we were the first company to ever go there... [for support of] a regulatory experiment.” 

In a pre-Investigational New Drug meeting with the FDA, Intrinsic Medicine was told its 3’SL candidate could indeed go directly from the preclinical stage to a phase 2 trial enrolling adult rheumatoid arthritis patients for up to 24 weeks of dosing. Given that the average cost of IND-enabling toxicology testing and conducting a phase 1 trial is several million dollars and many months if not years, the savings would be staggering for just that one HMO, he says. 

“3’SL is [just] one of over 200 different HMOs and all the science shows that each one has a distinct biological profile,” Martinex continues. For example, the isomer 6’SL has completely different properties than 3’SL even though they’re comprised of the same components. “The only difference is a bond.”  

The GIBA terminology helps “reframe” thinking about multifactorial disorders, says Martinez. New research about the gut-immune-brain-axis is coming out almost every day now, including studies providing evidence that it exerts strong influence over functions that are vital to even athletic and cognitive performance. 

Synthetic biology has matured to the point that manufacturing human-identical HMOs at scale is feasible, he adds. However, the market for the products has not evolved quite as much—at least not yet.  

Preparing for Clinical Trials

Consideration of the immune system component is important because the gut environment is a “thin pink line to the outside world... [and] a completely different ecosystem versus inside the body,” Martinez says. “During feeding, a border crossing happens, and that’s why 70% of our immune cells are in our GI tract.” 

Immune cells are “mobilized where there is the highest risk of a pathogen [invasion],” he continues. “Absent a wound, where are you going to stage all your soldiers? On a border with potential invaders.” 

The gut environment is also “where immune cells are trained to recognize self from non-self and discern friendly microbes from bad microbes,” says Martinez. 

With GIBA, “we are trying to encompass the whole system,” he says. Pharma development has become “very reductionist,” often overlooking the fact that “a human being is a complex ecosystem whose key mediators are the immune cells.” 

Intrinsic Medicine originally focused on IBS, but it has proven to be a challenging indication because clinical trials need to be large owing to the high placebo response rate, he explains. “The etiology is still very emergent; IBS is likely to be reclassified as a gut-brain axis disorder in the near future.”  

In the case of Parkinson’s, where no meaningful drug treatment advances have been made in 50 years—and the current investigational pipeline is comprised mainly of cell therapies suitable for the more severe patients—the clinical need is great and assays for early detection of the telltale alpha-synuclein deposits are becoming available, says Martinez. “What’s fascinating is that neurologists have long seen that constipation is one of the preceding symptoms of Parkinson’s.” 

In a landmark study with more than 24,000 Parkison’s patients published last year in Gut (DOI: 10.1136/gutjnl-2023-329685), researchers found that people with constipation-dominant IBS had over four times the odds of developing the disease. Investigators were testing Braak’s hypothesis, based on longstanding knowledge that most people with Parkinson’s have very different oral, pharyngeal, and gut microbiomes, Martinez says. In 2016, another group of scientists showed that transplanting the microbiome of a Parkinson’s patient into a mouse would cause the animal to develop the disease.  

Coupled with the fact that up to 80% of people with Parkison’s have constipation “basically demands that we test causation and see if we can treat or improve symptoms through the gut,” he says. Intrinsic Medicine is working with two principal investigators in Australia to test just that. 

Intrinsic Medicine’s phase 2 trial will study 2’FL in 180 Parkison’s disease patients, says Martinez. “We are still doing some fundraising to support initiating the program, but it has been HREC [human research ethics committee]-approved to begin dosing.” Separately, the HMO-derived compound is being used for an ongoing investigator-initiated study of pediatric IBD at Cincinnati Children’s Hospital that will include 200 patients.