In the not-too-distant future, diseases of the central nervous system (CNS) may be treated by therapies derived from living gut bacteria. Such therapies are in development at 4D pharma, a company that is also working toward more immediate goals, such as microbiome therapeutics for autoimmune diseases, respiratory diseases, and forms of cancer. The most immediate applications are, of course, in gastrointestinal diseases.

Describing itself as a fully integrated microbiome company that can “progress from research to production to clinic,” 4D pharma specializes in the development of Live Biotherapeutics. Such products contain a live organism, such as a bacterium, that is applicable to the prevention, treatment, or cure of a disease.

“We’re looking to push the boundaries of microbiome therapeutics further,” says Duncan Peyton, the co-founder and CEO of 4D pharma. He notes that human trials are underway to assess the company’s Live Biotherapeutic Product (LBP) candidates against cancer and other conditions, and that the company expects to begin a first-in-human trial in Parkinson’s patients in early 2022. “We also have identified other LBP candidates that have shown positive effects on autism in animal models,” he continues. “With this as a foundation, we are looking to target the gut-brain axis to treat diseases of the CNS.”

Emphasizing functionality

The company’s approach to the microbiome and the development of LBPs is based on functionality. “We select our LBP strains based on drug-like activity, not correlative studies comparing healthy vs. disease states,” Peyton states. “We are looking for causation, not correlation.”

According to Peyton, 4D pharma’s research teams investigate the LBPs’ mechanisms of action by identifying “the effector molecules produced or modified by the strain, and the host biological pathways involved in the therapeutic response.”

In the course of this work, the research teams determine strain-level specificity. “Two strains of the same species can have vastly different genetic content and genetic output and, thus, activity,” Peyton notes. “This is often overlooked and underappreciated.”

The company is unusual in that rather than attempting to modulate or repopulate the microbiome to a healthy state, it is developing oral biological therapeutics that act via the gut and specific pathways.

Accepting bigger challenges

Like most companies in the microbiome space, 4D pharma first reached for relatively low-hanging fruit, specifically, microbiome therapeutics for gastrointestinal diseases. One of 4D pharma’s first programs was in inflammatory bowel disease, where the company showed that a single strain of its LBP reduced inflammation locally. Once this was demonstrated, 4D pharma then moved on to systemic inflammation.

“As a result of our achievements in local gut inflammation,” Peyton recalls, “we started to investigate diseases like asthma and other autoimmune-inflammatory diseases like multiple sclerosis and arthritis,” Peyton says. (The company currently has an asthma treatment in a Phase I/II trial.)

Successfully downregulating the immune system using gut bacteria made 4D pharma’s team wonder whether gut bacteria could also be used to stimulate the immune system for oncology therapeutics. “We screened our LBP library for potent immunostimulatory, nonpathogenic strains,” Peyton notes. This work led to 4D pharma’s lead oncology candidate, MRx0518, which produces a TLR5 agonist that stimulates the immune system.

In 2020, 4D pharma announced two sets of results. One set of results came from a two-part Phase I study of MRx0518 monotherapy in treatment-naïve subjects undergoing surgical resection of solid tumors—a study that yielded what Peyton calls the first-ever positive clinical data of a microbiome therapy in cancer. The MRx0518 monotherapy was shown to have a significant impact on tumor immune infiltration and other immune biomarkers.

The other set of results came from a two-part Phase I/II trial in which MRx0518 was administered in combination with Keytruda (pembrolizumab), Merck & Co.’s immune checkpoint inhibitor immunotherapy, to members of a very difficult patient population, specifically, heavily pretreated metastatic patients with solid tumors refractory to immune checkpoint inhibitors.

“After completing Part A [the first part of the two-part combination trial], we saw a 42% clinical benefit rate,” Peyton reports. “This improvement was seen in end-of-line patients who had already had multiple treatments, including immune checkpoint inhibitors like Keytruda. Although it was observed in a relatively small population, this improvement far exceeds the 10% threshold that had been specified in an agreement between us and Merck.

“Importantly, we are seeing durable responses with meaningful impacts for these end-of-line patients, with some now on treatment for two years or more. MRx0518 has been able to re-engage patients’ response to checkpoint immunotherapy, with no increase in side effects.”

Moving from success to success

4D pharma is the result of a search by two venture capitalists—Peyton and the company’s other co-founder, Alex Stevenson, PhD, who is currently 4D pharma’s CSO. They were looking for therapies that offered better safety and toxicity profiles than other emerging therapeutics. Live biotherapeutics met that requirement, presenting an opportunity to de-risk and accelerate drug development.

Peyton says that at the time, no one had investigated the full potential of live biotherapeutics in a rational, scientifically driven way. Therefore, one of the first hurdles was convincing people that the development of live biotherapeutics was serious science. “Many couldn’t get past the idea of using commensal bacteria as therapeutics without [thinking of] probiotics and food supplements,” Peyton recalls.

Now people understand that the microbiome has a significant effect on human health, so the challenge is to identify the most effective ways to harness the microbiome and to develop platforms to identify the best candidates. To do so, 4D pharma can exploit its patent portfolio. The company has more than 1,000 granted patents, which range over 65 patent families.

4D pharma went public on the United Kingdom’s AIM stock exchange in 2014. In March 2021, the company launched a dual listing on Nasdaq, becoming the first British biotechnology company to list via a special purpose acquisition company (SPAC). This was a significant step in building a greater presence in the United States.

“The SPAC route provided certainty and immediate cash, through funds held by the SPAC plus a concurrent private investment in public equity, and a timeline that suited our ambitions,” Peyton says. “As we already were a public company in the United Kingdom, this made more sense than a traditional initial public offering process.”

Now 4D pharma is looking toward the latter half of this year, when it anticipates updates on Part B of the trial of MRx0158 in combination with Keytruda in patients refractory to immune checkpoint inhibitors; preliminary clinical and biomarker data from a study assessing MRx-4DP0004 in patients with poorly controlled asthma; and regulatory discussions to identify pivotal strategies for a Phase III trial of Blautix (MRx1234) for irritable bowel syndrome.

During the fourth quarter of 2021, 4D pharma expects preliminary data from MRx0518 for pancreatic cancer. The company is also anticipating the launch of a trial assessing MRx0518 in combination with Bavencio (avelumab) as first-line therapy for urothelial carcinoma. During the first quarter of 2022, 4D pharma plans to launch a Phase I/II trial of MRx0029/MRx0005 in the company’s first-in-human trial in Parkinson’s patients.

Managing the risks of success

To rapidly select bacteria that have a therapeutic effect in specific diseases, 4D pharma relies on its own discovery platform, which is called MicroRx. “It has proven its ability to target an incredibly wide range of diseases and disease mechanisms,” Peyton asserts. “Because we, like other companies, have limited resources and bandwidth, we may be unable to realize the full value of all of these opportunities ourselves.”

With so many opportunities, 4D pharma has to avoid spreading itself too thin or pursuing any but the most promising projects. According to Peyton, the company is concentrating “on areas where we believe we can make a significant impact, such as oncology and CNS disease, … while retaining a ‘multiple shots on goal’ approach across different programs and indications to de-risk the pipeline.”

To further de-risk development and fill an early gap in the industry, 4D pharma developed its own cGMP-certified manufacturing facility. It boasts two 3,000-L fermenters to supply late-stage clinical and small-scale commercial product production.

A GMP-certified manufacturing facility that covers about 1,500 square meters gives 4D pharma end-to-end development capabilities, allowing the company to scale its products from glassware in the laboratory to commercial-scale production. From 5-L pilot-scale through to 3,000-L fermentation, 4D pharma can optimize the development of its products in-house, without relying on external manufacturers.

That these advances are possible now is the result of years of work throughout the scientific community. “It is exciting to see that, in parallel to our own work, there is an increasing recognition of the role of the microbiome in oncology in the wider medical community,” Peyton observes. “Some exciting studies have been published in recent years that support the central idea and provide some external validation.

“There is huge potential for microbiome therapeutics. We want to continue to push the field to realize the potential of live biotherapeutics in diseases beyond the gut … including in CNS diseases and cancer.”

Previous articleAn Innovative, Multiomics Approach to Early Cancer Detection
Next articleOptimizing LC-MS Analysis of Limited Sample Volumes