Medical treatments based on administration of bacteria are not new, but they are still considered “out there.” Leeds, UK-based 4D pharma hopes to change that perception through its development program based on “Live Biotherapeutic Products (LBP),” which are defined by the FDA as live organisms, such as bacteria, applied to treating disease.

Most of us are familiar with the recommendation to take “beneficial bacteria” to replenish gut microbes wiped out by antibiotic therapy. Less familiar, perhaps, are fecal transplants to treat C. difficile infections and other ailments. Work at 4D (and others) suggests that therapeutic bacteria could play a much larger role in modern medicine.

The company has programs for treating irritable bowel syndrome (IBS) but also for cancer. 4D researchers have found, for example, that short chain fatty acids from M. massiliensis enhance the production of effector cytokines in CD8+ cells. Even more interestingly, 4D’s MRx0518 live biotherapeutic, is currently under investigation as an adjuvant treatment (with Keytruda) for a variety of cancers.

4D’s LBP discovery platform, MicroRx, is focussed on a bacterial strain’s functionality rather than abundance or taxonomy, says Duncan Peyton, CEO. MicroRx characterizes a strain’s activity against diseases, focusing on specific mechanisms and therapeutic hypotheses of interest.

“Strains are evaluated through relevant in vitro and in vivo assays, before being tested in animal models of disease with translational value,” he tells GEN. “In this context the tools of microbiome analysis are not dissimilar to the tools of traditional drug discovery and development. We also have a complementary microbiome analysis bioinformatics platform, MicroDx, which we use to conduct microbiome metagenomic sequencing and metabolomic analysis of patient samples from our clinical trials.”

Monoclonal strains isolated from gut microbiomes

4D’s LBPs are monoclonal strains isolated from the gut microbiomes of healthy human donors, which are characterized, cell-banked, and produced in-house at 4D pharma’s cGMP facility in fermenters of up to 3,000 liters.

“We extract the bacterial cells by centrifugation, and lyophilize the bacteria into a powder, which is encapsulated for administration,” explains Peyton. “The basic infrastructure for LBP manufacturing is not new or particularly complex. The skill is in optimizing the conditions to maximize the delivery of viable cells.”

The gastric-resistant oral capsules survive the stomach intact and reach the intestine, where the pH change causes the capsule to dissolve, releasing the LBP contents into the intestine, where it is active.

Because LBPs are harvested from healthy donors, and with no systemic distribution, they provide the critical advantage of inherent safety. 4D pharma has observed clinical efficacy and “placebo-like safety profiles” in dosing 500+ patients with four unique LBP candidates, in multiple clinical settings.

Alternatives or standard-of-care treatments for conditions under investigation by 4D typically show much higher toxicity than LBPs, according to Peyton. These conditions include immuno-oncology for a range of cancers and settings, CNS disorders, respiratory indications, autoimmune conditions, and gastro-intestinal conditions.

Aside from drastically reduced clinical development risk, a key advantage of LBPs’ favorable safety profiles is to accelerate the timeline for generating clinical proof of concept data,” he says. Regulators routinely allow developers to skip traditional Phase I safety and move directly into the target patient population.

“LBPs represent an exciting new way to tackle complex diseases,” continues Peyton. “Rather than the traditional ‘one drug one target’ model of drug development, LBPs have the potential to hit multiple targets with a single ‘drug substance.’ This raises the possibility of addressing multiple aspects of complex, multi-factorial diseases.”

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