CEO Mark McKenna told BioWorld that San Diego-based Prometheus Biosciences Inc. has "cracked the code" in inflammatory bowel disease (IBD) – progress underscored by the firm's deal with Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, which brings an undisclosed up-front payment and as much as $420 million more if development, regulatory and commercial milestones are reached in three programs.

The pair's pursuit of IBD therapies combines Prometheus' bioinformatics and companion diagnostic tools with Takeda's know-how in gastroenterology. Prometheus will be responsible for identifying and validating three unique drug targets for IBD, and for coming up with companion diagnostics to complement the candidates. Takeda will handle all drug discovery, clinical development and commercialization activities for the targeted therapies.

Created through the June 2019 acquisition of Prometheus Laboratories by Precision IBD, Prometheus has licensed from Cedars-Sinai Medical Center what's described as a highly curated biorepository containing more than 200,000 samples derived from more than 20,000 patients, collected over 15 years. The samples are linked with clinical and research metadata. The library contains "all the medical history, information on responders and nonresponders," McKenna said, along with serology and genomics info. "They tie all this together to understand pathways of disease and drug targets, instead of taking a one-size-fits-all approach, which is what medicine in inflammatory conditions is doing today."

Prometheus deploys data mining and machine-learning analysis to decipher the dominant disease biology in subgroups of IBD patients, allowing the company to design new drugs for specific patient groups, along with diagnostic tests. The firm's lead compound, antibody PR-200, targets TL1A, an approach that proved "impressive" recently for New York-based Pfizer Inc. with a candidate in midstage trials, McKenna noted. "We believe that we have a better antibody, and an ability through our platform to identify the right patients and expedite" the journey to market, he said. Precision medicine in oncology is "a little easier because it's one or two genes. Without the database, people are going to struggle to break down populations like we've done," he added.

Takeda's deep in IBD already. In 2014, after an FDA advisory panel backed Takeda's Entyvio (vedolizumab) for treatment of severe ulcerative colitis (UC) and moderate to severe Crohn's disease (CD), the FDA granted approval on its May 20 PDUFA date, making it the first integrin inhibitor to hit the market since Biogen Inc.'s Tysabri (natalizumab). Entyvio, which inhibits the alpha2beta7 integrin, is indicated for patients for whom one or more standard therapies, including corticosteroids, immunomodulators and tumor necrosis factor blockers, failed to produce adequate responses. Supporting data came primarily from two clinical trials involving about 900 patients, which showed that a greater percentage of participants treated with Entyvio vs. placebo achieved and maintained clinical responses. (See BioWorld, May 21, 2014.)

The pharma firm's further interest in the space was demonstrated about a year ago when Paris-based Enterome SA collected $50 million up front with the promise of up to $640 million more as goals are met in clinical development, regulatory and commercial realms. The global licensing and co-development deal with Takeda has the two companies jointly taking forward Enterome's lead candidate, FimH antagonist EB-8018 for CD. (See BioWorld, Oct. 24, 2018.)

Prometheus expects to start trials in humans with PR-200 in June of next year, taking aim at a population that represents up to 30% of CD patients. The numbers are higher in Japanese and other Asian cohorts – greater than 50%. "Obviously, not every target is going to be a massive home run," McKenna said. But winnowing the patient base will provide benefit to patients and insurers. "Right now they're paying for 80 percent of the patients that don't respond," he said. "These are expensive drugs. You've got to believe they're going to love this story because we're removing all the waste in the system."

As biotech and pharma firms work to invent still more new drugs for IBD, findings continue to roll out on how the condition might be relieved when prescription therapy can't do the job. Last week, a paper in Gastroenterology detailed a study done by scientists at King's College of London, who found benefit in a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (the oft-recommended FODMAP regimen) in patients with IBD who suffer gut symptoms despite their inflammation being under control. A four-week low FODMAP diet reduced stomach swelling and flatulence compared to a placebo diet.

'Much bigger deals to come'

Researchers performed a single-blind trial of 52 patients with quiescent CD or UC at two large gastroenterology clinics in the U.K. Patients were randomly assigned to groups that followed a diet low in FODMAPs (n=27) or a control diet (n=25), with dietary advice, for four weeks. Gut symptoms and health-related quality of life were measured using questionnaires. Stool and blood samples were collected at baseline and end of trial. The lab team assessed fecal microbiome composition and function using shotgun metagenomic sequencing and phenotypes of T cells in blood using flow cytometry.

Upshot: A higher proportion of patients reported adequate relief of gut symptoms following the low-FODMAP diet (14/27, or 52%) than the control diet (4/25, or 16%, p=0.007). Also, patients had a greater reduction in irritable bowel syndrome severity scores following the low-FODMAP diet (mean reduction 67; standard error 78) than the control diet (mean reduction 34; standard error 50), but the difference was not statistically significant (p=0.075). Following the low-FODMAP diet, patients had higher health-related quality of life scores (81.9±1.2) than patients on the control diet (78.3±1.2, p=0.042). A targeted analysis revealed that in stool samples collected at the end of the study period, patients on the low-FODMAP diet had significantly lower abundance of Bifidobacterium adolescentis, Bifidobacterium longum and Faecalibacterium prausnitzii than patients on the control diet, but microbiome diversity and markers of inflammation did not differ significantly between groups. The value of the FODMAP strategy for patients has been known anecdotally for years, but attacking IBD entails more than food choices.

McKenna pointed to "mixed views on the FODMAP diet," with some experts insisting that, "at the end of the day, you may need a nonsystemic antibiotic to at least set the microbiome. The problem is that there's more we don't know about the gut than what we know." Prometheus knows plenty, though, and lists plenty of scientific heavyweights on its board. He predicted "much bigger deals to come. We're in the process of raising our series C, and we're considering an IPO next year, depending on the market. I don't think we're going to have problems raising money."

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