LONDON – Enterome SA has raised €46.3 million (US$52.6 million) in a mixture of debt and equity, enabling it to take a new type of cancer vaccine, based on microbiome-derived antigens that mimic neoantigens expressed on tumor cells, into the clinic.

After being delayed by the COVID-19 pandemic, the first site visit took place last week in a phase I/II 32-patient study in glioblastoma. A second phase I/II in adrenal tumors will start imminently.

The microbiome-derived antigens in Enterome’s vaccines are selected based on two properties. The first is their ability to activate the CD8+ memory T cells that are the guardians of the interface between the gut and the rest of the body, attacking commensal bacteria that breach that barrier.

The second is that they have a very high amino acid sequence homology with known and well-characterized human tumor antigens.

The intention is that those “oncomimics” will activate gut-defending memory T cells to direct a targeted cell killing immune response against tumors. The lead product, EO-2401, combines three oncomimics present on the cell surface of aggressive cancers but not found elsewhere in the body.

“We are capturing the potential of memory T cells that are in principal there to prevent the body from being invaded by bacteria in the guts,” said Pierre Belichard, CEO of Enterome. “When [EO-2401] is put in the body, the immune system reacts as if it was an invasion of bacteria and invades the tumor, because the peptide sequence is close to [that of] the tumor antigens,” he told BioWorld.

Paris-based Enterome has demonstrated the immune response is increased when combined with checkpoint inhibitors and the two phase I/II trials will test EO-2401 in combination with Opdivo (nivolumab, Bristol Myers Squibb Co.).

Following behind EO-2041, Enterome is developing EO-2463, comprising oncomimics that are highly expressed on B-cell malignancies. Armed with the new funding, that program will enter the clinic in 2021.

The funding round comprised a series E and the first drawdown from a loan facility provided by the European Investment Bank under a 2018 agreement.

The series E attracted new investors including microbiome investment specialist Symbiosis LLC and Takeda Pharmaceutical Co. Ltd. Existing investor microbiome specialist Seventure Partners, Health for Life Capital, Principia, Omnes Capital and Nestlé Health Science followed on.

“It’s a nice composition of dilutive and nondilutive funding,” Belichard said. “We have a runway to the beginning 2023; most of the clinical data will be obtained by mid-2022, so we will have six to eight months to prepare for the next round.”

Scientific approach to the microbiome

Alongside the oncomimics programs, Enterome will also advance its endomimic technology, in which it is developing microbiome-derived proteins that act on human receptors, prompting endogenous production of therapeutic proteins.

The lead candidate, EM-101, is a human hormone mimetic produced by commensal bacteria that acts on an undisclosed receptor to promote local release of IL-10. “This is better than directly administering IL-10, because it is quickly broken down,” Belichard said. The product is in preclinical development in inflammatory bowel disease.

Although Takeda is investing in Enterome for the first time, the two have been working together since October 2018, when they agreed on a co-development deal for sibofimloc (EB-8018, TAK-018) as a treatment for Crohn’s disease. The deal included a commitment from Takeda to invest $15 million in Enterome at a future date.

The agreement with Takeda, as a leader in gastroenterology, was an endorsement of Enterome’s scientific approach to the microbiome, it which it foreswore probiotics in favor of developing entities with which pharma is familiar. Sibofimloc is a small-molecule antagonist of FimH, an adhesion protein expressed by gram-negative Enterobacteriaceae, including adherent-invasive E. coli, which Enterome’s research suggests is implicated in the pathogenesis of Crohn's. The compound was in-licensed from Vertex Pharmaceuticals Inc., in April 2016.

FimH binds both carcinoembryonic antigen-related cell adhesion molecule 6, which is expressed on ileal epithelial cells, and Toll-like receptor 4 (TLR4), which also binds bacterial lipopolysaccharide and mediates its inflammatory effects. TLR4 is barely present in the gut wall of healthy individuals, but is overexpressed in patients with Crohn's disease.

The findings of the phase Ib study are awaiting publication; however, Belichard said it had been shown that there was engagement of FimH on adherent-invasive E. coli. COVID-19 means there have been some delays in the phase II trial of sibofimloc, but that is now restarting. Enterome is paying 25% of the costs of clinical development of the drug.

While microbiome composition has a notoriously high level of variability among individuals, Enterome’s overarching metasecretome technology has enabled it to find some common threads, such as the correlation between Enterobacteriaceae levels and disease activity.

The technology also enables full genomic and functional analysis of the gut microbiome, opening up the body’s natural reservoir of safe and tolerized proteins produced by gut bacteria. “We are developing something different from other [microbiome] companies; we are more in the pharma space,” Belichard said.

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