Microbiome Offers Rich Pickings As Takeda Becomes Enterome's Second Big Pharma Crohn's Partner
Executive Summary
Takeda's $50m+ deal for Enterome's EB8018 is based on a separate platform from that being used under the French company's collaboration with Johnson & Johnson.
Takeda Pharmaceutical Co. Ltd. has agreed a second deal with French firm Enterome SA, which focuses on developing drugs based on understanding the behavior of the human gut microbiome. Takeda will pay $50m up front to collaborate on developing and marketing EB8018, an orally active, gut-restricted small-molecule drug aimed at a novel target in Crohn's disease.
The deal helps Takeda expand its R&D pipeline in a franchise in which it is traditionally strong (sales of its top-selling drug, Entyvio (vedolizumab) for Crohn's and ulcerative colitis, were ¥201bn ($1.79bn at today's exchange rate) in the most recent fiscal year, representing underlying growth of 36%). It also builds on prior deals the Japanese major has signed in the microbiome space.
Enterome's candidate has been shown to be safe with minimal blood absorption in a Phase Ia study in healthy volunteers and is now in a Phase Ib trial in Crohn's patients to evaluate safety, pharmacokinetic profile and preliminary efficacy signals. The company's CEO Pierre Belichard told Scrip that the first patient visit in a Phase IIb trial – which would trigger the first portion of up to $640m in additional potential milestone payments from Takeda – would probably happen in mid-2020.
The new collaboration is separate from a pre-existing agreement in the field of irritable bowel syndrome (IBS) and gut motility that Takeda and Enterome signed in 2016, which Belichard revealed has already reached yet to be disclosed milestones. [See Deal]
Under the new collaboration, which will see Enterome contribute 25% of the development costs and retain co-marketing rights in the all-important US market, the partners hope to develop a product that will be able to modify the disease rather than to treat the symptoms, which is what existing therapies including corticosteroids and TNF-alpha inhibitors like AbbVie Inc.'s Humira (adalimumab) and Johnson & Johnson's Remicade (infliximab) do.
EB8018 arose from work Enterome did following a cohort of 100 Crohn's patients for one year, collecting microbiome samples every month from each of them, then correlating the evolution of the gut microbiome with the evolution of the disease. "By doing this we have observed a pattern of gut microbiome composition in all Crohn's disease patients, which is that there is a blooming of Enterobacteriaceae all over the place in the microbiome of Crohn's patients compared to healthy volunteers," Belichard explained. "This is a feature of any kind of Crohn's patient whatever the level of activity of the disease, whatever country the patient is living in."
The company then identified a factor expressed by these bacteria which is not normally expressed, an adhesin called FimH, which allows the bacteria to adhere to the gut wall in the ileum of Crohn's patients and activate toll-like receptor 4 (TLR4), thereby inducing a cytokine storm and the formation of tumor necrosis factor (TNF) alpha.
"With the molecule that we are developing we are inhibiting the binding of the FimH of the bacteria to TLR4 because our drug has a very strong affinity for the FimH. We are literally clogging the bugs together, we are not killing the bacteria, and we are eliminating the bacteria in the intestinal fluid without killing it, so it is not inducing any resistance. And by doing this we are avoiding the formation of TNF-alpha, which is a very potent pro-inflammatory element," explained Belichard.
'Post-Cure' Positioning
Although still in Phase I studies, the CEO has a clear vision of how the drug would be used in clinical practice. "It's never too early to position a drug on its future market. This drug has a very clear positioning which is unique due to the fact that today there is no such drug on the market targeting disease modification: all the drugs you find on the market are targeting the symptoms of the disease, i.e., inflammation."
EB8018, with its expected good tolerability and safety profile, is being developed for positioning as a "post-cure" treatment. "That means whatever cure induces remission of the disease: it could be TNF-alpha treatment or surgery. Most Crohn's patients have surgery at some point to remove part of the ileum which is full of these bacteria. So once the surgery has been done – and that's what we'll focus on in Phase IIa – it is said that 90% of patients in the year following surgery have a recurrence of the disease." The intention would be to treat these patients with EB8018 to maintain remission by avoiding reinfection of the ileum with the Enterobacteriaceae "with an oral drug which is easy to use and has no side effects," Belichard told Scrip.
Datamonitor Healthcare analysts estimated that the Crohn's disease market was worth $5.8bn across the US, Japan and five major EU markets in 2016. They predict it will grow to $9.8bn in 2025, despite downward price pressure from biosimilar versions of anti-TNF inhibitors. They also predict that J&J's Stelara (ustekinumab), an IL-12/23 inhibitor launched for Crohn's in 2016 in the US, will become the market-leading brand in the market with 2025 sales of $2.2bn, tipping Entyvio from its top spot as gastroenterologists' preferred non-TNF biologic because of its faster onset of action and comparable safety profile. Datamonitor Healthcare forecasts Entyvio to generate sales of $1.0bn in Crohn's disease in 2025.
J&J Deal Difference
This program is distinct from the agreement Enterome has with Johnson & Johnson which is also focused on Crohn's disease. Under the J&J deal, a factor that is secreted by bacteria in normal conditions but not in the presence of Crohn's disease has been identified. "Consider that the gut microbiome is like an organ secreting a number of factors, an endocrine organ like the pancreas, say. When the pancreas is not producing insulin any more, you can develop diabetes: what we've tried to demonstrate in this collaboration with J&J is more on the causation side. The product we are developing with Takeda is more trying to alleviate the inflammation which is due to bacterial infection which is a consequence of Crohn's disease. It's not overlapping in any way: it's a different approach." Belichard added that the J&J collaboration was "progressing well" but that he could not share further information for confidentiality reasons.
Belichard underscored that unlike many other "microbiome" companies, Enterome is not developing live bacteria as therapeutics – or "bugs as drugs" – but rather it has platforms to understand what the bacteria in the human gut microbiome are producing, in terms of hormones, metabolites, peptides, proteins and so on.
Additional Programs
Aside from its deals with Takeda and J&J, Enterome is working on a diagnostic and therapeutic biomarker collaboration with Bristol-Myers Squibb Co., identifying differences in the gut microbiome composition of cancer patients who respond to checkpoint inhibitors compared with those who don't respond. And it has an internal program focused on microbiome-related antigen mimics of cancer antigens, dubbed onco-mimics. The lead product in this program is expected to go into clinical trials in glioblastoma in combination with checkpoint inhibitor therapy in mid-2019.
Previous microbiome-focused deals signed by Takeda include separate gastroenterology-focused collaborations with NuBiyota LLC[See Deal] and Finch Therapeutics Group Inc. [See Deal], both of which were agreed in April 2017 .
Takeda has also committed to making a future equity investment in Enterome.
For more details of Datamonitor Healthcare's analysis of the Crohn's disease market, click here.