DUBLIN – In a busy end-of-year round of dealmaking, Versant Ventures has backed two new start-ups, Montreal-based Inception IBD, which has closed a $14.1 million series A round and could get up to $40 million more in research funding from build-to-buy partner Celgene Corp., and Kyras Therapeutics Inc., Versant's first New York-based venture, which has raised an undisclosed sum to embark on a new approach to target Ras, that most elusive of cancer targets.

Inception IBD is following Versant's tried-and-trusted path for derisking new ventures by lining up a partner and an agreed exit deal from the get-go. Inception IBD, as the name suggests, is focused on new therapeutic approaches to inflammatory bowel disease (IBD), developed by a founding trio of French scientists: Eric Ogier-Denis, head of a Paris-based Inserm research unit on IBD, UMRS1149, and his collaborators Xavier Tréton and Yoram Bouhnik, both of Hôpital Beaujon, of Clichy. One of the therapeutic concepts Inception IBD will pursue is based on an understanding of the IBD pathology as an epithelial barrier dysfunction within the gut mucosa.

"Fundamentally this is a departure from the inflammation-driven targets we've seen so much of," Jerel Davis, partner at Versant Ventures, told BioWorld Today. It is based on extensive comparative genomic analyses of biopsies taken from patients during disease flares and during remission, as well as tissue samples taken from healthy volunteers.

"They found substantial differences in the genetic signatures," Versant's managing director, Brad Bolzon, told BioWorld Today. "They've developed something that looks like it could have real utility."

Inception IBD has access to tools and assays developed by its founding scientists, as well extensive repositories of patient biopsies. The licensed assets include a double-knockout mouse model of ulcerative colitis, which is deficient in interleukin-10 and NADPH oxidase 1 and which exhibits immune dysfunction as well as an endoplasmic reticulum stress response characteristic of the human disease. "It seems to recapitulate many features of the disease and also, in our hands, it's done well in tests with known treatments or with experimental compounds that did not work out in the clinic," Paul Anderson, chief scientific officer at Inception, told BioWorld Today.

The company already has genomic targets it is interested in pursuing, but it is also planning on discovering more, including potentially targets of relevance to both diseases. "We would welcome a unified approach, and we may find targets useful for both diseases, but we're also interested in targets that might be useful for one or the other disease," Anderson said.

Anderson, a medicinal chemist with 30 years of industry experience, will lead Versant's Inception Montreal site, which will boost Versant's staff of discovery and development scientists to about 75, situated across San Diego, Vancouver and Montreal. It is drawing on some of the personnel associated with the Merck Frosst Centre for Therapeutic Research in Kirkland, west of Montreal, which closed several years ago. "That was one of the most productive sites for Merck in its history," Bolzon said.

Celgene's participation in Inception is evidence of its deepening interest in that area, following its drug licensing deal with Dublin-based Nogra Pharma Ltd. for the Smad7-targeting antisense molecule GED-0301 and its $7.2 billion acquisition of San Diego based Receptos Inc. The venture is the second build-to-buy deal the Summit, N.J.-based firm has entered with Versant. Earlier this year, it triggered an option to acquire San Francisco-based oncology firm Quanticel Pharmaceuticals Inc., for $100 million up front plus up to $385 million in milestones. (See BioWorld Today, April 28, 2015.)

Versant led the series A round, with participation from Inserm Transfert Initiative, the technology transfer of Inserm, France's flagship biomedical research agency, and from Montreal-based Fonds de Solidarité FTQ.

CHASING RAS

In New York, meanwhile, Kyras, a start-up based on the research of Columbia University professor Brent Stockwell, will be the first to occupy a perch in Versant's Highline Therapeutics incubator in Chelsea. It has pulled in the first tranche of a $20 million reserve that Versant has set aside – it is open to a larger syndicated financing deal in the next 12 to 18 months.

The fund has seen about 100 projects since it began scouting for opportunities in the city. "This particular opportunity has really risen to the top in terms of the quality of the work," Carlo Rizzuto, venture partner at Versant, told BioWorld Today. For an academic project, it already had quite a comprehensive data package, he noted. "You have to have a certain healthy skepticism if you hear someone has drugged Ras," he said.

It has already won over some influential supporters. Joe Vacca, former head of structural chemistry at Merck & Co. Inc., was brought in to do due diligence work on the project – he is now the company's chief scientific officer (CSO). Biotech entrepreneur and Ras cancer biologist Frank McCormick, now on the faculty of the University of California, San Francisco, is chairing its scientific advisory board. Other members include Adrienne Cox and Channing Der, both of the University of North Carolina, Chapel Hill, and Martin McMahon, of the Huntsman Cancer Institute at the University of Utah.

Activating mutations in Ras, a key signaling protein involved in cell growth, differentiation and survival division, are associated with about one-third of all human cancers and up to 90 percent of certain cancer types. Yet it has evaded traditional drug discovery efforts for decades.

"It doesn't have deep pockets where typically you would have a drug dock," Rizzuto said. Stockwell has taken a computational approach to identifying several shallow pockets, to which drug fragments can bind. By linking them together, he has achieved potent Ras inhibition, evidenced in protein-protein interaction studies, cell-based assays and mouse xenograft models.

The approach exposes the shortcomings of traditional drug discovery approaches, which have so far only managed to address about 15 percent of human proteins.

"I think the problem has been – and I've been guilty of this myself in previous projects – that we rely too much on high-throughput screening," Stockwell told BioWorld Today. There's an underlying hypothesis that the chemical diversity in the libraries employed is sufficient to deliver good quality leads, although it's beginning to look as if that chemical space has been largely mined. His approach echoes that taken by Abbvie Inc. in the development of its Bcl-2 inhibitor venetoclax. "That's something that would not have come out of a high-throughput screen," he said. "It had to be built up."

Kyras is about three years from the clinic, CSO Vacca told BioWorld Today. It is currently in the early stages of lead optimization, but the early leads look promising. "They have activity in cells. They have shown reasonable activity in animal models. They seem to have drug-like pharmacokinetics," he said.

The company also represents the first test of the hypothesis that New York's research can support a biotech ecosystem. "What we have in New York City is great science. What we don't have is experienced biotech entrepreneurs who've done this again and again and again," Rizzuto said.

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