IDO1 x TDO

Celgene may be busy wrapping up the biggest deal in its existence — the proposed $74 billion sale to Bristol-Myers Squibb — but it’s still snapping up options to nascent immuno-oncology drugs while it can. The latest tie-up involves Kyn Therapeutics, a Boston startup backed by Atlas Venture and OrbiMed to go after metabolites that keep the immune system from attacking cancer. For $80 million upfront and an undisclosed equity investment, Celgene obtains exclusive options to two of these immunometabolism therapies — which they will make a decision about once Kyn is done with the Phase Ib. Both programs have something to do with TDO and IDO, the latter being a pathway Bristol-Myers has gambled $800 million on — only to hastily halt two Phase IIIs in the wake of a rout in the field. But instead of directly and only inhibiting IDO, Kyn has developed drugs to degrade kynurenine or antagonize the aryl hydrocarbon receptor to prevent their binding, which would result in broad suppression of the immune system. The collaboration signals Celgene’s “continued commitment to work with partners,” said Robert Hershberg, head of business development and global alliances. And not just with Kyn, either. Cambridge, MA-based Obsidian Therapeutics says it’s also scored a collaboration with Celgene featuring an exclusive option to in-license its destabilizing domain technology, which it calls an “operating system” for living medicines like CAR-T. It adds that the pact focuses on DD-regulated IL12 and CD40L, but is keeping quiet about the financials. Here’s CEO Michael Gilman on the experience: Needless to say, completing a deal with Celgene in the last couple of weeks has been… interesting. Kudos to their deal team who remained focused and professional despite the turmoil and uncertainty that was undoubtedly swirling around them. And thanks! — Michael Gilman (@michael_gilman) January 18, 2019 Once one of the industry’s most active dealmakers, Celgene has a rep for offering a supportive role for its smaller partners and paying top dollar for its best prospects.

Roche Could Take a $500M Hit Over Patent Losses As part of a portfolio update, Altas Ventures noted that Raze Therapeutics, a biotech launched in 2014, has closed its doors. As part of a portfolio update, Atlas Venture noted that Raze Therapeutics , a biotech launched in 2014, has closed its doors—if it had doors. Kristen Margeson, with Atlas Venture, told BioSpace , “Raze was actually shut down at the end of 2015 and did not actually have ‘doors’ to shut as it was incubating at Atlas.” Raze closed a $24 million Series A financing in October 2014. Investors included Atlas Venture, MPM Capital Management, MS Ventures, Partners Innovation Fund, Astellas Venture Management and Novartis . It was co-founded by Atlas Venture’s Peter Barrett, as part of the venture firm’s seed financing strategy. That strategy, as Atlas described in a 2013 blog post , which was recently reviewed, “takes nascent substrate around new drug discovery platforms or therapeutic assets and incrementally but materially derisks them before committing significant capital and reserves. This derisking process is a ‘search for signal’—what can we glean about the underlying science/technology/asset, the founding team, and the market’s responsiveness to the concept that gives us the confidence to press forward.” The focus of the company was to develop a new class of drugs for cancer that targeted mitochondrial one-carbon (1C) metabolism. Brittany Meiling, writing for Endpoints News, noted, “The space has emerged recently as a major driver of cancer proliferation, survival, and biomass accumulation. But apparently the tech was too tough to continue.” “Although it made intriguing progress, the underlying cancer metabolism biology was too complicated to warrant further investment,” said Bruce Booth , an Atlas partner, in the firm’s recent portfolio update. Raze wasn’t the only seed company in the Atlas portfolio to hit a snag. Booth also noted Quartet Medicine was recently shuttered, and Numerate , which is doing well, but took a different approach. In the case of Quartet, Booth wrote, “their once-promising neuropathic pain program hit an unmitigatable preclinical safety issue in August 2017 … that led to the recent shutdown of the company.” He wrote of Numerate, “This one is not a failure at all, as this cool artificial intelligence-led drug discovery software startup continues to deliver. But they’ve done so with a different, more service/collaboration business model than our drug discovery platform thesis (so Atlas went passive).” Atlas is supporting a new startup, called Kyn Therapeutics , that works in a related though not identical space. Today the company launched with a $49 million Series A raise funded by Atlas and OrbiMed. Kyn is focused on immunometabolism. Kyn has its own assets, including a clinical-stage program expected to enter the clinic in 2018. The company states that, “Each Kyn Therapeutics candidate is designed to reverse the effects of an immunosuppressive metabolite promoted by cancer cells, and therefore complement or enhance the outcomes achieved by checkpoint inhibitor therapies.” “The promise of immunometabolism lies in overcoming the barriers cancer creates against treatment, and we are very excited about the opportunities we’ve created by harnessing compelling research in this area,” said Mark Manfredi, Kyn’s chief executive officer, in a statement. “Our preclinical research has delivered exciting results both in single agent studies and in combination with leading checkpoint inhibitors and other mechanisms. We are moving rapidly to launch a clinical oncology study in 2018.” Manfred was the chief scientific officer of Raze, and is entrepreneur-in-residence at Atlas. He told Meiling that Raze still had assets and collaborations, but no longer employed anyone. She writes, “According to Booth Raze’s scientific assets went back into academia for further exploration.” Kyn Therapeutics’ lead program focuses on Kynase, an enzyme that breaks down kynurenine directly, which affects both IDO and TDO-related immunosuppression. The second program blocks immunosuppression regulated by the aryl hydrocarbon receptor. Its most clinically advanced program is ARY-007, which blocks the EEP4 receptor, involved in the prostaglandin E2 pathway. As was the case with Raze, Kyn is addressing complex pathway in immunology and metabolism. Of the money raised, $21 million is allocated to Arrys Therapeutics for the ARY-007 program.

June 8, 2017 By Mark Terry , BioSpace.com Breaking News Staff Ames, Iowa – NewLink Genetics announced that Genentech was returning the rights to its IDO inhibitor GDC-0919 (navoximod). However, the overall research collaboration the two companies have to identify the next generation IDO/TDO (tryptophan 2,3-dioxygenase) inhibitors will continue. The original deal had an upfront payment of $150 million and with milestones, could have hit over $1 billion. The deal was inked in October 2014. NewLink licensed GDC-0919, which was then called NLG919, to Roche/Genentech . Genetic Engineering & Biotechnology News writes , “The companies reasoned that targeting the IDO and TDO pathways represented a breakthrough approach to fighting cancer, citing earlier studies showing that the IDO pathway was active both within tumor cells as a direct defense against T-cell attack, and within antigen presenting cells in tumor-draining lymph nodes.” John Carroll, writing for Endpoints News , says, “This is the latest in a series of gut punches to NewLink, which was sent reeling last year and was forced to restructure in the wake of the failure of its pancreatic cancer vaccine. IDO, a hot ticket in biotech now with Incyte evidently well in the lead, was supposed to be its path back.” It was only a week ago that NewLink announced that its Phase II trial of indoximod plus taxane chemotherapy, either docetaxel or paclitaxel, did not meet its primary endpoints. The endpoints were a statistically significant difference in progression-free survival versus placebo plus taxane chemotherapy in metastatic breast cancer. “We are obviously disappointed in this decision,” said Charles Link , NewLink Genetics’ chief executive officer, in a statement. “We remain committed to advancing our IDO pathway inhibitor indoximod, which continues to generate exciting data in combination with anti-PD-1 agents, cancer vaccines, and chemotherapy in multiple cancer types including melanoma, prostate cancer, acute myeloid leukemia, and pancreatic cancer.” NewLink Genetics , which had been trending downward since March, took a hard hit and is currently trading for $10.62. Shares traded on March 31 for $24.10, dropped to $15.50 on April 13, climbed back to $19.05 on April 26 before beginning a strong drop. This drop follows only a few days after Michael Uln , an analyst with Baird, gave the stock an “Outperform” rating and a price target of $25 after hosting an investor lunch at ASCO in Chicago. At that time, Baird suggested that the IDO pipeline was underappreciated. Carroll writes, “The writing, though, was on the wall when investigators reported that GDC-0919 delivered only a 10 percent overall response rate in all tumor types in a combination study with Tecentriq—a PD-L1 checkpoint that is also under a cloud since the big Phase III failure in bladder cancer. Genentech is not known for pursuing futile work in cancer.” At one point in April, the idea of Gilead Sciences acquiring NewLink Genetics was floated. Generally, the top suggestion has been Incyte Corporation , at least until its baricitinib for rheumatoid arthritis was rejected by the U.S. Food and Drug Administration (FDA) . The rationale for NewLink was promising interim results from a Phase II trial of indoximod in combination with checkpoint inhibitors to treat advanced melanoma. Incyte’s epacadostat is an IDO inhibitor, and so is NewLink’s indoximod and GDC-0919. But NewLink is a lot less expensive than Incyte—even more so now. Todd Campbell, writing for The Motley Fool in April, said, “Despite the solid showing (of indoximod), many industry watchers believe that apacadostat delivers a better blend of efficacy and safety because it targets IDO directly. Unlike apacadostat, indoximod disables IDO via cell signaling.” But, depending on what NewLink plans to do with their newly reacquired IDO inhibitor, it may be a moot point.