Incro Pharmaceuticals Inc.

The K2 trial tested oditrasertib’s safety and ability to reduce the blood levels of neurofilament light chain, a biomarker of neuronal damage in multiple sclerosis. However, the trial failed to meet its primary and undisclosed key secondary endpoints, according to a filing ​. Multiple sclerosis is a degenerative and progressive disorder where the immune system attacks the insulation around nerve cells, leading to the death of the cells and to increasing disability in people with the condition, which number around 2.8 million ​. Oditrasertib is designed to block a protein called receptor-interacting protein kinase 1 (RIPK1), which is involved in cell death. Blocking RIPK1 could make nerve cells more resistant to the pathology and slow down the disease. Denali obtained oditrasertib in 2016 when it took over the previous developer Incro Pharmaceuticals. Sanofi then got in on the action when it inked a $1 billion strategic collaboration with Denali in 2018 to develop candidates for the treatment of immunological and neurological conditions. Numerous setbacks The partnership has faced numerous obstacles in the last few years. Another of the RIPK1 inhibitors in the deal flopped in a phase 1b trial for the treatment of Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) in 2020, leading the partners to focus on oditrasertib. In February this year, however, oditrasertib failed in a phase 2 trial for the treatment of ALS and Sanofi discontinued the trial. Another RIPK1 inhibitor in the sights of the partners is eclitasertib, which cannot penetrate the central nervous system and is in phase 2 development for the treatment of ulcerative colitis. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Denali Therapeutics raised $500 million in a private placement in February this year and its main candidate, an enzyme replacement therapy to treat the rare disease mucopolysaccharidosis type II, is in a phase 2/3 trial set to complete enrollment this year. The growing prevalence of multiple sclerosis is set to drive the global market ​ for treatments, which was worth $21.3 billion in 2023 and is projected to grow by 7.9% to $38.9 billion by 2032. Getting a RIPK1 blocker ​ to the market is proving difficult for many players, with a candidate developed by GlaxoSmithKline showing no efficacy signs in clinical results in patients with ulcerative colitis published ​ in 2021. Some of the most advanced RIPK1 contenders include phase 1-stage programs by China’s GenFleet Therapeutics, Roche’s U.S. company Genentech, and a compound developed by Eli Lilly and Rigel Pharmaceuticals.

Investor With the raise, the company’s market valuation is currently $1.7B. Denali Therapeutics , launched in May 2015 by three former Genentech researchers, just went public , raising $250 million with shares priced at $18. It is trading under the ticker DNLI. The company’s founders were Ryan Watts, former director of Genentech’s Department of Neuroscience, Alexander Schuth, former director and head of Genentech’s Neuroscience Partnering, and Marc Tessier-Lavigne, president of The Rockefeller University . The company focuses on translational research to develop drugs to treat neurodegenerative diseases like Alzheimer’s, Parkinson’s, ALS and others. The company’s short history has been marked by notable financial accomplishments—primarily raising $350 million in venture capital. Otherwise, the company’s approach is to look at targets like RIP1, ApoE and LRRK2. John Carroll, with Endpoints News, writes, “’This may sound like Drug 101,’ CMO (and Genentech vet) Carole Ho told me last year, but Denali’s success after so many failures will get down to its ability to engage the target, with the right kind of biomarkers in place to track their success. Developing biomarkers early, she adds, is critical. And the biology of these diseases is becoming more clear through the rapid advance of genetics research.” With the raise, the company’s market valuation is currently $1.7 billion. Not bad for a company that doesn’t have a product for sale and in the case of a biotech, is only just entering the clinic. On Aug. 25, the company announced its first Clinical Trial Application to start a Phase I trial. It has chosen four specific pathways: degenogenes, which cause neurodegenerative disease when mutated; defective intracellular trafficking; glial dysfunction; and axon degeneration. The company filed a CTA in Europe for a small molecule RIP1 inhibitor that can penetrate the central nervous system. RIP1 regulates inflammatory signaling and can affect glial dysfunction in the brain. Data from the study will hopefully be used to support later studies in ALS and Alzheimer’s disease. “Mounting genetic evidence points to glial dysfunction as an accelerator of neurodegeneration, and we believe that advancing our RIP1 inhibitor into human clinical testing is a significant step in bringing forward a novel mechanism to combat ALS and Alzheimer’s disease,” Ho said in a statement at the time. Denali was also investing its previously raised funds into acquiring San Diego-based Incro Pharmaceuticals. It also inked a license deal with Genentech for rights to develop and commercialize LRRK2 inhibitors for Parkinson’s disease, research and licensing agreements with Washington University School of Medicine in St. Louis to develop and commercialize antibodies that target ApoE, a risk factor for Alzheimer’s disease, a research collaboration and option deal with UK-based F-Star and a deal with Blaze Bioscience . The company also noted strategic partnership collaborations with ALS Therapy Development Institute (ALS TDI) , Aptuit , Evotec , Massachusetts General Hospital , the Michael J. Fox Foundation PatientsLikeMe and the University of California San Diego School of Medicine . Carroll writes, “Denali’s arrival on Nasdaq marks the 40 th U.S. biotech IPO of the year, outstripping most of the expert guesses that the industry would repeat or just edge out last year’s lean 28 biotech IPOs. And while it’s not a repeat of 2014, when Wall Street rarely failed to embrace any biotech looking to go public, the second half of 2017 has seen a fast clip of new offerings.”

January 9, 2017 By Mark Terry , BioSpace.com Breaking News Staff Denali Therapeutics was launched in May 2015 by three former Genentech researchers— Ryan Watts , former director of Genentech ’s Department of Neuroscience, Alexander Schuth , former director and head of Genentech’s Neuroscience Partnering, and Marc Tessier-Lavigne , president of The Rockefeller University . The company’s focus is on translational research for the development of drugs to treat neurodegenerative diseases such as Alzheimer’s, Parkinson’s, ALS and others. “Our team will place an emphasis on rigorous translational medicine for targeted drug development,” Watts, the Denali’s co-founder, president and chief executive officer said in a statement at the time, “seeking evidence of drug activity in the brain and identifying biomarker-defined patient populations to increase the probability of clinical success. We are committed to collaborating with leading academic groups, companies and advocacy groups.” Denali is researching newly discovered genes tied to degenerative brain diseases, which the company founders are calling degenogenes . Their focus is on the nascent field of how inflammation affects neural diseases. Company Leadership Ryan Watts — co-founder, president and chief executive officer . Watts previously was director of the Department of Neuroscience at Genentech. Alexander Schuth —co-founder and chief operating officer. Before joining Denali, Schuth was head of Neuroscience Partnering at Genentech. Carole Ho — chief medical officer . Prior to Denali, Ho was vice president of Genentech Early Clinical Development. Steve Krognes — chief financial officer . Before Denali, Krognes was chief financial officer and a member of the Executive Committee at Genentech. Before that he led the global Mergers & Acquisition team at Roche in Switzerland. Mark Dresser — head of development sciences . Prior to joining Denali, Dresser was the director and head of the Oncology Clinical Pharmacology Department and the Atezolizumab (anti-PDL1) Project Team Leader at Genentech. Cindy Dunkle —head of human resources. Before joining Denali, Dunkle had roles of increasing responsibility across corporate staffing and development functions at Avalanche Biotechnologies and Genentech. Joe Lewcock —head of biology discovery. Prior to Denali, Lewcock was director of the Department of Neuroscience at Genentech. Zach Sweeney —head of therapeutic discovery. Previously, Sweeney was a director of Global Discovery Chemistry and head of Analytical Chemistry at Novartis Emeryville. Company Financing Denali launched with $217 million in venture capital. Additional investors include Fidelity Biosciences , ARCH Venture Partners , Flagship Ventures , and the Alaska Permanent Fund , represented by Crestline . Other investors include sovereign wealth funds, public mutual funds and private family offices. On August 25, 2016, the company announced a $130 million Series B equity financing. All of its founding investors participated in this round, which was led by Baillie Gifford , a UK-based mutual fund and included several new and large institutional investors, who were not identified. Pipeline Denali also announced in August its first Clinical Trial Application (CTA) to initiate a Phase I trial. It has selected four specific pathways that are believed to be triggers or effectors of neurodegeneration. Those include degenogenes, defective intracellular trafficking, glial dysfunction, and axon degeneration. The CTA in Europe is for a small molecule RIP1 inhibitor with central nervous system (CNS) penetrant properties. RIP1 is a kinase that regulates inflammatory signaling and affects glial dysfunction in the brain. Data from the study would then be used to design studies for ALS and Alzheimer’s disease. “Mounting genetic evidence points to glial dysfunction as an accelerator of neurodegeneration, and we believe that advancing our RIP1 inhibitor into human clinical testing is a significant step in bringing forward a novel mechanism to combat ALS and Alzheimer’s disease,” said Ho in a statement last August. Market Competition The field of neurodegenerative research is a crowded one, with Biogen , Eli Lilly , Merck and Genentech (ROG) all working on Alzheimer’s and other CNS disorders. Dollars and Deals In August 2015, the company announced a number of deals and transactions. It acquired San Diego-based Incro Pharmaceuticals for access to its RIP1 inhibitor program, which came out of a license and collaboration deal with Harvard University . Denali also inked a license agreement with Genentech for exclusive global rights to develop and commercialize LRRK2 inhibitors for Parkinson’s disease. Denali signed a research collaboration and exclusive license agreement with Washington University School of Medicine in St. Louis to develop and commercialize antibodies targeting ApoE, a protein and genetic risk factor for Alzheimer’s disease. In addition, Denali has a research and option deal with UK-based F-star in support of the development of a platform technology that can deliver therapeutics across the blood-brain barrier. And Denali inked a collaboration and option deal with Blaze Bioscience for a novel blood-brain-barrier drug at the Fred Hutchinson Cancer Research Center . Other strategic partnerships include collaborations with ALS Therapy Development Institute , Aptuit , Evotec , Massachusetts General Hospital , The Michael J. Fox Foundation , PatientsLikeMe and the University of California San Diego School of Medicine . See Top Life Science Startups 2017 See Top Life Science Startups 2016 See Top Life Science Startups 2015