Catabasis Pharmaceuticals Inc.
This article was originally published in Start Up
Executive Summary
Catabasis Pharmaceuticals is drawing on research showing that salicylate, a close relative of aspirin, improves glucose homeostasis in people living with type 2 diabetes. Catabasis hopes that by combining salicylate with optimized forms of omega-3 fatty acids, it can come up with a safe and reimbursable drug that simultaneously inhibits pro-inflammatory pathways and activates anti-inflammatory pathways, with benefits for diabetes, dyslipidemia, and inflammatory diseases.
Combining long-familiar substances to treat diabetes
161 First Street
Suite 1A
Cambridge, MA 02142
Phone: (617) 349-1971
Web Site: www.catabasispharma.com
Contact: Jill Milne, PhD, CEO
Industry Segment: Biotechnology
Business: Diabetes therapeutics
Founded: June 2008
Founders: Michael Jirousek, PhD, CSO; Steven Shoelson, MD, PhD; Jill Milne
Employees: 7
Financing to Date: $7.7 million
Investors: SV Life Sciences; Clarus Ventures; MedImmune Ventures; Advanced Technology Ventures
Board of Directors: Christian Cortis, PhD (Advanced Technology Ventures); Maggie LeFlore, PhD (MedImmune Ventures); Jeffrey Leiden, MD, PhD (Clarus Ventures); Michael Ross, PhD (SV Life Sciences)
Scientific Advisory Board: Steven Shoelson (Harvard Medical School, Joslin Diabetes Center); Benjamin Cravatt, PhD (The Scripps Research Institute); C. Ronald Kahn, MD (Joslin Diabetes Center, Harvard University); Diane Mathis, PhD (Harvard Medical School); Ruslan Medzhitov, PhD (Yale University); Jerrold Olefsky, MD (University of California, San Diego)
Scientists first recognized a connection between inflammation and diabetes about 15 years ago. Evidence of the link is piling up, and companies large and small are trying to leverage the insight. Some are testing treatments approved for other inflammatory conditions such as rheumatoid arthritis (RA), while others raise antibodies against specific inflammatory factors, or create chemical mimics of hormones involved in glucose metabolism. As yet, though, no drug treating inflammation as an underlying cause of diabetes has been approved.
Catabasis Pharmaceuticals Inc. is betting it can develop a novel and effective anti-inflammatory treatment for diabetes by hooking together two exceedingly well-known compounds. The start-up is looking to leverage salicylate, a close relative of aspirin, and the subtype of omega-3 fatty acid called docosahexaenoic acid (DHA).
The pairing of salicylate and an omega-3 fatty acid "may sound simplistic," says company co-founder and CSO Michael Jirousek, "but there is quite a knowledge base behind our choices." Jirousek formerly led the metabolic therapeutic research group for Pfizer Inc., and later served as SVP of research for Sirtris Pharmaceuticals Inc. Another co-founder of Catabasis is Jill Milne, now its CEO. She also held senior research positions at Pfizer, and then via Polaris Venture Partners became part of the founding team at Sirtris. Both left Sirtris after it was acquired by GlaxoSmithKline PLC.
Milne and Jirousek say they became inspired to develop a platform for treating inflammation as a root cause of many diseases, beginning with diabetes, after pondering why existing anti-inflammatory treatments have not been more successful. Milne explains, "Most therapies inhibit a single pro-inflammatory factor like TNF-alpha. We thought an ideal drug would simultaneously influence a range of pro-inflammatory factors, and also activate the body's endogenous anti-inflammatory pathways." Investigating small molecules that might accomplish this led them to Steven Shoelson, the third co-founder of Catabasis. He is head of the section on cellular and molecular physiology at the Joslin Diabetes Center, and a professor at Harvard Medical School, both part of the Harvard University system.
Shoelson got the idea that salsalate might be a valuable treatment for diabetes, after discovering that obese diabetic patients have an elevated inflammatory state driven by NFkB. He suspected the inexpensive relative of aspirin, often prescribed for RA, might help calm the low-level inflammation that seems to impair insulin sensitivity and lead to diabetes. His work published in 2005 gave rise to a multi-city clinical trial of salsalate in type 2 diabetes. The trial results were published in March 2010, showing that patients who took the drug had lower glucose levels and lower triglycerides in their blood after three months. Those who took the highest dose, a hefty four grams three times a day, lowered their HbA1c levels, an important measure of blood glucose control.
Shortly before Catabasis was founded in June 2008, the US Food and Drug Administration announced that it would henceforth require companies developing potential treatments for type 2 diabetes to provide a minimum of two years of cardiovascular data on patients. Previously, controlled trials for this disease typically ran three to six months. The new stipulation proceeds from a conundrum: it seems that although normalizing blood glucose levels protects diabetics from microvascular complications such as retinopathy and neuropathies, these patients are also for some reason at increased risk of cardiovascular disease. It is in fact their leading cause of death. FDA's enhanced expectations are making diabetes "a more challenging area for drug development, but rightly so," Milne declares. No doubt the new regulations are easier to accept if one suspects, as she does, that her company's drug candidate "has the potential to be cardioprotective."
Catabasis is by no means the first company to bet that an omega-3 fatty acid can be developed into a patented drug that confers cardiovascular benefit. An Irish public company (with offices in Mystic, CT) called Amarin Corp. PLC presently has an ongoing Phase III clinical trial testing an "ultra-pure omega-3 form" in cardiovascular disorders. While it is common knowledge that omega-3 fatty acids obtained through foods such as cold-water fish, or as dietary supplements, help lower triglycerides, Amarin expects that its ethyl ester of eicosapentaenoic acid (ethyl-EPA) will prove better.
For its part, Catabasis believes that linking its own preferred form of omega-3 fatty acid to salicylate will yield a synergistic effect beneficial to treatment of diabetes and a range of other disorders with inflammation as an underlying cause. Catabasis developed the so-called SMART-linker technology that covalently bonds the compounds together into a new chemical entity.
At this point, the company has more than a hunch that the familiar molecules it has joined have a synergistic effect. Jirousek explains that Catabasis began working back when it first received seed funding to examine the effect of its chosen molecules, separately and together, in vitro and in vivo. "Though we say 'omega-3 fatty acid' the fact is that DHA and EPA have unique biologies associated with them. We've done a lot of research in order to understand which to conjugate and how to do that and how to target them to specific cell types," he says.
Genomic and proteomic technologies along with specialized methods for studying lipids and mapping molecular pathways have all been harnessed to help Catabasis investigate specific mechanisms by which its conjugated molecules may ameliorate inflammation. Jirousek explains, for instance, that the company has observed salicylate-inhibiting pro-inflammatory factors after it enters the nucleus of certain cells. He says one mechanism by which omega-3 fatty acids, and DHA in particular, appear to function as anti-inflammatories is transrepression, a process in which repression or inhibition of one protein also represses the activity of a second protein.
Jirousek says studies done by and for Catabasis show that its conjugate can down-regulate a range of inflammatory factors including IL-1 beta, IL-6, and TNF-alpha and up-regulate anti-inflammatory factors such as IL-10 and adiponectin. "You only need to modulate activity of NFkB by a small amount to get an effect [likely to be therapeutically relevant]," he notes.
The apparently broad action of the company's conjugate gives the founders confidence for competing against other drugs now in development. While a number of drugmakers including Xoma Corp., Novartis AG and Eli Lilly & Co. are aiming to treat type 2 diabetes with antibodies against IL-1 beta, Jirousek figures, "by more broadly targeting the immune response, we think we'll have a more robust effect on the underlying pathology of the disease." The way he sees it, companies touting more precise therapies will all help to establish the value of pursuing a more generalized effect.
Milne says Catabasis anticipates bringing a candidate molecule into clinical testing by the second half of 2011. The firm is currently developing a set of biomarkers that will be followed in the Phase I trial and onward, she says, adding, "We hope to show dose-ranging effects." Jirousek adds, "Thanks to the elegant work Steven Shoelson has done, we think we have an advantage and a head start in clinically validating markers of pro-inflammatory pathways." At present, he says the company is not using any particular platform to track biomarkers, "but that is not to say we won't develop one with someone." While both execs emphasize that Catabasis has no intention of developing a companion-diagnostic to accompany its drug, they say Catabasis may use biomarkers in a Phase II trial, to preferentially select for treatment diabetic patients "in an inflamed state" as evidenced by high levels of circulating markers of pro-inflammation.
Catabasis intends to seek a partner for its potential diabetes treatment at some point during its Phase II trial, when it has enough data to attract an organization with an established presence in diabetes and pockets deep enough to support the lengthy testing now expected of all comers in the space. Although Catabasis is targeting diabetes as its lead indication, Milne emphasizes that the company's technologies represent a platform that has already generated new chemical entities likely to be useful in other disease states, such as neurodegenerative disorders, inflammatory bowel disease and arthritic conditions. In those areas, the company will consider forming an early-stage partnership.
At the end of April 2010, Catabasis announced the first closing of its Series A financing, raising over $7 million of a committed $39.6 million from investors including SV Life Sciences, Clarus Ventures, MedImmune Ventures, and Advanced Technology Ventures. [See Deal] – Deborah Erickson