Marcadia Biotech Inc.
This article was originally published in Start Up
Executive Summary
Marcadia Biotech aims to attack diabetes through weight loss. The start-up struck a deal with Merck for a glucagon and GLP-1 dual agonist that suppresses appetite while increasing metabolism in animal obesity models. Marcadia also has a first-in-class GLP-1 and gastric-inhibitory peptide molecule now in Phase 1 testing, again designed to reduce appetite to control diabetes.
Aiming to improve diabetics' sugar and weight, simultaneously
11711 North Meridian Street
Suite 300
Carmel, IN 46032
Phone: (317) 566-2266
Web Site: www.marcadiabiotech.com
Contact: Fritz French, President & CEO
Industry Segment: Biotechnology
Business: Diabetes therapeutics
Founded: January 2006
Founders: Richard DiMarchi, PhD, CSO; Kent Hawryluk, VP, Business Development; Gus Watanabe, MD
Employees: 10
Financing to Date: $15 million
Investors: 5AM Ventures; Frazier Healthcare Ventures
Board of Directors: John D. Diekman, PhD (5AM Ventures); Richard DiMarchi; Fritz French; Patrick Heron (Frazier Healthcare Ventures); Randall Whitcomb, MD (Arete Therapeutics); William Ringo (formerly Pfizer)
Scientific Advisory Board: John Amatruda, MD (formerly Merck); Per-Olof Berggren, MD, PhD (Karolinska Institute); Alan Cherrington, PhD (Vanderbilt University); Phil Cryer, MD (Washington University); Suad Efendic, MD (Karolinska Institute); Matthias Tschöp, MD (University of Cincinnati); Randall Whitcomb
From the early years of the biotechnology industry well on into the 1990s, scientists working within companies tended to be rather reductionist in their thinking. There were good reasons for that. Novel drugs based on single genes, single proteins or even specific subunits of receptors could be more readily explained to anyone from investors to regulators, clinicians and patients. These days, researchers and regulators alike acknowledge that very few diseases are monogenic and that most human disorders involve several mechanisms or pathways.
The shift in thinking has paved the way for "polypharmacy," treating patients with multiple agents to address different aspects of a disease state. The contemporary view of disease not only considers its components or features but also how these evolve over time. As scientists learn more about where they can intervene in the disease process at a molecular level, clinicians are likewise increasingly considering where a patient is in terms of disease progression. All are aiming for sooner than later. Instead of seeking specificity, as they did 10 or 15 years ago, nowadays drugmakers strive to create compounds that can simultaneously influence more than one disease mechanism. A case in point is Crestor (rosuvastatin), developed to lower both cholesterol and triglycerides and so treat both high cholesterol and atherosclerosis.
Like cardiovascular disease before it, diabetes is becoming a condition where clinicians monitor and strive to treat multiple aspects of the disease – ideally with as few medications as possible. The drug-development efforts of Marcadia Biotech Inc. are right in line with the trends. The company is seeking to develop "dual agonists" that will essentially mimic two molecules that naturally occur in the body. If the research pans out in the way management hopes, Marcadia will develop drugs that not only lower blood glucose levels but also lessen obesity, a common and dangerous co-morbid condition of diabetes. The start-up based in Carmel, IN, counts among its key staffers highly experienced scientists and executives from nearby Eli Lilly & Co. and Guidant Corp.
Marcadia licensed exclusive rights for its first dual agonist to Merck & Co. Inc. in March 2008, [See Deal] but no financial details were disclosed about the profit-and-loss sharing deal. The start-up's executives credit the arrangement with supplementing their $15 million Series A financing, [See Deal] and say it is a key factor enabling Marcadia to pursue independent projects – including development of a second dual agonist. The arrangement with Merck centers on a compound that will agonize simultaneously two peptide hormones now known to be involved in glucose metabolism: glucagon and glucagon-like peptide-1 (GLP-1).
"Our work with Merck offers the potential for weight reduction in severely obese people," says Richard DiMarchi, Marcadia's CSO as well as a professor and former chemistry chairman at Indiana University. DiMarchi held senior management positions at Lilly over many years, including bearing global responsibility for biotechnology and running the endocrine group, which under his leadership developed drugs including the fast-acting insulin Humalog, and osteoporosis treatments Forteo (teriparatide) and Evista (raloxifene).
The dual agonist Marcadia is now developing on its own, MAR701, targets GLP-1 and gastric inhibitory peptide (GIP). In healthy individuals, levels of both hormones rise following a meal. GLP-1 has been recognized for at least 15 years as helping to lower blood glucose levels by stimulating release of insulin from the pancreas. Early efforts to develop a drug based on that hormone did not go smoothly, however, and so the first agonist of it only came to market in May 2005, marketed by Amylin Pharmaceuticals Inc. as Byetta (exenatide). Byetta is based on a compound discovered in the saliva of the Gila monster, which helps the giant lizard metabolize infrequent but huge meals. Competing molecules have since followed into that class of drugs, and their clinical success is encouraging other companies to consider how they, too, can leverage the knowledge that GLP-1 is a valid drug target.
MAR701 is intended to be a once-weekly injectable product "with all the advantages of the GLP-1 class and additional benefits associated with GIP," says Fritz French, Marcadia's CEO. Like Byetta and other GLP-1 agonists, as well as the potential drug candidate Marcadia has promised to Merck, MAR701 is intended to lower blood glucose and also lower body weight. Phase I clinical testing of MAR701 began in December 2009, "just 11 months after it was selected as a development candidate," French notes.
Although it is now accepted that agonists of GLP-1 can benefit diabetes patients, it took a while for scientists to figure out how best to pharmacologically leverage insights into the peptide's involvement in glucose metabolism. The same can be said of other peptide hormones developed as diabetes treatments, such as amylin. It is a case study of a natural molecule that was recognized as having clinical potential long before scientists figured out how to make the synthetic form now marketed as Symlin (pramlintide).
Researchers investigating GIP have likewise struggled to translate scientific insights about the molecule into a potential treatment for diabetes. Bickering about whether patients would benefit from compounds that mimic the molecule or inhibit it went on for years, and of course that is a fundamental question. The confusion stemmed in part, DiMarchi explains, "from use of a reagent reported to be an antagonist that we can not confirm in our work." Also, he says, a rodent bred to lack the gene for the GIP receptor stirred debate when scientists observed that "the animal does not gain weight even when fed a high-fat diet." Together those factors led some researchers to surmise that an antagonist, or inhibitor, would help lower glucose and body weight. DiMarchi says he is glad Marcadia decided to create a dual agonist of GIP and GLP-1: "Pharmacology models and an additional genetic model are revealing that we made the right choice."
Marcadia's confidence in its decision to agonize GIP got a boost at the end of February 2010, with the first published reports of a transgenic pig with a dominant negative mutation for the GIP receptor. DiMarchi explains, "In that animal model, the receptor for the hormone does not function in the pancreas and the pathobiology is very similar to the human disease. The animal displays compromised glucose tolerance, leading to what we believe will eventually be overt hyperglycemia."
Like drug developers in certain other competitive markets, such as oncology and rheumatology, Marcadia's managers know they must develop a medication that will complement existing treatments doctors consider essential for patient care. In diabetes, Glucophage (metformin) has top status because it remains the only drug definitively shown to prevent the cardiovascular complications of diabetes. The fact that metformin is available as a generic, and is widely perceived as safe, helps assure that any drug candidate will have to be tested in combination with that medication.
Marcadia is clearly already contemplating product-positioning strategy for MAR701, as DiMarchi proclaims that "Byetta and Victoza [liraglutide] are based on some impressive biology, but they fall short in the magnitude of body weight reduction and full glucose normalization. Gastrointestinal discomfort is also not uncommon." He says the side effects of current GLP-1 agonists are severe enough that "one in every three or four patients experiences significant discomfort, and some just cannot tolerate them. So our hope is to come up with a drug that is far less offensive and more effective at lowering HbA1c and body weight."
Marcadia has a third research program, aimed at developing a glucagon analog the company envisions as a replacement for the recombinant products marketed by Lilly and Novo Nordisk SA. French says that the molecule is in development and has been designed to be stable in solution so that it can be developed for delivery via a single-use pen-type injector. Marcadia would like to see this marketed as part of an emergency kit for diabetics, to treat hypoglycemia in much the same way that people allergic to bee stings are advised to carry epinephrine pens. Though neither DiMarchi nor French mention the connection, Lilly has a history of taking market share from competitors by packaging products to enhance patient convenience.
Like many start-ups of late, Marcadia maintains no laboratory space of its own and instead relies on collaborations and senior managers' existing relationships. Some 70 to 80 (as yet unpublished) animal studies of MAR701 were carried out in collaboration with Professor Matthias Tschöp at the University of Cincinnati's Obesity Research Center, French notes. And the company enjoys "a productive relationship" with DiMarchi's lab at Indiana University, where half of the nearly two dozen scientists are supported by the company. "Merck is not historically strong in this area of peptide drug development but the people at Marcadia and DiMarchi's lab are," French says. He emphasizes that Marcadia is "fully vested in wanting to see Merck and the glucagon co-agonists succeed; it was the first of what we've discovered and has a unique pharmacological profile ideally suited for enhancing glucose control and body weight reduction."
Merck could yet turn out to be the partner Marcadia intends to seek for Phase III development and marketing of MAR701. "We have the money and the team to take it through Phase II," French asserts, "but then we'll have to partner because the clinical trials necessary to reach immense markets like diabetes and obesity will be extremely expensive – into the hundreds of millions of dollars to develop a drug for either indication." The costs Marcadia could have anticipated when it was founded in 2006 jumped up in March 2008, when the US Food and Drug Administration announced that it would henceforth expect a minimum of two years data on cardiovascular effects of any potential treatment for type 2 diabetes. In place of taking a Big Pharma partner, Marcadia would also consider other creative approaches to accelerating development such as a merger or acquisition: whatever makes the most sense for shareholders, employees, and, ultimately, advancing the technology to help patients.
Marcadia's Series A financing of $15 million was co-led by 5AM Ventures and Frazier Healthcare Ventures. Founding investor Twilight Ventures also participated. [See Deal] – Deborah Erickson