Article reprint from Start-Up - March 31, 2009
Catena Pharmaceuticals is seeking anti-angiogenic GPCR-antagonist compounds, and has a license to one that targets a subset of GPCRs specific for lysophosphatidic acid (LPA). LPA is one of a family of fatty molecules called lysophospholipids that is generating increasing interest among scientists for their role in cell proliferation and inflammation. The company says its small molecules have shown early promise in a number of indications, from oncology to fibrosis and neuropathic pain. Catena will concentrate initially on developing antagonists to LPA receptors for the treatment of solid tumors.
A decade ago, few scientists studying cellular structures and mechanisms paid any attention to the fatty molecules known as lysophospholipids (LPLs). With no known function, the lipids were assumed to have none, and accepted simply as being present in cells—much as the long stretches of DNA between recognized genes are usually dismissed as "junk" DNA. The past few years, however, have seen this scientific backwater become an epicenter of exploration, as researchers have woken up to the fact that the fatty blobs they used to ignore actually do have compelling functions, including as mediators of inflammation, cell migration, and cell proliferation.
A pair of chemists from the University of Virginia (UVA) can be credited as kicking off the craze for LPLs. Timothy Macdonald, PhD, and Kevin Lynch, PhD, shared the first research grant from the National Institutes of Health to investigate the molecules, and their research proved fruitful. The duo studied similar members of the LPL family, including lysophosphatidic acid (LPA) and sphingosine-1-phosphase (S1P), and created agonists and antagonists of LPL receptors through traditional medicinal chemistry and structure-activity studies. Lynch and Macdonald's work led Novartis AG to collaborate with them on a molecule suspected to operate through LPL biology. The compound, known as FTY-720 or Fingolimod, was shown through that collaboration to affect S1P signaling, causing lymphocytes to get stuck in lymph nodes—thereby limiting the inflammation these white cells would cause if they were circulating freely. Fingolimod has since advanced through Phase III clinical trials for multiple sclerosis, and results of the trial are expected later this year.
Most Big Pharmas now have research programs on S1P—and the interest in it could soon extend to LPA, which appears to be involved with angiogenesis, the formation of new blood vessels. So says Ian Mehr, PhD, the president of Catena Pharmaceuticals Inc. and its sole employee at present. Mehr is also the managing director of Golden Pine Ventures, a seed-stage investment fund based in North Carolina. In May 2008, Golden Pine backed the start-up along with Drs. Lynch and Macdonald. Catena has also received financial support from the North Carolina Biotechnology Center.
Catena is intent on commercializing small molecules, created by Lynch and Macdonald, that will act as antagonists to a subset of receptors for LPA. The chemists, who remain tenured professors at UVA, also licensed to Catena patents covering LPA receptor agonists and LPA synthesis enzyme inhibitors. Mehr says Catena's small molecules have shown an array of effects in animal models that make them promising candidates to treat a number of indications, from oncology, to fibrosis, to neuropathic pain.
The tiny start-up will concentrate initially on developing antagonists to receptors for LPA, as a treatment for solid tumors. The receptors belong to the pharmaceutically rich class of proteins known as G-protein coupled receptors (GPCRs). At least 30 % of drugs now in development target this class of proteins—and that kinship is another factor that Catena believes bodes well for its aspirations. "We're coming at a validated target class, to a different disease path," Mehr declares. Still, he says Catena is more interested in LPA biology than in particular receptors. In addition to researching inhibitors of specific GPCRs for LPA [formerly known as EDG receptors], Mehr says Catena is also investigating the medical relevance of "overall effects of LPA."
Speaking of LPA in the singular may give the impression that it is a discrete entity, Mehr acknowledges, but he emphasizes that such acids are comprise chains of carbon molecules—Catena means "chain" in Latin—and that different bonding between these carbons creates essentially a "family" of LPA molecules. Scientists don't yet know how to leverage this insight for pharmacological benefit, he says, "but different saturation levels may have different effects" and Catena will "try to parse them down."
The company's research is as yet restricted to animals only, and is entirely out-sourced, but Mehr expects the firm will start IND-enabling studies of its lead compound, VPC51299, by the end of 2009. "Ovarian cancer might be the best indication," Mehr muses, noting that LPA has been broadly implicated as a primary factor in that disease. In fact, the activity behind ovarian cancer activating factor (OCAF), a pro-growth cancer signal, has been identified to be predominantly from LPA. Furthermore, the LPA synthesis enzyme, Autotoxin, is a recognized oncogene. Because of the many links of LPA to ovarian cancer, Mehr and his colleagues at Catena suspect their LPA-blocking compounds have significant promise.
A self-professed proponent of systems biology, and therefore someone who believes that genetics and biology are intimately linked, Mehr notes that "knock-down" animal models that eliminate signaling of the LPA receptor offer "some tantalizing data that suggest if you can pharmacologically block LPA, you can ameliorate problems."
It's not just Catena's own research results that Mehr finds encouraging. The explosion of interest in LPL signaling in the past few years is generating more knowledge about mechanisms and structures related to LPA, and Mehr figures the credibility will rub off on Catena's efforts. "We're attacking angiogenesis, a proven anti-cancer approach, using the novel mechanism of lysophospholipid biology, through GPCRs, a target class that everyone considers validated."
Catena is seeking $5 million in Series A funding.
—Deborah Erickson
This article is reprinted from Start-Up – March 31, 2009. Click here to start your 30-day, risk-free trial of Start-Up
