By Marie Powers, News Editor : BioWorld Today
Four years after its launch, Xtuit Pharmaceuticals Inc. came out of virtual mode with a $22 million series A that should suffice to advance its lead candidates in oncology and liver fibrosis through human proof-of-concept studies. The financing was led by New Enterprise Associates (NEA) and joined by founding investor Polaris Partners, which earlier provided $1.5 million in seed funding, and new investors CTI Life Sciences, Arcus Ventures and Omega Funds.
Xtuit, of Cambridge, Mass., is another start-up from the prolific Robert Langer, professor at the Massachusetts Institute of Technology, who serves as scientific founder along with Rakesh Jain, professor at Harvard Medical School and director of the Edwin L. Steele Laboratory for Tumor Biology at Massachusetts General Hospital, and Ronald Evans, professor and director of the Gene Expression Laboratory at the Salk Institute for Biological Studies. The trio led the work that underlies the company’s initial drug candidates and platform technology, which seeks to modulate the role of the microenvironment on disease progression and on drug and immune resistance.
Xtuit also has a biomarker platform that’s intended to accelerate its clinical programs, especially in oncology, according to Alan Crane, partner and entrepreneur at Polaris and a co-founder of Xtuit, where he is serving as CEO.
The syndicate came together fairly quickly with NEA in the lead and support from Polaris, which essentially reached out to some of its traditional venture partners, Crane said. In connection with the financing, David Mott, NEA general partner, will join Xtuit’s board.
One of the primary attractions was the pedigree of the scientific founders, who approached Polaris in 2011 with the idea of starting a company that would seek to tamp down the effect of the disease microenvironment, or stroma, in diseases marked by inflammation. Their goal was to develop drugs that would silence activated stromal cells, including cancer-associated fibroblasts and stellate cells, to improve the effectiveness of existing agents used to treat human disease.
“In cancer, we have very potent agents that almost universally will kill tumor cells in vitro,” Crane explained. “We also have very good success actually curing animals with xenografts.”
Those efforts don’t translate very well in developing therapies to treat people, however, and “it turns out the microenvironment is probably the major difference,” Crane told BioWorld Today.
For example, he pointed out, pancreatic cancer – one of the most intractable forms of the disease – is typically more than 80 percent stroma and less than 20 percent cancer cells. At the other end of the spectrum, testicular cancer typically contains virtually no stroma and has a curative rate of nearly 100 percent.
The difference is that the stroma exists in a pro-inflammatory state, forming a support matrix through the deposition of extracellular components, including collagen and hyaluronan, which are stabilized by matrix molecules. Stromal cells then expand and are reprogrammed to an active state, resulting in up-regulation of several key signaling pathways in the stroma.
In addition to contributing to disease progression, the stroma incites treatment resistance through three mechanisms, according to Crane, citing the formation of the matrix; the recruitment of fibroblasts, microphages, monocytes and other abnormal cells; and the creation of abnormal signaling.
“The solid pressure from the matrix and the added cells compresses blood vessels and causes hypoxia, which makes it difficult for immune cells to infiltrate tumors in an active form,” he explained, noting that discussions at the American Society of Clinical Oncology pointed to that problem as a major drawback in the development of checkpoint inhibitors.
The stroma is a bad actor in fibrotic disease, as well. “When we started working with the founders, we realized this could represent a breakthrough area for therapeutics,” Crane said.
FORGING A RAPID PATH TO HUMAN PROOF OF CONCEPT
Scientific exploration of the tumor microenvironment and pursuit of drugs at least indirectly targeting the stroma have quickened in recent years. In 2009, animal studies conducted by Ohio State University researchers that were published in Nature showed that the action of the tumor suppressor phosphatase and tensin homolog, or Pten, was important mainly because it affected not just tumor cells themselves but also the stromal cells that comprised the tumor microenvironment. (See BioWorld Today, Oct. 22, 2009.)
Three years ago, researchers at the University of California at Los Angeles reported in Proceedings of the National Academy of Sciences that uncontrolled cell growth can be instigated not just by cancer cells but also by changes in the stroma. (See BioWorld Today, Dec. 28, 2012.)
Technically speaking, vasculature-targeting drugs such as Avastin (bevacizumab, Roche AG) are stroma-targeting agents. In addition to big biotech and pharma, several smaller companies now are advancing candidates that directly target the tumor microenvironment. For example, Nektar Therapeutics Inc., of San Francisco, has a preclinical candidate, NKTR-214, targeting the IL-2 receptor complex that represents the first application of the company’s polymer conjugate technology platform to target a receptor subtype in the tumor microenvironment. L-DOS47 is an immunoconjugate-based drug candidate from Helix Biopharma Corp., of Aurora, Ontario, designed to modify the micro-environmental conditions of cancer cells to lead to their destruction. Some other companies in the space include Biothera Inc., of Eagan, Minn., Cytomx Therapeutics Inc., of South San Francisco, Noxxon Pharma AG, of Berlin, and Telormedix SA, of Bioggio, Switzerland. (See BioWorld Today, Oct. 17, 2013, and Dec. 3, 2013.)
In oncology, Xtuit is focused mainly on solid tumors, where its candidate could be broadly combined with other cancer agents, especially immunotherapeutics. The company has demonstrated preclinically that its cancer candidate, when combined with checkpoint inhibitors, dramatically increases their effectiveness, Crane said. The drug also enhances the activity of targeted cancer therapies and chemotherapies.
In fibrosis, the company is looking at single-agent activity, initially in liver cirrhosis and nonalcoholic steatohepatitis (NASH). In preclinical models, Xtuit’s candidate showed the ability to reverse severely damaged liver tissue to normal physiology “in a matter of a few weeks,” Crane said.
With such dramatic activity, the company expects to forge “a rapid path” to human proof-of-concept data, he added. Studies in liver cirrhosis and NASH could enroll a relatively small number of patients, Crane said, while the company plans to use biomarkers to help demonstrate the cancer molecule’s effectiveness.
Not surprisingly, Xtuit already has received overtures from potential partners, but “unless we see something extremely compelling” the company plans to move forward alone for now. With six employees and plans to hire aggressively this year in its biology, chemistry and clinical operations, “we’re charging ahead to realize the full opportunity of the products,” Crane said.