Luke Timmerman : Timmerman Report
Logic would say cancer drugs can’t work if something is keeping them out of the tumor. The latest startup from the Bob Langer/Polaris Partners factory floor just got $22 million to clear out some of the barriers around tumors, and make it easier for some of the exciting new immuno-oncology drugs to do what they do best.
Cambridge, Mass.-based Xtuit Pharmaceuticals, founded in 2011 by Polaris, is announcing today it has pulled in $22 million in Series A financing. NEA led the round, and was joined by Polaris, and new investors CTI Life Sciences, Arcus Ventures and Omega Funds. The scientific founders are Rakesh Jain of Massachusetts General Hospital, Robert Langer of MIT, and Ron Evans of the Salk Institute. Alan Crane of Polaris is the founding CEO.
The main idea at Xtuit is to get rid of some stubborn barriers in the microenvironment around tumors. The company’s experimental drugs are supposed to inhibit a single molecular target, a master regulator, that is thought to foster extracellular matrix structures that shield tumors, and activate pathways that suck the oxygen out of the environment, among other things. Xtuit says it has found a way to work on three mechanisms at once, by making the environment less hypoxic, blocking the abnormal accumulation of stiff matrix components like collagen and hyaluronan, and by interfering with cell signals that recruit more stromal cells to the tumor neighborhood. When those cells arrive, they create a multi-faceted hostile environment with inflammation, blood vessel compression, fluid pressure and mechanical stresses. By going after that action on the periphery, Xtuit holds out hope it can create more favorable conditions for chemotherapies, targeted drugs, and immunotherapies to do their thing and kill the tumor.
While it’s likely that Xtuit will have to test its drug candidates in combination with other cancer drugs to see efficacy, introducing multiple variables into its clinical pathway, that’s not the only potential application. The company has shown an effect in animal models with its compounds as single agents against fibrotic diseases like liver cirrhosis and non-alcoholic steatohepatitis (NASH).
“The excitement over this area has only been building in the scientific literature,” Langer said in an e-mail. “There has been an increasing appreciation of the critical mechanisms in cancer and fibrosis. A fundamental issue has been how to target the multiple disease processes related to the microenvironment. This is a challenge that has been solved by Xtuit’s very compelling therapeutics.”
Timing for the startup is about as good as it gets. Data from multiple presenters at the recent American Society of Clinical Oncology (ASCO) meeting hammered home the effectiveness of checkpoint inhibitor drugs that “release the brakes” on the immune system, especially by binding with PD-1/PD-LI or the CTLA-4 targets. Evidence is mounting that checkpoint inhibiting drugs work best when immune system T-cells can infiltrate the tumor. There are many reasons why a patient’s immune cells may not infiltrate, but one idea is that it can’t happen if the microenvironment is too hypoxic, or there are too many extracellular matrix obstacles. One specific idea is that a protein called semaphorin-4D (SEMA4D) helps form a defensive ring around many tumors. A few research groups, including a privately held company, Rochester, NY-based Vaccinex, have studied the role of that protein in enabling immune cells to get in the tumor. Every company working on checkpoint inhibitors is thinking hard about how to get them to better infiltrate tumors.
“It’s all about the tumor microenvioinrment now,” said David Miller, a portfolio manager at Seattle-based Alpine Bioventures who follows cancer stocks.
Also at this year’s ASCO, San Diego-based Halozyme Therapeutics presented clinical data that said its experimental drug that interferes with hyaluronan, a major component of the extracellular matrix, appeared to help patients with pancreatic cancer who have tumors with high levels of that substance in the microenvironment. Pancreatic cancer is a notoriously tough malignancy that often has significant microenvironment, or stromal, barriers around it. Biopsies of patients from a clinical trial showed that patients were alive without tumor progression for a median time of 9.2 months on the Halozyme drug and chemotherapy, compared with 4.3 months for those on the chemo alone, when high amounts of hyaluronan were observed in their tumor biopsies.
“The Halozyme approach works and that provides proof of concept for the general concept,” said Paul Rennert, a Boston-based consultant. Peter Blume-Jensen, Xtuit’s chief scientist, said the Halozyme data were important because it showed a significant clinical effect with a drug that interacts with just one part of the microenvironment that Xtuit has in its cross-hairs.
Many details on Xtuit’s approach are being kept hush-hush. The molecular target, the types of compounds in its pipeline, and its clinical trial timetable are all undisclosed. While it may not be relevant to the company, Jain, the scientific co-founder, described some of his research interest on his lab web page: “We recently proposed the novel hypothesis that the anomalous assembly of the collagen network can prevent the penetration of therapeutic agents in tumors, and showed that the hormone relaxin, bacterial collagenase and MMP1/8 can improve drug distribution by modifying this network.” Langer, of course, is well known for his interest in targeted drug delivery.
Scientists starting talking more excitedly in public about the microenvironment about four years ago, around the time of Xtuit’s founding, but the best way to go about attacking the wide array of microenvironment structures hasn’t been obvious. Data has continued to accumulate, however, that shows a correlation between stromal structures and hard-to-treat tumors like pancreatic or ovarian cancer. On the other end of the spectrum, testicular cancer is mostly curable, and one hypothesis is that may because is because of its relatively accessible microenvironment, Crane said. If Xtuit can modify the microenvironment safely and clear the way for other anti-tumor drugs in multiple solid tumors, to make them more accessible like that, the impact could be far-reaching. “This is potentially a new defining area for oncology,” Crane said.
Xtuit is still tiny with just six employees. Blume-Jensen, the former chief scientist at Metamark Genetics, joined the startup a year ago. With the new funding, the company will go to work on building a quantitative, tissue-based platform for evaluating biomarkers. The idea is to get tumor biopsies that can be assessed upfront to help select patients likely to respond in clinical trials.
One of the challenges will be dealing with the dynamic nature of tumors, and their bewildering heterogeneity. The differences in genetics from one part of the tumor to the next are thought to be one reason why chemotherapies and traditional targeted drugs sometimes appear to shrink tumors on classic RECIST criteria, but only provide a fleeting effect. While there are many potential reasons why that occurs, one possible explanation is that the microenvironment shields part of the tumor, helping it withstand the stress of a cytotoxic drug so it can spread later. So if Xtuit is right, and its drug can break down some of the tumor’s microenvironment defense mechanisms, then, theoretically, it should deliver longer-lasting responses.
Xtuit plans to move ahead with both its cancer and fibrosis programs in parallel. Crane wouldn’t say when he hopes to bring them to clinical trials. But if the cancer work stalls, Xtuit should still be able to continue to maintain investor interest. Non-alcoholic steatohepatitis (NASH), the fatty-liver condition, is another red-hot area in drug development (See this Timmerman Report story from March). Results from animal models have shown Xtuit can reverse fibrosis, which is more than most of the NASH drug candidates in the pipeline can say today. Crane added that the anti-fibrotic benefits came quickly, within weeks. “Absolutely spectacular,” Crane said of the results.