Dunsire Joins XTuit to Fight Microenvironment

Deborah Dunsire could have done many different things after her stint at an Alzheimer’s startup wound down in May. The well-known biotech executive, through her network of scientists and investors, got to look at one exciting venture after another percolating in the Boston cluster.

By Luke Timmerman / March 8, 2017
Deborah Dunsire could have done many different things after her stint at an Alzheimer’s startup
wound down in May. The well-known biotech executive, through her network of scientists and
investors, got to look at one exciting venture after another percolating in the Boston cluster.

One idea stuck with her:

Is it now possible to attack fibrotic diseases, and certain cancers, not exactly by aiming at
diseased cells themselves, but rather by breaking down the protective shields in the
microenvironments around those diseased cells?
Deborah Dunsire, CEO, XTuit Pharmaceuticals

“I really examined the waterfront,” Dunsire said. “I wanted to be in Boston. I wanted to be at a
place to build a team, and to work with great people on great ideas. You can do that in a big
company. But this kept coming back to me.”

Waltham, Mass.-based XTuit Pharmaceuticals, a startup backed by NEA and Polaris Partners with a $22
million Series A in June 2015, is announcing today that Dunsire is joining as CEO and a member of
the board. Alan Crane, a serial entrepreneur at Polaris, is stepping aside to make room for the new
day-to-day leader. He will stay involved as chairman.

Dunsire is known across the industry for her prior work heading up North American oncology for
Novartis, and for leading Millennium Pharmaceuticals during its rise to prominence as a cancer
drugmaker with the multiple myeloma drug bortezomib (Velcade). She also happens to be an inspiring
figure to many women in the biotech industry, and today’s announcement is timed to coincide with
International Women’s Day.
XTuit, for those new to the story, brought together scientific founders Rakesh Jain of
Massachusetts General Hospital, Robert Langer of MIT, and Ron Evans of the Salk Institute.

Here’s how I described the science two years ago:
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.

Each scientific founder brings something specific to the table. As Langer put it, “The key points
are ways to regulate the micro environment so all kinds of drugs can get to the “entire” tissue or
tumor based on Rakesh’s work, much better and selective delivery (ours) and potential new drugs

XTuit has multiple programs progressing in the preclinical stage, in parallel, Dunsire said. It
will probably be 4-6 months before all the data are in before the company will set clinical
development priorities, she said. For fibrosis, the big indications on the drawing board are for
idiopathic pulmonary fibrosis, liver, kidney, and pancreas. She didn’t discuss specific molecular
targets, but did say the work remains focused on “master regulators” which establish diseased
microenvironments, so this isn’t simply a matter of busting up rugged stromal tissue. “By hitting
the master regulatory switches, you can normalize the entire process, and get the microenvironment
back into a state of quiescence,” Dunsire said.

Work on the tumor microenvironment has been filling up the scientific literature for several years,
particularly with efforts to coax tumors from a “cold” to a “hot” state in which they allow for
immune system cells to infiltrate tumors. XTuit remains excited about internal programs for cancer,
although the preclinical work is just a little behind the fibrosis work on schedules, she said.
Dunsire notes that XTuit has to be selective in its work on the tumor microenvironment. Some tumors
– pancreatic, bladder, ovarian, and endometrial to name a few – present the kinds of collagen and
hyaluronan that make for a particularly hostile microenvironment in need of breaking down. Halozyme
Therapeutics, for one, has validated the approach to an extent by generating some positive Phase II
data for a drug candidate against hyaluronan against certain types of pancreatic cancer patients.

Other tumor types, such as testicular, don’t present the same kind of challenge. This will require
some focus and discipline as XTuit moves to the clinic, presumably to avoid getting spread too
thin. The company is also working on developing biomarkers that can help it pick the ideal patients
most likely to benefit, to maximize its resources and increase its odds of success in the clinic.
“I’m not a fan of being a mile wide and an inch deep,” Dunsire said.

XTuit has only announced its $22 million Series A financing from June 2015, but it has been
efficient with its money and still has some runway left, Dunsire said. Another
financing is in process, she said.