By Allison Proffitt
July 13, 2015 | In January 2013, David de Graaf laid
out a new vision and direction for Selventa, the Cambridge-Massachusetts
biotech that started life as Genstruct. The company was working on a “systems
diagnostics” approach, a family of “SysDx” tests primarily for autoimmune
diseases. The first target? A decision-support tool to identify rheumatoid
arthritis (RA) patients that won’t respond to first-line therapy, anti-TNFs.
Earlier this month, the Selventa team published in BMC Medical Genomics the results of a
study showing that their tool—ClarifyRA—identified nearly a third of patients
who didn’t respond to anti-TNF treatment (doi: 10.1186/s12920-015-0100-6).
Identifying non-responders will let those patients move on to second or third
line therapies without a costly and painful trial and error period.
In rheumatoid arthritis, de Graaf says the major unmet
medical need is to identify when the standard of care will not work for a
particular patient. In RA, this saves time because there are other
alternatives. “Luckily there are a large number of therapies that are second
line that are—on average—as effective and as safe as first line therapies, as
anti-TNFs,” de Graaf says.
Training the Classifier
In the new paper, Selventa authors wrote: “We identified a
gene expression classifier to predict, pre-treatment, which RA patients are
unlikely to respond to the anti-TNF infliximab. The classifier was trained and
independently evaluated using four published whole blood gene expression data
sets.”
The study was a small meta-analysis—116 RA patients from four previous studies for whom the authors had
gene expression data and confirmation that they took infliximab, a common
first-line anti-TNF treatment. The patients’ response to infliximab was noted
at 12-14 months after treatment began, and prior gene expression data was used
to test the classifier to see if it predicted which patients would respond to
anti-TNFs and which wouldn’t.
The test identified nearly a third of non-responders. “Given
this classifier performance, treatment of predicted non-responders with
alternative biologics would decrease their chance of non-response by between a
third and a half, substantially improving their odds of effective treatment and
stemming further disease progression,” the authors said.
The technology underlying the ClarifyRA test is driven by
RNAseq or gene expression from whole blood. That wet lab science is then
plugged into Selventa’s proprietary analytical platform for interpreting
complex biology.
“The classifier consisted of 18 signaling mechanisms, which
together indicated that higher inflammatory signaling mediated by TNF and other
cytokines was present pre-treatment in the blood of patients who responded to
infliximab treatment,” the paper authors explained. “In contrast,
non-responders were classified by relatively higher levels of specific
metabolic activities in the blood prior to treatment.”
Settling on Systems Diagnostics
The findings are promising. Selventa’s next step is a
1,000-person study to validate its findings, and the company is engaged in two
ongoing partnerships to use the next generation of the ClarifyRA test to
profile patients in clinical trials.
It’s a marketing path forward for a company that has had a
quiet past two and a half years. The website lists only two press releases in
2014 and none this year. The company is "operating on its own steam," de Graaf says, citing partnerships with pharma as the source of the most recent funding. Moving forward, the company is, "looking at other sources of funding" for upcoming clinical trials. "We have access to capital; I don't know if we're going to use it."
De Graaf, who has been at the helm since 2010, says
the company had a “pivot” in 2013, and in the intervening years, the company’s
thinking has become, “far more mature.” Since then, Selventa has
done four projects specific to RA: four drugs and four different mechanisms of
action with four different partners. But the company also wants to reach
consumers directly. The published paper is the first step in dealing with
public data, de Graaf says.
“We’ve learned a ton and it’s been successful in many
ways—becoming a company that has pharma relationships and works with pharma
partners, but also brings out its own product was something that we didn’t know
was going to work. But now we see a path to that.”
After taking control of the company, de Graaf started
looking for a sustainable business and application for the company’s
12-year-old systems biology technology. He spent time finding the intersection
between the needs of the patients, their physicians, pharma companies and
payers—“the four Ps”.
De Graaf decided on chronic autoimmune diseases—starting
with rheumatoid arthritis—a market for which all four needs align, and one he
believes is ripe for the systems diagnostics approach.
Patients and their physicians want their disease to be
well-managed: patients are happier, more comfortable, he explains. Payers are
pleased because well-managed care costs much, much less; a patient with RA who
has achieved remission can cost $10,000-$12,000 less per year than a patient
whose disease is not controlled. Pharma wants the right patients identified for
their drugs, particularly for drugs that are currently considered second or
third line therapies.
De Graaf believes it’s the right market for a systems
diagnostic approach.
Systems diagnostics is the opposite of companion diagnostics,
he explains. While companion diagnostics find the right patient for a given
drug, in Selventa’s view, systems diagnostics seeks the right drug for a
specific patient.
The ClarifyRA test should help patients who are unlikely to
respond to first line therapies move more quickly to a second line therapy that
may help. It could be a very effective solution, de Graaf says, increasing the
rate of remission for RA in the United States from 35% to about 45%.
“But the goal ultimately is to give people a molecular
profile, molecular information on the basis of their disease, and then have
their physician decide the best course of treatment,” he explains.
It’s a goal not unlike Foundation Medicine’s model for
cancer testing, de Graaf acknowledges, though there are differences in
technology and area of focus. It’s a business model he feels could be
profitably applied to many areas. “There’s lots of room for other people to
move into this space,” he says. “I’d love to see someone, for example, focus on
pre-diabetics and diabetics.”
Looking Forward
For now, Selventa and de Graaf are perusing several
approaches: working closely with pharma, developing the commercial ClarifyRA
test, and working on companion diagnostics as well.
ClarifyRA is just the start. He says Selventa is actively
working on tests including ClarifyLupus, ClarifyMS, ClarifyIBD, and
more—“though I’m not telling you those are going to be the exact brand names!”
he jokes. “The concept here is to use Selventa’s technology to understand
exactly what’s going on at the molecular level—what’s making them sick—and then
pairing that with therapy.”
Tackling chronic autoimmune diseases will mean looking at
RNAseq and proteins, not just DNA. It also means developing tests that patients
would take regularly to monitor their disease over time. De Graaf’s goal is to
find markers that would signal a disease flare or episode before they start,
and then help patients medicate accordingly, precisely.
“We don’t think DNA is going to get you there,” he said. “DNA
is the book that was written at the beginning. You need to look at dynamic
outputs like RNA or protein in order to predict these types of things.”