PredictImmune is a spin-off from the University of Cambridge, UK.
Diagnosing inflammatory bowel disease (IBD) is relatively straightforward. Through a combination of tests — blood tests, endoscopic procedures and imaging — a gastroenterologist can usually determine whether someone has Crohn’s disease or ulcerative colitis (the main forms of IBD), and rule out other possible causes of intestinal distress. Deciding what to do next, however, is not quite so clear-cut.
For people with full-blown IBD, physicians usually prefer an immediate and aggressive course of treatment, with highly effective, but potentially toxic, antibody drugs. People with less severe disease typically start with milder anti-inflammatory agents, which have fewer side effects and cost much less than biological therapies. If the gentler measures fail to control the condition, treatment can then escalate to corticosteroids, immunomodulators and eventually antibodies.
But working out how aggressive a person’s disease is, and therefore which approach is most appropriate, can be difficult. Currently, clinicians look at factors such as age, smoking history and broad molecular indicators of inflammation. “But we know that the clinical parameters perform really badly when it comes to predicting disease course,” says Tariq Ahmad, a gastroenterologist at the University of Exeter Medical School, UK, “and so we’ve been hunting for a biomarker.”
A genetic signature of immune dysfunction discovered by clinical immunologist Kenneth Smith and his colleagues at the University of Cambridge School of Clinical Medicine, UK, now offers just such a biomarker — one that the team has shown can accurately predict long-term disease outcome at the time of IBD diagnosis.
Smith’s team first characterized this gene-expression profile in 2011 in purified T cells, showing that it could divide people with the disease into two otherwise indistinguishable subgroups: people with chronically active gut inflammation, and people with more indolent disease1. “It was very clear immediately this would be useful to clinicians and patients,” Smith says. “There’s a real thirst for that kind of information.” But the cell-separation steps involved meant that the assay was “too hard and laborious to be scaled”, he says.
So, the Cambridge group spent several years adapting its technique to work on whole blood samples. Using machine learning, the researchers found a panel of 17 genes with expression patterns in the blood that closely mirrored the transcription signature previously identified in the purified T cells2. In people with aggressive disease, some of these genes are upregulated and some are downregulated (see ‘Gauging autoimmune severity’). The researchers further validated the blood test in cohorts of people with Crohn’s disease and ulcerative colitis.
That independent corroboration, says Smith, “gave us the confidence this really works: this test predicts outcomes”. What’s more, his team provided a biological rationale for the test’s diagnostic accuracy3. It showed that a state of immune dysfunction known as T-cell exhaustion, which is usually detrimental for people with chronic infections or cancer, can actually be a plus in autoimmune and inflammatory diseases.
A greater degree of exhaustion, Smith’s team found, correlates with lower risk of persistent, aggressive autoimmune disease. By scrutinizing genetic indicators of exhaustion, the test offered a window into the likelihood of IBD flare-ups — clinicians could then use this information to customize treatment plans.
With immunogeneticists Eoin McKinney and Paul Lyons, both at Cambridge, Smith formed PredictImmune. In April 2019, the firm began rolling out the blood test commercially to IBD specialists around the world.
Séverine Vermeire, a gastroenterologist at University Hospitals Leuven in Belgium, is an early adopter. She has tried the test, known as PredictSURE, with a handful of her patients, and says the results are often “striking”.
Last year, for example, Vermeire diagnosed a 23-year-old woman with ulcerative colitis just a month before she was scheduled to spend a semester studying in Canada. Vermeire ordered the PredictSURE test and, while waiting for the results to come back, started the woman on a standard anti-inflammatory treatment plan. She responded well to the therapy, so Vermeire gave her the green light to travel overseas.
It was only after the woman landed in Canada that the PredictSURE results came back. They indicated that she was in the high-risk group. “She never presented with a very aggressive disease,” Vermeire says. Based on her symptoms, “I would never have predicted” she was likely to experience severe, relapsing gut problems, she says. It took only a few months, however, for the biomarker test to be proved correct.
Debilitating flare-ups soon forced the woman to cut short her time abroad. She returned to Belgium to undergo treatment with infliximab, a potent antibody drug that costs more than €1,000 (US$1,100) per dose. She now receives infusions of the therapy every eight weeks, and her disease has stabilized.
“If I would have known the results of PredictSURE from the beginning, I would have done things differently,” says Vermeire, acknowledging that she would have monitored the woman more closely and considered earlier use of aggressive treatment.
Caren Heller, chief scientific officer at the Crohn’s and Colitis Foundation (CCF) in New York City, hopes that PredictImmune’s test can help to take much of the guesswork out of drug selection for people with IBD. PredictSURE, she says, “should help dramatically in the decision-making on who needs to be on what therapy”.
The test needs further validation, however, before it can be used routinely. In late 2019, the CCF teamed up with PredictImmune to launch a 200-person trial designed to confirm whether the test can accurately stratify people with IBD in the United States — the country’s demographics, lifestyle factors and health-care practices could affect the biomarker’s performance. “We’re excited about PredictSURE because it is based on 15 years of science and a biologic rationale that makes sense,” Heller says. “Nobody else is taking that rigorous approach” to biomarker development.
Smith, who is chief medical officer at PredictImmune, says that the same basic idea holds true for other autoimmune diseases, including lupus and vasculitis3,4. Blood tests for these conditions are in late-stage development at PredictImmune; a test for multiple sclerosis is not far behind. The genes profiled can differ from one disease-specific test to the next, “but the biological principles are the same”, says company chair Andrew Sandham.
Several pharmaceutical companies have expressed interest in using PredictSURE as a screening tool to find the people most likely to benefit from experimental biological therapies. With one of the world’s largest drug makers, PredictImmune is now performing retrospective data analyses to determine the test’s value as an enrolment aid.
PredictSURE doesn’t come cheap, however. And health-care providers might baulk at routinely paying £1,250 (US$1,570) per test for every person newly diagnosed with IBD. But, according to Smith, this up-front expense could reduce medical expenditures in the long run if it leads to more-effective treatment plans that reduce the incidence of complications such as hospitalization and surgery. “Our health economic prediction is this will save a lot of money,” he says.
The company is now conducting a large, randomized, prospective trial to confirm that the test improves, by facilitating personalized therapy, clinical outcomes for people with IBD. “We don’t know for certain without the gold-standard, randomized, biomarker-stratified trial,” says Ahmad.
Ahmad is one of around 50 investigators across the United Kingdom who, through this study5, is randomly assigning people newly diagnosed with Crohn’s disease to receive either aggressive or mild therapy. If, as suggested, the participants who do best on antibody drugs are those identified by PredictSURE as individuals likely to have aggressive, relapsing disease — but people predicted to have more indolent disease fare better on the gentler approach — Ahmad expects clinical uptake of the test to skyrocket. “If that is successful,” he says, “it will be a game changer.”