IBD Biomarker Unknowns Complicate Treatment

Ingrid Hein

December 17, 2019

The lack of biomarkers for inflammatory bowel disease makes it impossible to predict patient response to TNF inhibitors, anti-adhesion molecules, anti-cytokines, and JAK inhibitors.

Nobody really knows how to prescribe "the right drug for the right person at the right time," said Stephen Hanauer, MD, from the Northwestern University Feinberg School of Medicine in Chicago.

"Personalized medicine in IBD is fake news," he said during his lecture last year at the Advances in Inflammatory Bowel Diseases (AIBD) meeting. And that's still true, he told Medscape Medical News.

"But I'm an optimist. Things are gradually evolving," said Hanauer, who presented a keynote address at this year's AIBD meeting in Orlando, Florida.

One of the greatest challenges in prioritizing treatment options for inflammatory bowel disease has been a lack of head-to-head studies comparing treatments, "but there are a number currently underway," he reported.

In fact, the first comparison of biologic agents for the treatment of ulcerative colitis — the VARSITY study — was published just a few months ago. In the phase 3b head-to-head study, clinical remission and endoscopic improvement were better with intravenous infusions of vedolizumab (Entyvio, Millennium Pharmaceuticals), an anti-adhesion agent, than with subcutaneous injections of adalimumab (Humira, AbbVie), a TNF inhibitor, in patients with moderate to severe active ulcerative colitis. However, there was no difference in steroid-free clinical remission between the two treatments.

VARSITY also showed that biologic-naïve patients who are treated early respond better to treatment. "Your first love is your best love. Make that first drug work best," Hanauer explained.

The important thing is getting treatment to patients early, he pointed out. We have been leaning heavily on the treat-to-target concept. "If you don't meet your target, you intensify treatment until you get there."

"Until the past decade, we've been treating according to symptoms. Now, we are going deeper," he said. "We've evolved to try to treat to endoscopic healing, which has reduced hospitalizations and surgery," he said.

"We are also seeing the first iterations of histologic healing," he added. "We know the deeper you go into reducing a remission, the better the patient prognosis.

But "we don't have a predictor to tell us who is going to respond better" to which drug, so targeting and monitoring are key, he said. Only 25% to 30% of patients are able to get off steroids.

Currently, there is no way to prioritize drugs for patients with moderate to severe inflammatory bowel disease, and the drug landscape continues to bring challenges.

No Way to Prioritize

Just 6 months ago, a boxed warning was added to tofacitinib (Xeljanz and Xeljanz XR, Pfizer) by the US Food and Drug Administration, advising that a higher dose —10 mg twice a day — increases the risk for pulmonary embolism and death in patients with ulcerative colitis, as reported by Medscape Medical News.

Specifically, "they changed the label for moderate to severe ulcerative colitis patients who had inadequate responses to TNF inhibitors," which doesn't make sense, said Hanauer.

Patients with an inadequate response to TNF inhibitors need a higher dose of tofacitinib to maintain remission, he explained, but "the FDA has restricted the drug for our patients least likely to respond and most likely to develop adverse events."

The advantage of tofacitinib is that it is a pill that can be started and stopped, unlike biologic agents — such as TNF inhibitors, vedolizumab, and ustekinumab — which are administered by parenteral infusion or injection.

But none of the drugs are associated with or indicated for any specific patient profile. When choosing a treatment, the clinician has to consider available information, disease profile, disease severity, lifestyle factors, and patient preference.

Some patients prefer infusion, others a pill, and still others an injection. "We sit with patients, we talk to them, we explain the pros and cons of different medicines," Hanauer said.

The choice for a patient "who has 20 bowel movements a day is different than for someone who can't get off prednisone and wants an alternative." Those are two ends of a spectrum, he pointed out, but the available options are the same.

And there's another confounder.

"Our shared decision-making is corrupted by third-party payer decisions," Hanauer said. At the end of the day, the high cost of biologics and JAK inhibitors means that authorization is needed for all medicines.

So after spending 45 minutes talking to a patient about the advantages of one drug or another, "the insurance companies decide," he said. "Third-party payers are getting rebates from the companies to lower their costs, so they are prioritizing drugs based on cost rather than doctor and patient choice."

But with the biosimilars emerging, this could change. The infliximab biosimilar CT-P13 was shown to be noninferior to the originator in patients with active Crohn's disease in a study published earlier this year.

And the biosimilar BI 695501 is as effective and safe as adalimumab in patients with moderate or severe active Crohn's disease, according to results from a phase 3 study presented by Hanauer at the AIBD meeting, as reported by Medscape Medical News.

There are a lot of different things driving inflammation of the bowel.

"We have a lot of difficulty determining who will respond to what drug," said Bruce Sands, MD, from the Icahn School of Medicine at Mount Sinai in New York City. "There is an element of trial and error; symptoms don't always match what's going on in the bowel."

One conjecture is that inflammatory bowel disease is actually a set of very heterogeneous conditions. "There are a lot of different things driving inflammation of the bowel, and we're not smart enough yet to know what's driving what in each individual," he told Medscape Medical News.

But finding a single biomarker will likely not solve the problem, he cautioned. "I think there will be a number of predictive biomarkers."

Until then, "a real-world evidence approach and network med analysis" is being used to compare different agents and get the most out of available drugs, Sands said.

"We are increasingly using the treat-to-target approach, incorporating not only symptomatic targets, but also objective targets," he said. "And we're getting treatment to patients earlier, which makes a difference, particularly in Crohn's disease."

Advances in Inflammatory Bowel Diseases (AIBD) 2019. Presented December 12, 2019.

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