CALMing Insights That Make a SONIC Boom

Digestive Disease Week (DDW) 2017

Stephen B. Hanauer, MD


June 23, 2017

Symptoms or Biologic Targets?

Several presentations at this year's Digestive Disease Week have the potential to make an immediate impact on our practices.

When it comes to clinical endpoints, we have recognized for several years that symptoms do not correlate well with endoscopic or other "biologic" targets, such as C-reactive protein or fecal calprotectin. Symptom-directed therapies may improve an individual's quality of life, but they do not alter the disease progression or risk for hospitalization or surgery. Hence, several recent analyses, such as the cluster-randomized REACT (Randomised Evaluation of an Algorithm for Crohn's Treatment) trial, have evaluated patients treated for both symptomatic and biologic outcomes.[1]

In the phase 3 CALM trial[2]—a prospective, open-label, multicenter, active-controlled study—investigators assessed the benefit of treating to more stringent endpoints. They compared treatment with an 8-week "burst and taper" of prednisone according to symptoms alone (assessed by the Crohn's Disease Activity Index) with treatment to symptoms and a C-reactive protein level < 5 mg/L and a fecal calprotectin level < 250 µg/g.

The CALM investigators enrolled patients who were naive to immunosuppressive agents and biologics and were escalated to induction and maintenance with adalimumab, which could then be increased to weekly therapy with or without azathioprine according to the clinical or biomarker targets. The primary endpoint was a Crohn's Disease Endoscopic Index of Severity < 4 and absence of deep ulcers after 48 weeks at ileocolonoscopy.

Patients who were randomly assigned to the combined clinical and biomarker arm were more rapidly escalated to higher doses of anti-tumor necrosis factor therapy (or combination with azathioprine). Forty-five percent of patients were "stepped up" to combination therapy or weekly adalimumab, versus 14% of those in the conventional management group. At the 48-week endpoint, significantly more patients in the treat-to-target group (46% vs 30%; P = .01) met the primary endpoint and achieved steroid-free remission (60% vs 39%; P < .001), versus those in the conventional management group.

The authors concluded that the treat-to-target approach led to both superior endoscopic responses and deep remission outcomes compared with symptom-driven care.

Concentrated Efforts

Therapeutic drug concentrations, which have been demonstrated to correlate with clinical, biological, and endoscopic endpoints,[3] offer another type of target. We have learned across virtually all clinical trials with biologic agents that combining them with immunosuppressive agents decreases clearance of the biologic, increases biologic drug levels, and reduces antidrug antibodies to biologics. This is perhaps best demonstrated by the SONIC study, which compared treatment with infliximab alone, azathioprine alone, or a combination of the two in patients who were naive to prior therapy with biologics and immunosuppressive agents.[4]

In a post hoc analysis of the SONIC study, investigators asked whether the benefits of combination therapy were due to synergy between the separate agents' mechanisms of action or were primarily related to increased drug levels of infliximab.[5] Patients were divided into quartiles on the basis of their trough infliximab concentrations, with the proportion of patients achieving clinical or endoscopic outcomes in each quartile assessed.

As would be expected, the higher quartiles of infliximab concentrations comprised relatively more patients who received combination therapy with azathioprine. However, within each quartile, the proportions of patients achieving the clinical or endoscopic endpoints were similar, regardless of whether patients were receiving combination therapy.

The study was not "powered" to test these post hoc analyses, and there were some exceptions to the associations with quartile levels (eg, endoscopic outcomes were improved in patients in the lower quartiles of infliximab for patients on azathioprine with infliximab). Nevertheless, the study suggests that monotherapy with a biologic can be as effective as combination therapy if therapeutic drug concentration targets can be achieved and maintained. Alternatively, combining biologics with immunomodulators may also be more cost-effective than using higher doses of biologics, but requires appropriate monitoring of the separate agents' efficacy and potential risks.

As these two studies demonstrate, we continue to learn how to optimize and personalize care for patients with inflammatory bowel disease according to both clinical and biological endpoints, and the drug concentrations necessary to achieve the therapeutic goals.

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