At ACG this year I presented a “Product Theater” for an industry partner focusing on early (earlier) treatment of Crohn’s disease. The discussion focused on the Love-CD trial comparing earlier versus later treatment of moderate-to-severe Crohn’s disease. In this study, early was defined as less than two years of disease duration compared to patients with a greater than two-year duration. Moderate-to-severe disease was defined as CDAI 220–450 with presence of ulceration at baseline (SES ~9.5 in early versus ~13 for late patients). Early Crohn’s disease patients were previously treated with corticosteroids and/or immunomodulators only, whereas patients with late Crohn’s disease had prior exposure to corticosteroids, immunomodulators, and anti-TNF therapy. The primary endpoint was deep remission (CDAI <150 and SES-CD <4) at both weeks 26 and 52 and, as one would anticipate, early patients had a 33% benefit compared with late patients.
My discussion points focused on the, now, well-recognized benefit of early treatment of Crohn’s disease to prevent disease progression of transmural disease as well as how we should be diagnosing moderate-to-severe disease based on the PROFILE study. In PROFILE, patients were randomized to top-down versus step-up therapy with infliximab in patients with newly diagnosed Crohn’s disease (within six months, [HBI>7], either serum CRP above the upper limit of normal, fecal calprotectin >200 μg/g or both, and SES-CD ≥4 for ileal-only disease or ≥6 for ileocolonic/colonic disease). In PROFILE, the median time from diagnosis to treatment initiation was 12 days. At the end of 48 weeks, top-down patients achieved steroid and surgery free remissions (HBI <5, CRP<ULN, and calprotectin <200 mcg/g) in 80% of patients versus 15% in the step-up group and endoscopic remissions (SES-CD without ulcers) in 67% versus 44% of patients.
Although PROFILE was open-label, no other clinical trial has demonstrated clinical and endoscopic results comparable to the earliest treatment possible. In contrast, in most clinical trials of advanced therapies (biologics or small molecules) the average disease duration has been ~seven to eight years for bio-naïve patients and ~10 to 12 years for bio-exposed patients.
Hence, by changing one variable, disease duration, we can nearly double clinical and endoscopic outcomes: all in favor of as early as possible intervention in patients presenting with Crohn’s disease with risk factors for progression to hospitalization or surgery. The risk factors for disease progression are primarily biologic (disease extent, EIMs, evidence of transmural disease [strictures, fistula], high inflammatory burden, and visible ulcers at endoscopy) that can all be confirmed at diagnosis. In these patients, ACG, AGA, and ECCO guidances all recommend a top-down versus step-up approach. Yet, phase 3 trials based on (historical) regulatory guidance, have required entry criteria of >3 months after diagnosis with inadequate response to prior “conventional therapy” (aminosalicylates, steroids, immunomodulators).
The practical outcome in the U.S. has been third-party payers necessitating “treatment failure” prior to approving effective therapies such as biologics and small molecules that have demonstrated steroid-sparing effects. It is obvious to experienced IBD clinicians that these requisites for approval are reducing the long-term benefits of early intervention and lead to limited responses and loss of response due to transmural progression during conventional treatments.
How do we move forward? Firstly, pharma has not been innovative with regards to early intervention. The well-tread path has been to enroll patients with inadequate responses to conventional therapy (delaying effective interventions) rather than newly diagnosed patients with evidence of moderate-severe risks of progressing based on clinical and biologic criteria (evidence of active inflammation, e.g., elevated CRP or Calprotectin, endoscopic ulcers, EIMs, metabolic complications such as anemia or low albumin, etc.).
The PROFILE entry criteria provide a working basis for clinicians and pharma to approach regulatory agencies for clinical trial approvals as early as diagnostic criteria allow. Looking to the future, as we begin to clarify prediagnostic criteria that predict the development of Crohn’s disease, where disease interception becomes possible, we cannot remain complacent regarding delaying effective interventions to maintain the health and well-being of our patients with Crohn’s disease until curative strategies are developed.
The author has received consulting fees from Abbvie, Celltrion, Johnson & Johnson, Lilly, and Takeda. He has also received payment for lectures including service on speakers bureaus from Abbvie, Lilly, Johnson & Johnson, and Takeda.
