Addressing the “Therapeutic Ceiling” in Drug Discovery for Ulcerative Colitis

Reviewers addressed potential reasons for the shortcomings of newer therapies and proposed solutions to increase treatment efficacy in ulcerative colitis.

In a review article published by the Lancet Gastroenterology and Hepatology, authors addressed the low remission rates of patients with ulcerative colitis (UC) in drug induction trials. Novel therapeutics for UC appear to have reached an efficacy “ceiling”, with just 20-30% of study cohorts achieving remission. In their review, investigators address potential reasons for the shortcomings of newer therapies and propose solutions to increase treatment efficacy in UC.

Since 2000, 3 new classes of biologics have been developed and approved for the treatment of moderate to severe ulcerative colitis: anti-tumor necrosis factor alpha (anti-TNFα) therapies, anti-integrins, and inhibitors of interleukin 12 (IL-12) and IL-23. Additionally, Janus kinase inhibitors represent the first biologic targeting small molecules in UC.

However, despite this “wealth of treatment options”, authors write, treatment success rates in UC remain suboptimal, at just 20-30% across trials. Moreover, many practitioners report struggling to select the most appropriate therapy from the broad spectrum of potential options. Authors describe these combined phenomena as a “therapeutic ceiling”: while myriad new treatment options are assessed in clinical trials, none appear to increase overall remission rates.  The potential reasons for the “ceiling” are manifold, write investigators, and include the complex pathogenesis of the disease.

Many trials enroll both patients with refractory UC and patients with newly diagnosed UC. Remission in the latter category is typically much higher with novel therapies compared with the former category. To increase success rates in clinical trials, investigators recommended limiting enrollment to drug-naïve patients. Patients with refractory UC can instead be targeted for surgical intervention or other therapies with a “multi-omics approach”, rather than monotherapy with drugs.

Similar to the newly diagnosed vs refractory diagnostic categories, investigators hypothesize that patients have “differ[ing]…molecular drivers” of UC pathogenesis. This difference likely leads to “non-responsiveness to drugs that target molecules that are not pathologically involved” in certain patient subgroups. As such, future clinical trials should investigate the predictive utility of molecular biomarkers for treatment response. Additionally, head-to-head trials comparing the relative efficacies of drugs for patients with different molecular profiles are essential to enriching the landscape of UC therapies.

Beyond the molecular and clinical aspects of UC treatment, authors also addressed obstacles in trial design. The use of the Mayo Endoscopic Subscore to assess treatment response is insufficient. Instead, a scoring system that considers both the extent and severity of inflammation may better identify patients experiencing improvements with treatment. Further, current clinical trials of UC are complex, with stringent enrollment requirements and long follow-up periods.

Authors suggested the use of more flexible trial designs to increase study output. For example, dose-finding analyses can be used to administer the optimal dose to each patient, shortening the follow-up period and decreasing time to clinical response. Finally, an algorithmic approach incorporating data from prior trials can be used to “rank” drugs by their proposed efficacy in patient subgroups defined by biomarkers, disease severity, and disease duration.

While the landscape of treatment options for UC has expanded considerably in recent years, the “therapeutic ceiling” remains a major obstacle. “To address [the ceiling],” investigators concluded, “efforts should simultaneously be devoted to three major areas: [1] to move to adaptive trial designs for new agents targeting the appropriate patients depending on the mode of action of that agent … [2] to formulate clear treatment algorithms at the population level and incorporate predictive markers to tailor these drugs to the individual patient; and [3] to start using state-of-the-art analytical … techniques to classify patients in molecularly defined, biomarker-positive subgroups that can be given highly specific drugs targeting the molecular hubs controlling the underlying disease network.”

Disclosure: Several study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Alsoud D, Verstockt B, Fiocchi C, Vermeire S. Breaking the therapeutic ceiling in drug development in ulcerative colitis. Lancet Gastroenterol Hepatol. Published online May 18, 2021. doi: 10.1016/S2468-1253(21)00065-0