A survey of Trialtrove Informa database (Pharma Intelligence) in April 2019 revealed 47 companies conducting studies with more than 70 investigational or approved drugs in the IBD therapeutic area, composed of 43 compounds for UC, 29 for CD, and 6 for both indications.1
During the 10-year period from 2010 to 2020, the number of clinical trials in the IBD therapeutic area almost doubled due to a combination of factors including continuous development of biologics, discovery of new pathways,
and consequently new classes of medications. This rapid increase was driven primarily by the development of new biologics, biosimilars, and various small molecule drugs such as JAK–STAT pathway inhibitors. According to ClinTrials.gov website, there were 331 recruiting interventional IBD clinical trials in October 2022, including 73 Phase 2 and 54 of Phase 3 studies.2
IBD (both UC and CD) is a chronic inflammatory condition that is currently incurable and requires lifelong therapy. Conventional therapy
methods, including 5-aminosalicylates, corticosteroids, thiopurines, anti-TNFs, and others, are generally effective in controlling symptoms and, to some extent, pathological changes. Adverse side effects such as immunosuppression, systemic fungal infections, and possible cancer development may have an overall negative impact on the disease outcome.For instance, all anti-TNF-α drugs in the US carry a boxed warning due to the increased risk of infections. Treatment failure is a significant issue of anti-TNF-α drug therapy in 25–30% of patients, with limited treatment options afterwards. Etrolizumab was a potentially promising drug that was thought to close this gap, but as of etrolizumab met its primary endpoint of inducing remission versus placebo for patients with UC, in only two out of five studies and failed to meet its primary endpoint versus placebo as maintenance therapy.3 Even considering that no unexpected safety signals have been revealed, the efficacy results are rather disappointing.
Currently, the drugs under investigation belong to four therapeutic classes with several mechanisms of action:
3. immunosuppressants (S1P receptor modulators)
4. antisense therapy (ICAM1 antagonists TLR9 agonists).
In such a competitive landscape with a growing number of compounds utilizing different mechanisms of action, it is critical to understand how a potential drug may fit the major unmet needs in IBD management.
Based on the literature analysis and feedback from clinical trial investigators (and indirectly from the patients), we can conclude that the primary unmet need in management of moderate to severe IBD is lack of oral drug formulations: patients would prefer an oral formulation
over the subcutaneous or intravenous administration. If the disease progresses further, requires hospitalization and IV corticosteroids, treatment options are limited with options of infliximab or cyclosporin, that in turn have significant side effects and they are at risk of toxic megacolon or bowel perforation with subsequent surgery. Prevention of this outcome is another focus of drug development – finding effective drugs for a late-stage disease.
The first oral drug for UC was tofacitinib, a small molecule directed against the JAK/STAT pathway, blocking the inflammatory cascade, which received the FDA approval for this
indication in 2018. The efficacy of tofacitinib for the treatment of moderately to severely active UC was demonstrated in three placebo-controlled clinical trials.
It was initially thought the incidence of tofacitinib-related adverse events (AEs) in a UC setting did not differ from that of patients with rheumatoid arthritis (the primary indication for this drug), and there were no particular safety concerns. However, after one year of use in UC patients, the FDA issued a black box warning for the 10-mg, twice-daily dosage of tofacitinib in patients with UC due to a potential for increased blood clots and death risks that were seen in a rheumatoid arthritis trial.4 Detailed results were recently announced from a pivotal, placebo-controlled Phase 3 trial evaluating oral Zeposia (ozanimod), an oral, sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. The purpose of the drug is to be used as an induction and maintenance therapy in adult patients with moderate to severe ulcerative colitis (UC) who did not adequately respond to prior treatment. The study demonstrated statistically significant and clinically meaningful results for clinical remission as compared to a placebo at induction and in maintenance. The overall safety observed was consistent with the known safety profile for Zeposia in patients with moderate to severe UC. 5
The first drug in this class, Gilenya (fingolimod), has been used in the treatment of multiple sclerosis, and recently raised some concerns due to first-dose bradycardia and atrioventricular block. However, fingolimod safety data cannot be directly extrapolated to ozanimod, as the adverse effects’ profile depends on the particular receptors targeted by the drug. S1P2 and S1P3 receptors are associated with cardiovascular, pulmonary, and theoretical cancer-related risks, and targeting S1P1 receptors proved to be beneficial for inflammatory conditions. Fingolimod is a non-selective S1P modulator targeting S1P1, S1P3, S1P4, and S1P5 receptors, leading to a wide range of adverse events. The current focus of drug development in this indication is on selective S1P modulators that predominantly or exclusively target S1P1 receptors. In addition to ozanimod, two S1P modulators with differing selectivity for S1P receptors are in clinical development for IBD: etrasimod and amiselimod. Recently published results of a Phase 2 placebo-controlled study of amiselimod at a dose of 0.4 mg for 12 weeks in moderately to severely active CD was not superior to placebo for the induction of clinical response. Treatment was generally well tolerated without new safety concerns.6 A Phase 2 study data on etrasimod, a selective S1P1, S1P4, and S1P5 receptor modulator, concluded that the dose of 2 mg was more effective than placebo for improving the modified Mayo Clinical Score at week 12 in patients with moderately to severely active UC. However, the study has limitations: this was an induction study with only 12 weeks in duration and 156 patients randomized, and the safety and efficacy of longer-term maintenance therapy was not investigated.7
Pilot results from the Phase 3 clinical study were announced in March 2022: etrasimod patients achieved statistically significant improvements in the primary endpoint of clinical remission at week 12 as compared with placebo. Statistically significant improvements were achieved in all key secondary endpoints in the trial as well. The safety profile was consistent with previous Phase 2 studies.8
Focus on JAK inhibitors for treatment of ulcerative colitis
Designing of clinical trials in accordance with drugs’ individual safety profiles (“one size does not fit all”)
Long-term follow-up for detection of delayed side effects
Development of therapy for non-responders to anti-TNF therapies
Revision of treatment goals in IBD clinical trials.