With the advent of small-molecule drugs, treatment of inflammatory bowel disease (IBD) has reached a new stage. In contrast to biologics, small-molecule drugs can be made into oral dosage forms with a short half-life and are suitable for administration 1–2 times a day. Small-molecule drugs work by inhibiting the transmission of key intracellular signaling pathways in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD) [Figure 1]. They do not induce anti-drug antibodies in patients or lead to loss of response after treatment.

Figure 1:

Mechanisms of action of small-molecule drugs for inflammatory bowel disease. PED4: Phosphodiesterase 4; TGF-β1: Transforming growth factor-β1; S1P: Sphingosine-1-phosphate; SMAD: Mothers against decapentaplegic homolog 7; JAK: Janus kinase; TNF-α: Tumor necrosis factor α; STAT: Signal transducer and activator of transcription; NF-κB: Nuclear factor kappa B; MADCAM-1: Mucosal addressin cell adhesion molecule 1.

Janus kinase (JAK) inhibitors. The JAK protein family is a non-receptor protein tyrosine kinase family consisting of four proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2. In the context of IBD, JAK is an important intracellular signaling medium that transduces signals from cytokine receptors on the cell surface to the nucleus. Dysregulation of JAK can lead to the pathological process of IBD.

Tofacitinib: Tofacitinib is a rapidly acting, oral, small-molecule JAK inhibitor approved by the United States Food and Drug Administration (FDA) for induction and maintenance treatment of moderate to severe UC. The results of a phase III controlled trial of tofacitinib[1] showed that the tofacitinib group had a higher response rate than the placebo group in both OCTAVE Induction 1 and 2 trials. In both trials, treatment outcomes were similar in patients who had previously received tumor necrosis factor (TNF) antagonists and those who had not. In the OCTAVE Sustain trial, the tofacitinib group outperformed the placebo group. Tofacitinib had higher overall and severe infection rates than placebo in OCTAVE Induction 1 and 2 trials. In maintenance trials, the most frequently reported adverse events (excluding worsening UC) were nasopharyngitis, arthralgia, and headache.

Upadacitinib: Upadacitinib is an oral, selective, small-molecule inhibitor of JAK1 that is currently approved for the treatment of UC. A phase III clinical study evaluated the efficacy and safety of upadacitinib as a treatment for induction and maintenance of moderately to severely active UC.[2] The results showed that clinical remission was better in the three experimental groups (UC1, UC2, and UC3) compared with the control group. The most common adverse events in UC1 were nasopharyngitis, elevated creatine phosphokinase, and acne. In UC2, the most common adverse event was acne. In UC3, the most frequently reported adverse events were exacerbation of UC, nasopharyngitis, elevated creatine phosphokinase, joint pain, and upper respiratory infections.

In two phase III induction trials (U-EXCEL and U-EXCEED) of CD,[3] both clinical remission and endoscopic responses were significantly better in the upadacitinib 45-mg group compared with the placebo group at week 12. In the U-ENDURE trial, clinical remission and endoscopic responses to upadacitinib were better than placebo at week 52. Common adverse reactions were herpes zoster infections. In maintenance therapy, hepatic disorders and neutropenia were more common in the upadacitinib 30-mg group. In May 2023, the FDA approved upadacitinib for the treatment of CD indications.

Filgotinib: Filgotinib, an oral JAK1 inhibitor with a half-life of 6 hours, was recently approved for the treatment of UC in Europe. Phase II trial of CD has been completed.[4] By week 10, 47% of patients treated with filgotinib (200 mg/day) achieved clinical remission compared with 23% in the placebo group. At week 20, 50% of initial responders in the filgotinib 100-mg group and 71% in the filgotinib 200-mg group maintained clinical remission. A phase IIb/III clinical study (NCT02914522) evaluated the efficacy and safety of filgotinib in the treatment of moderate to severe UC.[5] Patients with UC were enrolled in two induction studies, divided into Study A (no biologics used) and Study B (biologics used), based on their prior biologics. The results showed that the filgotinib 200-mg group was superior to placebo in terms of endoscopic and histological responses at weeks 10 and 58. The rates of adverse events were similar among the three groups.

Sphingosine-1-phosphate (S1P) receptor modulators. S1P is an endogenous lysophospholipid molecule that is widely expressed on lymphatic endothelial cells in a variety of organs and tissues. S1P and its receptor S1PR1 can mediate T cell migration out of the thymus and peripheral lymphoid organs, and within non-lymphoid tissues. Small-molecule compounds that inhibit immune cell migration by modulating S1P/S1PR1 signaling have been used in a variety of autoimmune diseases and graft rejection.

Ozanimod: Ozanimod is a S1P receptor modulator that binds with high affinity to S1P subtypes 1 and 5 (S1P1 and S1P5), leading to internalization of S1P1 receptors in lymphocytes and the prevention of lymphocyte mobilization to inflammatory sites. The True North Clinical Trials (NCT02435992) evaluated the efficacy and safety of ozanimod in induction and maintenance treatment of severe active UC.[6] Patients with UC were divided into an oral ozanimod group (1 mg q.d.) and placebo group. A higher clinical response rate and endoscopic remission were observed in the oral ozanimod group; at week 52, the clinical response rate and endoscopic improvement were better than the placebo group. The incidence of infection (at any severity) for ozanimod was similar to placebo during induction and higher than placebo during maintenance. Less than 2% of patients in each group developed serious infections during the 52-week trial. Elevated liver transaminase levels were more common in patients treated with ozanimod. Bradycardia was more likely to occur in patients treated with ozanimod compared with placebo during induction but not maintenance. Ozanimod can cause anemia, nasopharyngitis, and liver insufficiency. Ozanimod was approved by the FDA for treatment of moderate to severe UC in May 2021.

Etrasimod: Etrasimod is an oral agonist of S1P1, S1P4, and S1P5 receptors that was recently approved for the treatment of moderate and severe UC. A phase III clinical trial of etrasimod for the treatment of patients with moderate and severe UC has been completed.[7] Etrasimod was effective and well tolerated during both induction and maintenance therapy. In the ELEVATE UC 52 study, proportions of patients in the etrasimod group who achieved clinical remission during induction (27% vs. 7%) and maintenance (32% vs. 7%) were significantly higher compared with the placebo group. In the ELEVATE UC 12 study, clinical remission in the etrasimod group (25%) was significantly better compared with the placebo group (15%) at the end of the 12-week induction period. Common adverse events were worsening of UC, anemia, and headache. Etrasimod was approved by the FDA for the treatment of moderate to severe UC in October 2023.

Phosphodiesterase-4 (PDE4) inhibitors. Phosphodiesterase is an enzyme that degrades second messengers such as cyclic phosphate adenosine (cAMP) and cyclic guanosine phosphate. Elevated intracellular cAMP levels generated by PDE4 inhibitors lead to downregulation of the inflammatory response by modulating expression of nuclear factor κB, TNF-α, interleukin (IL)-1β, IL-17, and other pro-inflammatory molecules released in the mucosa of patients with IBD.

Apremilast, also known as CC-10004 (CAS Registry Number 608141-41-9), is one of the most recently developed PDE4 inhibitors and can block cAMP degradation by binding to the catalytic site of PDE4. Patients in a phase II clinical trial of apremilast for active UC (NCT02289417) were divided into 30-mg, 40-mg, and placebo groups.[8] The results showed that clinical remission was not statistically significant compared with the placebo group at week 12, however, endoscopic remission was better in the 30-mg group compared with the placebo group. At week 52, clinical remission was 40.3% in the 30-mg group and 32.7% in the 40-mg group. The most common adverse events associated with apremilast were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis.

Mothers against decapentaplegic homolog 7 (SMAD7) inhibitors. SMAD7 is a cytoplasmic protein that inhibits transforming growth factor-β1 (TGF-β1). The anti-inflammatory activity of TGF-β1 is dependent on the phosphorylation of SMAD2 and SMAD3, which form trimer complexes with SMAD4 and are involved in regulating gene transcription in the nucleus. SMAD7 binds stably to type I receptors, preventing the phosphorylation of SMAD2 and SMAD3, resulting in TGF-β not exerting its anti-inflammatory properties.

Mongersen (GED-0301, Celgene) is an antisense oligonucleotide that can specifically bind SMAD7 mRNA, induce its degradation, and upregulate TGF-β1 signaling. A phase III clinical trial for CD showed no significant difference in clinical remission or endoscopic remission between mongersen and placebo groups at weeks 12 and 52; accordingly, mongersen did not show significant efficacy for the treatment of CD.[9]

Anti-integrins and anti-adhesion molecules. Integrins are cell surface glycoprotein receptors that interfere with leukocyte transport. They consist of a variety of α and β subunits that bind to tissue-specific cell adhesion molecules (CAMs). For example, α4β1 mediates lymphocyte migration in the gut and brain, while α4β7 promotes lymphocyte migration into the gut.

AJM300 is an oral formulation that inhibits the binding of lymphocyte integrins to endothelial CAMs involved in inflammatory responses. A completed phase III clinical study of AJM300 for moderately active UC showed that clinical response and endoscopic remission in the AJM300 group were significantly higher compared with the placebo group at week 8. At week 24, clinical response and endoscopic remission were also significantly better for induction.[10] There were no significant differences in the incidence of adverse events between the two groups or after repeated use of AJM300. The most common adverse event was nasopharyngitis.

Overall, the development of novel oral small-molecule drugs is promising, with available data showing good safety and efficacy, and patients with IBD benefiting from a wider selection of therapeutic agents. However, in the absence of head-to-head randomized controlled trials, positioning of oral small-molecule agents for the treatment of IBD is challenging.

1. Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2017;376:1723–1736. doi: 10.1056/NEJMoa1606910. 2. Danese S, Vermeire S, Zhou W, Pangan AL, Siffledeen J, Greenbloom S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet 2022;399:2113–2128. doi: 10.1016/S0140-6736(22)00581-5. 3. Loftus EV Jr, Panés J, Lacerda AP, Peyrin-Biroulet L, D’Haens G, Panaccione R, et al. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med 2023;388:1966–1980. doi: 10.1056/NEJMoa2212728. 4. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. Clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 2017;389:266–275. doi: 10.1016/S0140-6736(16)32537-5. 5. Feagan BG, Danese S, Loftus EV Jr, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet 2021;397:2372–2384. doi: 10.1016/S0140-6736(21)00666-8. 6. Sandborn WJ, Feagan BG, D’Haens G, Wolf DC, Jovanovic I, Hanauer SB, et al; True North Study Group. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2021;385:1280–1291. doi: 10.1056/NEJMoa2033617. 7. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet 2023;401:1159–1171. doi: 10.1016/S0140-6736(23)00061-2. 8. Danese S, Neurath MF, Kopoń A, Zakko SF, Simmons TC, Fogel R, et al. Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis. Clin Gastroenterol Hepatol 2020;18:2526–2534.e9. doi: 10.1016/j.cgh.2019.12.032. 9. Sands BE, Feagan BG, Sandborn WJ, Schreiber S, Peyrin-Biroulet L, Frédéric Colombel J, et al. Mongersen (GED-0301) for Active Crohn’s Disease: Results of a Phase 3 Study. Am J Gastroenterol 2020;115:738–745. doi: 10.14309/ajg.0000000000000493. 10. Matsuoka K, Watanabe M, Ohmori T, Nakajima K, Ishida T, Ishiguro Y, et al; AJM300 Study Group. AJM300 (carotegrast methyl), an oral antagonist of α4-integrin, as induction therapy for patients with moderately active ulcerative colitis: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Gastroenterol Hepatol 2022;7:648–657. doi: 10.1016/S2468-1253(22)00022-X.