About drug options for IBD
Inflammatory bowel disease (IBD) refers to some chronic inflammatory conditions, mainly primarily Crohn’s disease (CD) and ulcerative colitis (UC). These autoimmune conditions against gut mucosa cause pain, bloating, indigestion and even bleeding with acute abdominal emergencies, severely impairing the quality of life in the long term. Initially, when the underlying autoimmune nature is not known, pharmacological therapy consists of anti-inflammatories directly on the intestinal mucosa, such as sulfasalazine (poi substituted by mesalazine) and corticosteroids, which associate the anti-inflammatory effect apart from that immunosoppressor. Once deciphered the autoimmune component of IBD, drugs that manipulate or antagonize the immune response have become the primary approach to the treatment of IBD.
These include immunomodulators, as well as biologics, most commonly those targeting the tumor necrosis factor alpha (TNF-α), as well as monoclonal antibodies (mAbs) like anti-integrins. People with IBD often fail all available drugs initially or following a relapse, with less than 60% response rates in clinical trials. However, many new IBD drugs are under development or have been approved that elicit promising responses in moderate-to-severe IBD after treatment failures with several other drugs. Newer IBD drugs may be classified as anti-TNFα agents, anti-adhesion agents, cytokine inhibitors, Janus kinase inhibitors (JAKI), phosphodiesterase inhibitors (PDEI), sphingosine-1 phosphate receptor modulators (S1PRM), and micro-ribonucleic acid (RNA)-124 upregulators (miR-124U).
JAK inhibitors
JAK inhibitors are oral agents that block the intracellular signaling JAK-STAT pathway, which regulates pro-inflammatory target genes. Most cytokines, indeed, employ the JAK-STAT signaling platform to regulate (enhance) inflammatory reactions. They are generally effective, but they are contraindicated in some settelemtens, like pregnancy. Tofacitinib, a JAK1-JAK3 inhibitor approved for UC, may trigger severe infection and thrombotic complications at higher doses. The reasons for the lack of efficacy in Crohn’s disease as opposed to ulcerative colitis may be multiple and explained by different disease characteristics, its cellular biology, patient characteristics (high steroid intake) and trial design (e.g. no central endoscopic reading). Derivatives like Filgotinib and Upadacitinib are currently being investigated in phase II/III trials.
S1P receptor modulators
Sphingsine-a-phosphate (S1P) is a lipid molecule derived from ceramide, that triggers S1P1 – S1P5 receptors to regulate lymphocyte migration from the primary lymphoid organs into the bloodstream. S1PRMs (e.g. fingolimod) blocks this signaling pathway, thereby causing S1P to break down. In addition to reducing inflammation, these agents may also lead to lymphopenia and cardiovascular events, thus necessitating rigorous patient selection. Ozanimod is an oral drug used for the treatment of moderate-to-severe ulcerative colitis and is currently being evaluated in phase III trials for CD.
Etrasimod is another promising oral drug that has completed phase III trials. In the earlier phase II dose-ranging OASIS study, patients with moderate-to-severe ulcerative colitis were given etrasimod 1 mg QD, etrasimod 2 mg QD or placebo. A dose-dependent significant response was observed in the primary (change from baseline in three components of the Mayo Clinic score) and secondary endpoints (endoscopic improvement, clinical response and clinical remission).
Phosphodiesterase (PDE) inhibitors
PDE inhibitors reduce the transcription of pro-inflammatory cytokines like TNF-α and IL-23 while upregulating immunomodulatory cytokines like IL-10. There are several forms of PDE, from 1 to 14 known in humans, They have pretty good specificity of subtrates and roles, though some redundancy ha been met. They regulate cyclic nucleotides (second messengers) metabolism and several of them have also a very specific tissue distribution. These are in a very early stage of development. One of them preconized for clinical application is Apremilast, a PDE4 inhibitor. It enhances cyclic AMP cellular production, which in immune cells is associated with attenuated inflammatory reponses.
Anti-TNFα agents
Anti-TNFα agents are the first line of therapy for both UC and CD and include infliximab, adalimumab, and golimumab, as well as newer drugs. Infliximab is preferred for perianal fistulating CD. The biosimilar to infliximab, CT-P13, may be administered subcutaneously, whereas infliximab requires intravenous (IV) administration. About 8% of CT-P13 users developed infliximab antibodies. Newer oral (PO) agents can treat the diseased gut directly, thereby reducing systemic exposure, which is associated with the risk of opportunistic infection, reactivation of tuberculosis, and cancer. These include AVX-470 and AVX-470m, which are bovine colostrum-derived drugs that act like infliximab. OPRX-106 (rTNFR-Fc) is a plant cell that expresses a recombinant TNF fusion protein that is protected against stomach acid by cellulose. PRA023, which is currently being investigated in phase III trials, is an upstream regulator that antagonizes TNF-like cytokine 1A (TL1A) prior to TNF generation.
Anti-adhesion agents
Anti-adhesion agents are mAbs targeting the leukocyte surface adhesion molecule α4β7 integrin. This integrin acts with mucosal addressin-cell adhesion molecule 1 (MAdCAM-1) on the intestinal blood vessels to trigger lymphocyte migration into the gut. Anti-adhesion agents include SC vedolizumab, which produced remission in 50% of treated IBD patients, as well as etrolizumab, which has produced mixed results. Ontamalimab is associated with selective high-affinity binding to MAdCAM-1 and has shown early promise in phase 2 trials.
Cytokine inhibitors
These agents inhibit pro-inflammatory cytokines like interleukins (ILs), especially IL-12 and IL-23. Ustekinumab is the first anti-IL drug to be developed or approved for IBD and blocks both IL-12 and IL-23 through their p40 subunit. Other cytokine inhibitors are being developed, including an oral capsule that will deliver the ustekinumab biosimilar RT-111 selectively to the gut wall with SC-like bioavailability. The proposed RaniPill could be extended to all parenterally administered drugs. Risankizumab is an IL-23 inhibitor newly approved in the United States and United Kingdom for moderate-to-severe Crohn. Risankizumab is associated with good remission induction in phase III trials. Other cytokine inhibitors include mirikizumab and guselkumab.
MicroRNA-124 (miR-124) upregulators
MicroRNAs (miRs) are oligonucleotides that control multiple genes to regulate inflammation, often through the STAT pathway. Patients with ulcerative colitis often exhibit deficient miR-124. Obefazimad is an miR-124 upregulator currently being evaluated in phase III trials.
The future
A combination of infliximab with azathioprine was found to be more effective than monotherapy, as it improves infliximab bioavailability and reduces infliximab antibody formation. Concomitant immunosuppressive therapy enhances remission rates at all drug concentrations, even with drug antibodies present. Currently, combinations of biologicals and small molecules are being explored, especially for high-risk IBD patients, those with poor response, or those who have other immunologic inflammatory diseases.
Biologicals like vedolizumab, ustekinumab, and an anti-TNF agent are combined, or alternatively, small molecules with tofacitinib and vedolizumab/ustekinumab. There is little data on the safety and tolerability of these regimens, as these drug combinations may trigger severe infection and other unknown long-term complications. Fecal microbial transplant (FMT) is also used by some in IBD but should be restricted to clinical research, with little evidence to support its utility.
Early trials have presented candidates like the IL-22 blocker UTTR1147A, which strengthens the intestinal barrier and enhances healing without systemic inflammation. Likewise, cobitolimod, a Toll-like receptor 9 (TLR-9) activator with an anti-inflammatory effect, has been formulated as a topical enema. SER-287 also replenishes gut levels of the beneficial bacterial genus Firmicutes. Stem cells can regenerate and repair damaged mucosa and may maintain remission. However, this treatment approach can cause severe immunosuppression, leading to death or graft rejection in Crohn patients.
Undoubtely, there are many opions to be evaluated; the feeling is not every one of them may appliable to the same category of patients.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Kumar A, Smith PJ. eGastroenterology 2023; in press.
Bonelli M et al. Ann Rheum Dis. 2023 Nov 3:ard-2023-223850.
Chu X et al. BMC Gastroenterol. 2023 Oct 6; 23(1):346.
Yewale RV et al. JGH Open. 2023 Aug 10; 7(9):599-609.
Di Petrillo A et al. Inflamm Bowel Dis. 2023 Aug 5:izad161.