Charting the future of IBD treatment: From immune modulators to microRNA therapies

Inflammatory bowel disease (IBD) refers to a spectrum of chronic bowel inflammatory conditions, primarily ulcerative colitis (UC) and Crohn’s disease (CD). These autoimmune mucosa-damaging conditions cause pain, bloating, indigestion, and acute abdominal emergencies, severely reducing the quality of life in the long term.

Newer therapies have emerged based on a better understanding of the pathophysiology of IBD. A recent paper in eGastroenterology discusses current and future aims and methods for treating IBD.

Study: Horizon scanning: new and future therapies in the management of inflammatory bowel disease. Imsge Credit: Jo Panuwat D / Shutterstock.com Study: Horizon scanning: new and future therapies in the management of inflammatory bowel disease. Imsge Credit: Jo Panuwat D / Shutterstock.com

Treatment options for IBD

Drugs that manipulate or antagonize the immune response form the primary approach to the treatment of IBD. These include immunomodulators, as well as biologics, most commonly those targeting the anti-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).

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 (SC),  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 CD. Risankizumab is associated with good remission induction in phase III trials. Other cytokine inhibitors include mirikizumab and guselkumab.

JAK inhibitors

JAK inhibitors are oral agents that block the intracellular signaling JAK-STAT pathway, which regulates pro-inflammatory target genes but is contraindicated in pregnancy. The UC-approved tofacitinib, a JAK1-JAK3 inhibitor, may trigger severe infection and thrombotic complications at higher doses. Filgotinib and Upadacitinib are currently being investigated in phase II/III trials.

S1P receptor modulators

S1P is a lipid molecule that triggers S1P1 - S1P5 receptors to regulate lymphocyte migration from the primary lymphoid organs into the bloodstream. S1PRM 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 UC and is currently being evaluated in phase III trials for CD. Etrasimod is another promising oral drug that has completed phase III trials.

PDE inhibitors

PDE inhibitors reduce the transcription of pro-inflammatory cytokines like TNF-α and IL-23 while upregulating immunomodulatory cytokines like IL-10. These are in a very early stage of development.

MicroRNA-124 (miR-124) upregulators

MicroRNAs (miRs) are oligonucleotides that control multiple genes to regulate inflammation, often through the STAT pathway. UC patients 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 CD patients.

What are the conclusions?

Several small-molecule drugs are being used or repurposed for IBD therapy; however, real-world safety and efficacy data are still needed. These treatments are less immunogenic than biologicals, can be used orally, and are associated with better patient and healthcare provider satisfaction.

Compliance issues, the need for more robust data, and adverse event risks, including teratogenicity, are important challenges associated with IBD therapies.

It is now important to understand and develop a precision medicine strategy which factors in medical history, predictors of response, preference of administration, future family planning and disease characteristics.”

Journal reference:
  • Kumar, A. & Smith, P. J. (2023). Horizon scanning: new and future therapies in the management of inflammatory bowel disease. BMJ Journals: eGastroenterology. doi:10.1136/egastro-2023-100012.
Dr. Liji Thomas

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Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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