From immunomodulatory drugs to microRNA therapy

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

Newer treatments have emerged based on a better understanding of the pathophysiology of IBD.recent papers electronic gastroenterology We discuss current and future goals and methods for treating IBD.

study: Horizon scanning: a new future therapy in the management of inflammatory bowel disease. Image credit: Jo Panuwat D / Shutterstock.com

Treatment options for IBD

Drugs that manipulate or antagonize immune responses represent a major approach to the treatment of IBD. These include immunomodulators and biologics, most commonly those targeting anti-tumor necrosis factor alpha (TNF-α), and monoclonal antibodies (mAbs) such as anti-integrins. Masu.

Patients with IBD often fail to respond to all available drugs, either initially or after relapse, with response rates of less than 60% in clinical trials. However, after treatment with several other drugs failed, a number of new IBD drugs are in development or approved that elicit promising responses for moderate to severe IBD.

New IBD drugs include anti-TNFα agents, anti-adhesion agents, cytokine inhibitors, Janus kinase inhibitors (JAKIs), phosphodiesterase inhibitors (PDEIs), sphingosine-1 phosphate receptor modulators (S1PRMs), and microribonucleic acid (RNA ) may be classified as )-124 upregulator (miR-124U).

Anti-TNFα agent

Anti-TNFα drugs are the first line of treatment for both UC and CD and include infliximab, adalimumab, golimumab, and newer agents. Infliximab is recommended for CD that forms perianal fistulas.

Infliximab biosimilar CT-P13 can be administered subcutaneously (SC), whereas infliximab requires intravenous (IV) administration. Approximately 8% of CT-P13 users developed infliximab antibodies.

New oral (PO) agents can directly treat the affected intestine, thereby reducing systemic exposures associated with opportunistic infections, tuberculosis reactivation, and cancer risk. These include AVX-470 and AVX-470m, drugs derived from bovine colostrum that act similarly to infliximab.

OPRX-106 (rTNFR-Fc) is a plant cell expressing a recombinant TNF fusion protein that is protected from stomach acid by cellulose. PRA023, currently being investigated in a phase III trial, is an upstream regulator that antagonizes TNF-like cytokine 1A (TL1A) prior to TNF production.

anti-adhesion agent

Antiadhesives are mAbs that target the leukocyte surface adhesion molecule α4β7 integrin. This integrin interacts with mucosal addressin cell adhesion molecule 1 (MAdCAM-1) on intestinal blood vessels to trigger lymphocyte migration into the intestine.

Antiadhesion agents include SC vedolizumab, which produced remission in 50% of treated IBD patients, and etrolizumab, which produced mixed results. Ontamalimab is associated with selective high-affinity binding to MAdCAM-1 and has shown early promise in phase 2 trials.

cytokine inhibitor

These drugs inhibit proinflammatory cytokines such as interleukins (ILs), particularly IL-12 and IL-23. Ustekinumab was the first anti-IL drug developed or approved for IBD, blocking both IL-12 and IL-23 via the p40 subunit.

Other cytokine inhibitors are also in development, including oral capsules that selectively deliver the ustekinumab biosimilar RT-111 to the intestinal wall with SC-like bioavailability. The proposed RaniPill has the potential to be extended to all parenterally administered drugs.

Risankizumab is a newly approved IL-23 inhibitor for moderate to severe CD in the US and UK. Risankizumab is associated with good remission induction in phase III trials. Other cytokine inhibitors include mirikizumab and guselkumab.

JAK inhibitor

JAK inhibitors are oral drugs that block the JAK-STAT pathway, an intracellular signaling pathway that controls pro-inflammatory target genes, but are contraindicated during pregnancy. UC-approved tofacitinib, a JAK1-JAK3 inhibitor, can cause serious infections and thrombotic complications at high doses. Filgotinib and upadacitinib are currently being investigated in Phase II/III trials.

S1P receptor modulator

S1P is a lipid molecule that causes S1P₁ -S1P_Five The receptor regulates the migration of lymphocytes from primary lymphoid organs into the bloodstream. S1PRM blocks this signaling pathway, thereby making S1P ineffective. In addition to reducing inflammation, these drugs can cause lymphopenia and cardiovascular events, necessitating rigorous patient selection.

Ozanimod is an oral drug used to treat moderate to severe UC and is currently being evaluated in a phase III trial for CD. Etrasimod is also a promising oral drug that has completed Phase III trials.

PDE inhibitor

PDE inhibitors reduce the transcription of proinflammatory cytokines, such as TNF-α and IL-23, and upregulate immunomodulatory cytokines, such as IL-10. These are in a very early stage of development.

MicroRNA-124 (miR-124) upregulator

MicroRNAs (miRs) are oligonucleotides that regulate multiple genes and regulate inflammation, often through the STAT pathway. UC patients often exhibit miR-124 deficiency. Obefazimad is a miR-124 upregulator currently being evaluated in Phase III trials.

future

The combination of infliximab and azathioprine was found to be more effective than monotherapy as it increased infliximab bioavailability and decreased infliximab antibody formation. Concomitant immunosuppressive therapy improves remission rates at all drug concentrations, even in the presence of drug antibodies.

Combinations of biologics and small molecules are currently being investigated, particularly for high-risk IBD patients, poor responders, or patients with other immunoinflammatory diseases. Combining biologics such as vedolizumab, ustekinumab, anti-TNF drugs, or small molecules with tofacitinib and vedolizumab/ustekinumab.

There is little data regarding the safety and tolerability of these regimens, as the combination of these drugs can cause severe infections and other unknown long-term complications.

Fecal microbial transplantation (FMT) has also been used in some cases of IBD, but there is little evidence to support its usefulness and it should be limited to clinical studies.

Early trials are presenting candidates such as the IL-22 blocker UTTR1147A, which strengthens the intestinal barrier and promotes healing without causing systemic inflammation. Similarly, cobitolimod, a Toll-like receptor 9 (TLR-9) activator with anti-inflammatory effects, is formulated as a topical enema. SER-287 also replenishes intestinal levels of beneficial bacterial genera Firmicutes.

Stem cells can regenerate and repair damaged mucosa and may maintain remission. However, this therapeutic approach can cause severe immunosuppression, leading to death or graft rejection in CD patients.

What is the conclusion?

Several small molecule drugs have been used or repurposed for IBD treatment. However, real-world safety and efficacy data are still needed. These treatments are less immunogenic than biologics, can be used orally, and improve patient and provider satisfaction.

Compliance issues, the need for more robust data, and the risk of adverse events, including teratogenicity, are important challenges associated with IBD treatment.

It is now important to understand and develop precision medicine strategies that take into account medical history, predictors of response, dosing preferences, future family planning, and disease characteristics.”