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Although biologics blocking tumor necrosis factor (TNF) have significantly advanced the treatment of inflammatory bowel disease (IBD), a significant number of patients are refractory to treatment.

Some 10% to 40% of Crohn's disease and ulcerative colitis (UC) patients are primary non-responders, and as many as 50% experience secondary loss of response after 12 months on therapy. In an from March, for example, 62% of Crohn's patients were responding inadequately to advanced therapy with TNF inhibition a year after starting treatment.

Outcomes like these have driven researchers to seek new therapeutic targets for durable treatment -- and ones that, unlike anti-TNF agents, do not raise the risk of some cancers by compromising immune status.

"There have been some very exciting developments," said Adeeti Chiplunker, MD, of Ohio State University Wexner Medical Center in Columbus, Ohio. "We've come a long way in the past decade in developing new treatments and refining the ones we have to be more precise."

Some new treatments are already approved, while others are queuing in the research pipeline, waiting to enter clinical trials.

In Clinical Use

This past May, the FDA approved the selective Janus kinase inhibitor upadacitinib (Rinvoq) for use in Crohn's patients who failed TNF inhibition. This small-molecule oral agent, which has a number of subtype receptors, has already been approved for the treatment of rheumatoid arthritis and psoriasis.

The approval emerged after one maintenance and two induction trials showed that a significantly higher proportion of patients who received 45 mg of oral upadacitinib once daily for 12 weeks experienced clinical remission and endoscopic response compared with those who received placebo.

Another recent arrival on the Crohn's landscape is risankizumab (Skyrizi), a monoclonal antibody that blocks the inflammatory pathway of interleukin (IL)-23. A cousin drug, ustekinumab (Stelara), has also proven effective in dermatology and blocks both IL-12 and IL-23. "In a recent head-to-head trial, results suggested risankizumab produced better endoscopic outcomes than ustekinumab," said Arun Swaminath, MD, of the Inflammatory Bowel Diseases Program at Lenox Hill Hospital in New York City.

The phase IIIb of Crohn's patients found that at week 24, clinical remission rates were 58.6% and 39.5% in the risankizumab and ustekinumab arms, respectively, and at week 48 the endoscopic remission rate was 31.8% in the risankizumab group and 16.2% in the ustekinumab arm. "Endoscopic remission is a very significant marker of disease status and treatment durability," Swaminath said.

For Chiplunker, this targeted anti-IL-23 agent, which homes in specifically on the p19 subunit of IL-23, has been a treatment breakthrough. "Targets are getting more refined. I had patients who were doing okay on ustekinumab, which targets both IL-12 and IL-23, but who are now doing great on risankizumab with just the IL-23 p19 target. Their bowel movements are under control and they look great on the scope."

A bonus, she added, "is that we have an option unlike anti-TNF immunosuppressants that doesn't increase the risk of melanoma in users."

Swaminath stressed that such new targets are especially important for those who have not responded to previous biologic therapy. "These patients tend to be more refractory, and another option may bypass that resistance hurdle and be effective even in patients who have failed older biologics."

In terms of delivery modes, the FDA a biologics license application for the subcutaneous administration of the integrin receptor antagonist vedolizumab (Entyvio) for maintenance therapy in adults with moderately to severely active Crohn's disease after induction therapy with intravenous vedolizumab, offering these patients the convenience of self-injecting it at home.

In addition, the FDA also the subcutaneous administration of an infliximab biosimilar (Zymfentra), for maintenance therapy in adults with moderately to severely active Crohn's and UC.

Another pharmaceutical newcomer under study for Crohn's disease is etrasimod (Velsipity). This is a selective sphingosine-1-phosphate (S1P) receptor modulator that demonstrated induction and maintenance efficacy in active UC, and was recently approved for that condition. The expectation is that its mechanism of action will also work for Crohn's.

"This agent has a novel mechanism of action that blocks the process by which lymphocytes leave their home in the lymph nodes and travel in the bloodstream to the gut to cause intestinal inflammation," explained Swaminath.

Researchers are also considering a potential role for stem therapy, he added. This modality has been approved for perianal fistulas in France and Japan, but is not likely to be approved here soon. "In a recent study by Takeda, this therapy failed to reach its primary endpoint, but there may be a future path forward for this approach," he noted.

Could genetic manipulation offer a cure for Crohn's? Chiplunker said she is doubtful. "Crohn's is too much of a multifactorial disease to be susceptible to gene management. And there are many environmental elements that we do not understand," she added.

As the range of treatment options expands, the abiding challenge for physicians is to find which therapeutic modality works best for which patient, said Swaminath, and to that end, gastroenterologists should take a page from the oncologists' handbook. "We need to get to the same level of individualized precision that's been achieved in cancer treatment. We also need to look at large patient populations to establish what will work for the greatest number and to identify what adverse effects may emerge."

Further Back in the Pipeline

Half of all Crohn's patients will develop disease complications, including fibrostenosis, in which the build-up of scar tissue obstructs the gastrointestinal tract. Fibrotic strictures are also a serious problem in UC, with an approximate 8% incidence over a patient's lifetime. Currently there is no clinical solution for treating fibrostenosis apart from surgical intervention.

"So we and others are investigating antifibrotic agents that could be developed for the treatment of fibrostenosis," said Andrés Hurtado-Lorenzo, PhD, senior vice president of translational research and IBD ventures at the Crohn's & Colitis Foundation in New York City. "We're also addressing unmet needs with innovative treatments that help biologic-refractory patients."

The two main therapeutic goals are the prevention of fibrosis and mucosal healing and the restoration of gut barrier integrity.

One approach under study is glutamate carboxypeptidase II (GCPII) inhibition. GCPII is an inflammatory protein that is upregulated in patients with more severe Crohn's and UC. Currently under investigation in animal models of colitis, the oral small-molecule GCPII inhibitor has been shown to improve the health of colonic tissue by reducing monocytic inflammation and protecting against gut barrier permeability. "The expectation is that (S)-IBD3540 could be effective in both Crohn's and UC," Hurtado-Lorenzo said.

Another potential molecular strategy is inhibition of plasminogen activator-1 (PAI-1), an inflammation- and fibrosis-associated protein that is upregulated in the intestines of biologic-refractory IBD patients exhibiting more severe disease. "Decreasing PAI-1 activity with small-molecule inhibitors may directly induce epithelial restitution, leading to mucosal healing and reduction of inflammation," Hurtado-Lorenzo explained.

Supplementation with the anti-inflammatory fatty-acid derivative resolvin E1 (RvE1) could be another option. This molecule is a lipid mediator of immune homeostasis, and supplementation with it can shift the inflamed mucosa toward immune homeostasis and promote intestinal barrier repair, noted Hurtado-Lorenzo. being developed to deliver RvE1 to the GI tract and may be ready for safety and tolerability trials in healthy subjects next year, he said.

Human monoclonal antibodies to TNF-like cytokine 1A (anti-TL1A), an upstream regulator of pro-inflammatory cytokines and profibrotic pathways, also appear to have the potential to reduce tissue fibrosis and disease severity in both Crohn's and UC.

In a small of refractory patients, for example, the anti-TL1A antibody PRA023 demonstrated proof of concept in refractory Crohn's disease, with 49% of patients on the medication entering remission versus 16% of placebo recipients. The patients in the study had Crohn's for 10 years on average and a history of intolerance or insufficient response to conventional or biologic therapies.

"Another anti-TL1A antibody under development for both types of IBD is , which has shown promise in a UC clinical trial," said Hurtado-Lorenzo.

He also highlighted a potential benefit from activation of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist. PPARγ is a nuclear receptor involved in regulating inflammatory and fibrotic pathways, whose agonists can inhibit the fibrosis regulator transforming growth factor-β. The is a partial selective agonist designed to bind to PPARγ. "It has an excellent safety profile and has limited systemic exposure, supporting its positioning for Crohn's disease," Hurtado-Lorenzo noted.

These and other new agents hold the promise of treating complications such as fibrostenosis and promoting endoscopic healing, with no detrimental impact on the immune system. They may also bypass the treatment resistance shown by biologic-refractory IBD patients.

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