Emerging therapies in IBD
Over the last decade-plus, the introduction of several key therapies has shaped the management of inflammatory bowel disease.
Drugs like Humira (adalimumab, AbbVie), Remicade (infliximab, Janssen) and Entyvio (vedolizumab, Takeda) have helped patients achieve meaningful endpoints of clinical remission and mucosal healing. They have also helped many patients avoid colectomy, an outcome once much more common before the expansion of the IBD medicine cabinet.
In a study presented at The American College of Gastroenterology Virtual Annual Scientific Meeting, Miguel Regueiro, MD, from Cleveland Clinic, and colleagues explored the trends of colectomy in biologic use in patients with ulcerative colitis from 2000 to 2019. Over that 20-year period, the prevalence of colectomy decreased from more than 10% to just over 2%. This decrease was associated with an increase in prevalence of biologic medicine, which started at just 0.5% in 2000 to more than 12% in 2019.
“This is the first study that’s really shown in a large scale that our biologic therapies are decreasing the need for surgery,” he told Healio Gastroenterology in an interview.
Despite the prevalence and efficacy of newer biologic therapies in IBD, there are still significant unmet needs.
There are three areas where biologic therapies leave clinicians wanting a little more: efficacy, precision and safety.
Edward V. Loftus Jr., MD, from the Mayo Clinic in Rochester, Minnesota, said the clinical trials of these drugs show a clear limitation of their efficacy.
“If you use the denominator of all the people who start the trial, at the end of the year only about 20% to 30% of patients meet the endpoint for clinical remission,” he told Healio. “Part of that may just be that IBD is a heterogeneous disease with multiple pathways of inflammation to get to the final, common manifestation, and it speaks to the lack of predictive biomarkers. We don’t know in advance which patient is going to respond to which therapy.”
This lack of precision can lead to issues, particularly if a patient received treatment with an anti-TNF agent first. Anita Afzali, MD, from The Ohio State University, said that the efficacy of other biologics can depend on a patient’s prior exposure to anti-TNF.
“Patients who are TNF-naive and start Entyvio or Stelara [ustekinumab, Janssen] do better compared with those who are TNF-exposed,” she said. “We need to determine which patients will respond to what as a first-line option so we can reduce the risk for them potentially not responding. It’s great to have this blossoming medicine cabinet, but how do we position it?”
Regueiro said decisions on first-line therapies often come down to what insurers will pay for, and clinicians’ hands are tied. That means the lack of precision can be costly.
“We can try a biologic, but we don’t know if that’s going to work,” he said. “We give it to a patient, and if it works, great. If it doesn’t, we switch to the next one.
“It would be great to pick a medicine from the start that had higher remission and response rates rather than kind of guessing and going through each option.”
In addition to these unmet needs of efficacy and precision, Loftus hopes that newer therapies can address concerns of safety — many current therapies carry black box warnings of serious infection and malignancies — as well as cost and access.
“Even in today’s world, there are still patients that run into difficulties saying that they can’t afford medications,” he said. “That’s a shame.”
Filgotinib, a selective JAK 1 inhibitor, is one of the promising new therapies currently in the pipeline for UC. It was the subject of the SELECTION study, a phase 2b/3 study, presented this year at UEG Week.
In the study, researchers assessed the efficacy and safety of the drug for induction of UC in two cohorts, patients who were biologic-naive but failed conventional therapy and patients who had failed prior biologics.
In the induction study, researchers randomly assigned patients to receive either 200 mg or 100 mg of the drug or placebo. The primary endpoint was endoscopic/rectal bleeding/stool frequency (EBS) remission at week 10, defined by a Mayo endoscopic subscore of no greater than 1, a decrease of at least 1 in stool frequency subscore from baseline and a stool frequency subscore no greater than 1.
In both the biologic-naive and biologic-exposed groups, a greater proportion of patients who received 200 mg of filgotinib achieved EBS remission. In the biologic-naive group, a greater proportion of patients also achieved key secondary endpoints of Mayo Clinic Score remission, endoscopic remission and Geboes histologic remission at week 10.
Researchers also conducted a double-blind study of filgotinib as maintenance therapy in patients who achieved clinical or Mayo Clinic Score response after 10 weeks of induction with either dosing level or placebo. The primary endpoint was EBS remission at week 58.
Investigators found that a greater proportion of patients in both dose groups achieved EBS remission compared with placebo.
Afzali said the results of the SELECTION study were fairly impressive, particularly when you consider what filgotinib offers as an orally delivered drug.
“When you take a step back and ask what our patients want — obviously, they want appropriate therapy that works,” she said. “But if you ask if they want an infusion or an oral drug, most would want an oral drug. It also has an early response and is durable. Our patients want that, so it adds a lot of appeal.”
Since filgotinib is a selective JAK1 inhibitor, Loftus said it could provide better efficacy than the currently available general JAK inhibitors without sacrificing safety. While Xeljanz (tofacitinib, Pfizer) had somewhat concerning safety signals during clinical trials, including for herpes zoster, filgotinib studies have shown less safety concerns.
“In filgotinib, there was less zoster, less than 2%,” Loftus said. “The other concern was venous thromboembolism. There were only two cases of that, and they were in placebo-treated patients. That’s reassuring to see.”
Zeposia (ozanimod, Bristol-Myers Squibb), like filgotinib, it is an orally delivered drug. Afzali said by modulating the sphingosine-1-phosphate receptor, the drug affects the way lymphocytes leave the lymph nodes and go to the periphery.
“This basically works at the position of adhesion or trafficking of inflammatory cells,” she said. “It prevents the exiting of lymphocytes that can go on a create more inflammation.”
In the TRUE NORTH study, also presented at UEG week this year, researchers explored the efficacy and safety of the drug for induction and maintenance of UC.
In the induction study, more than 18% of patients who received ozanimod achieved clinical remission at week 10 compared with just 6% of those who received placebo (P < .0001). The drug also helped patients achieve higher rates of clinical response, endoscopic improvement and mucosal healing.
In the maintenance study, ozanimod therapy resulted in a higher rate of clinical remission at week 52 (37% vs. 18.5%; P < .0001). The drug also met secondary endpoints of clinical response, endoscopic improvement, maintenance of remission, corticosteroid-free remission, mucosal healing and durable remission.
As an oral small molecule, ozanimod, like filgotinib, could see use as a first-line option. Although that is largely dependent on payer and insurance approval, they both have benefit over existing biologics.
“They’re easy to take, they don’t have immunogenicity like our monoclonal antibodies, and from what we can tell, the safety looks very good with both of them,” he said. “Other than insurance, there’s no reason to think that we would not look to move to first-line therapy with these agents. Time will tell, but based on the data we have so far, they’re really attractive as first-line therapies for patients with ulcerative colitis.”
Loftus sees these small molecules as sort of a bridge between conventional therapies and biologics.
“There’s a bit of a chasm,” he said. “You might be a patient with mild disease. Maybe you’re on 5-ASAs and the occasional steroid taper, and then all of a sudden, you’re on biologics. This would be a logical place to use some of these small molecules.”
Mirikizumab and Selective IL-23 Inhibitors
Another drug in the pipeline is mirikizumab (Lilly), which along with other drugs in its class, like Skyrizi (risankizumab, AbbVie) and Tremfya (guselkumab, Janssen), is a selective interleukin-23 inhibitor. Gastroenterologists already have an IL-12/23 inhibitor in their medicine cabinet in ustekinumab, but Afzali said these pipeline drugs are more targeted.
“These therapies work in the p19 subunit of therapies,” she said. “They’re very specific and are working on more of an upstream target where they can achieve really impressive clinical remission and response, as well as endoscopic improvement.”
In a recent study published in Clinical Gastroenterology and Hepatology, researchers assessed mirikizumab for extended induction in patients with UC. They enrolled patients who did not achieve clinical remission at week 12 of the initial randomized controlled trial to participate in an open-label extended induction period in which they received either 600 mg or 1,000 mg of the drug for an additional 12 weeks.
Among study participants who did not respond to the initial induction dosing of mirikizumab, 50% of those who received 600 mg and 43.8% who received 1,000 mg in the 12-week extension achieved a clinical response, whereas 15% and 9.4% achieved clinical remission, respectively. Among patients in the 600 mg group, 20% achieved endoscopic remission, while 15.6% of patients in the 1,000 mg group reached this endpoint.
Regueiro said mirikizumab and the other IL-23 inhibitors look appealing because they can be used at high doses and have good safety profiles. Because they are monoclonal antibodies, there is still a chance for immunogenicity, but Regueiro said so far, immunogenicity rates seem low.
“They will require an injection,” he said. “I’m not saying that’s a downside. Some patients actually like ustekinumab because they’ll have to do six injections a year and otherwise, they forget about it in between.”
Future of Development
As these drugs, and others, progress through development and trials, our experts said it is going to be critical to gather more information on how they compare with each other, as well as currently available therapies. Loftus said upcoming head-to-head trials and comparisons will inform clinicians and help them make decisions when it comes to positioning medications.
“There’s a series of head-to-head trials that are in development that will probably be read out in the next year or two,” he said. “The corollary to that is you’re going to see fewer placebo-controlled trials other than for registrational purposes.”
While comparison trials are underway to test available drugs like adalimumab and ustekinumab, Regueiro said head-to-head trials will provide important data on where to place newer drugs like the oral small molecules and IL-23 inhibitors. Although they provide easy delivery and dosing, a trial showing the efficacy of filgotinib or ozanimod over monoclonal antibodies would go a long way.
“If you found that there definitely was a significant improvement or trend toward the small molecules, the question is, would we leave the monoclonal antibodies behind,” Regueiro said. “I don’t think we’re there yet, but that would be a game changer if these head-to-head studies were to show that.”
As a principal investigator on many IBD trials, Afzali said it has been exciting to see in the development phases to see what works for patients. The potential of an expended medicine cabinet is particularly exiting for her.
“We’re going to have the data not just to prove that it’s effective, but also these new targets for working toward mucosal and histologic healing, as well as patient reported outcomes,” she said. “All together, we’re going to be able to position our therapies so that they provide better outcomes for our patients.”
- Danese S, et al. Abstract LB10. Presented at: UEG Week Virtual; Oct. 11-13, 2020.
- Feagan BG, et al. Abstract LB19. Presented at UEG Week Virtual; Oct. 11-13, 2020.
- Khoudari G, et al. Abstract P1478. Presented at: The American College of Gastroenterology Virtual Annual Scientific Meeting; Oct. 26-28, 2020.
- Peyrin-Biroulet L, et al. Abstract B20. Presented at UEG Week Virtual; Oct. 11-13, 2020.
- Sandborn WJ, et al. Abstract LB02. Presented at: UEG Week Virtual; Oct. 11-13, 2020.
- Sandborn WJ, et al. Clin Gastroenterol Hepatol. 2020;doi:10.1016/j.cgh.2020.09.028.