The medication landscape in IBD care: Personalizing patient care
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Inflammatory bowel disease is a debilitating condition that takes a lifetime of treatment to control. Over the years, medical therapies for the disease have evolved greatly, but the approval of anti-tumor necrosis factor alpha therapy for the treatment of Crohn’s disease in 1998 was a turning point in IBD treatment management.
Some of the common names in IBD treatment now, such as Humira (adalimumab, AbbVie) and Remicade (Infliximab, Janssen), are anti-TNF agents.
Since then, new advances have brought along more therapies with different mechanisms of action to add to the armamentarium, including Entyvio (vedolizumab, Takeda) and Stelara (ustekinumab, Janssen). One of most recent additions to the GI medicine cabinet was Xeljanz (tofacitinib, Pfizer), an oral Janus kinase (JAK) inhibitor. JAK inhibitors are changing the landscape of IBD care.
Healio talked with Anita Afzali, MD, of The Ohio State University, about anti-TNFs and JAK inhibitors and how they fit into the treatment of patients with IBD. She said there are several factors that help determine which treatment is right for each patient.
“There are certain therapies that may or may not work depending on the patient,” Afzali said. “It’s based on where their disease is, how severe it is and if they have any medical comorbidities. Cost and insurance factors must also be considered.”
Pros and cons
While there may be some situations where an anti-TNF is a better choice, Afzali said there are also certain patients who have a low albumin or a very high inflammatory burden who might benefit from the efficiency in absorption that comes with tofacitinib. Additionally, JAK inhibitors do not have the risk for immunogenicity or antibody development concerns that are also associated with anti-TNF.
Infliximab has a solid role as a rescue therapy in hospitalized patients who fail to respond to steroids, but current research is investigating whether tofacitinib may have a role as well, according to Afzali.
“We have good research and data that show that by day 3, you may start seeing improvement in symptoms of rectal bleeding and fecal urgency or diarrhea,” she said. “We might end up seeing tofacitinib have a role in lieu of steroids. This is all to be determined with more data and research. It’s hard to say exactly what the advantages are of one vs. the other when it comes to JAK and anti-TNF.”
The current literature places both drug classes around the same area in efficacy, however Afzali noted that it is important to recognize that these drugs have not been compared in head-to-head trials. Results from two induction studies (OCTAVE) have shown tofacitinib to have higher clinical responses (59.9% and 55%) compared with placebo (32.8% and 29%), which are comparable responses to the initial studies that explored anti-TNF drugs. Clinical remission rates are also similar between the drug classes, Afzali said. An important study endpoint, mucosal healing occurred in 31.3% and 28.4% of patients treated with tofacitinib induction groups vs. 15.6% and 11.6% of placebo groups.
“This treatment target is more specific” Afzali said.
Data on sustained mucosal healing among these patients occurred in 33.3% in the 5-mg tofacitinib group and 49.4% in the 10-mg group compared with 8.9% in the placebo group. Similarly, anti-TNF therapies are also more effective than placebo for induction of mucosal healing (45% vs. 30%) and sustained mucosal healing (33% vs. 18%, respectively) in ulcerative colitis.
Future research
Afzali said JAK inhibitors are uniquely positioned to line up with future treatment targets. For instance, tofacitinib works on a number of JAK pro-inflammatory pathways so future research efforts are exploring more selective JAK therapies.
“Tofacitinib is a general or non-selective JAK inhibitor, but what if we narrow it down?” she said. “What is the role of a selective JAK 1 inhibitor in IBD? Would that be more selective and possibly safer? So, it aligns pretty nicely with future therapies that are currently in clinical trials and development.”
Safety concerns
As with many therapies, these drugs come with safety concerns. A higher risk for herpes zoster is associated with the 10-mg twice daily induction dosage of tofacitinib as compared to 5-mg twice a day maintenance dose as well as anti-TNFs. Afzali said there are also concerns of venous thromboembolism or pulmonary emboli for tofacitinib, with a recent FDA warning based on the post marketing study of patients with rheumatoid arthritis (RA) aged older than 50 years who had failed methotrexate and on higher doses than approved for RA patients (10 mg twice a day) and with at least one cardiovascular risk factor. There was an increased safety signal with blood clots and mortality associated with this higher dosing among the RA treated patients.
“These risks have not been reported in the IBD or ulcerative colitis literature specifically,” she said. “This perhaps was seen among the rheumatology patients who were receiving doses higher than approved and who were also at baseline either on concomitant methotrexate or with at least one major cardiovascular risk factor. Our patients with active inflammation are at risk for venous thromboembolism even without exposure to tofacitinib. But still, we need to view risks of treatments and benefits of other options.”
Malignancy is also concern for these drugs. Patients on anti-TNF have a higher risk for melanomatous skin cancers and patients on tofacitinib have a higher risk for non-melanomatous skin cancers.
“Other malignancy risks are uncommon for both,” Afzali said. “There is a potential risk for lymphoma associated with TNF, that may be mostly driven by additional or prior exposure to thiopurines. The risk is still incredibly low.”
Treatment in pregnancy
Another challenge, according to Afzali, is that none of these therapies have been studied in pregnant women as clinical trials exclude pregnant patients. However, there are data for anti-TNFs based on registries and long-term, real-world studies, and these therapies are safe with pregnancy and do not increase risk for congenital malformations, and other birth outcomes risks are generally very low, Afzali said.
Among a very small sample size of women (n = 11) enrolled in UC interventional studies on tofacitinib and with maternal exposure either before or at the time of conception or during pregnancy, a healthy newborn was the most common outcome with no fetal deaths or congenital malformations reported.
“Until we develop a longer-term exposure, we won’t have enough data,” Afzali said. “Rheumatology patients taking tofacitinib are typically older patients, whereas IBD patients are more commonly of child-bearing age and typically become pregnant while taking IBD medications. As such, IBD patients will likely help provide more data over time on the safety of tofacitinib and pregnancy.”
References
- Cholapranee A, et al. Aliment Pharmacol Ther. 2017;doi:10.1111/apt.14030.
- Bressler B, et al. Abstract 40. Presented at: American College of Gastroenterology Annual Meeting; Oct. 25-30, 2019; San Antonio.
- Mahadevan U, et al. Inflamm Bowel Dis. 2018;doi:10.1093/ibd/izy160.
- Olivera P, et al. Gastroenterology. 2020;doi:10.1053/j.gastro.2020.01.001.
- Sandborn WJ, et al. Clin Gastroenterol Hepatol. 2018;doi:10.1016/j.cgh.2018.11.035.
- Sands BE. Abstract 416a. Presented at: Digestive Disease Week 2019. May 18-21; San Diego.
- Sands BE, et al. Abstract 833. Presented at: Digestive Disease Week; May 18-21, 2019; San Diego.
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