Introduction
Crohn disease is a chronic disease of the small bowel characterized as transmural inflammation of the GI mucosa, especially in the terminal ileum.1 Etiology is unknown but can include a combination of infections, genes, and immunology. The first incidence of Crohn can occur in adults in their 20s or 30s and the second peak incidence between their 60s and 80s.1 Smoking can increase the incidence of Crohn, and NSAIDs can trigger flares. Clinically, Crohn disease presents as diarrhea, abdominal pain, malaise, hematochezia, malnutrition, and/or perianal lesions.1
According to Mayo Clinic, more than 500,000 Americans live with Crohn disease. There is currently no cure, but there are therapies that can alleviate symptoms and long-term complications.2 These current therapies are injectable and may not be best option for patients with needle phobia. On May 18, 2023, the FDA approved upadacitinib (Rinvoq), the first oral pill treatment, for moderate to severe Crohn disease.3,4 Of note, Rinvoq has prior FDA-approved indications such as rheumatoid arthritis and atopic dermatitis.
Mechanism of Action
Rinvoq is a reversible Janus kinase (JAK) inhibitor. Janus kinases are intracellular enzymes that transmit signals from cytokines and growth factor receptors to influence cellular processes of hematopoiesis and immune cell function. According to the package insert, Rinvoq modulates the signaling pathway of JAKs and prevents the phosphorylation and activation of transcription. Rinvoq essentially helps block the signals that cause inflammation.
Clinical Trials U-EXCEL, U-EXCEED, U-ENDURE
The safety and efficacy of Rinvoq were evaluated in two multicenter, randomized, placebo-controlled, double-blind induction trials: U-EXCEL and U-EXCEED.5 Participants in U-EXCEL had experienced failure of conventional or biological therapies, and participants in U-EXCEED had experienced failure of biological therapies. U-EXCEL was conducted from December 2017 to January 2022, and U-EXCEED was conducted from November 2017 to August 2021 at 277 sites. Eligible participants were adults 18–75 years of age who had experienced moderate to severe Crohn disease for at least 3 months and for whom at least one biological therapy had failed. The primary end point was clinical remission and endoscopic response.5 Endoscopic response was defined as a greater than 50% decrease from baseline in the Endoscopic Score for Crohn’s Disease, where scores range from 0 to 52, with higher scores associated with severity. A total of 1021 participants were randomized to receive a once-daily 45-mg tablet of either Rinvoq or placebo for 12 weeks. Five hundred two participants who had achieved a clinical response by week 12 were enrolled in the maintenance trial (U-ENDURE) and randomly assigned to 15 mg of Rinvoq, 30 mg of Rinvoq, or placebo for 52 weeks.5
Results of U-EXCEL, U-EXCEED, U-ENDURE
A total of 1021 participants were randomized into induction trials of U-EXCEL and U-EXCEED. Of the 1021 participants, 502 had a clinical response in the induction trials and were enrolled in the maintenance trial of U-ENDURE. In U-EXCEL, 49.5% of patients achieved clinical remission, and in U-EXCEED, 38.9% achieved clinical remission by week 12. In U-EXCEL, 45.5% achieved an endoscopic response and 34.6% in U-EXCEED. In U-ENDURE, 37.3% in 15-mg upadacitinib group achieved clinical remission, 47.6% in the 30-mg upadacitinib group. 27.6% in the 15-mg upadacitinib group, and 40.1% in the 30-mg upadacitinib group had an endoscopic response.5
Trial | Clinical Remission by Week 12 | Endoscopic Response by Week 12 |
U-EXCEL | 49.5% vs. 29.1% (p<0.001) | 45.5% vs. 13.1% (p<0.001) |
U-EXCEED | 38.9% vs. 21.1% (p<0.001) | 34.6% vs. 3.5% (p<0.001) |
| | | |
| | Clinical Remission by Week 52 | Endoscopic Response by Week 52 |
U-ENDURE | 15 mg: 37.3% vs. 15.1% 30 mg: 47.6% vs. 15.1% (p<0.001) | 15 mg: 27.6% vs. 7.3% (p<0.001) 30 mg: 40.1% vs. 7.3% (p<0.001) |
Figure 1. Effects of Rinvoq on achieving clinical remission and endoscopic response in Crohn disease.
Adverse Events
In U-EXCEL, U-EXCEED, and U-ENDURE, adverse events were dose-dependent. Herpes zoster infections were common in the groups receiving 45 mg and 30 mg of upadacitinib.5 Other adverse events reported were hepatic disorders and neutropenia in the group receiving 30 mg of upadacitinib.5 Gastrointestinal perforations developed in four patients who received 45 mg of upadacitinib and in one patient each who received 30 mg or 15 mg of upadacitinib.
Trial | Herpes Zoster | Hepatic Disorders | Neutropenia | GI Perforations |
U-EXCEL | 45 mg: 2.9% | Placebo: 0 | 45 mg: 2.9% | Placebo: 2.3% | 45 mg: 2.6% | Placebo: 0.6% | 45 mg: 0.2% | Placebo: 0 |
U-EXCEED | 45 mg: 1.5% | Placebo: 0 | 45 mg: 2.5% | Placebo: 3.5% | 45 mg: 1.2% | Placebo: 0 | 45 mg: 0.2% | Placebo: 0 |
U-ENDURE | 15 mg: 4% 30 mg: 7.2% | Placebo: 4.7% | 15 mg: 7.4% 30 mg: 10.2% | Placebo: 2.8% | 15 mg: 2% 30 mg: 3% | Placebo: 0.9% | 15 mg: 0.2% 30 mg: 0.2% | Placebo: 0 |
Figure 2. Adverse events of Rinvoq vs. placebo.
Use in Special Populations
According to the package insert, Rinvoq can cause fetal harm. In addition, lactating women are advised against breastfeeding during treatment and for 6 days (10 half-lives) after the last treatment (dose). Pregnancy status and contraception use of young women must be verified during treatment and 4 weeks after the final dose of Rinvoq. Patients in the U-EXCEL and U-EXCEED trials were 56% men, and 68% were White; the median age was 39.3 years (±14 years).5 For severe renal impairment – eGFR 15–30 mL/minute – patients received 30 mg once daily for induction and 15 mg once daily for maintenance.5 Use is not recommended in those with an eGFR less than 15 mL/minute.5 Rinvoq has not been studied in severe liver impairment.
Patient Education
Rinvoq is the first oral reversible JAK inhibitor for moderate to severe Crohn disease. Before starting, patients should establish a baseline with laboratory values of lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Patients should make sure they are up-to-date with all of their vaccines before treatment and avoid live vaccines during treatment. The recommended induction dose is 45 mg once daily by mouth for 12 weeks, followed by a maintenance dose is 15 mg once daily. A 30-mg once-daily maintenance dose can be considered in refractory or severe disease. The most common adverse reactions reported were upper respiratory tract infections, anemia, pyrexia, and herpes zoster. If no therapeutic response is achieved with the 30-mg maintenance dose, Rinvoq should be discontinued. According to the package insert and Lexicomp, patients should talk to their physician if the following adverse effects do not resolve: upset stomach, signs of a common cold, headaches, pimples, and cold sores.
References
1. Hemstreet BA. Inflammatory bowel disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 10th ed. McGraw-Hill, 2017. Available at http://accesspharmacy.mhmedical.com.neomed.idm.oclc.org/content.aspx?bookid=1861§ionid=146059124.
2. Mayo Clinic. Crohn’s Disease. Available at https://www.mayoclinic.org/diseases-conditions/crohns-disease/symptoms-causes/syc-20353304#:~:text=Different%20areas%20of%20the%20GI,are%20living%20with%20Crohn's%20disease.
3. U.S. Food and Drug Administration (FDA). FDA Approves First Oral Treatment for Moderately to Severely Active Crohn’s Disease. Available at https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-oral-treatment-moderately-severely-active-crohns-disease.
4. Murez C. FDA Approves First Pill to Treat Moderate to Severe Crohn’s Disease. Available at https://www.usnews.com/news/health-news/articles/2023-05-19/fda-approves-first-pill-to-treat-moderate-to-severe-crohns-disease#:~:text=FRIDAY%2C%20May%2019%2C%202023%20(,pill%20called%20Rinvoq%20(upadacitinib).
5. Loftus EV Jr, Panés J, Lacerda AP, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med 2023;388:1966-80.