Y-ECCO Literature Review: Aditi Kumar

Upadacitinib is a selective oral Janus kinase-1 (JAK) inhibitor that has recently been approved for the treatment of Ulcerative Colitis. In this paper, Loftus et al. report on results from a phase 3 trial on the efficacy and safety of upadacitinib in patients with moderate-to-severe CD [6].

Methods and key findings

A total of 1523 patients were recruited across 43 countries and 277 sites into two induction trials and one maintenance trial. In both induction trials, U-EXCEL and U-EXCEED, patients were randomly assigned to either upadacitinib 45 mg or placebo once daily for 12 weeks in a 2:1 ratio. The main difference between the induction trials was that U-EXCEL allowed the recruitment of patients with a history of failure of one or more conventional or biologic therapies and thus could include patients who were biologic naïve. By contrast, in U-EXCEED all patients had previously been on one or more biologic therapy. Patients who had responded by week 12 proceeded to enter the maintenance trial, U-ENDURE, where they were re-randomised to receive either upadacitinib 15 mg, upadacitinib 30 mg or placebo once daily in a 1:1:1 ratio until 52 weeks. Across the three trials, approximately 75% of patients had previously been exposed to one biologic whilst 30% of them had already been exposed to three or more biologics.

The two primary endpoints, assessed at weeks 12 and 52, were clinical remission and endoscopic response. Clinical remission was defined as a Crohn’s Disease Activity Index (CDAI) score of less than 150. Endoscopic response was defined as a decrease in the Simple Endoscopic Score (SES-CD) of more than 50% from baseline.

By week 12 in U-EXCEL, a significantly higher percentage of patients who received 45 mg upadacitinib, compared to those who received placebo, met the primary endpoints of clinical remission (49.5% vs 9.1%, p<0.001) and endoscopic response (45.5% vs 13.1%, p<0.001). By week 12 in U-EXCEED, the primary endpoints of clinical remission (38.9% vs 21.1%, p<0.001) and endoscopic response (34.6% vs 3.5%, p<0.001) were more often achieved by patients receiving 45 mg upadacitinib than by those receiving placebo. Furthermore, in both the induction trials, upadacitinib provided rapid symptom relief at week 2 and week 4, with reduced C-reactive protein and improvement in faecal calprotectin which was maintained at weeks 12 and 52. There was also early discontinuation of glucocorticoids, higher endoscopic remission rates and improvement in fatigue and quality of life IBDQ32 scores. Hospitalisation rates and resolution of extraintestinal manifestations, however, did not differ significantly at week 12.

The most common adverse events documented in patients receiving upadacitinib were nasopharyngitis (7.1%), acne (6.9%), anaemia (6.3%), headaches (6.2%), worsening disease (5.9%) and upper respiratory tract infections (5.2%). Overall, there were similar rates of non-serious infections in the two groups. Two patients on upadacitinib developed Pneumocystis pneumonia (PCP) and cytomegalovirus. Herpes zoster infection was reported in 15 patients receiving upadacitinib compared to none in the placebo group. No active tuberculosis, cancers or cardiovascular or thromboembolic events were reported in the treatment groups.

At week 52 of U-ENDURE, significantly higher percentages of patients receiving 30 mg and 15 mg upadacitinib, compared to those receiving placebo, achieved both clinical remission (47.6% vs 37.3% vs 15.1%, p<0.001) and endoscopic response (27.6% vs 40.1% vs 7.3%, p<0.001). Whilst both the 30-mg and the 15-mg dose resulted in improved IBDQ-32 quality-of-life scores, only the 30-mg dose demonstrated reduced fatigue and improved resolution of extraintestinal manifestations at week 52. No deaths were reported in either group, with similar rates of infection between all groups and exacerbation of CD the most frequently reported adverse event. One case of PCP and one case of oesophageal candidiasis were reported in the 15-mg and the 30-mg treatment group, respectively, with higher numbers of herpes zoster infections, hepatic disorders, neutropenia and creatine kinase elevations in patients receiving 30 mg upadacitinib. Two cases of cancer (colorectal and breast) were noted in the 30-mg group (0.7 events per 100 person-years), with one case of metastatic ovarian cancer in the 15-mg group (1.2 events per 100 person-years). Of concern, this study demonstrated four cases of gastrointestinal perforation with occurrences in all three treatment groups and the placebo group. However, in all four cases, the perforation occurred with active disease or with secondary complications such as the presence of stricture, obstruction and fistula.

Clinical implications

The results from this phase 3 trial programme are promising, demonstrating efficacy of an oral JAK inhibitor for the first time in CD. The data have subsequently been used to gain approval for licensing of the treatment for Crohn’s Disease across a range of regions around the world. Whilst clinical remission rates were below 50% for patients on upadacitinib, these rates were double that achieved with placebo; similarly, endoscopic response was achieved three times more frequently. This was so despite the fact that a high proportion of patients had failed to respond to prior biologic treatments. It is well known that patients are less likely to achieve remission when on their second- or third-line therapy [7, 8].

Although the results reported by Loftus and colleagues are encouraging, they must be interpreted with caution as this trial adopted a ‘responder’ methodology whereby only patients who responded during the induction trials were re-randomised to the maintenance trial. It must be recognised that efficacy outcomes would be lower if the ‘net’ remission rates were to be reviewed, reflecting the actual percentage of patients enrolled during induction who demonstrate remission at the end of maintenance [9].

Conclusions

In summary, Loftus and colleagues report findings that demonstrate upadacitinib to be the first effective oral JAK inhibitor for achieving and maintaining clinical remission and endoscopic response in CD patients, regardless of previous failure to respond to biologic therapy. Furthermore, upadacitinib demonstrated a rapid onset of action with additional improvements noted in extraintestinal manifestations, fatigue and overall quality of life scores. Evidence regarding an increased risk of malignancy and gastrointestinal perforation with the use of upadacitinib is currently inconclusive and further long-term follow-up from the U-ENDURE trial will be required to provide more definitive data.

References

1. Cushing K, Higgins PDR. Management of Crohn disease: A review. JAMA 2021;325:69–80. doi:10.1001/jama.2020.18936.
2. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn's disease. Ann Surg 2000;231:38–45. doi:10.1097/00000658-200001000-00006.
3. Rutgeerts P, Geboes K, Vantrappen G, Kerremans R, Coenegrachts JL, Coremans G. Natural history of recurrent Crohn's disease at the ileocolonic anastomosis after curative surgery. Gut 1984;25:665–72. doi:10.1136/gut.25.6.665.
4. Santiago P, Braga-Neto MB, Loftus EV. Novel therapies for patients with inflammatory bowel disease. Gastroenterol Hepatol (N Y) 2022;18:453–65.
5. Hazel K, O'Connor A. Emerging treatments for inflammatory bowel disease. Ther Adv Chronic Dis 2020;11:2040622319899297. doi:10.1177/2040622319899297.
6. Loftus EV, Jr., Panes J, Lacerda AP, et al. Upadacitinib induction and maintenance therapy for Crohn's disease. N Engl J Med 2023;388:1966–80. doi:10.1056/NEJMoa2212728.
7. Allez M, Vermeire S, Mozziconacci N, et al. The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn’s disease after failure of two other anti-TNF antibodies. Aliment Pharmacol Ther 2010;31:92–101. doi:https://doi.org/10.1111/j.1365-2036.2009.04130.x.
8. Singh S, George J, Boland BS, Vande Casteele N, Sandborn WJ. Primary non-response to tumor necrosis factor antagonists is associated with inferior response to second-line biologics in patients with inflammatory bowel diseases: A systematic review and meta-analysis. J Crohns Colitis 2018;12:635–643. doi:10.1093/ecco-jcc/jjy004.
9. Kayal M, Ungaro RC, Bader G, Colombel JF, Sandborn WJ, Stalgis C. Net remission rates with biologic treatment in Crohn's disease: A reappraisal of the clinical trial data. Clin Gastroenterol Hepatol 2023;21:1348–50. doi:10.1016/j.cgh.2022.02.044.

Aditi Kumar - Short Biography

Dr Aditi Kumar is a Gastroenterology trainee in the West Midlands, UK. She has recently obtained her PhD and has a sub-specialist clinical and academic interest in IBD. She has completed her medical degree from the University of Birmingham in the UK and BSc Honours in Biomedical Sciences at the University of Ottawa, Canada. She is currently the trainee representative for the British Society of Gastroenterology IBD sub-committee and the West Midlands Clinical Research Network. She also has an interest in medical publishing and is an Associate Editor for Frontline Gastroenterology.