New hopes for chronic inflammatory bowel diseases?

Two recent studies look at the efficacy of mirikizumab and upadacitinib in ulcerative colitis and Crohn's disease. Can IBD patients benefit?

Upadacitinib as induction and maintenance therapy in Crohn's disease

Crohn's disease is characterised on the transmural inflammation of the intestinal wall, mostly affecting the terminal ileum. The activation of signal transducers, and transcription activators mediated by Janus kinases (JAKs) in T cells play an important pathogenic role in Crohn's disease. Upadacitinib, an oral, reversible JAK inhibitor, is approved for the treatment of ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis and ankylosing spondylitis.

In the phase III trial Upadacitinib Induction and Maintenance Therapy for Crohn's Disease (DOI: 10.1056/NEJMoa2212728), two studies were conducted with upadacitinib as induction therapy and one study as maintenance therapy in Crohn's disease.

In the first induction study, compared with placebo, a significantly higher percentage of patients treated with 45 mg upadacitinib met the primary endpoints of clinical CDAI remission (49.5% vs 29.1%, P<0.001) and endoscopic response (45.5% vs 13.1%, P<0.001) at week 12.

In the second induction study, both clinical and endoscopic remission were also achieved in a significantly higher percentage of patients in the intervention group.

Adverse events associated with JAK inhibition (including severe infections, opportunistic infections, anaemia, neutropenia, and increased creatine kinase) were observed more frequently in patients receiving upadacitinib than in patients receiving placebo. In the maintenance study, a dose-dependent effect of upadacitinib therapy was observed in herpes zoster infections, liver dysfunction, neutropenia and creatine kinase elevation. Four cases of gastrointestinal perforation were reported with 45 mg upadacitinib. Three new cancer cases were diagnosed in total (one colorectal carcinoma, one breast carcinoma and one ovarian carcinoma).

Mirikizumab as induction and maintenance therapy in ulcerative colitis

Mirikizumab is a p19-targeted antibody against interleukin-23 and is intended to inhibit the inflammation of the mucosal layer in the rectum and colon. The immunotherapy has already shown a good effect in the phase II trial Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis (DOI: 10.1056/NEJMoa2207940).

In the placebo-controlled phase III trial, 1,281 patients were randomised to induction therapy, and 544 of those who had shown a good response to therapy were further randomised in maintenance therapy.

A significantly higher percentage of patients in the mirikizumab group experienced clinical remission at week 12 of the induction study (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance study (49.9% vs. 25.1%, P<0.001).

Adverse events such as nasopharyngitis and arthralgia were reported more frequently with mirkizumab than with placebo. Of the 1,217 patients treated with mirkizumab in the two studies during the controlled and uncontrolled periods (including the open-label extension and maintenance phases), 15 had an opportunistic infection (including 6 with herpes zoster) and 8 patients developed malignancies (including 3 with colorectal cancer). Patients receiving placebo in the induction study were diagnosed with herpes zoster infection. No malignancies were detected.

Inflammatory bowel disease: What are the benefits of the new drugs?

Both upadacitinib and mirikizumab show promising results with high remission rates in severe inflammatory bowel disease. The major drawback is the increased number of opportunistic infections due to immunosuppression. The sporadic new malignancies are also somewhat worrying, but there is no certain causal relationship.

The new active substances being tested open up new possibilities for patients who have not been able to get better with previously available active substances.

  1. Ng SC, Shi HY, Hamidi N et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2018; 390: 2769-2778
  2. Loftus EV Jr, Panés J, Lacerda AP, Peyrin-Biroulet L, D'Haens G, Panaccione R, Reinisch W, Louis E, Chen M, Nakase H, Begun J, Boland BS, Phillips C, Mohamed MF, Liu J, Geng Z, Feng T, Dubcenco E, Colombel JF. Upadacitinib Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2023 May 25;388(21):1966-1980. DOI: 10.1056/NEJMoa2212728. PMID: 37224198.
  3. D'Haens G, Dubinsky M, Kobayashi T, Irving PM, Howaldt S, Pokrotnieks J, Krueger K, Laskowski J, Li X, Lissoos T, Milata J, Morris N, Arora V, Milch C, Sandborn W, Sands BE; LUCENT Study Group. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023 Jun 29;388(26):2444-2455. DOI: 10.1056/NEJMoa2207940. PMID: 37379135.