First Oral Medication to Treat Moderate-to-Severe Crohn’s Disease Earns FDA Approval

First Oral Medication to Treat Moderate-to-Severe Crohn’s Disease Earns FDA Approval

Upadacitinib, the first oral treatment for Crohn's disease, has been approved by the Food and Drug Administration. The approval came in part through a Mount Sinai-led clinical trial that showed it to be more efficacious than placebo.

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Physicians treating patients with moderate-to-severe Crohn’s disease have a new therapy in their armamentarium thanks in part to Mount Sinai-led research.

The Food and Drug Administration (FDA) on Thursday, May 18, approved upadacitinib, a breakthrough, once-daily oral medication, for treatment of Crohn’s disease, based on results from phase 3 clinical trials published in The New England Journal of Medicine.

“Upadacitinib addresses an unmet need in the treatment of Crohn’s disease and allows patients access to an oral medication that could put them in clinical and endoscopic remission,” says Jean-Frederic Colombel, MD, Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai and senior and corresponding author of the New England Journal article. “This therapy has the potential to transform the lives of individuals battling this chronic condition and offers a new hope for improved quality of life.”

Previous therapies for Crohn’s disease, including anti-TNF alpha antibodies such as infliximab and adalimumab; an anti-integrin antibody (vedolizumab); an anti-IL12/23 antibody (ustekinumab); and an anti-IL23 antibody (risankizumab), are all injectable, raising barriers to adherence for some patients. They also often fall short of achieving sustained remission and controlling symptoms.

Upadacitinib is a selective Janus kinase (JAK) inhibitor. It precisely targets the underlying pathways of inflammation, thereby mitigating the symptoms and potentially minimizing the risk of adverse events associated with immunosuppression.

Results of these phase 3 international trials showed that upadacitinib demonstrated superior efficacy over placebo, with a statistically significant proportion of patients achieving clinical remission after induction therapy. During the maintenance phase, the therapy substantially reduced the rate of disease relapse, illustrating its potential as a long-term treatment option for Crohn's disease.

Upadacitinib addresses an unmet need in the treatment of Crohn’s disease.

- Jean-Frederic Colombel, MD

The study spanned 43 countries and 277 sites, and enrolled a diverse group of patients 18 to 75 years old who had moderate-to-severe Crohn’s disease for at least three months. Participants were randomly assigned to receive 45 mg of upadacitinib or placebo (2:1) for induction therapy to assess effectiveness in achieving remission in two double-blind phase 3 trials, U-EXCEL and U-EXCEED. The medication was taken once daily for 12 weeks.

Patients who had a clinical response to upadacitinib induction therapy were then randomly assigned in the U-ENDURE maintenance trial to receive 15 mg or 30 mg of upadacitinib, or placebo (1:1:1) once daily for 52 weeks. The maintenance phase evaluated the drug's ability to sustain remission and prevent relapse. (U-EXCEED had an additional 12-week open-label, active single-group induction period to allow for the accrual of enough patients for entry into U-ENDURE.)

The primary endpoints for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn’s Disease Activity Index score of <150 on a range of 0 to 600, with higher scores indicating more severe disease activity) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn’s Disease [SES-CD; range of 0 to 56, with higher scores indicating more severe disease] of >50 percent from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]).

A dose effect on the risk of herpes zoster infection was observed in the study, which is consistent with known class effects of the JAK inhibitors. Dr. Colombel notes that in clinical practice this side effect can be mitigated by vaccination against herpes zoster. Another relatively common side effect was acne. Several cases of intestinal perforations were observed in patients, but the trial was not large enough to determine whether upadacitinib is associated with a risk of perforations above the risk linked to progression of the disease, he says.

As with all JAK inhibitors, the FDA recommends that upadacitinib be used only for patients who have failed anti-TNF therapy. No head-to-head trials of upadacitinib and other therapies have yet been conducted, but Dr. Colombel noted that incidences of clinical remission and endoscopic response observed were greater than those observed in most studies of biologic drugs to treat Crohn’s disease.

Although FDA approval of upadacitinib is an important step forward in Crohn’s disease treatment, Dr. Colombel notes that more research is needed.

“There is still a therapeutic ceiling despite the improving efficacy of these drugs,” he says. “Research at Mount Sinai is trying to fill this gap by working on predictors of response to medication (personalization), combination of drugs, and finally prediction and prevention of IBD.”


Jean-Frederic Colombel, MD

Jean-Frederic Colombel, MD

Professor of Medicine (Gastroenterology)

Bruce E. Sands, MD, MS

Bruce E. Sands, MD, MS

Dr. Burrill B. Crohn Professor of Medicine; Chief, Dr. Henry D. Janowitz Division of Gastroenterology