The first oral advanced therapy for adults with moderate to severely active Crohn’s disease has been approved by the Medicines and Healthcare products Regulatory Agency (MHRA).
The approval of upadacitinib (Rinvoq; AbbVie) marks the first marketing authorisation globally for the use of the Janus kinase (JAK) inhibitor in the treatment of the condition.
There is no cure for Crohn’s disease — an inflammatory bowel disease (IBD) — but treatment can control or reduce the symptoms.
Current treatment options range from steroids, such as prednisolone; immunosuppressants, such as azathioprine; and biological medicines, such as adalimumab, which are given via infusion every two to eight weeks.
Like biologic drugs, JAK inhibitors are ‘targeted’ therapies that work on the immune response. However, unlike biologics, they can be taken in tablet form as they are small molecule therapies. Upadacitinib, which was approved for the treatment of ulcerative colitis — another IBD — in 2022, can be taken as a once-daily pill.
Crohn’s disease is a chronic, systemic disease that manifests as inflammation within the gastrointestinal tract, most commonly in the area between the small intestine and the colon. It can be a progressive disease and the pain, physical symptoms and complications can have a significant impact on patients’ quality of life.
It is estimated that there are more than 155,000 adults living with the condition in the UK, and 40% have moderate or severe disease.
James Lindsay, consultant gastroenterologist at the Royal London Hospital, Barts Health NHS Trust, said: “There have been limited new treatment options approved for Crohn’s disease in recent years and many people struggle to stay in remission, demonstrating a clear unmet need.
“We’ve seen in clinical trials that upadacitinib has the potential to help people gain control of their disease and, with this MHRA approval, we now have an approved advanced treatment option in a new class of therapy that can be taken as a once-daily pill.”
According to a press release published by AbbVie on 2 February 2023, the MHRA’s decision was supported by data from three phase III randomised control trials.
Two of these were induction studies (U-EXCEED and U-EXCEL) which evaluated the efficacy and safety of upadacitinib 45mg once daily as induction therapy compared to placebo. The third (U-ENDURE) was a maintenance study, in which those who had responded to induction therapy in the first two studies were re-randomised to receive upadacitinib 15mg, upadacitinib 30mg, or placebo, as a maintenance therapy.
Across all three studies, significantly more patients treated with upadacitinib achieved the co-primary endpoints of clinical remission and endoscopic response, compared to placebo.
In the U-ENDURE study, a significantly greater proportion of patients treated with either 15mg or 30mg of the drug achieved clinical remission and an endoscopic response at week 52 (clinical remission: 36% and 46%, respectively, endoscopic response: 28% and 40%, respectively) compared to those taking placebo (clinical remission: 14%, endoscopic response: 7%).
In addition, the safety profile was consistent with the known safety profile of the drug in other licensed indications.
Speaking to The Pharmaceutical Journal, Mohammed Allah-Ditta, an advanced gastroenterology pharmacist, specialising in IBD medicines management, at Calderdale and Huddersfield NHS Foundation Trust, described the approval as a “significant advancement”.
“It will be the first new oral therapy available for use in Crohn’s disease,” he said.
“We do still use oral therapies such as azathioprine but these have largely been superseded with more and more biologics becoming licensed for Crohn’s disease.
“Just as with ulcerative colitis, the trial data in Crohn’s disease and post-hoc analysis have shown it is effective, has a rapid onset of action and a safety profile in keeping with what we already know.”
Allah-Ditta said the availability of a once-daily pill would “overcome” the need for patients to attend infusion units, thereby relieving pressures on hospitals, and that it would also be “welcome” for patients who struggle with frequent cannulation or injections.
“Given its rapid onset of action, it may allow practitioners to hold back on prescribing concomitant steroid courses, as is the case otherwise when commencing conventional therapies and/or biologics,” he added.
“What remains to be seen is how it fairs in patients with a penetrating phenotype of Crohn’s disease (fistulising disease).”
Upadacitinib will now undergo appraisal by the National Institute for Health and Care Excellence before it becomes available for use in Crohn’s disease.
In November 2022, the MHRA said it will look at safety measures around JAK inhibitors, following recommendations from the European Medicines Agency (EMA), introduced to minimise the risk of serious side effects, such as blood clots and cancer, associated with use of these medicines.
On 28 October 2022, the EMA’s safety committee recommended that JAK inhibitors should be used only if no alternative can be found in those aged 65 years and over; those at increased risk of major cardiovascular problems; those who smoke or have done for a long time in the past; or those at an increased risk of cancer.