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Take a look at a selection of our recent media coverage:
17th October 2022
Combining guselkumab and golimumab as an induction therapy for patients with ulcerative colitis with guselkumab as a maintenance treatment, gave rise to a higher level of clinical remission than monotherapy with either agent, according to the findings of a phase 2a, randomised, double-blind study presented at the United European Gastroenterology (UEG) week.
Inflammatory bowel disease includes both ulcerative colitis (UC) and Crohn’s disease and the prevalence of UC in Europe ranges from 0.9 to 24.3 per 100,000 person-years. UC is a chronic inflammatory condition and typically, those who are affected can experience loose and urgent bowel movements, blood stools, abdominal cramps and pains.
In recent years, the use of biological therapy with monoclonal antibodies such as guselkumab and golimumab have provided significant benefit for patients with ulcerative colitis. Guselkumab (brand name Tremfya) is an antagonist of the p19 subunit of IL-23 and approved to treat plaque psoriasis and psoriatic arthritis. In contrast, golimumab (brand name Simponi) is an antagonist of TNFa and is approved for the treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy.
The value of guselkumab in UC was examined in the QUASAR Induction Study in which enrolled patients with moderately to severely active ulcerative colitis previously unsuccessfully managed with conventional or advanced therapy that was intolerable or inadequate. Both a lower and higher dose of guselkumab were used and the results showed that clinical remission occurred in 25.7% and 25.2% of patients receiving the lower and higher dose respectively.
In the VEGA trial presented at UEG, researchers examined the safety and efficacy of combination therapy with guselkumab and golimumab. All patients were naïve to TNFa antagonists and refractory or intolerant to conventional therapy and randomised to receive intravenous guselkumab, golimumab or both agents combined as induction therapy. After 12 weeks, patients randomised to monotherapy continued their initially assigned treatment through to week 38, whereas patients given the combination switched to guselkumab maintenance therapy. Clinical remission was based on the total Mayo score, as well as the modified Mayo score components, symptomatic remission, endoscopic improvement, endoscopic normalisation, histologic remission and composite histologic-endoscopic endpoints were assessed.
Guselkumab-golimumab and clinical remission
A total of 214 patients were randomised to one of the three treatment options although 13.1% discontinued before week 34.
Using the modified Mayo score, clinical remission occurred in 47.9% of those receiving combination induction treatment compared to 20.8% for the golimumab and 31% in the guselkumab monotherapy groups and in both cases this difference was statistically significant.
Safety events were similar between the three groups as were the rates of serious adverse events.
The authors concluded the use of combination induction therapy followed by maintenance with guselkumab experienced greater rates of clinical remission, endoscopic improvement, endoscopic normalization, and both histologic remission and endoscopic improvement
2nd August 2022
Upadacitinib approval has been granted by the MHRA for use in patients who have moderate to severe active ulcerative colitis according to a press release from the manufacturer AbbVie.
Ulcerative colitis (UC) represents a chronic idiopathic inflammatory bowel disorder of the colon that causes continuous mucosal inflammation extending from the rectum to the more proximal colon with an estimated prevalence of 7.6-245 cases per 100,000 persons/year. In the UK alone, ulcerative colitis has been estimated to affect 1 in every 420 people, amounting to around 146,000 people. Symptoms of UC will include abdominal pain, bloody diarrhoea, severe urgency for a bowel movement, weight loss and fatigue. Both the severity of symptoms and uncertainty surrounding flares give rise to a substantial burden and often disability among those living with the disease.
Treatment for UC includes amino-salicylic acid, oral steroids and immunosuppressive drugs such as azathioprine and 6-mercaptopurine. However, 20% to 40% of UC patients do not respond to conventional medications and various biologics that target specific immunological pathways have been studied as potential treatments. In a 2014 network meta-analysis, the authors concluded that compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. In addition, data also supports the use of Janus kinase inhibitors in the management of UC, with a study of patients having moderately to severely active ulcerative colitis, finding that tofacitinib gave rise to a better clinical response and remission compared to those receiving placebo. The AbbVie press release describes how the approval of upadacitinib, was based on the results from three phase 3 clinical trials.
Upadacitinib clinical efficacy
The clinical efficacy comes from two induction trials, U-ACHIEVE induction and U-ACCOMPLISH and a single maintenance study U-ACHIEVE maintenance which are detailed in a single publication. Patients aged 16 -75 years and with moderately to severely active ulcerative colitis for at least 90 days, were randomly assigned 2:1 to oral upadacitinib 45 mg once daily or placebo for 8 weeks. Patients who achieved the primary outcome after 8 weeks, which was an adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding score ≥1 or an absolute rectal bleeding score ≤1, were re-randomised 1:1:1 to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks for the maintenance phase of the study. The results showed that significantly more patients achieved clinical remission with upadacitinib 45 mg, 26% and 34% in both the induction trials (p < 0.001 for both trials) compared to the placebo group (5% and 4% for the two trials). In the second phase of the trial, clinical remission was achieved by significantly more patients (p<0·0001) receiving upadacitinib 15 mg (42%) and 30 mg (52%) compared to those receiving placebo (12%).
The press release quotes Professor James Lindsay, Consultant Gastroenterologist at the Royal London Hospital Barts Health NHS Trust, who said that “in clinical trials, upadacitinib showed its ability to rapidly control symptoms in eight weeks for many participants and sustained responses at one year. I believe these results could make a positive difference for many people with ulcerative colitis for whom previous treatment options have not worked.”
17th August 2021
Ulcerative colitis is a bowel disease characterised by inflammation in the large bowel and rectum. It is a chronic, relapsing, remitting disease with an estimated prevalence of 9 to 20 cases per 100,000 people per year and which causes diarrhoea, abdominal pain and rectal bleeding. While the underlying aetiology is uncertain, it is believed to arise from exposure to environmental triggers in susceptible individuals. Furthermore, it is widely accepted that treating the disease at an earlier stage is the preferred strategy, particularly as once the diagnosis is established, bowel damage is already present in the majority of patients highlighting the need to identify possible early disease markers. Though research has already identified several inflammatory protein biomarkers that are predictive of Crohn’s disease within 5 years, there are currently no known relevant protein biomarkers for ulcerative colitis.
In trying to identify any such relevant protein biomarkers, a team from the Department of Gastroenterology, Faculty of Medicine and Health, Orebro University, Sweden, performed a case-control study comparing pre-diagnostic plasma samples of those who later developed ulcerative colitis (cases) with those who remained free of the disease (controls). In an effort to determine the influence of genetics and environmental factors, the researchers also examined twin pairs and healthy controls. The team used principal component analysis to identify specific proteins that were elevated in either case or control patients.
The researchers focused on 92 different potential protein biomarkers and obtained pre-diagnostic plasma samples from 72 individuals who later developed ulcerative colitis and 140 matched healthy controls. The median age of both case and control cohorts was 50 years (47% male) and the median time from when the pre-diagnostic samples were taken before diagnosis was 4.8 years. Analysis of the protein biomarkers revealed a total of six specific proteins that differentiated between cases and controls (p < 0.05) and which remained significantly elevated (after adjustments for age, sex and smoking status). An analysis of the area under the receiver operating curves showed that these six proteins had a valve of 0.92. Among the of twin samples, only four of these six proteins were discriminatory for ulcerative colitis.
In a discussion of their findings, the authors highlighted the importance of identifying predictive signatures for ulcerative colitis and concluded that the up-regulation of these six protein biomarkers were highly predictive of the subsequent development of ulcerative colitis and concluded that this provided a novel means of identifying patients who were likely to develop the disease in the future.
Bergemalm D et al. Systemic inflammation in pre-clinical ulcerative colitis. Gastroenterology 2021