ECCO 2016: Dr Charlie Lees (Edinburgh, UK), Dr Ailsa Hart and Marian O’Connor (Harrow, UK), Dr James Lindsay (London, UK) and Dr Peter Irving (London, UK) discuss the new therapeutic landscape in IBD since changes to guidance by NICE and SMC over the last year
New drugs in IBD – by Maria Dalby
Two randomised placebo-controlled phase 3 studies (OCTAVE Induction 1 and 2) show that tofacitinib, an oral small-molecule Janus kinase (JAK) inhibitor, is significantly more effective than placebo for inducing remission in patients with moderate to severe UC, irrespective of previous anti-TNF therapy. These two identical studies included a total of 1,139 adult patients with moderate to severe UC who had previously failed treatment with one or more therapies including steroids, azathioprine, 6-mercaptopurine, or anti-TNF. Patients were randomised 4:1 to receive tofacitinib, 10 mg bd or placebo for 8 weeks; the primary endpoint was remission at week 8, defined as a total Mayo score of ≤ 2, with no sub-score of >1, and a rectal bleeding sub-score of 0. Mucosal healing at week 8 was a key secondary endpoint. Remission rates at week 8 were 18.5% and 16.6% in the tofacitinib groups, compared with 8.2% and 3.6% in the placebo groups (p=0.007 and 0.0005, respectively). Mucosal healing rates at 8 weeks were 31.3% and 28.4% in the tofacitinib groups versus 15.6% and 11.6% in the placebo groups (p=0.0005 and 0.0002, respectively). Similar efficacy rates were noted in anti-TNF-naïve and anti-TNF-treated patients. The clinical effect in the tofacitinib groups was evident from as early as week 2 of treatment. No new safety signals were detected and the investigators concluded that tofacitinib was superior to placebo for inducing remission in moderate to severe UC.
Filgotinib is an oral, selective JAK 1 inhibitor which has been shown to be safe and effective for the treatment of rheumatoid arthritis (RA). In a phase 2 study in moderate to severe CD, 175 patients were randomised to receive filgotinib, 200mg once daily or placebo for 10 weeks. Both anti-TNF-naïve patients and patients who had failed anti-TNF therapy were included. After the 10-week period, patients continued on filgotinib, 200mg or 100mg once daily or placebo for a further 10 weeks. The primary endpoint was the proportion of patients achieving clinical remission, defined as a CDAI of <150, at week 10. A total of 48% of patients in the filgotinib group achieved clinical remission, compared with 23% in the placebo group (p<0.05). Filgotinib-treated patients also had significantly higher response rates (60% vs 41%; p<0.01) and greater improvement of IBD quality of life scores from baseline (33.82 points vs 17.56 points; p=0.0045). Filgotinib was well tolerated with a safety profile consistent with that recorded in RA trials). The investigators concluded that filgotinib, the first JAK inhibitor to show efficacy in moderate to severe CD, is capable of inducing clinical remission and response and improving quality of life, with a favourable risk/benefit profile.
Ustekinumab is a fully human IgG1k monoclonal antibody that targets the p40 subunit of interleukins 12 and 23, which are key cytokines in the pathogenic immune cascade in CD. The phase 2b CERTIFI study showed that ustekinumab is effective for inducing remission in moderate to severe CD refractory to anti-TNF therapy.1 The objective of the UNITI-1 study was to evaluate efficacy and safety in a Phase 3 setting. Eligible for inclusion in UNITI-1 were patients with moderate to severe CD who had failed or were intolerant to at least one anti-TNF agent. Patients were randomised to receive single intravenous doses of placebo, ustekinumab 130mg, or weight-based ustekinumab at a dose of approximately 6mg/kg. The primary endpoint was clinical response at week 6, defined as a reduction of CDAI from baseline of at least 100 points or CDAI <150.
A total of 741 patients were randomised in UNITI-1. Clinical response rates at week 6 were 34.3% in the ustekinumab 130 mg group and 33.7% in the weight-based ustekinumab group, compared with 21.5% in the placebo group (p= 0.002 and 0.003, respectively). Clinical remission at week 8, a key secondary endpoint, was noted in 15.9% of patients in the ustekinumab 130 mg group and 20.9% in the weight-based group, compared with 7.3% in the placebo group (p=0.003 and p<0.001, respectively). Both ustekinumab groups experienced significant improvements in CDAI, IBDQ scores, C-reactive protein (CRP), faecal lactoferrin, and calprotectin compared with placebo. Both ustekinumab regimens were well tolerated and the investigators concluded that the UNITI-1 results confirmed the findings of the CERTIFI study.
- Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519-28.