– Sanborn discusses study results, JAK Inhibitors, IBD trial design
Positive results of a phase 2 clinical trial of upadacitinib, an oral JAK1 inhibitor, in Crohn’s disease patients were presented during the Late-Breaking Abstract Plenary Session at Digestive Disease Week 2017 in Chicago. The CELEST dose ranging study demonstrated endoscopic improvement and clinical benefit of upadacitinib in adult patients with moderate-to-severe refractory Crohn’s disease. These positive results support advancement of the program into Phase 3, according to AbbVie, the company sponsoring the trial.
CELEST is a randomized, double-blind, placebo-controlled phase 2 study evaluating the safety and efficacy of multiple dosing regimens of upadacitinib after 16 weeks of treatment. Patients had a Crohn’s Disease Activity Index (CDAI) score between 220-450, an average daily liquid/soft stool frequency (SF) ≥2.5 or daily, abdominal pain (AP) score ≥2.0, and Simplified Endoscopic Score for Crohn’s Disease (SES-CD) ≥6 or ≥4 for those with isolated ileal disease. Of the 220 subjects enrolled in the trial, 180 (82%) completed 16 weeks of induction treatment. The co-primary endpoints were the proportion of patients who achieved clinical remission (SF ≤1.5 and AP ≤1, and both not worse than baseline) at week 16 and endoscopic remission (SES-CD ≤4 and ≤2 point reduction from baseline) at week 12 or 16.1
Results showed that more patients achieved endoscopic remission with upadacitinib compared to placebo; specifically within the 24 mg twice daily treatment group 22% of patients (n=8/36) achieved endoscopic remission with upadacitinib compared to 0% of patients (n=0/37, P0.01) taking placebo. Additionally, significantly more patients receiving upadacitinib 6 mg twice daily achieved clinical remission (27%, n=10/37) compared to placebo (11%, n=4/37, P≤0.1).1 Secondary endpoint results included the finding that nearly twice as many patients achieved clinical response with upadacitinib (61 percent, n=22/36 and 57 percent, n=21/37 in the 24 mg and 6 mg twice daily groups, respectively) compared with the placebo group (32 percent, n=12/37, P≤0.05 for both comparisons).1
In this study, the safety profile was consistent with that observed in the upadacitinib investigational rheumatoid arthritis clinical trials. While overall adverse events (AEs) and infections were numerically higher with upadacitinib than placebo, these events did not appear to be dose-related.1 Serious AEs and discontinuations were similar in all groups, except for numerically greater events in the 12 mg twice daily group.1 One case of non-melanoma skin cancer was reported in the 24 mg twice daily group.1 One death was reported during screening, but the patient did not receive study drug.1
In a recent interview with reporters conducted at DDW, William Sandborn, M.D., principal investigator and director, Inflammatory Bowel Disease Center Chief, Division of Gastroenterology and Professor of Medicine at the University of California, San Diego said of the CELEST patient population,
“It’s fair to say, as far as I know, this is the most refractory group of patients ever recruited – 96% anti-TNF failures, and half of those had failed two or more anti-TNFs, and then a third of the patients had failed vedolizumab, so the placebo rates, as you would expect in that patient population, were quite low.”
Another differentiating aspect of the study design, in comparison with other IBD trials, according to Sanborn, is that steroid doses were tapered in patients who were on corticosteroids at baseline.
“Historically, the thought has been that you would want to fix the steroid doses because tapering during an induction trial would be confounding for the primary outcome measure, but continuing 20-40 mg of prednisone for 12 weeks is an awfully long time, particularly if they’re feeling better. We made the decision to do a rapid taper to have steroid-free remission at the end of the trial, which went against the conventional wisdom, but we figured if you have a highly effective drug it should stand up to that and placebo probably wouldn’t. A real stress test for the drug, no other marketed drug has ever done that,” Sanborn said.
JAK (Janus kinase) inhibitors are orally administered small molecule drugs that work by inhibiting the activity of one or more of the Janus kinase family of enzymes, (JAK1, JAK2, JAK3, TYK2) thereby interfering with the JAK-STAT signaling pathway. JAK inhibitors have been studied in both Crohn’s disease and ulcerative colitis with varying degrees of success in recent years. While upadacitinib inhibits the JAK1 pathway, tofacitinib, another JAK inhibitor, inhibits JAK 1,3 and to a lesser extent 2. Researchers are not yet sure which pathways may be more effective in the treatment of Crohn’s disease and which may be more effective in treating ulcerative colitis.
According to Sanborn, “They really just have different cytokine signaling patterns and what wasn’t really clear is if you need JAK 1 and 3 or predominately JAK3, and there are compounds that would hit predominately JAK3 or predominately JAK1.”
Sanborn and his colleagues have conducted a phase 3 induction and maintenance trial of tofacitinib in patients with moderate to severe ulcerative colitis. The positive results of the study, “Tofacitinib induction and maintenance therapy for ulcerative colitis” were recently published in the New England Journal of Medicine. While tofacitinib showed efficacy in ulcerative colitis in this study, it did not meet primary endpoints in previous Crohn’s disease trials.
“There were a couple of studies done with tofacitinib in Crohn’s disease that both missed their endpoints and the placebo rates were fairly high in both trials. Trials sometimes get designed by committee; they’re not exactly the way I would design a trial, in terms of controlling the placebo rate and so we were left being uncertain whether JAK inhibition sort of broadly didn’t work in Crohn’s disease or whether the JAK 1, 3 combination didn’t work or whether it was technically a failed clinical trial due to design issues.”
Last year, a trial of filgotinib, a JAK1 inhibitor, failed to meet its endpoints in Crohn’s disease as well. Sanborn said of the filgotinib trial,
“The filgotinib data last year suggested maybe there was going to be a benefit for JAK1 in Crohn’s but the endoscopy data were not totally consistent, so that will get further explored. This current trial with upadacitinib was really awaited for that reason.”
Comparing the outcome of the upadacitinib trial with the filgotinib data is difficult, according to Sanborn,
“There are several differences which make it somewhat hard to compare. The filgotinib trial had some patients who were naïve to anti-TNF drugs and, at least with other classes of drugs, usually those patients will have high clinical remission rates, so straight up comparing the clinical remission rates is hard.”
Sanborn said that some of the failure of JAK inhibitor trials may be attributed to older trial designs and that newer efficacy measures more recently established by the FDA in IBD trials may lead to more realistic trial outcomes.
“It’s been a pretty new trend to use centrally read colonoscopy by blinded central reader to ensure that the patients have not only symptoms but active ulceration that can’t be upcoded by a local investigator and these patients had that. And so, there are two things you need to do, one is to control the placebo rate, which didn’t happen in the prior Crohn’s disease tofacitinib studies, and then see what you got on top of what is hopefully a low placebo rate, that’s where we got to here.”
Regarding the CELEST trial design, Sanborn explained that the trial was designed a few years ago when the FDA had decided to push away from using the CDAI as an outcome measure and moved to patient reported outcomes, and how that influenced the design of the current study.
“It takes many years to get a qualified patient reported outcome and so we used a sort of interim strategy and at that time we started looking at some of the outcomes from the CDAI – stool frequency and abdominal pain, but we were still learning. If you took those items in isolation, what’s an important level of active disease? And what level of disease would be a cut point for clinical remission of symptoms?
The initial data sets were in mild-to-moderate Crohn’s disease so when we designed the study we took some outcome measures and they’re ok here, but what’s come out in the meantime is the more sensitive way of measuring – what seems to be a clinically relevant change in endoscopy, is to see a 50% reduction from baseline.”
As general rule, the advice he would give to anyone designing a clinical trial would be to use these evolved out come measures – 50% reduction from baseline in the endoscopy score and reductions in stool frequency and abdominal pain.
When asked about the future of JAK inhibitors and where they may ultimately fit in the IBD treatment algorithm, Sanborn said that the experience with JAK inhibitors is still heavily in the failure patients and that he thinks the numbers seen in the upadacitinib trial of failure patients is fairly impressive.
Speculating on the use of JAK inhibitors in treatment naïve patients, he said,
“You could make an educated guess that the magnitude of response may be even greater in bio-naïve patients, but of course we’ll need to do the clinical trials to show that and usually the safety data improves a little bit in those earlier, less refractory patient populations. Without a doubt this is going to have a good place in the failure patients and I would suspect that this will be a good option, based on convenience, for oral administration, as first line therapy, but we’ll have to see how the safety and efficacy profile plays out there and with the evolving biosimilars we’ll have to look at cost effectiveness as well as other small molecules that may be entering the market.”
The trial is ongoing and will evaluate patients up to 52 weeks. More information can be found on clinicaltrials.gov (NCT02365649).
– Tracey Gratch
1 Sandborn WJ, Feagan B, Panes J, et al. Safety and Efficacy of ABT-494, an oral JAK1 inhibitor, as induction therapy in patients with Crohn’s disease: Results from CELEST. Digestive Disease Week; May 6-9, 2017; Chicago, IL. Presentation 874h.