Y-ECCO Literature Review: Stephany Barreda
Efficacy of filgotinib in patients with ulcerative colitis by line of therapy in the phase 2b/3 SELECTION trial
Dotan I, Feagan BG, Taliadouros V, et al.
J Crohns Colitis 2023 Mar 16. doi:10.1093/ecco-jcc/jjad039. Online ahead of print.
In recent years, there has been significant optimism in the field with the arrival of newer licensed therapies for patients living with IBD . Alongside the welcome arrival of new therapeutics, there has also been an appreciation that many (but not all) patients may have preferences for oral medications . In particular, targeting Janus kinases (JAKs) with oral small molecule treatments has proved to be a promising strategy. Indeed, tofacitinib, a pan-JAK inhibitor, was shown to have efficacy in patients with Ulcerative Colitis (UC), even in some instances where there had been loss of response or non-response to all prior licensed biologic options . With growing understanding of the pathways involved in UC, preferential inhibition of JAK1 has been investigated in the field of IBD, including with the JAK1 inhibitor, filgotinib. This is a medication already licensed for some rheumatological conditions and it was recently assessed in the context of UC in the phase 2b/3 SELECTION trial – with the results having previously been published, and demonstrating superiority of filgotinib over placebo in UC . In this current study, Dotan et al. assess efficacy of filgotinib based on prior treatment exposure and number of lines of therapy for instances of previous exposure to biologic therapy, based on a post-hoc analysis of data from the SELECTION trial. This study contributes to our understanding of how to sequence and position a new advanced therapy, in the context of a growing armamentarium of treatment options for patients living with UC.
Methods and key findings
Rapid response to filgotinib in both biologic-naïve and biologic-experienced patients.
First, the authors assessed rapidity of response to treatment through the use of daily symptom diaries over a period of 15 days. A similar speed of response was achieved with filgotinib 200 mg across biologic-naïve and biologic-experienced patients. Indeed, when response was compared against placebo at week 10, both biologic-experienced [odds ratio (OR)=3.91 (1.33–11.48)] and biologic-naïve [OR=1.98 (1.14–3.44)] patient groups were statistically more likely to achieve clinical remission. An intriguing finding that may help positioning was that efficacy of filgotinib over placebo was still demonstrated when accounting for number of previous biologic therapies or number of classes of biologic therapies. However, it should be noted that numerical values for response were lower in instances where more distinct biologic classes had been used previously.
Clinical and endoscopic outcomes improved with filgotinib in both biologic-naïve and biologic-experienced patients.
Similar to the week 10 findings, further outcome measures were assessed at week 58, the end of primary follow-up for the SELECTION trial. There was a greater likelihood of clinical remission (defined as a Mayo Endoscopic Score of 0 or 1) and Mayo Clinical Score (MCS) response (defined as a reduction of 3 or more points in the MCS) compared to placebo in both biologic-naïve and biologic-experienced patients. When assessing the effect of lines of therapy, failure of more than one anti-tumour necrosis factor (anti-TNF) therapy in patients was associated with lower likelihood of achieving either clinical remission or MCS response. However, in the biologic-experienced group of patients, even with prior treatment with other biologic therapies or sequences, filgotinib did demonstrate numerical benefit over placebo. Nevertheless, it is important to note that these findings were not statistically significant.
Time to disease worsening generally increased based on number of previous biologic therapies, and number of prior biologic classes.
The authors next considered time to protocol-specific disease worsening (PSDW). Given the efficacy demonstrated by filgotinib over placebo in the trial overall, it was perhaps not surprising that time to PSDW was shorter in patients treated with filgotinib 200 mg compared to placebo. This was the case for both biologic-experienced and biologic-naïve patients. Specifically, in patients who had received more than one previous anti-TNF therapy, no difference was noted in time to PSDW compared to placebo. Overall, the data appeared to demonstrate that biologic-experienced patients who had multiple prior biologic therapies and/or multiple previous classes of biologic therapies were more likely to have a shorter time to PSDW.
Arguably the key clinical question surrounding treatments in IBD relates to sequencing and positioning . Particularly in view of a growing number of treatment options, this is a challenge and one that is likely to increase over the coming years.
In this study by Dotan et al., the authors delve into a recent late-phase trial programme to help better understand how best to position filgotinib when considering sequencing of treatments in UC. The authors themselves highlight the exploratory nature of post-hoc analyses, including lack of correction for multiplicity, and the comparatively small number of biologic-experienced patients in this study. In addition, it should be noted that the time to PSDW was based on clinical data alone and did not incorporate more objective measures of inflammation such as endoscopic outcomes.
However, to date there has been limited information to help clinicians and patients understand how best to position and sequence available treatment options. In this regard, this study by Dotan and colleagues provides welcome data to help better understand the positioning of a new therapy. It is likely that future drug development programmes will need to routinely build in analyses that consider efficacy of therapy in light of previous treatments. Indeed, such data will hopefully help us to better understand how to sequence and position therapies – to achieve the best possible outcome for patients living with IBD.
- Hindryckx P, Vande Casteele N, Novak G, et al. The expanding therapeutic armamentarium for inflammatory bowel disease: How to choose the right drug[s] for our patients? J Crohns Colitis 2018;12:105–19. https://doi.org/10.1093/ecco-jcc/jjx117.
- Shivaji UN, Nardone OM, Cannatelli R, Smith SC, Ghosh S, Iacucci M. Small molecule oral targeted therapies in ulcerative colitis. Lancet Gastroenterol Hepatol 2020;5:850–61. https://doi.org/10.1016/S2468-1253(19)30414-5.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2017;376:1723–36. https://doi.org/10.1056/NEJMoa1606910.
- Feagan BG, Danese S, Loftus EV, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet 2021;397:2372–84. https://doi.org/10.1016/S0140-6736(21)00666-8.
- Hahn GD, Golovics PA, Wetwittayakhlang P, Al Khoury A, Bessissow T, Lakatos PL. Is there a best first line biological/small molecule in IBD: Are we ready for sequencing? Biomedicines 2022;10:749. https://doi.org/10.3390/biomedicines10040749
Stephany Barreda - Short Biography
Stephany Barreda is a Clinical Fellow in Gastroenterology currently working at Cambridge University Hospitals in the UK. Prior to working in Cambridge, Stephany had gained clinical and research experience across the world, including at the China Medical University (Shenyang, China), the Spanish National Research Council (CSIC) (Valencia, Spain) and the Friedrich-Alexander University Institute of Clinical Immunology (Erlangen, Germany). She currently has a clinical and academic interest in exploring the shared mechanisms underlying different autoimmune and inflammatory conditions.