Y.Ber

FUZION, guselkumab in perianal fistulising Crohn's, presented to week 48 by Ailsa Hart as a late-breaker at UEG. It is the first large phase 3 trial dedicated to perianal fistulas to show a systemic drug works since ACCENT II with infliximab in 2004. The local stem-cell option, darvadstrocel, worked in ADMIRE-CD in 2016, but failed its confirmatory trial and has left the EU market. 286 adults with at least one draining perianal fistula, confirmed on blinded central MRI, were randomised 2:2:1 to guselkumab 200 mg IV at weeks 0, 4 and 8, then 100 mg subcutaneous every 8 weeks or 200 mg every 4 weeks, or placebo. Setons came out between weeks 4 and 12. Most were luminally quiet (78% had a CDAI of 220 or less) and nearly two-thirds had already had a biologic. At week 24, 28% on 100 mg and 27% on 200 mg reached combined fistula remission, against 10% on placebo: every external opening closed, no drainage even on gentle compression, and no collection over 2 cm on MRI. Response, at least 50% fewer draining fistulas, was 33% and 36% against 14%. At week 48, combined remission was 35% on 100 mg and 26% on 200 mg. That isn't a dose effect. 49% of the 100 mg group (55 of 113) hadn't responded by week 24 and were escalated, blind, to 200 mg every 4 weeks, but stayed in the 100 mg group, while non-responders on 200 mg had a sham escalation. So the 35% reflects stepping up the people who hadn't responded. There is no placebo comparison at week 48, because placebo non-responders switched to guselkumab. Safety: serious adverse events 16% on 100 mg, 8% on 200 mg and 14% on placebo. Serious infection (12%) and anal abscess (12%) were higher on 100 mg, in small numbers. Two cancers on 200 mg were judged unrelated. Guselkumab has an excellent safety profile across many studies now, so I have zero concerns here. My read: about 1 in 4 heal against 1 in 10 on placebo, and it holds to week 48. No filing for perianal disease has been announced yet, but surely will follow. It is fantastic to have controlled data to support p19 therapies for fistulising Crohn's - such a hard phenotype to treat especially after TNF failure. Most of us will still use infliximab plus azathioprine first in these patients. The MRI part of the primary endpoint only rules out a collection over 2 cm, and so few patients had one that combined and clinical remission came out identical. Guselkumab improved MRI fistula activity more than placebo at week 24 (MAGNIFI-CD change −1.4 and −1.7 v −0.4, nominal p 0.034 and 0.004), but we haven't yet seen MRI response, remission or week 48 scans.