An investigational oral Janus kinase (JAK) inhibitor, filgotinib, has shown mixed results in a Phase III trial (DIVERSITY) for patients with moderate to severe Crohn's disease. While the drug met some endpoints in specific patient subgroups and during the maintenance phase, it failed to achieve several primary endpoints in the induction studies, raising questions about its efficacy and the trial's design.
The DIVERSITY trial, consisting of two induction studies and a maintenance study, evaluated the efficacy and safety of filgotinib in adults aged 18-75 with moderately to severely active Crohn's disease. The results, published in The Lancet Gastroenterology & Hepatology, indicate that filgotinib 200mg only met one of its four primary endpoints for clinical remission and endoscopic response across the two induction studies.
Induction Phase Results
In the induction study involving patients previously treated with a biologic, a significantly higher proportion of patients receiving filgotinib 200 mg achieved clinical remission at week 10 based on a patient-reported two-point scale (PRO2) compared to placebo (30% vs 18%, P = 0.0039). However, this benefit was not observed in biologic-naive patients (33% vs 26%, P = 0.096). Furthermore, the co-primary endpoint of endoscopic response was not met in either the biologic-naive or biologic-experienced groups.
Maintenance Phase Results
In the maintenance phase of the trial, patients who responded to filgotinib during induction were re-randomized to receive either filgotinib 200 mg or placebo for 58 weeks. At the end of this period, both clinical remission (44% vs 26%, P = 0.038) and endoscopic remission (30% vs 9%, P = 0.0038) rates were significantly higher in the filgotinib group compared to the placebo group.
Dose-Dependent Response and Safety
Further analysis using the Crohn's Disease Activity Index (CDAI) suggested that the 200-mg dose of filgotinib showed a benefit for clinical remission in both the induction and maintenance phases. However, a lower dose of 100 mg did not demonstrate any significant benefit in either phase of the trial. The study authors reported that filgotinib treatment was well-tolerated, with no new safety signals identified. Filgotinib is currently approved in Europe for rheumatoid arthritis and ulcerative colitis.
Expert Commentary on Trial Design
In an accompanying editorial, Dr. Mark Ainsworth from Odense University Hospital in Denmark highlighted several limitations in the DIVERSITY trial design that may have obscured the true efficacy of filgotinib. One concern was the early assessment of endoscopic response at week 10, which may not have allowed sufficient time for the drug to exert its full effect. For instance, upadacitinib (Rinvoq) induction studies in Crohn's disease evaluated efficacy at week 12.
Another potential confounding factor was the allowance of substantial doses of corticosteroids for up to 14 weeks in DIVERSITY participants, which could have led to high placebo response rates and masked the effect of filgotinib. In contrast, the upadacitinib induction studies tapered corticosteroids after week 4, with most patients off corticosteroids by week 11.
Dr. Ainsworth also pointed out that the upadacitinib studies used higher doses for induction than for maintenance, whereas DIVERSITY used the same dose for both phases. This consistent dosing might have been insufficient to induce remission effectively.
Implications and Future Directions
"To unequivocally rule out or confirm an effect of filgotinib in induction of remission in Crohn's disease, further studies avoiding these pitfalls seem necessary. Whether there is a commercial interest remains to be seen," Ainsworth concluded. The mixed results from the DIVERSITY trial underscore the challenges in developing effective treatments for Crohn's disease and highlight the importance of optimizing trial design to accurately assess drug efficacy.
