Introduction
Filgotinib (FIL) is an oral, once-daily, Janus kinase 1 preferential inhibitor. We evaluated the safety of FIL in Crohn’s disease (CD) in the DIVERSITY1 study and compared it with previously reported FIL safety data in ulcerative colitis (UC) from the SELECTION study.1
Aims & Methods
The phase 3 double-blind, placebo-controlled DIVERSITY1 trial (NCT02914561) randomized adults aged 18–75 years with moderately to severely active CD 1:1:1 to receive FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo (PBO) once daily for 10 weeks in Induction (IND) Study A (biologic-naive and biologic-experienced) or B (biologic-experienced). FIL-treated patients who met either co-primary endpoint (clinical remission or endoscopic response) at week 10 were rerandomized 2:1 to receive their IND dose or PBO in the Maintenance (MNT) Study to week 58. Safety and tolerability were assessed throughout the study in all patients who received at least one dose of FIL or PBO within each study part. The SELECTION (NCT02914522) study evaluated the same FIL doses as DIVERSITY1.1 Proportions of patients with treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were compared between DIVERSITY1 (CD) and SELECTION (UC). Efficacy data have been reported elsewhere.1,2
Results
In CD IND studies A and B, 707 and 665 patients respectively, were randomized to receive FIL200 (n=223; n=204), FIL100 (n=245; n=230) or PBO (n=239; n=231). In the MNT Study, FIL200-induced patients received FIL200 (n=118) or PBO (n=56), FIL100-induced patients received FIL100 (n=105) or PBO (n=56) and PBO-induced patients received PBO (n=146). Safety outcomes in CD and UC IND studies are reported in the Table. In the MNT studies, infection rates ranged from 25.5–33.9% and 22.6–35.1% in CD and UC, respectively; serious infections were reported in nine patients (1.9%) with CD and eight patients (1.2%) with UC. In the MNT studies, malignancy (excluding non-melanoma skin cancer) was reported in one FIL100-FIL100-treated patient (1.0%; lung metastases) with CD, and in one FIL200-FIL200-treated patient (0.5%; malignant melanoma) and one FIL100-FIL100-treated patient (0.6%; colon cancer) with UC. Venous thromboembolism (VTE) was reported in one FIL200-FIL200-treated patient (0.8%) with CD and one PBO-PBO-treated patient (1.1%) with UC in the MNT studies. Major adverse cardiovascular events (MACE) were reported in one patient (0.4%; IND Study B FIL100) with CD and five patients with UC (IND PBO [n=1; 0.4%]; FIL200-FIL200 [n=2; 1.0%], FIL100-FIL100 [n=1; 0.6%]; PBO-PBO [n=1; 1.1%]). No deaths were reported in DIVERSITY1; two deaths were reported in SELECTION, but neither was considered related to treatment by the investigator.
Table. Summary of safety outcomes in the DIVERSITY1 and SELECTION IND studies.
| Patients, n (%) | DIVERSITY1 IND Study
A
(Crohn’s disease)
FIL200
n=222 | DIVERSITY1 IND Study
A
(Crohn’s disease)
FIL100
n=245 | DIVERSITY1 IND Study
A
(Crohn’s disease)
PBO
n=237 | DIVERSITY1 IND Study
B
(Crohn’s disease)
FIL200
n=202 | DIVERSITY1 IND Study
B
(Crohn’s disease)
FIL100
n=228 | DIVERSITY1 IND Study
B
(Crohn’s disease)
PBO
n=229 | SELECTION1 IND Studies
A & B (ulcerative colitis)
FIL200
n=507 | SELECTION1 IND Studies
A & B (ulcerative colitis)
FIL100
n=562 | SELECTION1 IND Studies
A & B (ulcerative colitis)
PBO
n=279 |
| TEAEs | 114 (51.4) | 136 (55.5) | 137 (57.8) | 141 (69.8) | 154 (67.5) | 156 (68.1) | 272 (53.6) | 283 (50.4) | 157 (56.3) |
| Serious TEAEs | 18 (8.1) | 16 (6.5) | 15 (6.3) | 19 (9.4) | 36 (15.8) | 26 (11.4) | 22 (4.3) | 28 (5.0) | 13 (4.7) |
| TEAEs leading to discontinuation of study drug | 16 (7.2) | 15 (6.1) | 13 (5.5) | 24 (11.9) | 31 (13.6) | 19 (8.3) | 23 (4.5) | 20 (3.6) | 14 (5.0) |
| Infections | 39 (17.6) | 38 (15.5) | 41 (17.3) | 47 (23.3) | 58 (25.4) | 59 (25.8) | 92 (18.1) | 82 (14.6) | 39 (14.0) |
| Serious infections | 8 (3.6) | 2 (0.8) | 0 | 5 (2.5) | 8 (3.5) | 7 (3.1) | 3 (0.6) | 6 (1.1) | 3 (1.1) |
| Gastrointestinal perforations (post hoc adjudication of these events in DIVERSITY1 by external expert committee determined none of the events were considered related to study treatment, but were related to underlying disease) | 2 (0.9) | 4 (1.6) | 0 | 1 (0.5) | 2 (0.9) | 2 (0.9) | 0 | 0 | 1 (0.4) |
| Malignancies (excluding non-melanoma skin cancer) | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.2) | 1 (0.2) | 0 |
| Venous thromboembolism (adjudicated by external expert committee; this was a post hoc adjudication of events in SELECTION) | 0 | 0 | 0 | 0 | 0 | 1 (0.4) | 1 (0.2) | 0 | 0 |
| Major adverse cardiovascular events (adjudicated by external expert committee; this was a post hoc adjudication of events in SELECTION) | 0 | 0 | 0 | 0 | 1 (0.4) | 0 | 0 | 0 | 1 (0.4) |
Conclusion
FIL treatment was well tolerated. FIL showed a safety profile in CD that was generally consistent with that in UC, and no new safety signals were observed.1 The numbers of malignancy, VTE and MACE events for FIL were low in CD and UC clinical trials.1
References
1. Feagan BG et al. Lancet 2021;397:2372–84.
2. Vermeire S et al. Abstract submitted to the United European Gastroenterology Week, 14–17 October 2023, Copenhagen, Denmark.
Disclosure
SS reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos/Gilead, Hikma Pharmaceuticals, I-Mab, Janssen Pharmaceuticals, Morphic, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma and UCB.
SV reports grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; consulting and/or speaker fees from AbbVie, AbolerIS Pharma, Agomab, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Eli Lilly, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma and Zealand Pharma.
DTR reports personal fees from AbbVie, AltruBio, Biomica, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos, Dizal Pharmaceuticals, Eli Lilly, Galenpharma/Atlantica, Gilead Sciences, GSK, InDex Pharmaceuticals, Janssen Pharmaceuticals, Pfizer, Prometheus Laboratories, Reistone Biopharma, Roche/Genentech, Takeda and TECHLAB; and grants from Takeda.
SD reports personal fees from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen Pharmaceuticals, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB and Vifor.
RM declares no competing interests.
XR reports personal fees from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly, Galapagos, Janssen Pharmaceuticals, MSD, Pfizer, Takeda and Theradiag.
PK is an employee of Gilead Sciences Inc.
PvH reports consulting fees from AOP Health, Aspen, Astellas Pharma, Galapagos and Sanofi; and employment by Janssen, MSD and Schering-Plough.
TM, RB and F-OLB are employees and shareholders of Galapagos NV.
MW has received grants or contracts from AbbVie, Alfresa Pharma, EA Pharma, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda and Zeria Pharmaceutical; consulting fees from AbbVie, EA Pharma, Eli Lilly Japan, Gilead Sciences, Nippon Boehringer Ingelheim and Takeda Pharmaceutical; and honoraria from Celltrion Healthcare, EA Pharma, Eli Lilly Japan, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer Japan, Takeda Pharmaceutical and Zeria Pharmaceutical.
The DIVERSITY1 study was sponsored by Galapagos NV (Mechelen, Belgium). Gilead Sciences Inc. (Foster City, CA, USA) was a collaborator for the study.
Medical writing support for the development of this abstract was provided by Michelle Antoni, PhD, of PharmaGenesis London, London, UK, and was funded by Galapagos NV.