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Filgotinib in CD

FITZROY Phase 2 and global DIVERSITY Phase 3 program in CD

CD is an IBD of unknown cause, resulting in chronic inflammation of the gastrointestinal (GI) tract with a relapsing and remitting course. The market today for CD treatments is estimated to approximately €1.8 billion in the five largest European markets.

Today, with the most advanced therapies, only 30 – 40% of CD patients on treatment achieve prolonged clinical remission. There are currently no highly effective oral therapies approved for CD and, like RA, treatment is dominated by injectable, biological treatments including anti-TNF therapies. Anti-TNF agents have improved the management of CD; however, not all patients respond to these drugs, and secondary loss of response during the first year is reported in up to 50% of patients annually in placebo-controlled trials. Therefore, a considerable unmet need remains with existing treatments.

Dysregulation of the JAK signaling pathway has also been associated with CD, which suggests that filgotinib, with its preferential selectivity for JAK1, may offer an attractive alternative for the treatment of CD. It is hypothesized that with preferential inhibition of JAK1, unwanted side effects such as anemia may be reduced. This is of particular importance to IBD patients, who frequently experience fecal blood loss.

The FITZROY Phase 2 trial (NCT02048618) evaluated the efficacy and safety of 200mg once-daily filgotinib in 174 patients with moderate to severe active CD and mucosal ulceration, who were either anti-TNF naive or anti-TNF failures. As reported in The Lancet (Vermeire et al. 2016), the FITZROY trial achieved the primary endpoint of clinical remission at week 10, and filgotinib demonstrated a favorable tolerability profile consistent with the DARWIN trials in RA.

Gilead initiated the Phase 3 DIVERSITY trial (NCT02914561) with filgotinib in CD in November 2016. In October 2021, we announced the completion of patient enrollment with topline data anticipated in the first half of 2023. The DIVERSITY Phase 3 trial investigates the efficacy and safety of 100mg and 200mg filgotinib once-daily compared to placebo in patients with moderate to severe active disease including those with prior antibody therapy failure. The DIVERSITY trial enrolled 1,374 patients from the U.S., Europe, Latin America, Canada, and Asia/Pacific regions. Men and women in the DIVERSITY trial will be randomized to receive placebo, 100mg, or 200mg filgotinib. Due to preclinical findings with filgotinib regarding semen parameters, in the U.S. randomization to 200mg was restricted to male patients who failed at least one anti-TNF therapy and vedolizumab.

Following the amended agreement with Gilead, Galapagos will now become the sole sponsor of the DIVERSITY trial and the long-term extension study. The parties intend to complete the transfer no later than 30 June 2022. Under the terms of the agreement and upon completion of the transfer, Gilead will make a one-time payment of $15 million to Galapagos. From 1 April 2022, Galapagos will also be solely responsible for all development costs for DIVERSITY. In addition, if the EMA grants regulatory approval of filgotinib for the treatment of CD based on data from the DIVERSITY trial, then royalties payable by Galapagos to Gilead will be reduced by 30% across all filgotinib indications and will become 5.6 to 10.5% of net sales in Europe. These royalties are payable as of 2024. Gilead remains responsible for commercial activities outside of Europe.

Phase 3 DIVERSITY in CD

Phase 3 DIVERSITY in CD (graphic)
Filgotinib is not approved in CD by any regulatory authority

Adjacent to the filgotinib Phase 3 programs, we and Gilead are conducting dedicated studies evaluating the potential impact of filgotinib on semen parameters in male CD and UC patients (MANTA) and in male RA, PsA, and AS patients (MANTA-RAy).

In March 2017, Gilead initiated a Phase 2 study in small bowel CD (DIVERGENCE 1, NCT03046056) and a Phase 2 study in fistulizing CD (DIVERGENCE 2, NCT03077412). Gilead stopped recruitment in DIVERGENCE 1 early, completing the randomized, placebo controlled trial at week 10 for 46 patients, 75% of whom were biologic experienced. Filgotinib demonstrated a similar level of CDAI remission in DIVERGENCE 1 as in the TNF experienced cohort of the FITZROY Phase 2 study in CD (see graph below).

CDAI remission in DIVERGENCE 1

CDAI remission in DIVERGENCE 1 (graphic)
Notes: data on file, CDAI remission = CDAI <150, recruitment for the DIVERGENCE 1 study was stopped early
CDAI
Crohn’s Disease Activity Index, evaluating patients on eight different factors, each of which has a pre-defined weight as a way to quantify the impact of CD
DARWIN
Phase 2 program for filgotinib in RA. DARWIN 1 explored three doses, in twice-daily and once-daily administration, for up to 24 weeks in RA patients with insufficient response to methotrexate (MTX) and who remained on their stable background treatment with MTX. DARWIN 2 explored three once-daily doses for up to 24 weeks in RA patients with insufficient response to methotrexate (MTX) and who washed out of their treatment with MTX. DARWIN 1 and 2 were double-blind, placebo-controlled trials which recruited approximately 900 patients globally and for which results were reported in 2015. DARWIN 3 is a long term extension trial in which all patients are on 200 mg filgotinib, except for U.S. males who are on 100 mg. The week 156 results from DARWIN 3 were reported in 2019
DIVERGENCE
Phase 2 programs with filgotinib in Crohn's disease. DIVERGENCE 1 was an exploratory study in small bowel CD and DIVERGENCE 2 in fistulizing CD
DIVERSITY
Phase 3 program evaluating filgotinib in CD
EMA
European Medicines Agency, in charge of European market authorization of new medications
FITZROY
A double-blind, placebo controlled Phase 2 trial with filgotinib in 177 CD patients for up to 20 weeks. Full results were published in The Lancet in 2016
Filgotinib
Formerly known as GLPG0634, commercial name is Jyseleca. Small molecule preferential JAK1 inhibitor, approved in RA in European Union, Great Britain, and Japan, and in UC in European Union and Great Britain. Application for approval for ulcerative colitis was filed in Japan. Filgotinib is partnered with Gilead. Filgotinib currently is in Phase 3 trials in CD, and in a Phase 4 trial in RA
IBD
Inflammatory Bowel Disease. This is a general term for an autoimmune disease affecting the bowel, including CD and UC. CD affects the small and large intestine, while UC affects the large intestine. Both diseases involve inflammation of the intestinal wall, leading to pain, bleeding, and ultimately, in some cases, surgical removal of part of the bowel
MANTA
A Phase 2 semen parameter trial with filgotinib in male patients with CD or UC