Filgotinib in IBD
Current treatments for IBD, including UC and CD, are dominated by anti-TNF agents.
We observed high activity and a favorable tolerability profile in a Phase 2 trial with filgotinib in CD, as reported in The Lancet (Vermeire et al. 2016). We and Gilead reported that filgotinib achieved the primary endpoint in the SELECTION Phase 3 trial in UC in 2020.
Should filgotinib be approved commercially for IBD indications, Galapagos will be lead commercial sales responsible in Europe. All other countries ex-Europe will be Gilead’s commercial sales responsibility.
Global SELECTION Phase 3 program in UC
UC is an inflammatory bowel disease resulting in ulcerations and inflammation of the inner layer of the colon and rectum. We estimate that the current market for UC treatments worldwide is $5 billion and in Europe €0.8 billion.
Although the introduction of advanced therapies has improved the treatment of some patients, 30% of patients experience primary non-response,1Allez M et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological aspects. J Crohns Colitis. 2010 Oct;4(4):355-66 and 19% to 59% of initial responders do not sustain treatment response.2Ma C et al. Outpatient Ulcerative Colitis Primary Anti-TNF Responders Receiving Adalimumab or Infliximab Maintenance Therapy Have Similar Rates of Secondary Loss of Response. J Clin Gastroenterol. 2015 Sep;49(8):675-82, 3Shmidt E et al. Predictors and Management of Loss of Response to Vedolizumab in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2018 Oct 12;24(11):2461-2467 The medical need for improved efficacy is high.
SELECTION was a global Phase 3 trial (NCT02914522) investigating efficacy and safety of 100 mg and 200 mg filgotinib once-daily compared to placebo in 1,348 patients with moderately to severely active disease including those with prior antibody therapy failure. Men and women in SELECTION were randomized to receive placebo, 100 mg, or 200 mg filgotinib. Due to preclinical findings with filgotinib regarding semen parameters, in the U.S., randomization to 200 mg was restricted to male patients who have failed at least one anti-TNF therapy and vedolizumab, a monoclonal anti-integrin antibody marketed by Takeda. Adjacent to the filgotinib Phase 3 programs, we and Gilead are conducting dedicated studies evaluating potential impact of filgotinib on semen in male CD and UC patients (MANTA) and in RA, PsA, and AS patients (MANTA-RAy).
We announced topline data from the SELECTION trial in May 2020. Filgotinib 200 mg achieved all primary endpoints in the SELECTION study, inducing clinical remission at week 10 and maintaining clinical remission at week 58 in a significantly higher proportion of patients compared with placebo. Filgotinib 100 mg did not achieve statistically significant clinical remission at week 10.
In the SELECTION trial, clinical remission was defined as an endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and ≥ 1 point decrease in stool frequency from baseline to achieve a subscore of 0 or 1. Among the biologic-naïve cohort (Cohort A induction trial; n=659), 52 percent of patients had a baseline Mayo Clinic Score (MCS) of nine or higher. In the biologically-experienced cohort (Cohort B induction trial; n=689), 74 percent of patients had a baseline MCS of nine or higher, and 51 percent were previously treated with two different classes of biologics (TNFα antagonists and an integrin receptor antagonist).
Rates of serious infections, herpes zoster, venous thrombosis, pulmonary embolism and gastrointestinal perforation were low and comparable across treatment groups in both the induction and maintenance phases of the study. Two deaths were observed in the filgotinib 200 mg treatment group in the maintenance trial. One patient with pre-existing asthma died due to asthma exacerbation, and the second patient with pre-existing atherosclerosis died due to left ventricular heart failure per autopsy report. Neither death was deemed as related to study drug by the investigator.
We recently announced the interim results and primary endpoint of the ongoing MANTA and MANTA-RAy studies. The data are expected to be submitted to relevant regulatory authorities by our collaboration partner Gilead.
Applications for approval of filgotinib in UC
We announced validation of the marketing application for filgotinib in the treatment of UC by the European Medicines Agency in November 2020. We anticipate that Gilead will submit filgotinib for approval in UC to the Japanese Ministry of Health, Labor, and Welfare (MHLW) in the first half of 2021. We and Gilead expect decisions on potential approvals in Europe in the course of 2021 and in Japan in the first half of 2022.
A further, potential regulatory path for approval in UC and CD in the U.S. is pending the discussion of the MANTA and MANTA-RAy semen parameter studies with FDA.
Commercialization of filgotinib in UC
We are responsible for commercial sales operations for UC in Europe, pending approval in that indication. We anticipate an incremental increase in commercial costs in 2021 for this potential additional indication. Gilead will be responsible for commercial sales outside Europe, should filgotinib be approved for UC outside of Europe.
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. We estimate that the global market size for CD treatments today is $14 billion, of which approximately €1.7 billion in the five largest European markets
Today, with the most advanced therapies, 30-40% of CD patients on treatment achieve prolonged clinical remission. There are currently no highly effective oral therapies approved for CD and, similar to 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 per year in placebo-controlled trials. In data with more recent compounds, the sustainability of response is decreased to 10-15% loss of efficacy per year. There continues to be a considerable unmet need with these existing treatments. Dysregulation of the JAK signaling pathway has also been associated with CD, which suggests that filgotinib, with its preferential selectivity for JAK1, is a highly attractive candidate for the treatment of CD. It is hypothesized that with preferential inhibition of JAK1, unwanted effects such as anemia may be reduced. This is of particular importance to IBD patients, who frequently experience fecal blood loss.
Our FITZROY Phase 2 trial (NCT02048618) evaluated the efficacy and safety of once-daily filgotinib in 174 patients with moderate to severe active CD and mucosal ulceration. Patients recruited 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. The DIVERSITY Phase 3 trial investigates the efficacy and safety of 100 mg and 200 mg filgotinib once-daily compared to placebo in patients with moderate to severe active disease including those with prior antibody therapy failure. Gilead will recruit approximately 1,300 patients from the United States, Europe, Latin America, Canada, and Asia/Pacific regions. Men and women in the DIVERSITY trial will be randomized to receive placebo, 100 mg, or 200 mg filgotinib. Due to preclinical findings with filgotinib regarding semen parameters, in the U.S. randomization to 200 mg was restricted to male patients who have failed at least one anti-TNF therapy and vedolizumab. Adjacent to the filgotinib Phase 3 programs, we and Gilead are conducting dedicated studies evaluating the potential impact of filgotinib on semen in male CD and UC patients (MANTA) and in male RA, PsA, and AS patients (MANTA-RAy). We anticipate that Gilead will complete recruitment for DIVERSITY in 2021.
In March 2017, Gilead initiated a Phase 2 trial in small bowel CD (DIVERGENCE 1, NCT03046056) and a Phase 2 trial in fistulizing CD (DIVERGENCE 2, NCT03077412). Gilead stopped recruitment early for DIVERGENCE 1 in small bowel CD, completing the randomized, placebo controlled trial to 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 trial in CD.
CDAI remission in DIVERGENCE 1
Notes: data on file, CDAI remission = CDAI <150, recruitment for the DIVERGENCE 1 study was stopped early.
Gilead retains operational responsibility for the current trials in Crohn’s disease pursuant to the binding term sheet for filgotinib which we entered into in December 2020.