Date: 2016-12-12
Type of information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in The Lancet
Company: Galapagos (Belgium) AbbVie (USA - IL)
Product: GLPG0634 (filgotinib)
Action
mechanism: janus kinase inhibitor.GLPG0634 is an orally-available, novel Janus kinase (JAK) inhibitor with selectivity for JAK1 developed by Galapagos. JAKs are critical components of signaling mechanisms utilized by a number of cytokines and growth factors, including those that are elevated in rheumatoid arthritis patients. JAK inhibitors have shown long-term efficacy in rheumatoid arthritis studies with an early onset of action. GLPG0634 differentiates from other JAK inhibitors in development by specifically targeting JAK1, a strategy which could result in a better efficacy and safety profile. In December 2015, Galapagos and Gilead entered into a global partnership for the development and commercialization of filgotinib for inflammatory indications for the development and commercialization of filgotinib for inflammatory indications.
Disease: Crohn's disease
Therapeutic area: Autoimmune diseases - Inflammatory diseases - Digestive diseases
Country: Belgium, Czech Republic, France, Germany, Hungary, Poland, Romania, Russian Federation, UK
Trial
details: The FITZROY Phase 2 study (174 patients) evaluated filgotinib once-daily versus placebo in patients with moderately to severely active Crohn's disease and mucosal ulceration. Patients recruited were either anti-TNF naïve or anti-TNF failures. The study comprised two parts, each of 10 weeks duration: the first part investigated the safety and efficacy of filgotinib 200 mg once daily versus placebo, while the second part of the study investigated continued treatment through 20 weeks in an observational exploratory design. (NCT02048618)
Latest
news: * On December 12, 2016, Galapagos reported publication of the FITZROY Phase 2 study with filgotinib in Crohn's disease in The Lancet. The FITZROY study achieved the primary endpoint of clinical remission at 10 weeks: the percentage of patients achieving a Crohn's Disease Activity Index (CDAI) score below 150 was significantly higher in patients treated with filgotinib versus patients receiving placebo. Improvement in quality of life, histopathology, endoscopy assessment and biomarkers of inflammatory activity were also observed at Week 10. Clinical responses were maintained from week 10 to week 20. Non-responders in the placebo arm from the first 10 weeks received filgotinib 100 mg in the second 10 weeks and showed improvement in clinical remission during the second part of the study. Overall, in the FITZROY study at 20 weeks of treatment, filgotinib demonstrated a favorable safety profile consistent with the previous DARWIN studies in RA. An increase in hemoglobin was also observed in FITZROY, without difference between filgotinib and placebo. No clinically significant changes from baseline in neutrophils or liver function tests were observed. * On September 26, 2016, Galapagos reports that Dr Severine Vermeire, principal investigator of the FITZROY Phase 2 study with investigational agent filgotinib in Crohn's disease, will present endoscopic and other key findings from the study in an oral session during United European Gastroenterology Week (UEG Week) in Vienna, Oct. 15 - 19, 2016. The FITZROY Phase 2 study randomized 174 patients with Crohn's disease. Across the study, the average baseline CDAI score was 293, with average baseline SES-CD score of 14.6. * On May 25, 2016, Galapagos announced the presentation of detailed results from the Phase 2 FITZROY study of filgotinib in Crohn's Disease, at Digestive Disease Week (DDW) 2016 in San Diego, CA, USA, held from 21-24 May. * On April 21, 2016, Galapagos reported 20-week results from the FITZROY study with filgotinib in Crohn's disease. 174 patients with moderately to severely active Crohn's disease were enrolled in this double-blind, placebo-controlled Phase 2 study. Patients recruited were either anti-TNF naïve or anti-TNF failures. The study comprised two parts each of 10 weeks duration: the first part - reported in December 2015 (see below) - investigated the safety and efficacy of filgotinib 200 mg once daily versus placebo. The FITZROY study achieved the primary endpoint of clinical remission at 10 weeks: the percentage of patients achieving a Crohn's Disease Activity Index (CDAI) score lower than 150 was significantly higher in patients treated with filgotinib versus patients receiving placebo. Improvement in histopathology and endoscopy assessments were observed at Week 10. Further evaluation is ongoing. The second part of the study investigated continued treatment through 20 weeks in an exploratory analysis that was not powered for statistical significance. Clinical responses continued from week 10 to week 20. Non-responders in the placebo arm from the first ten weeks received filgotinib 100 mg in the second ten weeks and showed improvement in clinical remission during the second part of the study. There were no new safety signals during the second part of the FITZROY study, consistent with the profile of filgotinib previously described. Most common adverse events observed during this study were infections, gastrointestinal disorders and nervous system disorders. There were no gastrointestinal perforations, no cancers and no deaths reported during the study. * On December 7, 2015, Galapagos announced that 200 mg filgotinib is shown to be effective and safe as once-daily, oral induction treatment in moderate to severe Crohn’s disease, based on the FITZROY phase 2 study at the 10-week interim analysis. The study achieved the primary endpoint of clinical remission: the percentage of patients achieving a CDAI score lower than 150 was significantly higher in patients treated with filgotinib versus patients receiving placebo. Filgotinib was shown to be well tolerated in the FITZROY study, strengthening its favorable safety profile. placebo filgotinib 200mg p-value Clinical remission 23 48 0.0067 (CDAI lower than 150) (%), ITT-NRI Clinical response 41 60 0.0386 (CDAI decrease 100 points or more) Total IBDQ score, 17.56 33.82 0.0045 mean change from baseline, ITTLOCF * On August 6, 2015, Galapagos announced that the last patient has been randomized in the FITZROY Phase 2 clinical study. The study evaluates the efficacy and safety of filgotinib, a selective JAK 1 inhibitor, during 20 weeks of treatment in 175 patients with Crohn's disease. The innovative design of the Phase 2 study with filgotinib evaluates induction of disease remission and explores early maintenance of its beneficial effects, potentially enabling a rapid entry into Phase 3 studies. Galapagos funded and conducted the Phase 2 study, recruiting patients with active Crohn's disease in 66 clinical centers in 9 countries throughout Western and Eastern Europe. Galapagos expects to announce topline primary endpoint results following 10 weeks of treatment in December 2015, with 20 weeks results expected in Q1 2016. The Phase 2 study in Crohn's disease is being performed in parallel with the DARWIN Phase 2B program for filgotinib in rheumatoid arthritis (RA). Galapagos expects to report final 24-week data from the second DARWIN study, evaluating filgotinib in a monotherapy setting, in August 2015. AbbVie has the exclusive right to license filgotinib upon its receipt of the final data package from the Phase 2B RA studies. In the event that AbbVie in-licenses filgotinib following receipt of the full data package from the DARWIN 1 and DARWIN 2 Phase 2B studies in RA, Galapagos will also be eligible to receive an additional $50 million payment if AbbVie elects to move forward with filgotinib in Crohn's disease after receipt of the complete data set from the Crohn's study. Galapagos is eligible to receive $50 M fee from AbbVie if AbbVie elects to in-license filgotinib after receipt of the full RA DARWIN 1 and 2 data and elects to move forward with filgotinib in Crohn's disease.
Variable/unit/population placebo filgotinib p-value
n=44 n=128
Clinical remission (CDAI<150), %, ITT-NRI 23 47 0.0077
SES-CD improvement by at least 50%, %, ITT-LOCF 13.6 25 NS
Overall total histopathology score, mean change from -0.6 -3.5 0.0359
baseline, ITT-LOCF
CDAI: Crohn's disease activity index; ITT: intent-to-treat; NRI: non-responder imputation; LOCF: last observation carried forward; SES-CD: simple endoscopic score for Crohn's disease; Histopathology score = Adaptation from histopathology score D'haens. Note that the FITZROY study was not powered for statistical significance on endoscopy.
Overall, filgotinib was safe and well tolerated. Similar incidences in early discontinuations, SAEs and AEs including infections were observed, with the majority of the SAEs related to worsening of CD. An increase in mean hemoglobin concentration was observed, without difference between filgotinib and placebo. No clinically significant changes from baseline in mean neutrophil counts or liver function tests were observed. Filgotinib showed a favorable lipid profile with an increase in HDL and no change in LDL, resulting in an improved atherogenic index.
Prof. Dr. Séverine Vermeire, the principal investigator of the FITZROY study, presented the results from this 174-patient study, initially reported in December 2015. Galapagos reported that the study achieved the primary endpoint of clinical remission: the percentage of patients achieving a Crohn's Disease Activity Index (CDAI) score lower than 150 was statistically significantly higher in patients treated with filgotinib versus patients receiving placebo. The oral presentation, "Filgotinib (GLPG0634), an oral JAK1 selective inhibitor, induces clinical remission in patients with moderate-to-severe Crohn's disease: results from the Phase 2 FITZROY study interim analysis," took place during the Clinical science late-breaking abstracts plenary session (abstract #2488299).
In this Phase 2 study, filgotinib also demonstrated improvement in quality of life (IBDQ). The rate of treatment-emergent adverse events was similar between the filgotinib and placebo arms. The results support further development of filgotinib in inflammatory bowel disease (IBD).
Galapagos also presented a poster entitled "The JAK1-selective inhibitor, filgotinib, reverses the disease signature of colon mucosa in experimental colitis." The authors reported filgotinib prevents the changes observed in mucosal gene expression induced by colitis, and that several of these genes also display changes in human IBD..
Galapagos and Gilead Sciences intend to submit the FITZROY 20-week results to future medical conferences. Gilead intends to initiate a Phase 3 study with filgotinib in Crohn's disease later in 2016.
175 patients with moderate to severe Crohn’s disease were enrolled in FITZROY, a double-blind, placebo-controlled study. Patients recruited were either anti-TNF naïve or anti-TNF failures. The full study has two parts of 10 weeks each: the first part – reported here - investigates the effect of filgotinib 200mg once daily versus placebo as induction therapy. As the study is still ongoing,
individual data remain blinded. Galapagos expects to report the full 20 week results for FITZROY in the first half of 2016.
Summary of clinical key endpoints after interim analysis at 10 weeks:
n=44 n=128
(%), ITT-NRI
Overall, in the FITZROY study, filgotinib demonstrated a favorable safety profile consistent with the previous DARWIN studies. Similar incidences in SAEs and AEs were observed between filgotinib and placebo, with the majority of the SAEs related to worsening of Crohn’s disease. In the FITZROY study, filgotinib showed a favorable lipid profile with an increase in HDL and no change in LDL, resulting in an improved atherogenic index. An increase in hemoglobin was also observed in FITZROY, without difference between filgotinib and placebo. No clinically significant changes from baseline in neutrophils or liver function tests were observed in this study. Galapagos now intends to move filgotinib to Phase 3.
