Clinical Trials

DARWIN 1 plans to enroll 595 patients with moderate to severe rheumatoid arthritis who insufficiently respond to methotrexate but remain on their background therapy of methotrexate. DARWIN 1 is a double-blind, placebo-controlled evaluation of three doses of GLPG0634, as once- and twice-daily administration. Following the closure of recruitment, the last patient will now be randomized in the study before the end of the month. Topline, blinded results from the first 12 weeks of treatment in DARWIN 1 are expected around the end of Q1 2015, with topline 24 weeks results expected three months later.

DARWIN 2 plans to enroll 280 patients with moderate to severe rheumatoid arthritis who insufficiently respond to methotrexate. DARWIN 2 is a double-blind, placebo-controlled investigation of three once-daily dose levels of GLPG0634 as monotherapy treatment. Completion of recruitment for DARWIN 2 is expected in the coming weeks. Topline results from 12 week results are expected in Q2 2015, with complete 24 week data package expected in Q3 2015. AbbVie will base its licensing decision on the complete 24 week DARWIN 1 and 2 data packages from GLPG0634.

* On November 8, 2015, Galapagos announced that it will present the full results from DARWIN 1 & 2 studies in rheumatoid arthritis, as well as other findings from research with filgotinib at the American College of Rheumatology (ACR) Annual Meeting in San Francisco, CA, from 8-10 November, 2015. These presentations and posters include:
Oral Presentation, abstract #1048 : “Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study,” Dr Rene Westhovens presenting. Over 12 weeks, filgotinib in combination with MTX demonstrated consistent efficacy on signs and symptoms of active RA with a rapid onset of action. The safety profile was favorable and consistent with previous studies conducted in RA with filgotinib.
Oral Presentation, abstract #1049: “Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective As Monotherapy in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study,” Dr Arthur Kavanaugh presenting. Over 12 weeks, filgotinib as monotherapy demonstrated clear efficacy in treating the signs and symptoms of active RA with a rapid onset of action. Overall safety profile was favorable and consistent with previous studies conducted in RA with filgotinib.
Poster presentation, abstract #1663: “Influence of Age and Renal Impairment on Pharmacokinetics of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor”. Higher age and mild to moderate impairment of renal function has a limited impact on the PK of filgotinib. In severe renal impairment, the exposure to filgotinib’s active metabolite is elevated, consistent with its renal elimination pathway. This was not associated with safety signals in these Phase 1 studies.
Poster presentation, abstract #1681: “4-Week Treatment of Rheumatoid Arthritis Patients with the JAK1-Selective Inhibitor Filgotinib (GLPG0634) Changes Lipid Profile with a Preferential Increase in HDL”. In RA patients treated for four weeks with filgotinib, the lipid profile changed, with a preferential increase in HDL, leading to an improvement in atherogenic index observed at 150 and 300 mg once-daily doses.
Poster presentation, abstract #1680: “Selective JAK1 Inhibition with Filgotinib (GLPG0634) Decreases Plasma Markers of
Inflammation and Joint Damage in Patients with Rheumatoid Arthritis” Treatment with filgotinib for four weeks in RA patients led to reductions in relevant inflammation biomarkers, indicating that JAK1 inhibition is sufficient to address inflammation in RA patients.
Poster presentation, abstract #2763: “Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, Shows Similar Pharmacokinetics
and Pharmacodynamics Profiles in Japanese and Caucasian Healthy Volunteers” Filgotinib showed comparable PK, PD and safety profiles in Japanese and Caucasian healthy volunteers. The similarity in the PK and PD response suggests that there are no relevant
differences among the groups in drug metabolism or selective inhibition of JAK1. These data support that filgotinib may be administered at similar doses in Japanese and Caucasian RA patients.
Poster presentation, abstract #2781:“Absence of Effects of Filgotinib on Erythrocytes, CD8+ and NK Cells in Rheumatoid Arthritis Patients Brings Further Evidence for the JAK1 Selectivity of Filgotinib”. In RA patients treated for 4 weeks with filgotinib, the absence of effects on numerous immune system factors and the improvement seen in hemoglobin demonstrated the high degree of
selectivity for JAK1 of filgotinib in RA patients.

* On August 10, 2015, Galapagos announced that filgotinib as once-daily monotherapy at week 24 showed further improvements in signs and symptoms of moderately to severe, active rheumatoid arthritis (RA) in the DARWIN 2 Phase 2B study. Filgotinib was well tolerated in this study. Hemoglobin levels increased. These final 24-week study results are consistent with the efficacy and safety profile of filgotinib observed in prior clinical studies. With these final results, the data package for AbbVie is complete, which triggers the start of the licensing decision period.

DARWIN 2 is a 24-week, double-blind, placebo-controlled evaluation of filgotinib, as once-daily administration (QD dosing) at 3 dose levels. Results were reported for 283 patients with moderate to severe rheumatoid arthritis who showed an inadequate response to methotrexate. Filgotinib or placebo was given as monotherapy. The patients were evaluated up to 24 weeks.

Summary of the ACR responses and DAS28(CRP) changes at 24 weeks of once-daily monotherapy:

ACR responses based on intent to treat (ITT) analysis, with non-responder imputation (NRI). Placebo was only given for a maximum duration of 12 weeks, so no comparisons were possible at Week 24. Mean baseline DAS28(CRP) varied between 6.0 and 6.2. The DAS28(CRP) is analyzed by ITT with last observation carried forward (LOCF).

The results from this study show a rapid onset of efficacy, as of week 1 for ACR and DAS28(CRP) responses. Maximum ACR20 and ACR50 responses were obtained at week 8 and week 12 respectively. Additional gain was reported for ACR70 and DAS28(CRP) during the second half of the study. In the highest dose groups, up to 50% of the patients reached low disease activity or remission. The 100 mg and 200 mg QD doses achieve similar levels of efficacy. Over all dose groups including placebo, 3.9% of patients stopped treatment during the study for safety reasons. A higher discontinuation rate for safety was observed for placebo (5.6%) during the first 12 weeks of the study compared to filgotinib treated patients (2.5%) up to week 24. Similar incidence of serious and non-serious treatment-emergent adverse events was reported, evenly spread over the dose groups including placebo. A higher rate of infections was observed in filgotinib (19% over 24 weeks) compared to placebo (10% up to week 12), with serious infections remaining limited (1.4% of filgotinib patients). No malignancies, TB, MACE, opportunistic infections, or death were reported. Consistent with its selective JAK1 inhibition, filgotinib treatment led to an improvement in hemoglobin (up to 0.4 g/dL, or 3.6% increase from baseline). Neutrophil levels remained stable after initial decline to mid-normal range at week 4. There was no impact on lymphocytes or liver function tests. The similar increases in LDL and HDL were maintained. Galapagos is now looking forward to Abbvie's in-licensing decision.

* On July 29, 2015, Galapagos announced that at week 24, patients treated with filgotinib showed further improvement in signs and symptoms of rheumatoid arthritis activity, as demonstrated by improved ACR responses, DAS28(CRP), and other scores, compared to week 12 in the DARWIN 1 Phase 2B methotrexate add-on study. In this study, filgotinib was well tolerated. The initial increase in hemoglobin levels was sustained to week 24. The higher relative increase in HDL compared to LDL remained stable over 24 weeks. Lymphocyte counts were not impacted by filgotinib. These 24 week results are consistent with the efficacy/safety profile of filgotinib previously observed.

DARWIN 1 was a 24 week, double-blind, placebo-controlled evaluation of filgotinib, as once- and twice-daily administration (QD and BID dosing) at 3 daily dose levels. Final results are reported for all 594 patients with moderate to severe rheumatoid arthritis who showed an inadequate response to methotrexate and who remained on their background therapy of methotrexate. These patients received filgotinib or placebo and were evaluated up to 24 weeks. 

Summary of the ACR/DAS28(CRP) scores at week 24:

* p< 0.05 vs. placebo; ** p

Overall, there was no statistically relevant difference between the once-daily and twice-daily dosing regimens. Since this is the final analysis, the 24-week DARWIN 1 safety data are unblinded. Over all dose groups including placebo, 3.9% of patients stopped treatment during the study for safety reasons. Patients reporting serious (2.5% overall) and non-serious treatment-emergent adverse events were evenly spread over the dose groups including placebo. Serious infections were reported in 6 patients, including one death on active treatment in the second half of the study and for which the DSMB (Data Safety Monitoring Board) did not see a reason to pause or change the study. No opportunistic infections were reported. Herpes zoster infection occurred in 5 patients, equally spread over placebo and filgotinib groups. Consistent with its selective JAK1 inhibition, filgotinib treatment led to an improvement in hemoglobin (up to 0.5 g/dL, or 4% increase from baseline). All lipid fractions including HDL and LDL increased, with the largest percentage increase in HDL. Lymphocytes were not impacted by treatment with filgotinib in this study. No clinically significant changes or discontinuations were observed for male reproductive hormones. Galapagos anticipate the DARWIN 2 week 24 results in just a few weeks, the AbbVie licensing decision after that, and the FITZROY Crohn's disease Phase 2 study 10 week interim results before year end.

* On June 10, 2015, Galapagos announced that the last rheumatoid arthritis patients in its DARWIN 1 and 2 dose finding studies with filgotinib have completed their final visit. This triggers the clinical research organization's process of last 24 week data collection from both studies, to be followed by final database lock and analysis. Galapagos expects to announce topline results in late July (DARWIN 1) and in August (DARWIN 2) 2015. The last patients in the studies have completed treatment and have now rolled over to DARWIN 3, the open-label, long-term extension study with filgotinib.

Results at 12 weeks: The DARWIN 1 and DARWIN 2 studies both met their primary endpoint at 12 weeks of treatment with the selective JAK1 inhibitor filgotinib. Patients in both studies showed improvements in signs and symptoms of active RA and both studies met key efficacy endpoints at 12 weeks of treatment with filgotinib: statistically significant ACR50 scores were achieved with all dose levels and dose regimens, and statistically significant improvement in DAS28(CRP) was seen within one week. Filgotinib was also well tolerated and showed a differentiated safety profile at 12 weeks in RA patients. Hemoglobin levels increased, consistent with JAK1 selectivity.

Completion 24 weeks: Filgotinib has now been evaluated in a global Phase 2B program (DARWIN 1, 2 and 3) in 886 RA patients. Topline results from 24 weeks' treatment in DARWIN 1 and 2 will include efficacy scores and unblinded lab and safety information.

* On April 27, 2015, Galapagos announced that the selective JAK1 inhibitor filgotinib as once-daily monotherapy showed rapid improvements in signs and symptoms of moderately severe, active rheumatoid arthritis (RA) and met key efficacy endpoints after 12 weeks of treatment in the DARWIN 2 Phase 2B study. The study achieved its primary endpoint at all doses and demonstrated statistically significant improvements in ACR20 response versus placebo after 12 weeks of treatment. In addition, statistically significant ACR50 response and DAS28(CRP) decrease were achieved with all dose levels. Filgotinib was well tolerated in this study. Hemoglobin levels increased. These first 12 week results in the ongoing 24 week study are consistent with the efficacy and safety profile of filgotinib observed in prior clinical studies. Results were reported for 283 patients with moderate to severe rheumatoid arthritis who showed an inadequate response to methotrexate. Galapagos expects to report the full 24 week results for DARWIN 2 in the 3rd quarter of this year. Summary of the ACR responses and DAS28(CRP) changes at 12 weeks of once-daily monotherapy:

* p< 0.05 vs. placebo; ** pACR responses based on intent to treat (ITT) analysis, with non-responder imputation (NRI).

Mean baseline DAS28(CRP) varied between 6.0 and 6.2. The DAS28(CRP) is analyzed by ITT with last observation carried forward (LOCF).

The results from this study show a rapid onset of efficacy, with ACR20 response, investigator's assessment of disease and patient-reported improvements (global assessment of disease and pain) reaching statistical significance after one week of treatment. Over all dose groups including placebo, 1.8% of patients stopped treatment during the study for safety reasons. Within this low number of discontinuations, the distribution across treatment groups is not disclosed to avoid individual treatment unblinding while the study is ongoing. Serious (2% overall) and non-serious treatment-emergent adverse events overall were evenly spread over the dose groups including placebo. Infections and infestations were the most common (15% for filgotinib vs 10% for placebo), with only 2 (0.7%) serious infections which remain blinded for the treatment group. Consistent with its selective JAK1 inhibition, filgotinib treatment led to a dose-dependent improvement in hemoglobin (up to 0.4 g/dL, or 3.4% increase from baseline). A decline in neutrophils, consistent with anti-inflammatory activity, was observed during the first 4 weeks, with stable levels in the normal range thereafter. No discontinuations due to anemia, neutropenia, or increase in transaminases were reported. Dose-dependent, well-balanced increases in LDL and HDL were observed.

* On November 24, 2014, Galapagos announced that recruitment of rheumatoid arthritis (RA) patients for the Darwin 2 study with GLPG0634 has been completed. The Darwin Phase 2B program is now fully recruited and will begin a series of topline readouts starting around end of the first quarter 2015. Topline results from 12 weeks are expected in April 2015, with complete 24 week data package expected in Q3 2015. AbbVie will base its licensing decision on the complete 24 week DARWIN 1 and 2 data packages from GLPG0634.

* On November 12, 2014, Galapagos announced that recruitment of rheumatoid arthritis  patients for the Darwin 1 Phase 2B study with GLPG0634 has been completed. Selective JAK1 inhibitor GLPG0634 (filgotinib) has shown a best-in-class profile in two 4-week Phase 2A studies in rheumatoid arthritis patients. GLPG0634 is currently in a global Phase 2B program (DARWIN) in 875 rheumatoid arthritis patients and in a Phase 2 study in 180 patients with Crohn's disease.

* On September 18, 2014, Galapagos announced that more than 100 patients have completed the six month Darwin 1 and 2 studies with GLPG0634 in rheumatoid arthritis and entered Darwin 3, the long term extension study. With the support of their treating physicians, over 90% of the patients who participated in Darwin 1 and Darwin 2 have chosen to participate in Darwin 3, in which all patients will receive long term treatment with Galapagos' highly selective JAK1 inhibitor. The Darwin Phase 2B program initiated last year with GLPG0634 includes two dose finding studies (595 patients: Darwin 1/methotrexate add-on and 280 patients: Darwin 2/monotherapy) and an open label extension study (Darwin 3). Over 1,000 patients have been screened to date, and overall recruitment is making good progress.

* On July 1, 2013, Galapagos has announced that the first rheumatoid arthritis patients have been screened for enrolment in the Phase 2B clinical program with GLPG0634, a selective JAK1 inhibitor. The DARWIN Phase 2B program includes two dose finding studies and an open label extension study. The dose finding studies will evaluate the efficacy and safety of GLPG0634 with 24 weeks of treatment in 875 moderate to severe rheumatoid arthritis patients refractory to methotrexate. The results of two 4-week Phase 2A clinical studies demonstrated the rapid clinical benefit and favorable safety profile of the drug, and supported the selection of the GLPG0634 doses that will be evaluated in the current Phase 2B program.  Galapagos started the 24-week global DARWIN Phase 2B program in RA to identify the dose and dose-regimen that offers optimal efficacy and safety of GLPG0634 in patients with moderate to severe RA.  Galapagos expects to report completion of recruitment by mid-2014 and 12-week topline data from the Phase 2B program in Q4 2014. By early 2014, Galapagos will have Phase 2 programs with GLPG0634 in RA and Crohn's, both with final readouts before mid-2015. Upon successful completion of the Phase 2B studies in RA, AbbVie will license the program and will assume sole responsibility for Phase 3 clinical development and global manufacturing.

* On April 17, 2013, Galapagos has announced an expansion of the Phase 2b program with GLPG0634 in rheumatoid arthritis. The total number of patients to be included in the Phase 2b program will be expanded to 875, which will facilitate a final dose and regimen selection for Phase 3 clinical studies. Galapagos expects to report topline data from the Phase 2b program in Q4 2014. AbbVie will provide an additional payment of $20 million to Galapagos prior to the start of the Phase 2b program in RA to fund the program's expansion to 875 patients. The scope of the Phase 2 'Darwin' studies is as follows:

Darwin 1 - Add-on to MTX

200 mg QD  85 patients (pt) ; 100 mg  QD 85 pt ; 50 mg  QD 85 pt ;

100 mg BID 85 pt ; 50 mg BID 85 pt ; 25 mg BID 85 pt ;

Placebo  85 pt  

TOTAL  595 pt