Filgotinib in RA
RA is a chronic autoimmune disease that affects approximately more than three million patients in the United States and Europe. RA is characterized by inflammation and degeneration of the joints. Patients suffer from pain, stiffness, and restricted mobility due to a persistent inflammation of multiple joints, ultimately resulting in irreversible damage of the joint cartilage and bone. The market for RA treatments in the EU5 currently is approximately €3.2 billion, with 60% of patients treated with advanced therapies, including injectables, biological therapies and tsDMARDS.
Despite there being many approved agents, considerable unmet need exists, as only one in five patients achieves full remission in the first year of treatment.
Oral therapies targeting the Janus kinase (JAK) signaling pathway are approved to treat inflammatory diseases. We discovered JAK1 in an inflammation target discovery assay in 2003 and subsequently developed filgotinib as a small molecule inhibitor with preferential selectivity for JAK1.
Filgotinib is a once daily, oral, preferential JAK1 inhibitor that has undergone extensive testing in Phase 1 and Phase 2 in RA, demonstrating a durable response with a consistent safety profile in RA patients. These studies supported progression to Phase 3 trials in RA. DARWIN 3 (NCT02065700), a multi-center, open-label, long-term follow up safety and efficacy trial of subjects who completed either DARWIN 1 or DARWIN 2 Phase 2b trials, is still ongoing today.
FINCH Phase 3 program
The safety and efficacy of 100 mg and 200 mg filgotinib once daily were investigated in the FINCH clinical Phase 3 program which was initiated in August 2016 and which includes four Phase 3, randomized, multicenter studies in patients with moderate to severe RA.
The studies were designed to characterize the efficacy and safety of filgotinib in several key patient populations following the typical RA treatment pathway. These included:
- Patients who had an inadequate response to methotrexate (MTX) (FINCH 1, NCT02889796)
- Patients with difficult-to-treat RA and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARDs) (FINCH 2, NCT02873936)
- MTX-naïve patients (FINCH 3, NCT02886728)
- Eligible patients could also roll-over into a long-term extension study which is still ongoing (FINCH 4, NCT03025308)
In animal toxicology studies in the preclinical phase, filgotinib at a certain high dose induced adverse effects on the male reproductive system. Consequently, Gilead and Galapagos are performing dedicated male patient semen analysis trials in inflammation (RA, CD, UC, AS, and PsA) patients, called MANTA and MANTA-RAy, concurrent to all Phase 3 programs.
Recently, we announced the interim results and the primary endpoint. In total, 248 patients were randomized 1:1 to receive filgotinib 200 mg once daily or placebo for an initial 13-week, double-blind treatment period. The primary endpoint in both trials was the proportion of patients who had a reduction of 50% or more in sperm concentration at week 13. Patients who met this endpoint discontinued study treatment at week 13, were switched to standard of care treatment and were monitored for reversibility every 13 weeks for up to 52 weeks.
Out of the 248 randomized patients, 240 reached week 13 with two evaluable semen samples at baseline and week 13. Of those, 18 patients showed a ≥50% decline in sperm concentration, with 10/120 (8.3%) patients on placebo and 8/120 (6.7%) patients on filgotinib. These studies, which were designed with the input of the relevant health authorities, are not powered for statistical comparison between groups. These data will now be submitted to relevant regulatory authorities.
Beyond the double-blind, placebo-controlled, 13-week period, for which MANTA and MANTA-RAy results are pooled, patients who did not meet the primary endpoint of 50% or more decline in sperm motility or morphology could continue under their respective trial protocol on blinded treatment, receive open-label filgotinib or receive standard of care therapy based on disease response, for another 13 weeks before entering a long-term extension period. At any point, patients exhibiting a predetermined sperm decline enter a monitoring phase in which they are assessed every 13 weeks for reversibility for up to 52 weeks.
As the MANTA and MANTA-RAy trials are ongoing, and to maintain data integrity, Galapagos and Gilead intend to report additional results only after all patients in the monitoring phase have completed the protocol-defined observation period.
When the MANTA and MANTA-RAy trials are completed, Galapagos and Gilead intend to submit the full results for publication in a peer-reviewed medical journal.
FINCH 1 results
The FINCH1-study achieved its primary endpoint for both doses of filgotinib in the proportion of patients achieving an American College of Rheumatology 20% response (ACR20) compared to placebo at week 12.
The FINCH 1 trial data were presented virtually at the 2020 Annual European Congress of Rheumatology (Combe et al. 2020) and published in The Annals of the Rheumatic Diseases (Combe et al. 2021).
FINCH 2 results
In the difficult to treat bDMARD insufficient responder population, filgotinib achieved its primary endpoint in the FINCH 2 trial in the proportion of patients achieving an American College of Rheumatology 20 percent response (ACR20) at week 12. The clinical efficacy and quality of life outcomes assessed at week 12 and week 24 were presented at the Annual ACR meeting 2019 (Genovese et al.) and the FINCH 2 results were published in The Journal of the American Medical Association, JAMA (Genovese et al. 2019).
FINCH 3 results
At week 24, the study achieved its primary endpoint of the proportion of patients achieving an American College of Rheumatology 20 percent response (ACR20). The proportion of patients achieving the primary endpoint of ACR20 response at week 24 was significantly higher for filgotinib 200 mg plus MTX and filgotinib 100 mg plus MTX compared with MTX alone.
The FINCH 3 trial data were presented at the 2019 virtual European League Against Rheumatism annual meeting (Westhovens et al. 2019) and published in The Annals of the Rheumatic Diseases (Westhovens et al. 2021).
FINCH safety data
We and Gilead presented integrated safety data from 7 RA studies at the Annual EULAR E-Congress of Rheumatology 2020 (Winthrop et al). Data were integrated from 3 Phase 3 trials (FINCH 1–3), 2 Phase 2 trials (DARWIN 1, 2), and 2 long-term extension (DARWIN 3, FINCH 4) trials including up to 5.5 years of filgotinib exposure. In this pooled analysis, filgotinib was well-tolerated, and no new safety concerns were identified. Adverse events of MACE and DVT/PE were rare and occurred in similar numbers among all treatment groups. Herpes zoster reactivation was not increased in the filgotinib groups compared with the other treatment groups. The data highlight the acceptable safety and tolerability profile of filgotinib as monotherapy and in conjunction with MTX/csDMARDs3csDMARD, conventional synthetic disease-modifying antirheumatic drugs in RA.
In animal toxicology studies in the preclinical phase, filgotinib induced adverse effects on the male reproductive system. Consequently, Gilead and Galapagos are performing dedicated male patient semen analysis trials in inflammation (RA, CD, UC, AS, and PsA) patients, called MANTA and MANTA-RAy, concurrent to all Phase 3 programs. Primary endpoint data from week 13 from the MANTA and MANTA-RAy studies were reported in March 2021.
FINCH 4 is a multi-center, open-label, long term extension study to assess the safety and efficacy of filgotinib in subjects with RA, enrolling patients who completed either FINCH 1, FINCH 2, or FINCH 3 studies.
Post EC approval completed clinical studies with filgotinib
A DDI study (NCT04608344) was conducted in the form of an open-label, randomized, two-way, crossover study in healthy adult volunteers (n=27), evaluating the effect of filgotinib on the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin, which are sensitive substrates for the OATP-1B1/1B3, and the short-term safety of administering filgotinib with or without statins. All study treatments were generally well tolerated. Co-administration with filgotinib did not have a clinically meaningful impact on the exposure of atorvastatin, pravastatin, and rosuvastatin.
Regulatory approvals of filgotinib in RA
Filgotinib (200 mg and 100 mg) was approved in the EU and Japan for the treatment of adult patients with moderate to severe RA in September 2020. Filgotinib, a once-daily, oral, JAK1 preferential inhibitor was discovered and developed by us using our target and drug discovery technology platform. Based on the robust clinical trial results from the global FINCH Phase 3 and DARWIN Phase 2 programs, including more than 4,500 patient years of RA clinical study experience, filgotinib has shown favorable results in terms of onset of action, efficacy, safety, and tolerability. Patients receiving filgotinib once daily showed improvements in clinical signs and symptoms, decreases in disease activity, and less progression of structural damage in joints. As only one in five RA patients achieves full remission in the first year, despite there being many approved agents, filgotinib offers a welcome new treatment option for adult patients struggling with this challenging and complex disease in Europe and Japan.
In the U.S., a CRL was received from the U.S. FDA for the New Drug Application (NDA) for filgotinib. The FDA requested data from the MANTA and MANTA-RAy studies before completing its review of the NDA. The MANTA and MANTA-RAy studies are designed to assess whether filgotinib has an impact on sperm parameters. The FDA also expressed concerns regarding the overall benefit/risk profile of the filgotinib 200 mg dose. After meetings with the FDA following the CRL, Gilead decided not to advance with resubmission of filgotinib in the US for approval as a treatment for RA.
Commercialization of Jyseleca in RA
We and Gilead prepared to co-commercialize filgotinib in Europe, with Galapagos leading on the commercial launches in 8 of the 27 countries. With the approval of filgotinib by the European Commission in September 2020, we and Gilead commenced negotiation of access for filgotinib in member countries. Following our revised agreement with Gilead for filgotinib in Europe, we are in the process of taking over full commercial responsibility for filgotinib in RA in all 27 countries in Europe, anticipated to be substantially completed by the end of 2021. The graphic below describes the planned transition timing and relative importance of each region in Europe. See details on the revised Gilead collaboration on filgotinib in the Notes to the consolidated financial statements.
The transition to take over full commercial operations in Europe has been planned to preserve launch momentum. We are in the process of establishing a competitive sales force to support current and potential future indications in Europe. Building this pan-European commercial operation is an acceleration of our commercial strategy in place for products under the separate ten-year research and development collaboration between us and Gilead, where we are responsible for all European commercialization.
1 csDMARD, conventional synthetic disease-modifying antirheumatic drugs