dm+d

39046711000001100

New Medicines

JyselecaRheumatoid arthritis (RA), moderate-to-severe

Information

Jyseleca
New molecular entity
Galapagos
Galapagos

Development and Regulatory status

Launched
Launched
Not approved
November 2020
Feb 21Gilead will not pursue US approval of filgotinib for rheumatoid arthritis and instead will pay Galapagos to take over most ongoing clinical trials and return responsibility for the drug in Europe, where it is approved and launched [28].
Dec 20US FDA reject the NDA for Jyseleca over safety concerns around its impact on sperm parameters in men and over the overall benefit/risk profile of the 200 mg dose.[27]
Nov 20Available in the UK. 100mg, 30=£863.10 and 200mg, 30=£863.10 (hospital only) [26].
Sep 20The EC has granted marketing authorization for filgotinib 200 mg and 100 mg tablets, a once-daily, oral, JAK1 inhibitor for the treatment of adults with moderate to severe active rheumatoid arthritis (RA) who have responded inadequately to, or are intolerant to, one or more disease modifying anti-rheumatic drugs [25].
Aug 20The US FDA have issued a Complete Response Letter (CRL) requesting data from the MANTA and MANTA-RAy studies (designed to assess filgotinib´s impact on sperm) before completing its review of the NDA. They also express concerns regarding the overall benefit/risk profile of the 200 mg dose. The company plan to work with the FDA to provide the data. Analysts suggest that the earliest timeline for approval in the US, if data support it, would be during 2022. [24]
Jul 20Recommended for EU approval by CHMP - the full indication is "for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). It is proposed that treatment with the medicine should be initiated by a physician experienced in the treatment of rheumatoid arthritis." [23]
Feb 20Analysts predict this will be one of the top 10 most-anticipated new US drug launches of 2020 based on estimated global sales in 2024 [22].
Dec 19Gilead has submitted a New Drug Application to the U.S. FDA for filgotinib, an investigational, oral, selective JAK1 inhibitor for the treatment of adults who are living with moderate-to-severe rheumatoid arthritis [21].
Oct 19Gilead announced plans to file an NDA with the FDA by the end of 2019. [20]
Aug 19Filed in the EU via the centralised procedure. The filing is based on the PIII FNCH studies. Gilead plans to file in the US before end 2019 [19].
Dec 17Galapagos takes up co-promotion rights for major European markets (Germany, France, Italy, Spain and the UK), plus the Benelux countries, and will share equally in profits / losses in those countries [11].
Aug 16PIII FINCH 2 study starts [10].
Dec 15Galapagos and Gilead are to partner for the global development and commercialization of filgotinib in inflammatory and autoimmune diseases, starting with initiation of PIII trials in RA. Gilead will be responsible for manufacturing and worldwide marketing activities. Galapagos has the option to co-promote filgotinib in the UK, Germany, France, Italy, Spain, Belgium, the Netherlands and Luxembourg [7].

Category

A selective JAK1 inhibitor.
Prevalence ranges from 0.5-1.5% of the population in industrialised countries. The incidence of the condition is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year [3].
Rheumatoid arthritis (RA), moderate-to-severe
Oral

Further information

Yes

Trial or other data

Oct 19Week 52 data from the Phase III FINCH 1 and FINCH 3 trials of filgotinib indicated a favorable safety profile seen in the first 24 weeks, inc. similar rates of thrombotic events as previously observed, as well as persistent efficacy.
Jul 19PIII FINCH 2 RCT (n=449) reported that more patients achieved the primary endpoint of ACR20 versus placebo at 12 weeks (filgotinib 200 mg, 66.0%, 100 mg, 57.5%, placebo 31.1%; difference vs placebo: 34.9% and 26.4%, respectively; both p>0.001) [18].
Jul 19Gilead announced plans to file a New Drug Application with the US FDA for filgotinib in RA after the PIII FINCH 3 trial acheived its primary endpoint.[17]
Apr 19PIII trial FINCH 1 evaluated filgotinib vs adalimumab or placebo, on a stable dose of methotrexate in patients with inadequate response to methotrexate. The study achieved its primary endpoint for both doses (100mg and 200mg) of filgotinib in the proportion of patients achieving an American College of Rheumatology 20 percent response (ACR20) compared to placebo at Week 12 (76.6%, 70.8% and 49.9% respectively) . The proportion of patients achieving ACR50 and ACR70 response was also significantly greater for filgotinib compared with placebo at Week 12, for both doses. Comparing low disease activity rates at Week 12, filgotinib 200 mg was non-inferior to adalimumab (49.7% vs 43.4%) [16].
Mar 19Positive 24-week results from the PIII FINCH 3 study have been announced. ACR20 achieved by 81% patients on filgotinib 200mg + MTX and 80.2% on filgotinib 100mg + MTX (p<0.001 and p<0.05 respectively compared to MTX alone [ACR20 71.4%]). Serious adverse events seen in 4.1%, 2.4%, 4.8% and 2.9% of patients receiving filgotinib 200mg + MTX, folgotinib 100mg + MTX, filgotinib 200mg monotherapy, and MTX alone. Major cardiovascular events were reported for patients treated with filgotinib 200mg + MTX (n=2), filgotinib 200mg monotherapy (n=1) and the MTX monotherapy arm (n=2). Serious infections were reported in all four treatment arms. The FINCH3 study is ongoing to 52 weeks [14,15].
Mar 19Filgotinib meets primary endpoint in ongoing 52-week PIII FINCH 1 RA study (n=1759). 76.6%, 69,8% and 49.9% of patients on 100mg, 200mg and placebo, respectively, achieved an ACR20 improvement response at week 12 (p<0.001 for both doses) [13].
Sep 18PIII study in adults with moderately-to-severely active rheumatoid arthritis and prior inadequate response/intolerance to biologic agents (FINCH 2), achieved its primary endpoint in the proportion of patients achieving an American College of Rheumatology 20 percent response (ACR20) at Week 12 ( 66.0% with filgotinib 200mg vs 31.1% with placebo) [12].
Aug 16FINCH 3 trial will enroll MTX-naïve patients [10].
Aug 16The FINCH trial program includes three studies with filgotinib. FINCH 1 is a 52-week, randomized, placebo- and adalimumab-controlled study in combination with methotrexate (MTX) in an expected 1,650 patients who have had inadequate response to MTX. The primary endpoint is ACR20 at week 12. The study will also include radiographic assessment at weeks 24 and 52 [9].
May 16Galapagos and Gilead confirm that their upcoming PIII trial will use 200-mg doses of filgotinib, putting to bed concerns that a link to testicular toxicity would force the partners to limit the amount of the drug administered in the study [8].
Sep 15PIII studies to commence in rheumatoid arthritis by early 2016. [6]
Jul 15The final results of the DARWIN 1 study have been reported. At 24 weeks, pts treated with filgotinib showed further improvement in signs and symptoms of RA activity. Up to 64% of pts achieved DAS28(CRP) remission or low disease state and up to 39% showed ACR70 response vs placebo (p<0.001). Overall, there was no statistically relevant difference between the once-daily and twice-daily dosing regimens. The safety profile was consistent with data at week 12: increased haemoglobin, higher increases in HDL than LDL, no change to lymphocyte counts [5].
Apr 15Filgotinib met the primary outcome vs. placebo in improving disease symptoms after 12 weeks in a study in RA pts who don´t respond to methotrexate. In the trial, all three dose levels of the oral treatment significantly outperformed placebo in getting patients to ACR20 (at least 80% of subjects charted a 20% or more reduction in symptoms). All three doses also hit statistical significance on ACR50, a secondary goal, but missed on ACR70 at 12 weeks. Each dose also marked a significant improvement in Disease Activity Score, a composite of RA measurements. Now the 283-patient trial will continue through 24 weeks [4].
Apr 15NCT01888874 = DARWIN 1. Patients are being recruited from sites worldwide including the US & EU (but not UK) [2].
Apr 15DARWIN 1 is an ongoing, 24 week, double-blind, placebo-controlled evaluation of filgotinib, as once- and twice-daily administration (QD and BID dosing) at 3 daily dose levels. Results were reported for 594 patients with moderate to severe RA 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 12 weeks, the time of the primary endpoint of the study. Galapagos expects to report the full 24 week results for DARWIN 1 around the middle of the year. Overall, there were no statistically relevant differences for the once-daily and twice-daily dosing regimens. The results suggest a rapid onset of activity, already after one week of treatment. Over all dose groups including placebo, 1.7% of patients stopped treatment during the study for safety reasons. Because of the low number of discontinuations, the actual distribution across treatment groups is not disclosed to prevent individual treatment unblinding while the study is still ongoing. Serious (1.3% overall) and non-serious treatment-emergent adverse events were evenly spread over the dose groups including placebo. The rare frequency adverse events remain blinded for the treatment group and include 3 cases (0.5% of patients) of serious infections. Consistent with its selective JAK1 inhibition, filgotinib treatment led to a dose-dependent improvement in hemoglobin (up to 0.4 g/dL, or 3.7% increase from baseline). All lipid fractions including HDL and LDL increased, with the largest percentage increase in HDL leading to an improved total cholesterol over HDL ratio (atherogenic index) at 200 mg/day [1].
Apr 15Filgotinib met primary and other endpoints in a PIIb study. Up to 80% of people in various dosing groups had a 20% improvement in disease symptoms over 12 weeks of add-on therapy to methotrexate. The primary endpoint was an improvement in ACR20 scores for a daily dose of 200 mg compared to a placebo. A total of 594 patients who had inadequate response to methotrexate were recruited for the study. Galapagos added that statistically significant ACR50 scores were also achieved with all dose levels and dose regimens, seeing a significant improvement after one week, indicating rapid efficacy for some patients [1].

Evidence based evaluations

JyselecaUlcerative colitis (UC)

Information

Jyseleca
Licence extension / variation
Galapagos
Galapagos

Development and Regulatory status

Pre-registration (Filed)
Launched
Phase III Clinical Trials
Nov 21Approved in EU [16].
Sep 21Recommended for EU approval by CHMP – the additional indication is “treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic agent” [15].
May 21Filed in UK [13]
Nov 20Filed in EU [11].
Dec 16PIII development has begun [1].
Dec 15Galapagos have a global agreement with Gilead to develop and commercialise filgotinib for inflammatory indications, with a co-promotion agreement for some European countries [5].

Category

A selective JAK1 inhibitor.
Ulcerative colitis is the most common type of inflammatory disease of the bowel. It has an incidence in the UK of approximately 10 per 100,000 people annually and a prevalence of approximately 240 per 100,000. Ulcerative colitis can develop at any age but peak incidence is between the ages of 15 and 25 years, with a second, smaller peak between 55 and 65 years [4].
Ulcerative colitis (UC)
Oral

Further information

Yes

Trial or other data

Jun 21Results of PIII SELECTION trial reported in The Lancet [12].
Dec 20The long-term, Phase III extension study (SELECTIONLTE, NCT02914535) in patients who have completed or met specified efficacy criteria in the pivotal IIb/III SELECTION trial is still recruiting. The estimated primary completion date is Sept 2022 [6]
May 20Topline results in PIII SELECTION trial report the higher dose, filgotinib 200 mg, achieved all primary endpoints in the study, inducing clinical remission at week 10 and maintaining clinical remission at week 58 in a significantly higher proportion of patients vs placebo. However filgotinib 100mg did not achieve statistically significant clinical remission at week 10. 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. Neither death was assessed as related to study drug by the investigator [9,10].
Dec 19The PIII SELECTION1 trial (NCT02914522) is ongoing, with an estimated primary completion date of Apr 2020. The long-term, PIII extension study (SELECTIONLTE, NCT02914535) in patients who have completed or met specified efficacy criteria in the SELECTION 1 trial is still recruiting. with an estimated primary completion date of Oct 2026 [7,8].
Dec 16Gilead Sciences and Galapagos plan to initiate an extension PII/PIII trial to observe the long-term safety of filgotinib 100mg and 200mg od in patients who have completed or met protocol specified efficacy discontinuation criteria in a prior Gilead-sponsored filgotinib treatment study in ulcerative colitis (NCT02914535). The trial will include a futility analysis, serving as the PIIb part of this study. The non-randomised, parallel, placebo-controlled trial will enrol approximately 1,300 patients in the US, Europe, Latin America, Canada, and Asia Pacific. First patient dosing is expected in Q4 16 [2].
Oct 16Gilead Sciences and Galapagos initiate a PII/III trial to evaluate safety and efficacy of filgotinib in the induction and maintenance of remission in patients with moderately to severely active ulcerative colitis (SELECTION; NCT02914522). The randomised, double-blind trial is designed to enrol approximately 1300 patients in the US. Collection of primary outcome data (proportion of participants achieving remission based on components of Mayo Clinic Score (MCS) at week 10) should complete Nov 19 [2,3].

Evidence based evaluations

JyselecaCrohn's disease

Information

Jyseleca
Licence extension / variation
Galapagos
Galapagos

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
May 21The PIII DIVERSITY1 trial (NCT02914561) is still recruiting, with an estimated primary completion date of Nov 22 [13]

Category

A selective JAK1 inhibitor.
The estimated prevalence of Crohn’s disease in England is 164 to 182 per 100,000 people, with approximately 4,500 new cases diagnosed each year. Approximately 40% of adults with Crohn’s disease have moderate or severe disease.
Crohn's disease
Oral

JyselecaPsoriatic arthritis with insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug

Information

Jyseleca
Licence extension / variation
Galapagos
Galapagos

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Dec 20Gilead and Galapagos recently paused clinical trials of filgotinib in several areas, including psoriatic arthritis, following receipt of a Complete Response Letter from the FDA; without a viable path forward in the United States, the companies no longer believe it is feasible to continue the current global development program for filgotinib for this indication. As a result, current trials will be stopped over the coming months [7].

Category

Janus kinase (JAK)-1 inhibitor
Data from a large UK GP database (1994-2010) indicated a UK population prevalence of 0.19% or 19 per 100,000 [2].
Psoriatic arthritis with insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug
Oral