Filgotinib in RA

Filgotinib in inflammation

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 U.S., EU5 and Japan was worth $28 billion in 2018, with 60% of patients treated with disease-modifying anti-rheumatic drugs (DMARDs), including injectable, biological therapies.1Sources: Decision Resources Group, Global Data, Galapagos Custom Research

Despite there being many approved agents, considerable unmet need exists, as only one in five patients achieve full remission in the first year.

Oral therapies targeting the Janus kinase (JAK) signaling pathway are approved to treat inflammatory diseases; some JAK inhibitors, however, are associated with a range of side effects, including pulmonary embolisms and aberrations in low-density lipoprotein (LDL, cholesterol) and red blood and NK cell counts. We discovered JAK1 in an inflammation target discovery assay in 2003 and subsequently developed filgotinib as a JAK1 specific small molecule inhibitor. We demonstrated that filgotinib has a nearly 30-fold selectivity for JAK1 over JAK2 and for JAK1 over JAK3. These findings were independently corroborated by Dr. Iain McInnes at the 2017 Annual Meeting of the ACR.

Filgotinib selectivity

High selectivity for JAK1

Filgotinib – High selectivity for JAK1 (bar chart)

DARWIN Phase 2b program

We reported positive results from the DARWIN 1 & 2 Phase 2b dose-range finding clinical trials in 2015 and these findings were published in the Annals of Rheumatological Diseases (Westhovens et al. 2016 and Kavanaugh et al. 2016).

DARWIN 3 was a multi-center, open-label, long-term follow-up safety and efficacy trial of subjects who completed either DARWIN 1 or DARWIN 2. All subjects started the trial at the same dose level, either at 200 mg filgotinib once-daily or at 100 mg filgotinib twice per day (except for males in the U.S. sites of these trials who received a maximum daily dose of 100 mg), depending on the regimen administered during the preceding trial, with DARWIN 1 subjects continuing to use filgotinib in combination with MTX.

We and our collaboration partner Gilead reported findings from DARWIN 3 at 156 weeks of treatment at ACR 2019. The data showed that filgotinib maintained its promising activity levels and that it had a favorable tolerability profile. Data in DARWIN 3 were consistent with the risk/benefit profiles reported in DARWIN 1 and 2, and were presented by Kavanaugh et al. at the 2019 Annual Meeting of the ACR.

Below is an overview of selected adverse events for filgotinib observed in DARWIN 3:

event per
100 PYE

filgotinib

50-200 mg

DARWIN 3
week 156

Data on file; DVT/PE = deep venous thrombosis/pulmonary embolism

*

one single patient experiencing DVT and PE

patient year exp.

2,203

serious infection

1.0

Herpes zoster

1.5

DVT/ PE

2/2,203*
0.1

deaths

0.2

FINCH Phase 3 program

The safety and efficacy of 100 mg and 200 mg filgotinib once daily have been 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)
  • Patients with difficult-to-treat RA and an inadequate response to biologic disease-modifying antirheumatic drugs (csDMARD) (FINCH 2)
  • Methotrexate-naïve patients (FINCH 3)
  • Eligible patients could also roll-over into a long-term extension study (FINCH 4)

In both rat and dog 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. These randomized, double-blind, placebo-controlled trials are intended to be combined to meet the requirement of 200 adult male inflammation patients with a treatment phase of up to 26 weeks. Recruitment into these trials is, at time of publication of this report,  paused in light of the COVID-19 pandemic. 

FINCH 1 results

The study achieved its primary endpoint for both doses of filgotinib in the proportion of patients achieving an American College of Rheumatology 20 percent response (ACR20) compared to placebo at week 12.

The proportion of patients achieving ACR50 and ACR70 response was also significantly greater for filgotinib compared with placebo at week 12, for both doses. Patients receiving filgotinib 100 mg or 200 mg had a statistically significant reduction in the Health Assessment Questionnaire Disability Index (HAQ-DI) at week 12 compared with those receiving placebo. The proportions of patients achieving clinical remission (DAS28(CRP) < 2.6) and low disease activity (DAS28(CRP) ≤ 3.2) at week 12 were significantly higher for patients in both filgotinib arms compared with placebo. When comparing low disease activity rates at week 12, filgotinib 200 mg was non-inferior to adalimumab. Filgotinib 100 mg and 200 mg also significantly inhibited the progression of structural damage at week 24 as assessed by change from baseline in modified total Sharp score (mTSS) compared with placebo.

Topline FINCH 1 efficacy2All efficacy time points assessed at Week 12 except mTSS which was assessed at Week 24 data are summarized in the table below:

 

filgotinib

filgotinib

adalimumab

placebo

200 mg

100 mg

40 mg

 

+MTX

+MTX

+MTX

+MTX

(n=475)&

(n=480)&

(n=325)&

(n=475)&

& Number of patients randomized to each treatment group and who received at least one dose of study drug

ACR20/50/70 represents American College of Rheumatology 20%/50%/70% improvements.

***

p <0.001, compared with placebo

$ p <0.001, non-inferiority to adalimumab

£ p <0.01, non-inferiority to adalimumab

¥ p <0.01, superiority to adalimumab

# Comparison not adjusted for multiplicity

ACR20 (%)

76.6***

69.8***

70.8

49.9

ACR50 (%)

47.2***

36.3***

35.1

19.8

ACR70 (%)

26.3***

18.5***

14.2

6.7

DAS28(CRP) ≤ 3.2
(low disease activity) (%)

49.7***$

38.8***

43.4

23.4

DAS28(CRP) < 2.6
(clinical remission) (%)

33.9***¥#

23.8***£#

23.7

9.3

HAQ-DI change

-0.69***

-0.56***

-0.61

-0.42

mTSS change

0.13***

0.17***

0.16

0.38

FINCH 2 results

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. Also at weeks 12 and 24, the proportion of patients achieving ACR50 and ACR70 response, low disease activity, and clinical remission were significantly higher for patients receiving once-daily filgotinib 100 mg or 200 mg compared to patients receiving placebo. 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).

Topline efficacy data are summarized in the table below:

non-responder imputation

week 12

week 24

placebo

filgotinib

filgotinib

placebo

filgotinib

filgotinib

 

100 mg

200 mg

 

100 mg

200 mg

(n=148)

(n=153)

(n=147)

(n=148)

(n=153)

(n=147)

ACR20/50/70 represents American College of Rheumatology 20%/50%/70% improvements.

*

p <0.05, compared to placebo

**

p <0.01, compared to placebo

***

p <0.001, compared to placebo

ACR20 (%)

31.1

57.5***

66.0***

34.5

54.9***

69.4***

ACR50 (%)

14.9

32.0***

42.9***

18.9

35.3**

45.6***

ACR70 (%)

6.8

14.4*

21.8***

8.1

20.3**

32.0***

DAS28(CRP) < 2.6
(clinical remission) (%)

8.1

25.5***

22.4***

12.2

26.1**

30.6***

DAS28(CRP) ≤ 3.2
(low disease activity) (%)

15.5

37.3***

40.8***

20.9

37.9**

48.3***

FINCH 3 results

The study achieved its primary endpoint in the proportion of patients achieving an American College of Rheumatology 20 percent response (ACR20) at week 24. 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 proportion of patients achieving ACR50, ACR70, and clinical remission (DAS28(CRP) < 2.6) at week 24 was also significantly higher for patients receiving once-daily filgotinib 100 mg or 200 mg plus MTX compared with patients receiving MTX alone. Additionally, those who received filgotinib experienced greater reduction in the Health Assessment Questionnaire Disability Index (HAQ-DI) compared with those receiving MTX alone at week 24. Filgotinib 200 mg monotherapy inhibited the progression of structural damage at week 24 compared with MTX alone as assessed by modified total Sharp score (mTSS).

Topline FINCH 3 efficacy3Efficacy assessed at Week 24 for all endpoints data are summarized in the table below:

 

filgotinib

filgotinib

filgotinib

MTX

200 mg

100 mg

200 mg

 

+MTX

+MTX

monotherapy

 

(n=416)&

(n=207)&

(n=210)&

(n=416)&

MTX, methotrexate

& Number of patients randomized to each treatment group and who received at least one dose of study drug

ACR20/50/70 represents American College of Rheumatology 20%/50%/70% improvements.

*

p < 0.05 compared with MTX

**

p <0.01, compared with MTX

***

p <0.001, compared with MTX

# Comparison not adjusted for multiplicity

ACR20 (%)

81.0***

80.2*

78.1

71.4

ACR50 (%)

61.5***

57.0**

58.1**#

45.7

ACR70 (%)

43.8***

40.1***

40.0***#

26.0

DAS28(CRP) < 2.6 (clinical remission) (%)

54.1***

42.5***

42.4***#

29.1

HAQ-DI change

-0.94***

-0.90**

-0.89*#

-0.79

mTSS change

0.20

0.22

-0.04**#

0.52

FINCH safety data

We and Gilead also announced interim safety information from four studies of the investigational compound filgotinib for the treatment of rheumatoid arthritis. The data include 24 week results of the Phase 3 FINCH 1, 2, and 3 trials in patients with RA and the pooled analyses from these 3 FINCH trials were presented at the Annual ACR meeting 2019 (Winthrop et al). In this pooled analysis, filgotinib was well-tolerated, no new safety concerns were identified, and the safety results were consistent with selective JAK1 inhibition. Adverse events of MACE and DVT/PE were rare and occurred in similar number among all treatment groups. Herpes zoster reactivation was not increased in the filgotinib groups compared with the other treatment groups. The data highlight the favorable safety and tolerability profile of filgotinib as monotherapy and in conjunction with MTX/csDMARD in RA.

Week 24 safety data from the FINCH 1, 2, and 3 studies are aggregated and summarized in the table below. Data from 3,452 patients are reported, including 2,088 patients who received filgotinib:

 

Placebo/
csDMARD

adalimumab

filgotinib

filgotinib

filgotinib

filgotinib

 

 

100 mg

200 mg

200 mg

total

 

+MTX
40 mg EOW

+MTX/
csDMARD

+MTX/
csDMARD

 

 

(n=1039)
no. (%)

(n=325)
no. (%)

(n=840)
no. (%)

(n=1038)
no. (%)

(n=210)
no. (%)

(n=2088)
no. (%)

MTX, methotrexate; EOW, every other week; csDMARD, conventional synthetic disease-modifying antirheumatic drug; DVT, deep venous thrombosis; PE, pulmonary embolism; NMSC, non-melanoma skin cancer; MACE, major adverse cardiac events

& Treatment-emergent events

μ Excludes one retinal vein occlusion

@ All events

serious infections&

10 (1.0)

8 (2.5)

13 (1.5)

13 (1.3)

3 (1.4)

29 (1.4)

Herpes zoster&

4 (0.4)

2 (0.6)

5 (0.6)

6 (0.6)

1 (0.5)

12 (0.6)

DVT/PE&

3 (0.3)

0 (0)

0 (0)

1 (0.1)μ

0 (0)

1 (<0.1)

death@

2 (0.2)

0 (0)

1 (0.1)

3 (0.3)

0 (0)

4 (0.2)

malignancy excluding NMSC&

4 (0.4)

1 (0.3)

1 (0.1)

0 (0)

0 (0)

1 (<0.1)

MACE&

5 (0.5)

1 (0.3)

2 (0.2)

2 (0.2)

1 (0.5)

5 (0.2)

Applications for approval of filgotinib in RA

Gilead announced acceptance of a Marketing Authorisation Application (MAA) by the European Medicines Agency in August 2019, submission of a New Drug Application (NDA) to the Japanese Ministry of Health, Labor, and Welfare (MHLW) in October 2019, and submission of an NDA (under priority review) to the United States Food & Drug Administration (FDA) in December 2019. We and our collaboration partner Gilead expect decisions on potential approvals in all these geographies in the course of 2020.

Commercialization of filgotinib in RA

If approved by the European Commission for RA indications, we expect to launch commercial sales activities in Belgium, The Netherlands, and Luxembourg where we are solely responsible for commercialization, and in France, Italy, and Spain where we will lead commercial sales responsibilities in RA, pursuant to the parties' joint commercialization of filgotinib in those countries. We are advanced in our preparations to launch in these countries in the course of 2020, pending approval of filgotinib. Gilead will launch commercial sales activities in RA in Germany and the UK, the remaining of the eight countries in which we and Gilead will equally split profits from filgotinib commercial activities, pursuant to the parties' joint commercialization of filgotinib in those countries. Gilead will be responsible for the commercial launches in all territories outside these eight European countries, should filgotinib be approved in these territories. See details on the Gilead collaboration in the Notes to the consolidated financial statements.

European commercial footprint

European commercial footprint (graphic)

1 Source: Decision Resources Group, Global Data, Galapagos Custom Research

2 All efficacy time points assessed at Week 12 except mTSS which was assessed at Week 24

3 Efficacy assessed at Week 24 for all endpoints