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Pharmacology: Pharmacodynamics: Mechanism of action: Filgotinib is an adenosine triphosphate (ATP) competitive and reversible inhibitor of the JAK family. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane. JAK1 is important in mediating inflammatory cytokine signals, JAK2 in mediating myelopoiesis and erythropoiesis and JAK3 plays critical roles in immune homeostasis and lymphopoiesis. Within the signalling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Filgotinib modulates these signalling pathways by preventing the phosphorylation and activation of STATs. In biochemical assays, filgotinib preferentially inhibited the activity of JAK1 and showed >5 fold higher potency of filgotinib for JAK1 over JAK2, JAK3 and TYK2. In human cellular assays, filgotinib preferentially inhibited JAK1/JAK3-mediated signalling downstream of the heterodimeric cytokine receptors for interleukin (IL)-2, IL-4 and IL-15, JAK1/2-mediated IL-6, and JAK1/TYK2-mediated type I interferons, with functional selectivity over cytokine receptors that signal via pairs of JAK2 or JAK2/TYK2. GS-829845, the primary metabolite of filgotinib, was approximately 10-fold less active than filgotinib in in vitro assays, while exhibiting a similar JAK1 preferential inhibitory activity. In an in vivo rat model, the overall pharmacodynamic effect was predominantly driven by the metabolite.
Pharmacodynamic effects: Inhibition of IL-6 induced STAT1 phosphorylation: Filgotinib administration resulted in a dose-dependent inhibition of IL-6 induced STAT1 phosphorylation in whole blood from healthy subjects. Filgotinib administration did not affect JAK2-associated GM-CSF induced STAT5 phosphorylation.
Immunoglobulins: In FINCH 1, 2, and 3, the median and interquartile ranges for serum IgG, IgM, and IgA values remained largely within the normal reference ranges through 24 weeks of treatment with filgotinib in patients with rheumatoid arthritis and through 58 weeks of treatment in patients with ulcerative colitis.
Haematologic effects: In FINCH 1, 2, and 3 in patients with rheumatoid arthritis, treatment with filgotinib was associated with a small, transient increase in mean ALC that remained within normal reference ranges and gradually returned to at or near baseline levels with continued treatment by week 12. In FINCH 1, 2, and 3, median haemoglobin values remained stable within the normal range through 24 weeks of filgotinib treatment. A slight decrease in median platelet counts occurred within the first 4 weeks of filgotinib treatment and remained stable thereafter through 24 weeks. Median platelet counts remained within the normal range.
In SELECTION, in patients with ulcerative colitis, median haemoglobin values remained stable through 58 weeks of filgotinib treatment.
C-reactive protein: Decreases in serum C-reactive protein (CRP) were observed as early as 2 weeks after starting treatment with filgotinib and were maintained through 24 weeks of treatment in patients with rheumatoid arthritis and through 58 weeks of treatment in patients with ulcerative colitis.
Clinical efficacy and safety: Rheumatoid arthritis: The efficacy and safety of filgotinib once daily were assessed in three Phase 3 studies (FINCH 1, 2, and 3). These were randomised, double-blind, multicentre studies in patients with moderate to severe active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria.
FINCH 1 was a 52-week study in 1,755 patients with rheumatoid arthritis who had an inadequate response to MTX. Patients received filgotinib 200 mg once daily, filgotinib 100 mg once daily, adalimumab every 2 weeks, or placebo, all added to stable background MTX. At week 24, patients receiving placebo were re-randomised to filgotinib 100 mg or 200 mg once daily through week 52. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.
FINCH 2 was a 24-week study in 448 patients with rheumatoid arthritis who had an inadequate response to bDMARDs. Patients received filgotinib 200 mg once daily, filgotinib 100 mg once daily, or placebo, all with a continued stable background dose of conventional synthetic DMARD(s) (csDMARD[s]: MTX, hydroxychloroquine, sulfasalazine, or leflunomide). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 12.
FINCH 3 was a 52-week study in 1,249 patients with rheumatoid arthritis who were naïve to MTX therapy. Patients received filgotinib 200 mg once daily plus MTX once weekly, filgotinib 100 mg once daily plus MTX once weekly, filgotinib 200 mg (monotherapy) once daily, or MTX (monotherapy) once weekly. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.
Clinical response: Higher response rates versus placebo or MTX were seen at week 2 for ACR20, and responses were maintained through week 52.
Treatment with filgotinib 200 mg resulted in improvements in all individual ACR components, including tender and swollen joint counts, patient and physician global assessments, Health Assessment Questionnaire Disability Index (HAQ-DI), pain assessment and high sensitivity CRP, compared to placebo or MTX. In two of the Phase 3 studies (FINCH 1 and FINCH 2), the comparison (versus placebo) was carried out on top of MTX or csDMARD(s) (see previously mentioned).
Low disease activity and remission: Across the Phase 3 studies, a significantly higher proportion of patients treated with filgotinib 200 mg plus MTX or other csDMARD achieved low disease activity and/or remission (DAS28-CRP ≤3.2 and DAS28-CRP <2.6) at weeks 12 and 24 as compared to placebo or MTX. Filgotinib 200 mg was non-inferior to adalimumab at week 12 for DAS28-CRP ≤3.2 in FINCH 1 (see Table 1).
Click on icon to see table/diagram/imageRadiographic response: Inhibition of progression of structural joint damage was assessed using the modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score, at weeks 24 and 52 in FINCH 1 and FINCH 3.
In patients who had an inadequate response to MTX, treatment with filgotinib plus MTX resulted in statistically significant inhibition of progression of structural joint damage compared to placebo plus MTX at week 24 (Table 2). Analyses of erosion and joint space narrowing scores were consistent with the overall scores. (See Table 2.)
Click on icon to see table/diagram/imagePhysical function response and health related outcomes: Treatment with filgotinib 200 mg resulted in a significant improvement in physical function, as measured by change from baseline in HAQ-DI (see Table 3).
Click on icon to see table/diagram/imageHealth status outcomes were assessed by the Short Form health survey (SF-36). Patients treated with filgotinib 200 mg plus MTX or other csDMARD demonstrated numerically greater improvement from baseline in the physical component summary score of SF-36 as well as in the Functional Assessment of Chronic Illness Therapy Fatigue score (FACIT-F) at weeks 12 and 24 compared to placebo plus MTX/csDMARD or MTX.
Long-term efficacy: DARWIN 3 was a long-term open-label extension study of patients who participated in one of the originator studies DARWIN 1 or DARWIN 2 (filgotinib versus placebo, with or without MTX) and who would continue to benefit from filgotinib treatment in the opinion of the investigator. A total of 739 patients were included. Mean duration of follow-up was 5.4 years with a maximum of 8 years. Concomitant MTX use at any timepoint during DARWIN 3 was reported for 70% of subjects.
At week 396, ACR20/50/70 responses rates were 87.3%/65.4%/47.8% among patients who remained on filgotinib with or without MTX (N=228/739). DAS28 (CRP) ≤3.2 low disease activity and DAS28 (CRP) <2.6 clinical remission rates were 75.5% and 62.8% at week 396 among patients who remained on filg otinib with or without MTX (N=196/739).
Ulcerative colitis: The efficacy and safety of filgotinib once daily were evaluated in a randomised, double-blind, placebo-controlled combined Phase 2b/3 study (SELECTION) in patients with moderately to severely active ulcerative colitis (Mayo Clinic Score 6 to 12; endoscopy subscore ≥2; rectal bleeding subscore ≥1; stool frequency subscore ≥1; and Physician's Global Assessment subscore ≥2). SELECTION included two induction studies (UC1 and UC2) followed by a maintenance study (UC3), with a total duration of 58 weeks of therapy. Patients were permitted to use stable doses of concomitant therapies for ulcerative colitis, including oral aminosalicylates, oral corticosteroids (prednisone equivalent dose up to 30 mg/day), and immunomodulators (azathioprine, 6MP, or methotrexate).
UC-1 was an 11-week induction study in 659 patients with ulcerative colitis who were naïve to biologic therapy and had an inadequate response, loss of response, or intolerance to corticosteroids or immunomodulators. Patients received filgotinib 200 mg once daily (N = 245), filgotinib 100 mg once daily (N = 277), or placebo (N = 137). At baseline, 56% of patients had an endoscopic subscore of 3; 24% were receiving oral corticosteroids only, 23% immunomodulators only, 7% corticosteroids and immunomodulators, and 47% neither corticosteroids nor immunomodulators.
UC2 was an 11-week induction study in 689 patients with ulcerative colitis who were biologic-experienced and had an inadequate response, loss of response, or intolerance to a tumour necrosis factor (TNF) blocker or vedolizumab. Patients received filgotinib 200 mg once daily (N = 262), filgotinib 100 mg once daily (N = 285), or placebo (N = 142). At baseline, 78% of patients had an endoscopic subscore of 3; 85% had failed at least 1 prior TNF blocker, 52% had failed vedolizumab, and 43% had failed at least 1 TNF blocker and vedolizumab; 36% were receiving oral corticosteroids only, 13% immunomodulators only, 10% corticosteroids and immunomodulators, and 41% neither cor ticosteroids nor immunomodulators.
The primary endpoint for UC-1 and UC-2 was the proportion of patients who achieved clinical remission at week 10. Clinical remission was defined as MCS endoscopy subscore of 0 or 1 (endoscopy subscore of 0 defined as normal or inactive disease and subscore of 1 defined as presence of erythema, decreased vascular pattern, and no friability), rectal bleeding subscore of 0 (no rectal bleeding), and at least a one point decrease in stool frequency subscore from baseline to achieve 0 or 1. Key secondary efficacy endpoints included MCS remission, endoscopic remission, and histologic remission at week 10.
UC3 was a 47-week maintenance study in 558 patients with ulcerative colitis who achieved clinical response or remission at week 10 from filgotinib in UC1 (N = 320) or UC2 (N = 238). Clinical response was defined as a decrease in MCS of ≥3 points and ≥30% decrease from baseline, with an accompanying decrease in rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1. Patients were re-randomised at week 11 to receive their induction dose of filgotinib or placebo through week 58. As in UC1 and UC2, patients were permitted to use stable doses of oral aminosalicylates or immunomodulators; however, corticosteroid tapering was required three weeks after entering this study. The primary endpoint was the proportion of patients who achieved clinical remission at week 58. Key secondary efficacy endpoints were MCS remission, sustained clinical remission, 6-month corticosteroid-free clinical remission, endoscopic remission, and histologic remission at week 58.
Clinical outcomes: Across the UC1 and UC2 studies, a significantly greater proportion of patients receiving filgotinib 200 mg achieved clinical remission at week 10 as compared to placebo (Table 4). A significantly greater proportion of biologic-naïve patients (UC1) receiving filgotinib 200 mg achieved MCS remission, endoscopic remission, and histologic remission at week 10 as compared to placebo (Table 4).
Efficacy in the filgotinib 100 mg group as compared to placebo was not statistically significant at week 10 in either UC-1 or UC-2. (See Table 4.)
Click on icon to see table/diagram/imageThe proportion of patients in UC-1 and UC-2 achieving a clinical response was 66.5% and 53.1%, respectively, for patients receiving filgotinib 200 mg compared with 46.7% and 17.6%, resp ectively, for patients receiving placebo at week 10.
In the maintenance study (UC3), a significantly greater proportion of patients receiving filgotinib 200 mg or filgotinib 100 mg achieved clinical remission at week 58 as compared to placebo. The proportion of patients achieving clinical remission is shown in Table 5. A significantly greater proportion of patients receiving filgotinib 200 mg achieved MCS remission, sustained clinical remission, 6-month corticosteroid-free clinical remission, endoscopic remission, and histologic remission at week 58 as compared to placebo.
Key secondary efficacy outcomes for treatment with filgotinib 100 mg as compared to placebo were not statistically significant at week 58. (See Table 5.)
Click on icon to see table/diagram/imageEndoscopic response: Endoscopic response was defined as an endoscopic subscore of 0 or 1. The proportion of patients in UC-1 and UC-2 achieving an endoscopic response was 33.9% and 17.2%, respectively, for patients receiving filgotinib 200 mg compared with 20.4% and 7.7%, respectively, for patients receiving placebo, at week 10. In UC-3, 40.7% of patients receiving filgotinib 200 mg versus 15.3% of patients receiving placebo achieved endoscopic response at week 58.
Health related quality of life (HRQoL) outcomes: Patients receiving filgotinib 200 mg reported increases (improvements) in the total and all four domain scores of the Inflammatory Bowel Disease Questionnaire ([IBDQ] bowel symptoms, systemic function, emotional function, and social function) at week 10 in UC-1 and UC-2, and at week 58 in UC-3.
Long term extension study: Patients who did not achieve clinical response or remission at week 10 in UC1 or UC2 had the option to receive open-label filgotinib 200 mg in the SELECTION LTE study. After 12 weeks of additional treatment with filgotinib 200 mg in the SELECTION LTE study, the proportion of patients from UC1 and UC2 achieving partial MCS remission was 17.1% (12/70) and 16.7% (15/90), respectively and partial MCS response was achieved by 65.7% (46/70) and 62.2% (56/90), respectively. Partial MCS remission was defined as partial MCS ≤1 and partial MCS response was defined as a reduction of ≥2 in partial MCS and at least 30% reduction from the induction baseline score, with an accompanying decrease of ≥1 in the rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1.
Other clinical safety studies: The effect of filgotinib 200 mg on spermatogenesis in men with inflammatory diseases were assessed in two randomized, double-blind, placebo-controlled, parallel-group, phase 2 studies; the MANTA study for active inflammatory bowel disease and the MANTA-RAy study for rheumatic diseases. Both studies had the same design and endpoint assessments through week 13. The patients who met a prespecified semen parameters (sperm concentration, total motility, and morphology) decrease threshold discontinued blinded study drug and entered the Monitoring Phase (MP) for up to 52 weeks or until reversibility was observed, whichever occurred first. The primary endpoint in both studies was the proportion of patients with a 50% or more decrease from baseline in sperm concentration at week 13. Across both studies, 248 patients were randomised to filgotinib or placebo. A total of 240 patients (filgotinib, n=120; placebo, n=120) took at least one dose of study drug, had two evaluable semen samples at baseline and at week 13, and were included in the semen analysis set.
The data from these two dedicated studies showed a similar proportion of patients who had a 50% or more decrease from baseline in semen parameters at week 13 pooled primary endpoint: 8 patients in the filgotinib group (6.7%), 10 patients in the placebo group (8.3%) (Table 6). All 10 patients in the placebo group who experienced a ≥50% decrease from baseline in sperm concentration achieved reversibility by the MP week 52 whereas 2 out of 8 patients in the filgotinib group did not achieve reversibility. One patient did not reverse by the MP week 52, and the other patient did not demonstrate reversibility at the MP week 13 and discontinued the study (patient withdrawal). The data did not show any relevant changes in sex hormone levels or change from baseline in semen parameters across treatment groups. (See Table 6.)
Click on icon to see table/diagram/imagePharmacokinetics: Absorption: Following oral administration, filgotinib was absorbed quickly and its median peak plasma concentration was observed 2 to 3 hours post-dose after multiple dosing; the median peak plasma concentrations of its primary metabolite GS-829845 were observed 5 hours post-dose after multiple dosing. Filgotinib and GS-829845 exposures (AUC) and Cmax were similar in healthy adult subjects and patients with rheumatoid arthritis and ulcerative colitis. Filgotinib and GS-829845 exposures (AUC) and Cmax are dose-proportional over the therapeutic dose range. Steady-state concentrations of filgotinib are achieved in 2-3 days with negligible accumulation after once daily administration. Steady-state concentrations of GS-829845 are achieved in 4 days with approximately 2-fold accumulation after once daily dosing of filgotinib.
There were no clinically relevant differences in exposures when filgotinib was administered with a high-fat or low-fat meal as compared to a fasted state. Filgotinib can be administered with or without food.
Steady state-exposures of filgotinib and GS-829845 are provided in Table 7. (See Table 7.)
Click on icon to see table/diagram/imageDistribution: Filgotinib and GS-829845 binding to human plasma proteins is low (55-59% and 39-44% bound, respectively). The blood-to-plasma ratio of filgotinib ranged from 0.85 to 1.1 indicating no preferential distribution of filgotinib and GS-829845 into blood cells. Filgotinib and GS-829845 are substrates of the P-gp transporter.
Biotransformation: Filgotinib is extensively metabolised with approximately 9.4% and 4.5% of an orally administered dose recovered as unchanged filgotinib in urine and faeces, respectively. Filgotinib is primarily metabolised by CES2, and to a lesser extent by CES1. Both CES2 and CES1 form GS-829845, an active circulating metabolite that is approximately 10-fold less potent than the parent compound. In a clinical pharmacology study, filgotinib and GS-829845 accounted for the majority of radioactivity circulating in plasma (2.9% and 92%, respectively). No other ma jor metabolites were identified.
As both filgotinib and GS-829845 contribute to efficacy, their exposures were combined into a single parameter, AUCeff. AUCeff is the sum of the AUC of filgotinib and GS-829845, corrected for their respective molecular weights and potencies.
Elimination: Approximately 87% of the administered dose was eliminated in the urine as filgotinib and its metabolites, while about 15% of the dose was eliminated in the faeces. GS-829845 accounted for approximately 54% and 8.9% of dose recovered in urine and faeces, respectively. The mean terminal half-lives of filgotinib and GS-829845 were approximately 7 and 19 hours, respectively.
Other special populations: Weight, gender, race, and age: Bodyweight, gender, race, and age did not have a clinically relevant effect on the pharmacokinetics (AUC) of filgotinib or GS-829845.
Elderly: There were no clinically relevant differences in mean filgotinib and GS-829845 exposures (AUC and Cmax) between older patients aged ≥65 years relative to adult patients aged <65 years.
Renal impairment: The pharmacokinetics of filgotinib and GS-829845 were unaffected in subjects with mild renal impairment (CrCl 60 to <90 mL/min). Increases in exposures (AUC) of filgotinib, GS-829845, and combined AUCeff (≤2-fold), were observed in subjects with moderate renal impairment (CrCl 30 to <60 mL/min). In subjects with severe renal impairment (CrCl 15 to <30 mL/min), filgotinib exposure (AUC) increased by 2.2-fold and GS-829845 exposure significantly increased by 3.5-fold leading to a 3-fold increase in AUCeff. The pharmacokinetics of filgotinib has not been studied in subjects with end stage renal disease (CrCl <15 mL/min).
Hepatic impairment: No clinically relevant changes in the exposures (AUC) of filgotinib and GS-829845 individually, or their combined exposure (AUCeff), were observed in subjects with moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of filgotinib has not been studied in subjects with severe hepatic impairment (Child-Pugh C).
Effect of filgotinib on other medicinal products: Potential interactions between filgotinib and co-administered medicinal products are listed in Table 8 as follows (increase is indicated as "↑", decrease as "↓", and no change as "↔"; no effect boundaries are 70-143% unless otherwise indicated). (See Table 8.)
Click on icon to see table/diagram/imagePotential for filgotinib to affect other medicinal products: In vitro data indicate that filgotinib and GS-829845 do not inhibit the activity of the following: CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations. The potential for filgotinib to induce CYP2B6 constitutive androstane receptor (CAR) mediated metabolism in vivo is unknown. No conclusion can be drawn from the in vitro data regarding the potential of filgotinib to inhibit or induce CYP1A2. In vivo data demonstrated no inhibition or induction of CYP3A4 mediated metabolism.
In vitro studies indicate that filgotinib and GS-829845 are not inhibitors of P-gp, BCRP, OCT1, BSEP, OAT1, OAT3 or OAT4 at clinically relevant concentrations.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology.
The carcinogenic potential of filgotinib was evaluated in a 6-month rasH2 transgenic mouse study and a 2-year rat study. Filgotinib was not carcinogenic in mice at up to 150 mg/kg/day, which resulted in exposures of approximately 25 and 12 times the exposures in humans at the 100 mg and 200 mg once daily doses, respectively. In the 2-year rat study, filgotinib treatment resulted in an increase in incidence and decrease in latency of benign Leydig cell tumours at the highest dose of 45 mg/kg/day (exposures of approximately 4.2 times exposures in humans at the 200 mg once daily dose); the clinical relevance of this finding is low.
Filgotinib was not mutagenic or clastogenic in the in vitro bacterial reverse mutation assay, in vitro chromosome aberration assay, and in vivo rat micronucleus assay.
Adverse findings of degeneration/necrosis of incisor ameloblasts were observed in rats at exposures 21- to 28-fold greater than clinical exposures at the 200 mg filgotinib dose, with exposure margins at the no observed-adverse-effect-level (NOAEL) ranging from 3.5- to 8-fold. The human relevance of these dental findings is considered low since in contrast to adult patients, ameloblasts in rats persist into adulthood to support lifelong continuous incisor growth.
Impaired spermatogenesis and histopathological effects on male reproductive organs (testes and epididymis) were observed with filgotinib in rats and dogs. The findings include lesions in testis which consisted of germ cell depletion/degeneration and/or tubular vacuolation with corresponding changes in epididymitis, such as reduced sperm content and/or increased cell debris. At the NOAELs in dogs (the most sensitive species), the exposure margin is 0.97- to 2.72-fold at the 200 mg once daily dose in humans. The severity of the histological effects was dose-dependent. Spermatogenic and histopathological effects were not fully reversible at exposure margins of approximately 7- to 9-fold the exposure at the 200 mg once daily dose in humans.
Embryo-foetal development studies in rats and rabbits demonstrated embryolethality and teratogenicity at exposures comparable to 200 mg filgotinib once daily dosing in humans. Visceral and skeletal malformations and/or variations were observed at all dose levels of filgotinib.
Filgotinib was administered to pregnant rats at doses of 25, 50, and 100 mg/kg/day. Dose-related increases in the incidence of internal hydrocephaly, dilated ureters, and multiple vertebral anomalies were seen at all dose levels. At 100 mg/kg/day, an increased number of early and late resorptions were noted together with a decreased number of viable foetuses. In addition, foetal body weights were decreased.
In rabbits, filgotinib caused visceral malformations mainly in the lungs and cardiovascular system, at a dose level of 60 mg/kg/day. Filgotinib caused skeletal malformations affecting the vertebral column region at dose levels of 25 and 60 mg/kg/day, mainly in vertebra, ribs and sternebrae. Fused sternebrae also occurred at 10 mg/kg/day filgotinib. Retarded skeletal ossification was evidenced at 60 mg/kg/day.
No adverse effects on pre-/postnatal development were observed in rats in a pre- and postnatal development study of filgotinib and GS-829845. Filgotinib and GS-829845 were detected in nursing rat pups after administration of filgotinib to lactating female rats from gestation day 6 through 10 days post-partum at dose levels of 2, 5, and 15 mg/kg/day, likely due to the presence of filgotinib in milk. At the highest tested dose, maternal systemic exposure (AUC) to filgotinib in rats was approximately 2 times the exposure in humans at the 200 mg once daily dose; exposures in nursing pups were less than 6% that of maternal exposure on day 10 post-partum. Due to the low exposure of the animals, the pre-/postnatal development study was considered inconclusive.
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