Filgotinib
[N-[5-[4-[(1,1-Dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide]
is the first orally-available, selective inhibitor of Janus Kinase 1 (JAK1). Filgotinib,
was shown to selectively inhibit JAK1-dependent signaling in cellular and whole
blood assays (WBAs) and showed remarkable efficacy in collagen-induced
arthritis (CIA) disease models for RA in both mouse and rat.
A detailed
structure-activity relationship in triazolopyridine series led to the
identification of Filgotinib as one of the lead compounds of the series.
Characterization of Filgotinib at the biochemical level indicated a selective
inhibition of JAK1 and JAK2 over JAK3 and TYK2 with a rank order potency of
JAK1 ~ JAK2 greater than TYK2 and JAK3. IC50 values determined in tyrosine
kinase inhibition assays correlated with Kd values determined in ligand displacement assays. It displayed a JAK1/JAK2 inhibitor profile in
biochemical assays, but subsequent studies in cellular and whole blood assays
revealed a selectivity of ~30-fold for JAK1- over JAK2-dependent signaling. Filgotinib
dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent
the differentiation of Th17 cells in
vitro. Filgotinib was well exposed in rodents upon oral dosing, and
exposure levels correlated with repression of Mx2 expression in leukocytes.
Oral dosing of Filgotinib in a therapeutic set-up in a collagen-induced
arthritis model in rodents resulted in a significant dose-dependent reduction
of the disease progression. Paw swelling, bone and cartilage degradation, and
levels of inflammatory cytokines were reduced by Filgotinib treatment. Efficacy
of Filgotinib in the collagen-induced arthritis models was comparable to the
results obtained with Etanercept [1,2].
Filgotinib is
being developed by the Belgian biotech company Galápagos NV, which believes that
the JAK1 selective inhibitor Filgotinib is a promising novel therapeutic with
potential for oral treatment of Rheumatoid Arthritis, Crohn’s Disease and
possibly other immune-inflammatory diseases. Galápagos plans
to take Filgotinib into Phase 3 in rheumatoid arthritis by early 2016.
Filgotinib has shown best-in-class efficacy and safety in the DARWIN Phase 2B
studies in rheumatoid arthritis. In September 2015, AbbVie who was collaborating
with Galápagos for Filgotinib decided to pull back, putting their efforts behind
in-house JAK1 inhibitor, ABT-494. Filgotinib is now fully owned by Galapagos.
The activity
of Filgotinib is as follows:
IC50 (JAK1 enzyme assay) = 10 ± 0.8 nM; Kd
= 11 nM
IC50 (JAK2 enzyme assay) = 28 ± 5.4 nM; Kd
= 32 nM
IC50 (JAK3 enzyme assay) = 810 ± 180 nM; Kd
= 300 nM
IC50 (TYK2 enzyme assay) = 116 ± 39 nM; Kd
= ND
Common Name: Filgotinib
Synonyms: Filgotinib; GLPG0634; GLPG-0634
IUPAC Name: N-[5-[4-[(1,1-Dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
CAS Number: 1206161-97-8
Mechanism of Action: Kinase Inhibitor; JAK1 Inhibitor; Janus
Kinase 1 Inhibitor
Indication: Immune-inflammatory Diseases; Treatment of Rheumatoid Arthritis;
Treatment of Crohn’s
Disease
Development Stage: Phase II
Company: Galápagos
NV
The JAKs
receive continued interest as therapeutic targets for autoimmune, inflammatory,
and oncological diseases. JAKs play critical roles in the development and
biology of the hematopoietic system, as evidenced by mouse and human genetics.
JAK1 is critical for the signal transduction of many type I and type II
inflammatory cytokine receptors.
Four
human JAKs have been described: JAK1, JAK2, JAK3, and TYK2. JAKs bind to the
intracellular moieties of type I and type II receptors, and JAK homo- or
heterodimers become activated upon ligand binding. The JAKs phosphorylate each
other followed by phosphorylation of tyrosine residues on the intracellular domains
of the receptors. These phosphorylated residues serve as docking sites for STAT
transcription factors. JAK phosphorylation of the STAT proteins results in
their nuclear translocation and provides transcriptional output for the
cytokine ligands. JAKs play important roles in the functioning of the immune
system. Mouse and human genetics studies linked deficiencies of JAK1 and JAK3
to severe combined immune deficiency and TYK2 to increased susceptibility to
infections. AK2 serves signal transduction for inflammatory cytokines such as
IFN-γ, IL-12, IL-23, and GM-CSF. Hence, JAKs have been targeted for their
therapeutic potential in immune-inflammatory disorders. In fact, small-molecule
JAK inhibitors proved efficacious in a range of animal disease models and have
already shown promise in the clinic for organ transplant rejection, rheumatoid
arthritis (RA), psoriasis, dry eye disease, myelofibrosis, inflammatory bowel
disease, and asthma. Recent findings suggest that JAK1 dominates JAK1/JAK3/γc
signaling, suggesting that JAK1 inhibition might be largely responsible for the
in vivo efficacy of JAK inhibitors in
immune-inflammatory diseases. These results indicate that a selective JAK1
inhibitor could provide an increased therapeutic window allowing for higher
dosing and efficacy while avoiding dose-limited pharmacology as observed for
the pan-JAK inhibitors [1].
Pre-Clinical Characterization
Characterization of Filgotinib at the
biochemical level indicated a selective inhibition of JAK1 and JAK2 over JAK3
and TYK2, whereas cellular and human whole blood assays (WBAs) revealed selectivity
for JAK1- over JAK2-dependent signaling in a cellular environment. Filgotinib efficiently
blocks cytokine-induced signaling cascades involving JAK1 in several cell lines
as well as in human primary cells. Moreover, Th1, Th2, and Th17 differentiation
driven by cytokine cocktails, including JAK1-dependent cytokines such as IL-2,
IL-4, and IL-6, is also inhibited by Filgotinib. These in vitro findings translate to
pharmacodynamic readouts in rodents showing that JAK1 signaling is blocked in vivo as measured by a reduction of
Mx2 mRNA levels. Using Tofacitinib and Baricitinib in the same assays for a comparison
with Filgotinib further
highlighted that Filgotinib selectively
inhibits JAK1-dependent signaling in a cellular environment and is more JAK1
selective than the other two drugs.
The pharmacokinetics of Filgotinib was determined in rats and mice. Following i.v. administration, Filgotinib displayed a
low to moderate plasma clearance, depending on the species tested. In mice, the
total clearance represented 58% of the liver blood flow, and in rats it
represented 41%. Steady-state volume of distribution ranged from ~1.7 l/kg in
rats to 6 l/kg in mice, implying a significant species difference in volume of
distribution. Half-life observed after oral administration was 1.7 h in mice
and 3.9 h in rats. Following oral administration, the absolute bioavailability
was moderate in rats (45%) and high in mice (~100%).
Furthermore, Filgotinib dose-dependently
reduces inflammation, cartilage, and bone degradation in the collagen-induced
arthritis (CIA) model in rats and mice [1]. In rats, doses of 1, 3, and 10
mg/kg Filgotinib reduced the clinical score to the same extent as Etanercept at endpoint. Different from the Filgotinib doses tested, the high dose of Etanercept
normalized the clinical score already from the start of dosing.
Galapagos has shown that Filgotinib is actually 3 times more selective than AbbVie’s ABT-494.
References:
1. Van Rompaey, L.; et. al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol 2013, 191(7), 3568-3577.
2. C. J.; et. al. Triazolopyridines as selective
JAK1 inhibitors: from hit identification to GLPG0634. J Med Chem 2014, 57(22), 9323-9342.
