Tuesday, May 5, 2015

Drugs in Clinical Pipeline: Filgotinib

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.

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.