Filgotinib

Filgotinib is an oral Janus kinase inhibitor with the molecular formula C21H23N5O3S. Filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have had an inadequate response to or are intolerant of one or more disease-modifying antirheumatic drugs(DMARDs). Filgotinib can be used as monotherapy or in combination with methotrexate (MTX).

Filgotinib is an adenosine triphosphate (ATP)-competitive and reversible inhibitor of Janus kinase inhibitor with selectivity for the JAK1 subtype of this enzyme. It is considered a promising agent because it selectively inhibits JAK1, similar to upadacitinib, which is already on the market. Filgotinib leads to inhibition of signaling of inflammatory cytokines. JAKs are intracellular enzymes that transmit signals triggered by the binding of cytokines or growth factors to the respective receptors on the cell membrane. Among other things, they play an important role in inflammatory processes, e.g. in rheumatoid arthritis. In the downstream complex signalling cascade, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression.

The recommended dose is 200 mg of filgotinib once daily. For patients 75 years of age or older or for patients with severe renal impairment (CrCl 15 to < 60 ml/min), a starting dose of 100 mg once daily is recommended.

The most commonly reported side effects with the use of Jyseleca are:

• Nausea (3.5%)
• Upper respiratory tract infection (3.3%)
• urinary tract infection (1.7%)
• Dizziness (1.2%)

Interactions with filgotinib may occur with the use of the following compounds:

• Carboxylesterase 2 (CES2) inhibitors such as fenofibrate, carvedilol, diltiazem or simvastatin: Filgotinib is mainly metabolised by CES2 The clinical relevance of this interaction is not known.
• CYP1A2 substrates with a narrow therapeutic range: In vitro studies are inconclusive regarding potential induction or inhibition of CYP1A2 by filgotinib. The potential in vivo effect of concomitant induction and inhibition of CYP1A2 by filgotinib is unknown, and therefore concomitant use of CYP1A2 substrates with a narrow therapeutic range should be used with caution.
• P-gp or BCRP Substrates: In vitro studies are inconclusive regarding potential inhibition of P-gp or BCRP by the primary metabolite of filgotinib, GS-829845. In vivo inhibition of these transporters cannot be ruled out, and caution should be exercised when substrates with a narrow therapeutic range (e.g., digoxin) are used together with filgotinib.
• OATP1B1 or OATP1B3 substrates e.g. valsartan, statins: In vitro studies suggest that filgotinib and its primary metabolite GS-829845 are inhibitors of OATP1B1 and OATP1B3. No clinical studies have been conducted to investigate interactions with OATP1B1 and OATP1B3 substrates. Therefore, it cannot be excluded that concomitant use may increase exposure to them.

Hypersensitivity to the active substance or any of the other ingredients mentioned in:

• Active tuberculosis (TB)
• active severe infections
• Pregnancy Side effects

Jyseleca® 100 mg Abacus film-coated tablets; Jyseleca 200 mg Abacus film-coated tablets.

September 2020: approval of filgotinib in both the EU and Japan.

Less selective JAK inhibitors (e.g. tofacitinib and baricitinib) have already been approved internationally. They show long-term efficacy in the treatment of various inflammatory diseases. However, their lack of selectivity leads to dose-limiting side effects. Inhibition of all JAK isoenzymes is thought to be beneficial in rheumatoid arthritis. However, pan-JAK inhibition could also lead to adverse side effects that do not outweigh the benefits. This is the reason for the development of newer and more selective inhibitors such as filgotinib. Filgotinib has 30-fold selectivity for JAK1 compared to JAK2 (Van Rompaey L et al. 2013).

1. Florence N et al (2014) Phase 1 and Phase 2 Data Confirm That GLPG0634, a Selective JAK1 Inhibitor, Has a Low Potential for Drug-Drug Interactions. Meeting Abstracts. 2014 ACR/ARHP Annual Meeting.
2. Genovese MC et al. (2019) Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial. JAMA 322:315-325.
3. Taylor PC et al (2017) Filgotinib for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 26:1181-1187
4. Van Rompaey L et al (2013) Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. Journal of Immunology 191: 3568-3577.