Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

(RA). It was developed by the

Belgian Belgian may refer to: * Something of, or related to, Belgium * Belgians, people from Belgium or of Belgian descent * Languages of Belgium, languages spoken in Belgium, such as Dutch, French, and German *Ancient Belgian language, an extinct language ...

Dutch Dutch commonly refers to: * Something of, from, or related to the Netherlands * Dutch people () * Dutch language () Dutch may also refer to: Places * Dutch, West Virginia, a community in the United States * Pennsylvania Dutch Country People E ...

biotech company

Galapagos NV Galapagos NV (formerly known as Galapagos Genomics) is a Belgian pharmaceutical research company which was founded in 1999. Its headquarters are located in Mechelen and has additional locations in Leiden, Romainville, Basel, Milan, Madrid, Boston a ...

. The most common side effects include nausea (feeling sick), upper respiratory tract infection (nose and throat infection), urinary tract infection and dizziness. Filgotinib was approved for medical use in both the European Union and Japan in September 2020.

Medical uses

Filgotinib is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to one or more disease‑modifying anti‑rheumatic drugs (DMARDs). Filgotinib may be used as monotherapy or in combination with

methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...

(MTX).

Mechanism of action

Filgotinib is a

Janus kinase inhibitor A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JA ...

with selectivity for subtype

JAK1 JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family (e.g. IL-2R, I ...

of this enzyme. It is considered a promising agent as it inhibits JAK1 selectively, similar to already marketed

upadacitinib Upadacitinib, sold under the brand name Rinvoq, is a Janus kinase (JAK) inhibitor medication for the treatment of moderately to severely active rheumatoid arthritis and psoriatic arthritis in adults where methotrexate (a drug used to treat act ...

. Less selective JAK inhibitors (e.g.

tofacitinib Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Common side effects include diarrhea, headache, and high blood pressure. Serious side eff ...

and

baricitinib Baricitinib, sold under the brand name Olumiant among others, is a medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2. ...

) are already being marketed. They show long-term efficacy in the treatment of various inflammatory diseases. However, their lack of selectivity leads to dose-limiting side effects. It is thought that inhibition of all JAK isoenzymes is beneficial in rheumatoid arthritis. However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits. This is the rationale for the development of newer and more selective inhibitors like filgotinib. The signal transmission of large numbers of

proinflammatory Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

is dependent on JAK1. Inhibition of JAK2 may also contribute to the efficacy against rheumatoid arthritis. Nonetheless it is thought that JAK2 inhibition might lead to

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

and

thrombopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...

by interference with

erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...

and

thrombopoietin Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the ''THPO'' gene. Thrombopoietin is a glycoprotein hormone produced by the liver and kidney which regulates the pro ...

and

granulocyte-macrophage colony-stimulating factor Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that ...

. Therefore, one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2. It is however still to be seen to what extent JAK2 inhibition should be avoided.

History

* June 2011: results of first Phase II trial * November 2014: initiation of DARWIN 1 and 2 trials * July 2015: DARWIN 1 results released * August 2015: DARWIN 2 trial results released * September 2015: AbbVie opted out of collaboration with Galapagos * December 2015: Galapagos signed partnership with Gilead to co-develop & co-commercialize Filgotinib for various diseases * December 2019: Gilead submitted a New Drug Application (NDA) with a

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

voucher to the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) for filgotinib. * On 23 July 2020, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...

(CHMP) of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

(EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Jyseleca, intended for the treatment of rheumatoid arthritis. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The applicant for this medicinal product is Gilead Sciences Ireland UC. * 19 August 2020: FDA rejects Gilead’s filing for approval of filgotinib over toxicity concerns * September 2020: Filgotinib was approved for medical use in both the European Union and Japan.

Research

Clinical trials

The efficacy of filgotinib is being studied in a Phase IIb program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn's disease patients.

Phase I study

It was shown in Phase I studies that the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of filgotinib metabolism is independent of hepatic

CYP450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compo ...

enzymatic degradation. The drug metabolism is however mediated by

carboxylesterase The enzyme carboxylesterase (or carboxylic-ester hydrolase, EC 3.1.1.1; systematic name carboxylic-ester hydrolase) catalyzes reactions of the following form: :a carboxylic ester + H2O \rightleftharpoons an alcohol + a carboxylate Most enzymes f ...

s. There is no interference reported with the metabolism of

nor with any of the investigated transport proteins.

Phase II study: Proof of concept (2011)

In November 2011 Galapagos released the results of their Phase II study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 rheumatoid arthritis patients were treated who showed a suboptimal clinical response to

treatment. Three groups of twelve patients were treated either with 200 mg filgotinib in a single dose, 200 mg divided in two doses or placebo. The primary end-point was the ACR20 score, which monitors improvements in the symptomatology of the patient. After the scheduled 4 weeks of treatment, 83% of the respondents showed an improved ACR20-score. Half of the treated patients showed a complete (or near complete) remission of the disease. There were no reports of

nor changes in lipidemia. The company stated in their press release that filgotinib is the first selective JAK1 inhibitor that shows clinical efficacy. As a result of this study, the company stated that "GLPG0634 shows one of the highest initial response rates ever reported for rheumatoid arthritis treatments".

DARWIN 1 trial

The DARWIN 1 trial was a 24-week

double blind In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

placebo-controlled Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed ...

trial with 599 rheumatoid arthritis patients enrolled. All participants had moderate to severe rheumatoid arthritis and showed an insufficient response to standard

treatment. The trial compared three dosages of filgotinib as a once or twice per day regimen. During the trial all participants remained on their methotrexate treatment. The trial completed in Feb 2015 and the results were released in July 2015. Galapagos announced that the drug met key efficacy endpoints, showed ACR70 responses up to 39%, and maintained its safety profile.

DARWIN 2 trial

The DARWIN 2 trial was a double blind placebo-controlled trial with 280 rheumatoid arthritis patients enrolled who show an insufficient response to standard methotrexate treatment. In contrast to the previous DARWIN 1 trial, methotrexate was discontinued. Therefore, this trial investigates filgotinib as a second-line monotherapy. The recruitment of DARWIN trial 2b ended in November 2014. In August 2015, Galapagos announced that the study confirmed previous results.

DARWIN 3 trial

Patients who completed DARWIN 1 and 2 were eligible for DARWIN 3. In November 2017, the company announced consistent safety findings and durable activity at week 84 in the trial. The estimated study completion timeframe is May 2019.

FINCH Phase III trials

FINCH 1 looks at patients where first-line treatment with

(MTX) is not working. It compares filgotinib versus

adalimumab Adalimumab, sold under the brand name Humira, among others, is a monoclonal antibody used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativ ...

/Humira versus a placebo. FINCH 2 looks at patients where a biologic is not working. FINCH 3 looks at filgotinib as a first-line treatment unlike previous studies that investigated the drug as a second-line treatment. FINCH 2 trial revealed patients with active rheumatoid arthritis who had an inadequate response or intolerance to one or more

DMARDs Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...

, filgotinib showed significance in treatment response compared with placebo.

MANTA

Due to concerns over testicular toxicity in males, the MANTA study is examining the safety of the drug in the context of treating ulcerative colitis. Despite these concerns, the FDA allowed a 200-mg daily dose for males in the Phase III FINCH trials.

References

External links

* * * * * * * * * {{Portal bar , Medicine Non-receptor tyrosine kinase inhibitors Triazolopyridines Cyclopropyl compounds Disease-modifying antirheumatic drugs