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Axial Spondyloarthritis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
In December 2021, tofacitinib became the first Janus kinase (JAK) inhibitor that was approved by the Food and Drug Administration (FDA) for the treatment of AxSpA. Promising data has also emerged for filgotinib and upadacitinib in the treatment of this disease.28–30 The mechanism by which these drugs may impact activity in AxSpA remains somewhat nebulous. Despite this, these drugs have demonstrated efficacy in phase 2 and/or 3 trials in ankylosing spondylitis. As of this writing, it remains unclear where these agents may establish their role in treatment of this disease, particularly in light of emerging safety data related to these medications in patients with RA who have cardiovascular risk factors.31
Medical Treatment of IBD
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Naveen Sharma, Michael R.B. Keighley, Severine Vermeire
Alternatively inhibiting the intracellular cytokine-mediated signals, typically via the Jak-Stat pathway, can also block inflammatory cytokine function. Janus kinases (Jaks) and signal transducers and activators of transcription (Stats) are intracellular signalling molecules that mediate the signal of initial ligand-receptor binding to modulation of gene expression. The mammalian Jak family consists of four members, Jak1, 2, 3 and TYK2, that each transduce the signal of a specific set of cytokines and thereby are highly involved in inflammatory responses. The relationship between Jak-Stat signalling (including their upstream ligand-receptor systems) and IBD has been extensively highlighted by animal studies, genetic association and increased levels of cytokines that converge to Jak-Stat. Since Jak-Stat signalling is involved in a number of inflammatory diseases, several oral small molecule inhibitors have been developed and some of them (tofacitinib, filgotinib) have been effective in pre-clinical studies and are currently being clinically tested for the treatment of IBD. Tofacitinib is an oral pan-Jak inhibitor that preferentially binds to Jak1 and 3 (and Jak2 at higher concentrations), hereby diminishing the downstream effects of several IBD associated cytokines. In patients with moderate-to-severe UC the oral administration of 10 mg tofacitinib resulted in significant, dose-related reduction of most clinical and endoscopic disease parameters as well as inflammatory biomarker levels at week 8.11,12 Tofacitinib was also superior to placebo to maintain remission in UC and the drug has been submitted to the regulatory agencies for approval. The phase-2 tofacitinib trial in Crohn’s disease on the contrary was less convincing than the UC trials and lacked significance.13 The explanation for the lack of efficacy in Crohn’s disease has been attributed to study design and high placebo response rates. However, this does not explain the absence of a dose effect as is the case in UC patients and it might very well be that these results reflect pathogenic differences between the two diseases. Filgotinib (GLPG0634) is a Jak1-selective (also Jak2 at higher dosage) small molecule inhibitor, potentially resulting in a better safety profile due to prevention of the neutropaenia associated with Jak3 inhibition. Promising results of a phase-2 trial of filgotinib in Crohn’s disease have recently been published and a large phase-3 program is on-going.14
Filgotinib in rheumatoid arthritis
Published in Expert Review of Clinical Immunology, 2023
In Darwin 2, 283 patients are treated. At week 12 significantly more patients receiving filgotinib monotherapy at any dose achieve an ACR20 responses versus placebo (primary outcome: 73% for 200 mg monotherapy filgotinib vs 29% in placebo). For other key end points at this moment of 12 weeks also significant differences from baseline in favor of filgotinib 100 and 200 mg versus placebo are seen that are maintained or improve through week 24. For most efficacy end points rapid improvement is demonstrated. Also a dose-dependent increase in Hb is noted. The percentage of patients with TEAE is similar in the placebo and filgotinib groups. Eight patients on filgotinib and one on placebo are reported having a serious TEAE. Four patients on filgotinib developed a serious infection but no tuberculosis or opportunistic infections are noted in this short trial.
Safety of JAK inhibitors: focus on cardiovascular and thromboembolic events
Published in Expert Review of Clinical Immunology, 2022
Fabiola Atzeni, Călin D. Popa, Valeria Nucera, Michael T. Nurmohamed
Filgotinib is selective JAK1 inhibitor filgotinib, that has been recently registered for the treatment of RA. Nowday, there are limited available data concerning the safety profile of filgotinib compared to tofacitinib or baricitinib. In the 2020 American College of Rheumatology (ACR) conference, an abstract reported integrated data from 3 phase III, 2 phase II and 2 LTE trials, including up to 5.5 years of exposure to filgotinib. The analysis included RA patients treated with placebo and patients treated with filgotinib 200 or 100 mg once a day for 12 weeks. The long-term analysis set included all available data for patients receiving more than one dose of filgotinib at either dosage. MACEs and VTEs were included in the analysis. From the RCTs data, the safety of filgotinib is comparable to adalimumab and MTX for both the used doses, 100 mg and 200 mg. In particular, MACEs were considered comparable between filgotinib and placebo. No VTEs were registered in the observation period of 12 weeks in comparison to placebo. The final analysis reported that VTE exposure adjusted rates for filgotinib 200 mg and 100 mg were 0.2 and 0 for 100 patient-years, respectively [48].
Treatment innovation for patients: a collaborative network in the Benelux and an inside view of 20 years of Galapagos
Published in Acta Clinica Belgica, 2022
Patrick Durez, André Hoekema, Tom Huizinga, Muriel Gazin, Erik Present, Dirk Veelaert, Piet Wigerinck, René Westhovens
After nearly 20 years of extensive collaborations and partnerships since the very start of the journey of target discovery, filgotinib has now been submitted for marketing approval. The knowledge and expertise brought in through these collaborations have been key in reaching this milestone for filgotinib, but the financial investment should not be overlooked. Meanwhile, the use of filgotinib is being explored in other indications, including Crohn’s disease, psoriatic arthritis and ankylosing spondylitis. An estimated total of €2.5 billion will be required from the first discovery all the way through to its availability for patients with rheumatoid arthritis, though this estimate also includes the ongoing development of filgotinib for other disease indications. Investments of this magnitude are not possible for a small company or academic centre. Large, continuous investments are needed from other partners and from government support. During the past 20 years, Galapagos has received €38 million in non-dilutive financial support from VLAIO, including €8 million for development of the discovery platform, and almost €5 million for R&D related to filgotinib. This support from government agencies has translated into substantial investments from Galapagos over time anchoring its presence and activities in Belgium.