Januskinase-Inhibitoren

Januskinase-Inhibitoren werden seit einigen Jahren in der Rheumatologie angewendet. Ich hatte mit bereits vor etwa 10 Jahren näher mit dem Thema auseinandergesetzt [1] und später auch auf den Hype hingewiesen [2]. Tofacitinib war in den USA (von der FDA) zugelassen worden, aber dann spielte die EMA in Europa nicht mit; es wurden zusätzliche studien verlangt. Heute sind drei Januskinase-Inhibitoren hier zugelassen: Baricitinib, Tofacitinib, Upadacitinb. Da ist es an der Zei, sich einmal näher mit ihnen zu beschäftigen.

Was sind Januskinase-Inhibitoren?

Es sind DMARDs und zwar tsDMARDs, das sind auf spezifische Molekularstrukturen abzielende (targeted) DMARDs. DMARD steht für disease modifying anti rheumatic drug, als Krankheit modifizierendes anti-rheumatisches Medikament. Januskinase-Inhibitoren sind Kinase-Hemmer, d.h. diese Medikamente hemmen einen bestimmten Typ von Kinase (das ist ein Enzym-Typ) - nämlich die Januskinasen (abgekürzt JAK).

Während die Biologika die Kommunikation zwischen Zellen unterbrechen, machen dies die Januskinase-Inhibitoren in der Zelle. Das Signal, das durch ein Zytokin am Rezeptor ausgelöst wird, wird durch die Januskinasen in STAT-Proteine übersetzt, die im Zellkern Gene aktivieren, die dann die Produktion bestimmter (entzündungsvermittelnde) Zytokine steuern [3,4]. STAT steht für "Signaltransduktoren und Aktivatoren der Transkription". Es sind bislang sieben STAT-Proteine bekannt.

Wie sind die Unterschiede der verschiedenen Medikamente zu erklären?

Von den Januskinasen gibt es vier unterschiedliche Typen: JAK1, JAK2, JAK3 und TYK2. Aus diesen bilden sich immer Paare, die dann die Bildung unterschiedlicher STAT-Proteine zur Folge hat. Die bekannten Januskinase-Inhibitoren hemmen unterschiedlich stark die verschiedenen Kinasen:

• Baricitinib hemmt hauptsächlich JAK1 und JAK2
• Tofacitinib hemmt hauptsächlich JAK1und JAK3
• Upadacitinib hemmt hauptsächlich JAK1
• Filgotinib hemmt hauptsächlich JAK1

Daraus sind unterschiedlichen Wirkungen zu erwarten.

Welche Zulassungen bestehen?

Baricitinib (Handelsname Olumiant) ist zugelassen für die Behandlung der mittelschweren bis schweren rheumatoiden Arthritis (RA) bei Erwachsenen mit und ohne Methotrexat, wenn andere Medikamente nicht gewirkt hatten oder Nebenwirkungen verursacht hatten.

Tofacitinib (Handelsname Xeljanz) ist zugelassen für die Behandlung der mittelschweren bis schweren rheumatoiden Arthritis (RA) bei Erwachsenen mit und ohne Methotrexat, wenn andere Medikamente nicht gewirkt hatten oder Nebenwirkungen verursacht hatten. Außerdem besteht eine Zulassung für die „aktive Psoriasis-Arthritis (PsA) bei erwachsenen Patienten, die auf eine vorangegangene krankheits-modifizierende antirheumatische (DMARD-) Therapie unzureichend angesprochen oder diese nicht vertragen haben“.

Updacitinb (Handelsname Rinvoq) ist zugelassen für die Behandlung der mittelschweren bis schweren rheumatoiden Arthritis (RA) bei Erwachsenen mit und ohne Methotrexat, wenn andere Medikamente nicht gewirkt hatten oder Nebenwirkungen verursacht hatten.

Filgotinib ist noch nicht zugelassen, die Zulassung ist beantragt.

Was halte ich von Januskinase-Inhibitoren?

Sie bereichern die Möglichkeiten bei der Therapie rheumatischer Erlkrankungen. Aber sie sind unverschämt teuer.

Die Tagesdosis von Olumint kostet etwa 42 €.

Die Tagesdosis von Rinvoc kostet etwa 45 €.

Die Tagesdosis von Xeljanz kostet etwa 36 €.

Zum Vergleich:

Die Tagesdosis von Metex 15 mg Tabletten beträgt etwa 0,12 € (Methotrexat wird wöchentlich eingenommen!).

Summenformeln:

Baricitinib C₁₆H₁₇N₇O₂S, Tofacitinib C₁₆H₂₀N₆O, Upadacitinib C₁₇H₁₉F₃N₆O, Methotrexat C₂₀H₂₂N₈O₅.

Fazit: die Januskinase-Inhibitoren stellen eine wichtige Innovation dar, aber wegen der horrenden Preise sind sie keine Medikamente für die erste Wahl.

Links:

[1] http://rheumatologe.blogspot.com/2011/10/new-kids-on-block-emerging-therapies-in.html

[2] https://rheumatologe.blogspot.com/2015/11/protein-kinase-inhibitors-after-acr.html

[3] https://www.pharmawiki.ch/wiki/index.php?wiki=Januskinase-Inhibitoren

[4] https://flexikon.doccheck.com/de/JAK-Inhibitor

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Filgotinib at the 2017 EULAR Annual Meeting in Madrid

Filgotinib (GLPG0634, GS-6034) is an oral, selective JAK1 inhibitor, which is studied in combination with methotrexate (MTX) or as monotherapy. I have already written about this protein kinase inhibitor several times [1,2,3].

At the 2017 EULAR Annual Meeting in Madrid we have seen seven studies being presented.

We have a post-hoc analysis from two phase 2b studies by R. Westhovens and colleagues [4]: Filgotinib once daily at 100mg and 200mg with or without MTX showed improved clinical outcomes compared to placebo, baseline CRP levels did not matter.

There were two studies on different mouse models concerning psoriatic arthritis.

One study looked at a multi-biomarker disease activity (MBDA) score, which measures 12 disease-related biomarkers of inflammation and joint injury in RA patient.

One study has been on the reduction in the levels of different “cytokines related to T_H1, T_H2, T_H17 and potentially B cells, as well as innate immunity” [5].

One study looked at the “effect of filgotinib on a background of MTX treatment on markers of inflammation in RA patients”[6]. Conclusion: “Treatment with filgotinib decreased several factors that have key roles in RA for matrix degradation, cartilage destruction, angiogenesis, leukocyte adhesion and recruitment.”

R. Alten and colleagues looked at long term safety and efficacy of filgotinib 200mg daily in patients from the DARWIN 3 Phase 2 open-label extension study [7]. The authors concluded: “With 1314 patient-years of exposure, the safety profile of filgotinib appears consistent with that of previously reported double-blind studies and the clinical response appears durable.”

Filgotinib has been tested further, but no data on a phase three study. Post-hoc analysis of former studies and new mouse model studies keep the pot warm, but in my opinion not simmering. Maybe filgotinib will fare better in the treatment of M. Crohn [8]. As baricitinib and tofacitinib already have been approved by EMA and are available on the market for treatment, I wonder, what Galapagos is waiting for. Let’s see if filgotinib will be marketed for indications like rheumatoid arthritis or psoriatic arthritis in the future. 

Links and references:

[1] http://rheumatologe.blogspot.de/2015/11/filgotinib-at-acr-2015-meeting-in-san.html

[2] http://rheumatologe.blogspot.de/2016/08/protein-kinase-inhibitors-small.html

[3] http://rheumatologe.blogspot.de/2014/07/glpg0634-at-eular-2014-in-paris.html

[4] Annals of the Rheumatic Diseases, volume 76, supplement 2, year 2017, page 148 / Session: From classics to new: synthetic DMARDs in RA , (Oral Presentations ) / DOI: 10.1136/annrheumdis-2017-eular.5428

[5] Annals of the Rheumatic Diseases, volume 76, supplement 2, year 2017, page 270 / Session: Rheumatoid arthritis - non biologic treatment , (Poster Presentations ) / DOI: 10.1136/annrheumdis-2017-eular.5814

[6] Annals of the Rheumatic Diseases, volume 76, supplement 2, year 2017, page 281 /

Session: Rheumatoid arthritis - non biologic treatment , (Poster Presentations ) / DOI: 10.1136/annrheumdis-2017-eular.5799

[7] Annals of the Rheumatic Diseases, volume 76, supplement 2, year 2017, page 267 / Session: Rheumatoid arthritis - non biologic treatment , (Poster Presentations ) / DOI: 10.1136/annrheumdis-2017-eular.5460

[8] http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2816%2932537-5.pdf

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High Hopes and Aspirations or how ASP015K / Peficitinib brings back the Small Molecule Hype

ASP015K, now called peficitinib is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3, developed by Astellas Pharma for treatment of rheumatoid arthritis (RA) and other autoimmune diseases [1]. A year later, as the hype about JAK and small molecules were cooling down, I’ve written: “Could ASP015K keep up with its’ aspirations at the EULAR 2013 meeting?” And: “My positive impression dwindles considerably! I hope we’ll see results from a phase 2b study later this year.” [2] So we already had a Phase 2b study presented at the EULAR 2013 Meeting.

As tofacitinib and baricitinib are approved in the EU right now, hype and hopes in protein kinase inhibitors return. Last year I’ve speculated: “I guess that the pharmaceutical industry isn’t prudent enough not to overprice small molecules, so that our patient's needs are addressed.” [3] And I’ve proven right. [4]

Recently Gregory M. Weiss, M.D. has published an article [5]: “JAK Inhibitor Peficitinib Reduces RA Symptoms”. He refers to a phase 2b study. So, it seemed to me nothing new under the sun. I stumbled over the sentence: “The authors suggest that rheumatoid arthritis patients with elevated C-reactive protein levels may respond better to higher doses of peficitinib than those with elevated sedimentation rates.” Most of my patients, who have elevated sedimentation rates also have elevated C-reactive protein levels, and vice versa.

There is already a phase 3 study on Peficitinib under way [6]. I’ve checked the abstracts for the 2017 EULAR Meeting (still under embargo), but there isn’t any study mentioned, so that I expect news on this study could be published at the ACR 2017 Meeting later this year.

There will be an open extension phase 2b study on filgotinib being presented at the EULAR 2017 Meeting. No study on decernotinib expected at the EULAR 2017 Meeting.

The race for the high end price level small molecules is open again. Let’s hope that besides the hype there’ll be some benefit for our patients.

Links:

[1] http://rheumatologe.blogspot.de/2012/12/asp015k-at-acr-2012-in-washington.html

[2] http://rheumatologe.blogspot.de/2013/06/asp015k-at-eular-2013-meeting.html

[3] http://rheumatologe.blogspot.de/2016/08/protein-kinase-inhibitors-small.html

[4] http://rheumatologe.blogspot.de/2017/05/tofacitinib-xeljanz-kommt-gerade-an.html Text in German.

[5] http://www.rheumatologynetwork.com/rheumatoid-arthritis/jak-inhibitor-peficitinib-reduces-ra-symptoms?GUID=71CAAEF6-94A2-4616-B379-17C18CF13750&rememberme=1&ts=30052017

[6] http://adisinsight.springer.com/drugs/800028907

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Filgotinib at the ACR 2015 Meeting in San Francisco

There have been seven publications on Filgotinib at the ACR 2015 Annual Meeting in San Francisco. Filgotinib (already known as: GLPG0634) is a novel oral, potent and selective JAK1 inhibitor.

R Westhovens and colleagues presented results from a phase 2B dose ranging study over 12 weeks. Conclusion: "Over 12 weeks, filgotinib in combination with MTX demonstrated consistent efficacy on signs and symptoms of active RA with a rapid onset of action. [...]"

Arthur Kavanaugh et al. also looked at results from a phase 2B dose ranging study over 12 weeks. The reported on filgotinib as monotherapy. Conclusion: "Over 12 weeks, filgotinib as monotherapy demonstrated clear efficacy in treating the signs and symptoms of active RA with a rapid onset of action. Overall safety profile was favorable and consistent with previous studies conducted in RA with filgotinib."

Namour Florence and colleagues presented data in the influende of age and renal impairment from phase 1 studies. Conclusion: "Higher age and mild to moderate impairment of renal function has a limited impact on the PK [pharmacokinetics] of filgotinib. In severe renal impairment, the exposure to filgotinib’s active metabolite is elevated, consistent with its renal elimination pathway. This was not associated with safety signals in these Phase 1 studies."

There were of course more studies: René Galien and colleagues (filgotinib) decreases plasma markers of inflammation and joint damage), René Galien and another team (filgotinib changes lipid profile with a preferential increase in HDL), Namour Florence et al. (filgotinib shows similar pharmacokinetics and pharmacodynamics profiles in Japanese and Caucasian healthy volunteers), and René Galien and colleagues (further evidence for the JAK1 selectivity of filgotinib).

All in all, filgotinib has presented data up to 12 weeks. We have to wait for a phase 3 study ... and much longer for data on radiographic progression.

References:

Westhovens R, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-an-oral-jak1-selective-inhibitor-is-effective-in-combination-with-methotrexate-in-patients-with-active-rheumatoid-arthritis-results-from-a-phase-2b-dose-ranging-study/. Accessed November 18, 2015.

Kavanaugh A, Ponce L, Cseuz R, Reshetko O, Stanislavchuk MA, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective As Monotherapy in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-an-oral-jak1-selective-inhibitor-is-effective-as-monotherapy-in-patients-with-active-rheumatoid-arthritis-results-from-a-phase-2b-dose-ranging-study/. Accessed November 18, 2015.

Florence N, Fagard L, Van der Aa A, Goss S, Harrison P, Tasset C. Influence of Age and Renal Impairment on Pharmacokinetics of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/influence-of-age-and-renal-impairment-on-pharmacokinetics-of-filgotinib-glpg0634-a-selective-jak1-inhibitor/. Accessed November 18, 2015.

Galien R, Van der Aa A, Blanque R, Darquenne S, Harrison P, Tasset C. Selective JAK1 Inhibition with Filgotinib (GLPG0634) Decreases Plasma Markers of Inflammation and Joint Damage in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/selective-jak1-inhibition-with-filgotinib-glpg0634-decreases-plasma-markers-of-inflammation-and-joint-damage-in-patients-with-rheumatoid-arthritis/. Accessed November 18, 2015.

Galien R, Harrison P, Brys R, Van der Aa A, van 't Klooster G, Tasset C. 4-Week Treatment of Rheumatoid Arthritis Patients with the JAK1-Selective Inhibitor Filgotinib (GLPG0634) Changes Lipid Profile with a Preferential Increase in HDL [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/4-week-treatment-of-rheumatoid-arthritis-patients-with-the-jak1-selective-inhibitor-filgotinib-glpg0634-changes-lipid-profile-with-a-preferential-increase-in-hdl/. Accessed November 18, 2015.

Florence N, Vayssière B, Galien R, Fagard L, Van der Aa A, Goss S, Harrison P, Tasset C. Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, Shows Similar Pharmacokinetics and Pharmacodynamics Profiles in Japanese and Caucasian Healthy Volunteers [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-a-selective-jak1-inhibitor-shows-similar-pharmacokinetics-and-pharmacodynamics-profiles-in-japanese-and-caucasian-healthy-volunteers/. Accessed November 18, 2015.

Galien R, Brys R, Van der Aa A, Harrison P, Tasset C. Absence of Effects of Filgotinib on Erythrocytes, CD8+ and NK Cells in Rheumatoid Arthritis Patients Brings Further Evidence for the JAK1 Selectivity of Filgotinib [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/absence-of-effects-of-filgotinib-on-erythrocytes-cd8-and-nk-cells-in-rheumatoid-arthritis-patients-brings-further-evidence-for-the-jak1-selectivity-of-filgotinib/. Accessed November 18, 2015.

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GLPG0634 at the EULAR 2014 in Paris

GLPG0634 is selective inhibitor of Janus kinase 1 (JAK-1) and I have been quite thrilled by this new drug since the ACR 2012 in Washington. The big news is, GLPG0634 has a name now: filgotinib.

F. Namour and colleagues presented [THU0123]: "DOSE SELECTION OF GLPG0634, A SELECTIVE JAK1 INHIBITOR, FOR RHEUMATOID ARTHRITIS PHASE 2B STUDIES: PK/PD AND EXPOSURE-DAS28 MODELING APPROACH". Conclusions: "Current modelling and simulation on the basis of early clinical data suggests that the pharmacokinetics of GLPG0634 is dose proportional at doses up to 200 mg QD, in agreement with observed data, and shows that both GLPG0634 and its main metabolite contribute to biomarker response. Simulations of the pSTAT1 and DAS28 dose-response relation suggest that the efficacy is favorable up to a daily dose of 200 mg GLPG0634, with clinical response in the range of that observed with registered compounds. A daily dose range from 50 to 200 mg is currently being tested in the DARWIN Phase 2B program."

C. Belleville-Da-Costa and colleagues presented [THU0138]: "GLPG0634M1, A MAJOR METABOLITE OF THE JAK1-SELECTIVE INHIBITOR GLPG0634, IS ALSO JAK1-SELECTIVE AND EFFICIENT IN THE RAT CIA MODEL". I skip this one.

F. Namour and colleagues presented [AB0460]: "GLPG0634, A SELECTIVE JAK1 INHIBITOR, CONFIRMS ITS LOW LIABILITY FOR DRUG-DRUG INTERACTIONS". Let's skip this one, too.

Darwin returned from his voyage with the beagle in 1836 and published his abstract "On the Origin of Species by Means of Natural Selection, or The Preservation of Favoured Races in the Struggle for Life" in 1859. Let's hope that the DARWIN study will publish results more quickly.

Links:

http://rheumatologe.blogspot.de/2013/06/glpg0634-at-eular-2013.html

http://rheumatologe.blogspot.de/2012/12/glpg0634-at-acr-2012-in-washington.html