Olokizumab at the 2020 EULAR Annual Online Meeting and a look at IL-6-Inhibitors

I've been interested in olokizumab for about decade now. In 2016 I've written: „UCB still hasn’t given up and keeps a low fire burning. I doubt that olokizumab will be approved as a drug against rheumatoid arthritis.” [1] And now, at the EULAR Meeting there are two studies. These studies concern rheumatology and not Covid-19.

Let's stay for a moment at the Covid-19 issue and the possible use of IL-6-inhibitors. In patients with dramatic infectious diseases, especially septic shock, IL-6 levels might increase 1000-fold creating cytokine storm or cytokine release syndrome. This is life threatening.

C. Zhang and colleagues published a paper [2] in which they discussed blocking IL-6 signal transduction pathway with tocilizumab, which could become an effective drug for patients with severe COVID-19.

D. McGonagle and colleagues published on the role of cytokines in Covid-19 induced pneumonia and macrophage activation syndrome-like disease [3]. They “discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.”

But back to rheumatology and the EULAR Annual Meeting. We already have tocilizumab (Actemra) and sarilumab (Kevzara), which were approved both by EMA (2009 and 2017) and FDA (2010 and 2017). So where is the niche for olokizumab? Maybe that's the reason why the development of the drug has been so slow. But maybe Covid-19 will also speed things up.

There has been a study by E. Nasonov and colleagues [4]: “OP0021 OLOKIZUMAB, MONOCLONAL ANTIBODY AGAINST IL6, IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: EFFICACY AND SAFETY RESULTS OF PHASE III CREDO-1 STUDY”. If you are surprised by he Russian names, don be as in July 2013 there had been an announcement by UCB: “UCB out-licenses RA drug olokizumab to Russia's R-Pharm”.Back to the study. “428 patients were randomized to OKZ 64mg q2w (n=143), OKZ 64mg q4w (n=142), and PBO (n=143).” The authors found: “Treatment with OKZ over a 24-week period was associated with significant improvements in the signs, symptoms and physical function of RA, ...” There has be a numerically higher rate of adverse events and one death due to septic shock. There were no differences between the two dosages of olokizumab in efficacy or safety outcomes.

The second study is on patient related outcomes. [5] Conclusion sny E. Nasonov and olleagues: „1. Treatment with OKZ over a 24-week period was associated with significant improvements in PRO in patients with moderate to severe RA. 2. There were no discernible differences between the two regimens of OKZ from patient’s perspective.”

Do we need another IL-6-Inhibitor? If we compare olokizumab to tocilizumab and sarilumab on the qualitativ level, there would not be need for it. If it comes to altered demand (quantitativ level), there might be need for it. But let's wait for the coming studies in rheumatology and how the world copes with Covid-19.

Links and References:

[1] https://rheumatologe.blogspot.com/2016/02/win-olokizumab.html

[2] Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55(5):105954. doi:10.1016/j.ijantimicag.2020.105954

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118634/

[3] McGonagle D, Sharif K, O'Regan A, Bridgewood C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun Rev. 2020;19(6):102537. doi:10.1016/j.autrev.2020.102537

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195002/

[4] E. Nasonov1, R. Stoilov2, T. Tyabut3, M. C. Genovese4 on behalf of Saeed Fatenejad (United States of America), Diana Krechikova, Elena Korneva,

Alexey Maslyansky, Tatiana Plaksina, Marina Stanislav, Sergey Yakushin, Elena Zonova (Russian Federation). OP0021 OLOKIZUMAB, MONOCLONAL ANTIBODY AGAINST IL6, IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: EFFICACY AND SAFETY RESULTS OF PHASE III CREDO-1 STUDY. DOI: 10.1136/annrheumdis-2020-eular.1688

[5] E. Nasonov1, M. Ivanova2, M. Samsonov3, T. Tyabut4, M. C. Genovese5 on behalf of Saeed Fatenejad (United States of America), Diana Krechikova, Sofia Kuzkina, Alexey Maslyansky, Tatiana Plaksina, Marina Stanislav, Sergey Yakushin, Elena Zonova (Russian Federation). THU0176 OLOKIZUMAB IMPROVES PATIENT REPORTED OUTCOMES IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE RHEUMATOID ARTHRITIS INADEQUATELY CONTROLLED BY METHOTREXATE: RESULTS FROM THE DOUBLE-BLIND, RANDOMIZED CONTROLLED PHASE III STUDY (CREDO-1). DOI: 10.1136/annrheumdis-2020-eular.2102

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Zu Abkürzungen von anti-rheumatischen Medikamenten

Ich las den den Artikel von T. Schmeiser et al.[1]. Und da waren sie wieder, die Abkürzungen, die ich so nicht mag. Ich halte es für eine gute Idee, Medikamente mit drei Buchstaben abzukürzen, aber es muss nicht jedes Land seine eigenen Abkürzungen produzieren. Flughäfen haben solche Abkürzungen mit drei Buchstaben. Der Flughafen Köln/Bonn wird CGN abgekürzt und kein Reiseveranstalter käme auf die Idee, plötzlich KLN oder KÖL zu benutzen.

Ich hatte bereits über diese Art von Abkürzungen vor etwa acht Jahren schon einmal berichtet [2].

Bei neun Medikamenten sind Abweichungen zum Gebrauch im Abstract-Band des 2019 ACR Meetings [3] vorhanden.

Bei Abatacept ist die von Schmeiser gewählte Alternative sogar besser, da weniger fehleranfällig gegenüber Adalimumab.

Baricitinib wird in den Studien des 2019 ACR Meeting mit bari abgekürzt. BAR ist prinzipiell in Ordnung, führt einen aber beim Suchen auf „bar“-Diagramme.

Certolizumab mit CMZ abzukürzen ist nur vom deutschen Medikamentennamen (Cimzia) her zu erschließen.

ETA für Etanercept finde ich nicht gut, weil es im Japanischen ein schlechten Beigeschmack hat [4].

Golimumab – warum nur GOM? GOL ist einsichtiger.

Für Infliximab war auch schon IFX in Gebrauch. IFN kann als Abkürzung von Infusion verwechselt werden.

Für SAR als Abkürzung für Sarilumab habe ich noch keinen Beleg. Wäre prinzipiell nichts gegen einzuwenden.

Für Tocilizumab hatte ich früher TOC gefunden, durchgesetzt hat sich TCZ. TOC wäre auch einleuchtender als TOZ.

Selbstverständlich kann jeder seine Abkürzungen so wählen, wie sie dann im Abkürzungsverzeichnis stehen. Verständlicher ist man aber, wenn man einen Konsens für Abkürzungen herstellt.

Links und Literatur:

[1] Schmeiser, T., Broll, M., Dormann, A. et al. Einstellung von Patienten mit entzündlich-rheumatischen Erkrankungen zur immunsuppressiven Therapie im Rahmen der COVID-19 Pandemie – eine Situationsanalyse. Z Rheumatol 79, 379–384 (2020). https://doi.org/10.1007/s00393-020-00800-8 ABC:

[2] https://rheumatologe.blogspot.com/2012/11/abkurzungen-fur-dmards-in-der-s1.html
[3] 2019-Abstract-Supplement.pdf https://acrabstracts.org/download-abstracts/
[4] https://rheumatologe.blogspot.com/2016/12/whats-in-names-of-drugs-in-rheumatology.html
Edward S. Herman, Noam Chomsky: Manufacturing Consent. Pantheon Books, New York 2002.

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Biosimilars und Biologika auf dem DGRh Kongress 2017 in Stuttgart

Warum ist die Politik so daran interessiert, warum Krankenkassen, Patientenverbände, Fachgesellschaften? Weil sie zuvor ihre Hausaufgaben nicht gemacht haben. Denn sie haben der Preisexplosion nicht Einhalt geboten. Das fing schon vor den Biologika an, aber hierbei ist es doch besonders offensichtlich – und ein Ende ist da nicht in Sicht, wenn wir an die small molecules wie Tofacitinib oder Baricitinib denken. So steigen die Preise weiter an. Der Markt wird immer unüberschaubarer.

Biosimilars kommen wie Innovationen daher, als hätte die Welt darauf gewartet, aber es sind schließlich nur  Imitate; die entscheidenden Ideen haben andere gehabt und in Studien die Wirksamkeit nachgewiesen. Die  Patienten jedenfalls werden damit überfordert. Insbesondere wo es neben Biosimilars auch schon Bioidenticals gibt. Auch wenn ich nicht auf Biosimilars gewartet habe, werde ich sie denooch anwenden, besser anwenden müssen.

Welche Biosimilars haben wir denn? Welche Biologika wurden denn vorgestellt? Gab es funkelnagelneue Bio***s? In dieser Übersicht werde ich mich auf den Einsatz dieser Medikamentengruppe in der Therapie der rheumatoiden Arthritis, der Psoriasisarthritis und den seronegatiben Spondyloarthritiden beschränken.

Biosimilar-Kandidaten zu Humira® (Adalimumab) BI 695501 von Boehringer Ingelheim - ENCORE.42 (Encore sind Poster, die bereits anderswo gezeigt wurden) - das Poster beschäftigt sich mit dem Autoinjektor. Encore.47 beschäftigt sich mit Wirksamkeit und Nebenwirkung und findet keinen wesentlichen Unterschied.

Ansonsten fanden sich viele Poster zu Secukinumab, aber auch Daten zu Tocilizumab, Certolizumab, Canakinumab, Sarilumab, Abatacept, Golimumab, Rituximab, Ixekizumab und Infliximab.

H. Kellner präsentierte Daten aus seiner Schwerpunktpraxis (EV.13): " Hohe Patientenakzeptanz bei Neueinstellung oder Umstellung von Originalabiologika (Enbrel, Remicade) auf Biosimilar-TNF Ak". Die Arbeit hat nur geringe Fallzahlen. In der Schlussfolgerung lesen wir: "Den angesprochenen Patienten ist die Möglichkeit einer substanziellen Kostenersparnis bei Einsatz von Biosimilar durchaus bewußt und ein wesentliches Element der Bereitschaft selbst Biosimilars zu verwenden." Das kann ich so aus den Ergebnissen nicht herauslesen. Ob eine Kostenersparnis dauerhaft gegenüber den Originalherstellern bestehen bleibt, muss die Zukunft zeigen, denn es wird wahrscheinlich zu Festpreisen kommen.

Zusammenfassend spielen die Biosimilars in der Wissenschaft eine untergeordnete Rolle. Das liegt in der Natur der gesetzlichen Bestimmungen, denn es muss nur der Nachweis von gleicher Effektivität und Nebenwirkung zum Orinalpräparat in einer Indikation nachgewiesen werden. Das sollte auch leicht möglich sein, wenn die Strukturgleichheit gegeben ist - und davon ist auszugehen. Für Infliximab haben wir die Biosimilars Remsima®, Inflectra® und Flixabi®, wovon Remsima® und Inflectra® bioidentisch sind, d.h. sie haben einen Hersteller und zwei Vertreiber. Für Etanercept haben wir die Biosimilars Benepali® und Erelzi™. Für Rituximab ist das Biosimilar Truxima® zugelassen. Für Adalimumab ist das Biosimilar Amjevita™ in den USA zugelassen und wird neben anderen hier in der nahen Zulunft erwartet [1].

Für die o.g. Originalpräparate ist eine Fülle von neuen Daten veröffentlicht worden. Allerdings habe ich nichts zu Mavrilimumab und Vobarilizumab gefunden.

Links:

[1] http://rheumatologe.blogspot.de/2016/12/possible-problems-with-piosimilars.html

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IL-6-Inhibitors in Rheumatoid Arthritis, where do we stand after the 2017 EULAR Annual Meeting?

Now, that we have several IL-6-inhibitors already available or shortly available, we should look, where we stand. Interleukin 6 is a cytokine relevant to many inflammatory diseases and others as well.

Tocilizumab

Tocilizumab is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R) [1]. Tocilizumab has been approved by EMA in 2009. It is used as infusions (linear at 8 mg per kg body weight with a ceiling dosage of 800 mg) q4w or 162 mg s.c. every week.

Siltuximab

Siltuximab is a chimeric monoclonal antibody that binds to interleukin-6, so IL-6 cannot bind to soluble and membrane bound interleukin-6 receptors [2]. Siltuximab is tested for the treatment of multicentric Castleman’s disease (MCD). That is, where tocilizumab also started. Nothing at the 2017 EULAR Annual Meeting on Siltuximab.

Clazakizumab

Clazakizumab (aka ALD518 and BMS-945429) is a aglycosylated, humanized monoclonal antibody against interleukin-6 [3]. I thought of clazakizumab as a promising drug candidate, but there had been no phase 3 studies back in 2014 [4]. No new study on clazakizumab at the 2017 EULAR Annual Meeting. Last news is a phase 2b study by M.E. Weinblatt and colleagues from 2015 [5]. My guess the reason for the company’s decision is too much competition in the IL-6 niche.

Olokizumab

Olokizumab binds to interleukin-6. In 2016 I had written: “These recent studies aren’t so interesting in the results, but still there is a story being told. UCB still hasn’t given up and keeps a low fire burning. I doubt that olokizumab will be approved as a drug against rheumatoid arthritis.” [6] And Adisinsight seems to back up my opinion [7]: “06 Mar 2017 Phase-III clinical trials in Rheumatoid arthritis in Lithuania (EudraCT2015-005309-35)”. But there’s no new study on clazakizumab at the 2017 EULAR Annual Meeting.

Sarilumab

I’ve just published a blogpost on sarilumab (ALX-0061) at the 2017 EULAR Annual Meeting in Madrid [8]. Sarilumab (Kevzara) received FDA approval on May 22, 2017. Sanofi and Regeneron Pharmaceuticals announced in April 2017, that the European Medicine Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the marketing authorization of Sarilumab (Kevzara). The dosage would be 200 mg s.c. q2w.

Sirukumab

I’ve just published a blogpost on sirukumab at the 2017 EULAR Annual Meeting in Madrid [9]. Sirukumab has been submitted for approval both to FDA and EMA during September 2016. Decisions should come soon. Or later. Sirukumab has been tested at 50 mg s.c. q4w and 100 mg s.c. q2w.

Tocilizumab Biosimilars

I haven’t seen anything on tocilizumab biosimilars at the 2017 EULAR Annual Meeting in Madrid. But the Generics and Biosimilar Initiative lists BOW070 (a tocilizumab biosimilar) by Epirus Biopharmaceuticals for the rare multicentric Castleman’s disease (MCD) [10]. LusiNEX is Taiwan based Mycenax’s biosimilar tocilizumab; “LusiNEX is under process development now and is expected to initiate phase I trial in 2017 in Europe and Taiwan” [11].

So, there will be lots of competition in the relatively small IL-6 part of the tart. The reason to change from Actemra/RoActemra to a tocilizumab biosimilar, sarilumab o sirukumab will be respecting prices and reimbursements dictated by health insurance companies. Please tell me, if you see a medical reason.

Links and references:

[1] https://en.wikipedia.org/wiki/Tocilizumab

[2] https://en.wikipedia.org/wiki/Siltuximab

[3] https://en.wikipedia.org/wiki/Clazakizumab

[4] http://rheumatologe.blogspot.de/2014/07/clazakizumab-at-eular-2014-meeting-in.html

[5] https://www.ncbi.nlm.nih.gov/pubmed/26138593

[6] http://rheumatologe.blogspot.de/2016/02/win-olokizumab.html

[7] http://adisinsight.springer.com/drugs/800029302

[8] http://rheumatologe.blogspot.de/2017/06/sarilumab-alx-0061-at-2017-eular-annual.html

[9] http://rheumatologe.blogspot.de/2017/06/sirukumab-at-2017-eular-annual-meeting.html

[10] http://www.gabionline.net/Biosimilars/General/Biosimilars-of-tocilizumab

[11] http://www.mycenax.com.tw/en/goods.php?act=view&no=12

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Biologics in Relapsing Polychondritis

Relapsing polychondritis is a rare, often severe, and untreated fatal connective tissue disease. The inflammation of the ear cartilage is often the initial symptom, at least in the patients, who had been referred to our center. We’re still lacking a specific lab test for relapsing polychondritis. We have different diagnostic criteria by McAdam, Damiani and Michet. I’ve already written about the disease on this blog, less than I should have considering the fact that I treat patients with this disease. There have been four abstracts at the 2016 ACR Annual Meeting. I’ll also talk about the abstracts/studies, which doesn’t concern biologics.

Guillaume Moulis and his more than 20 co-authors presented [#1329]: “Efficacy and Safety of Biologics in Relapsing Polychondritis: A National Multicenter Study in France”. Conclusion: “Overall, biologics are an interesting option for RP treatment. “ You might call this statement laconic, but there’s lots of work included. The authors saw 41 patients and had to try several drugs until one worked. The rate of partial and complete remission is about 60-70%, with anakinra and abatacept being lowest at 50-53%. The authors looked at all TNF alpha inhibitor, anakinra, abatacept, tocilizumab, and rituximab.

Marcela Ferrada and colleagues presented [#1330]: “Clinical Presentations of Relapsing Polychondritis: More Than a Swollen Ear”. The authors acquired data via an internet-based questionnaire to catalogue the variety of possible clinical presentations of relapsing polychondritis. They could evaluate 180 questionnaires. In results the authors point out: “Common initial symptoms included dizziness, eye inflammation, constochondritis, and shortness of breath, nose pain, and voice changes. Some patients also reported fatigue, flu-like symptoms, fever and difficulty swallowing as initial symptoms. Complications of RP included disability (25%), tracheomalacia (16%) and intubation related to RP (12%).”  The study has limitations as you can’t validate the diagnosis and there’s a recall bias. But still, I think the study is very valuable.

Chee Ken Cheah and collegues presented [#1331]: “Disease Patterns and Long Term Outcome Amongst Patients with Relapsing Polychondritis – Single Centre Experience”. Conclusions: “Our study revealed higher number of initial organ presentation, and younger age of disease onset correlated with potential diagnosis delay. Male gender with airway involvements correlated with higher number of organ damages and poorer outcome. Multicenter registries may lead to a better understanding of this disease.”

Toshiki Nakajima and colleagues looked at 33 patients with relapsing polychondritis in this study [#1332]: “Severe Complications and Immunosuppressive Treatments in 33 Patients with Relapsing Polychondritis”. In results the authors inform us about HLA haplotypes, which are associated with relapsing polychondritis: “Positivity of HLA-DQB1 05:02 was 17.6% (3/17),　higher than 2.6% in healthy Japanese.” [The authors recently reported an association of disease onset and 3 HLA haplotypes (DQB1*05:02, B*67:01 and DRB1*16:02 in linkage disequilibrium) in C. Terao et al.: Rheumatology (Oxford) doi: 10.1093/rheumatology/kew233]. “Methotrexate (MTX), azathioprine (AZP), intravenous cyclophosphamide (IVCY), infliximab (IFX) and tocilizumab (TCZ) were used along with glucocorticoid ….” Conclusion: “The linkage with certain haplotypes of HLA and the positivity of autoantibodies (~30%) consolidate that RP is an autoimmune disease. IVCY showed a good response in patients with TB lesions in the present study. The prognosis of patients with CNS lesions was poor. Further collection of cases is required to elucidate pathophysiology and improve treatments.”

So we have different approaches according to disease severeness, organ involvement, and activity. Immunosuppressants as well as biologics are used. As the disease is rare there won’t be any randomized controlled trials and any drug will be off label. Anyway, a partial remission of 50-70% is feasible with biologics. Hopefully one can speed up approval proceedings with insurance companies because of the off label use.

Links:

https://en.wikipedia.org/wiki/Relapsing_polychondritis

http://rheumatologe.blogspot.de/2011/12/biologics-in-relapsing-polychondritis.html

Moulis G, Pugnet G, Costedoat-Chalumeau N, Mathian A, Leroux G, Boutemy J, Bouillet L, Berthier S, Gaultier JB, Jeandel PY, Konaté A, Mékinian A, Solau-Gervais E, Terrier B, Wendling D, Garnier C, Cathebras P, Arnaud L, Cacoub P, Amoura Z, Piette JC, Arlet P, Palmaro A, Lapeyre-Mestre M, Sailler L. Efficacy and Safety of Biologics in Relapsing Polychondritis: A National Multicenter Study in France [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/efficacy-and-safety-of-biologics-in-relapsing-polychondritis-a-national-multicenter-study-in-france/. Accessed December 15, 2016.

Ferrada M, Choudhury SD, Newman K, Sinaii N, Guma M, Christie T, Katz JD. Clinical Presentations of Relapsing Polychondritis: More Than a Swollen Ear [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/clinical-presentations-of-relapsing-polychondritis-more-than-a-swollen-ear/. Accessed December 15, 2016.

Cheah CK, Sangle (Joint First Author) S, D'Cruz D. Disease Patterns and Long Term Outcome Amongst Patients with Relapsing Polychondritis – Single Centre Experience [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/disease-patterns-and-long-term-outcome-amongst-patients-with-relapsing-polychondritis-single-centre-experience/. Accessed December 15, 2016.

Nakajima T, Yoshifuji H, Terao C, Murakami K, Kuramoto N, Nakashima R, Imura Y, Tanaka M, Ohmura K, Mimori T. Severe Complications and Immunosuppressive Treatments in 33 Patients with Relapsing Polychondritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). http://acrabstracts.org/abstract/severe-complications-and-immunosuppressive-treatments-in-33-patients-with-relapsing-polychondritis/. Accessed December 15, 2016.