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

.

Clazakizumab at the EULAR 2014 Meeting in Paris

Clazakizumab is an anti-IL-6 MAB. I haven't written much on clazakizumab so far. Last year at the ACR 2013 Meeting in San Diego there had been a poster/abstract on clazakizumab, on which clazakizumab showed a higher potency than tocilizumab [#2385]. But will this be an advantage? Tocilizumab SC is already available and is still might take a while until clazakizumab comes to the market.

S. Du and colleagues presented the following study [SAT0210]: "X-RAY AND MRI RESULTS FROM A PHASE IIB STUDY OF

SUBCUTANEOUS ANTI-INTERLEUKIN-6 MONOCLONAL ANTIBODY CLAZAKIZUMAB WITH OR WITHOUT MTX IN ADULTS WITH MODERATE-TO-SEVERE ACTIVE RA AND INADEQUATE RESPONSE TO CONVENTIONAL DMARDS INCLUDING METHOTREXATE". Conclusions: Clazakizumab in combination with MTX demonstrated reduced progression of joint damage by MRI as early as 12 weeks and by X-ray after 24 weeks. Larger trials with clazakizumab in RA are warranted to confirm these findings." But good as preliminary data!

M. Weinblatt and colleagues presented [SAT0244]: "A PHASE IIB STUDY OF THE EFFICACY AND SAFETY OF SUBCUTANEOUS CLAZAKIZUMAB (ANTI-IL-6 MONOCLONAL ANTIBODY) WITH OR WITHOUT METHOTREXATE IN ADULTS WITH MODERATE-TO-SEVERE ACTIVE RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE". N=418 patients were randomized! In results we find: " The rates of serious adverse events ranged from 8.3 to 13.3% in CLZ arms versus 3.3% for pbo ...". Conclusions: "Clazakizumab as monotherapy or in combination with MTX demonstrated efficacy in controlling the signs and symptoms of RA. At Week 24, remission rates with clazakizumab + MTX trended higher than with ADA + MTX. Its safety profile was consistent with the known pharmacology of IL-6 blockade. Clazakizumab is a promising future treatment for RA that warrants further investigation." Still too early to call us off safety concerns!

E. Alemao and colleagues presented [AB0423] "IMPACT OF ANTI-IL-6 MONOCLONAL ANTIBODY, CLAZAKIZUMAB, ON PATIENT-REPORTED OUTCOMES IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO METHOTREXATE IN A PHASE IIB STUDY".

Conclusions: Treatment with clazakizumab with or without MTX resulted in improvements in multiple PROs and a greater proportion of patients achieved MCID (minimal clinically important differences) on these PROs (patient-reported outcomes) compared with MTX alone in patients with RA with an inadequate response to MTX."

Promising drug candidate, but still has to present phase 3 studies. I hope there won't be new safety concerns as I'm already alerted by the 8.3% to 13.3% serious adverse events in the clazakizumab arms versus 3.3% for placebo [SAT0244]; the authors of the study call the safety profile consistent with the known pharmacology of IL-6 blockade, however. Maybe, we'll get a new drug, but as there already exists an approved anti-IL-6 MAB, where's the niche for this one? Hopefully the company answers this question before coming to the market.