IL-33 and Rheumatoid Arthritis – an update

Three years ago I’ve published a blog post on IL-33 here (link: see below); as inhibition of IL-33 could be a potential therapeutic and/or diagnostic approach. Let’s look for the studies on IL-33, which have emerged during the past three years.

There has been a study by S. Tang and colleagues in 2013: “Increased : L-33 in synovial fluid and paired serum is associated with disease activity and autoantibodies in rheumatoid arthritis.” In results the authors found: “SF IL-33 was significantly higher in RA than in OA, which was correlated with disease activity score 28, erythrocyte sedimentation rate, rheumatoid factor (RF)-IgM, RF-IgG, glucose phosphate isomerase (GPI), and immunoglobulin. …” So they concluded that IL-33 played an important role in the local pathogenesis of rheumatoid arthritis.

J. Shen and colleagues presented a study at the 2014 ACR/ARHP Annual Meeting [Abstract No. 374]: “IL-33 and Soluble ST2 Levels As Novel Predictors for Remission and Progression of Carotid Plaque in Early Rheumatoid Arthritis: A Prospective Study.” The authors want to identify predictors for treatment response, which may help to develop a form of personalized medicine. In conclusion they tell us: “Lower baseline sST2 levels independently predict disease remission and baseline detectable IL-33 independently predicts carotid plaque progression in ERA patients. This study suggests that inflammation induced by the IL-33/ST2 axis may play a significant role in the development of cardiovascular disease in RA.” This may seem far from a personalized medicine, but it’s a step towards this goal.

J. Sellam and colleagues published a study at the 2014 ACR/ARHP Annual Meeting [Abstract No. 2928]: “Serum IL-33 Level Is Increased in Rheumatoid Arthritis and Predicts Response to Rituximab in Combination with High Serum IgG Level and Autoantibody Positivity: An Open-Label, Prospective, Multicentre Biological Trial. “ Conclusion: “Serum IL-33 level, intrinsically increased in RA, represents a simple marker predicting accurately clinical response to RTX, independently of and synergistically with auto-antibodies and serum IgG level.” Does this help us right now? No. We don’t have a commercially IL-33 test, which is reimbursed to use it. But I find the result “Using ROC curve analyze, 249 pg/mL was the optimal serum IL-33 level cut-off to discriminate responders from non-responders.” intriguing. It would tell us more, when not to use rituximab, than, when to use it.

F. Rivellese and colleagues published a stuy: “Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to Down-Regulate Monocyte-Mediated Immune Responses.” Conclusion: “When human mast cells are activated by IL-33, an immunomodulatory phenotype develops, with human mast cells gaining the ability to suppress monocyte activation via the release of IL-10 and histamine. These findings, together with the presence of synovial mast cell-monocyte interactions and the inverse association between the expression of mast cell genes at the synovial level and disease activity, suggest that these newly described mast cell-mediated inhibitory pathways might have a functional relevance in the pathogenesis of RA.” This is a more basic study and therefore it isn’t clear to what it might mean to gain more control on disease activity. IL-33 is upregulated in RA patients to suppress monocyte activation.

These studies show that we still have a lot to learn about the role of IL-33 in rheumatoid arthritis. I’m sure that there will be a useful tool, if commercially test of IL-33 will be available. But I also hope for a breakthrough to use IL-33 (or IL-10) as a target to treat rheumatoid arthritis and/or other inflammatory rheumatic diseases.

Links:
IL-33 at the EULAR 2013 - http://rheumatologe.blogspot.de/2013/07/il-33-at-eular-2013.html 
S. Tang: Increased : L-33 in synovial fluid - http://www.ncbi.nlm.nih.gov/pubmed/24106520 
J. Shen and colleagues: IL-33 and Soluble ST2 Levels As Novel Predictors for Remission and Progression of Carotid Plaque in Early Rheumatoid Arthritis: A Prospective Study. Abstract 374 at the 2014 ACR/ARHP Annual Meeting. http://acrabstracts.org/abstract/il-33-and-soluble-st2-levels-as-novel-predictors-for-remission-and-progression-of-carotid-plaque-in-early-rheumatoid-arthritis-a-prospective-study/ 
J. Sellam and colleagues: Serum IL-33 Level Is Increased in Rheumatoid Arthritis and Predicts Response to Rituximab in Combination with High Serum IgG Level and Autoantibody Positivity: An Open-Label, Prospective, Multicentre Biological Trial. Abstract 2928 at the 2014 ACR/ARHP Annual Meeting.  http://acrabstracts.org/abstract/serum-il-33-level-is-increased-in-rheumatoid-arthritis-and-predicts-response-to-rituximab-in-combination-with-high-serum-igg-level-and-autoantibody-positivity-an-open-label-prospective-multicentre/
F. Rivellese and colleagues: Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to Down-Regulate Monocyte-Mediated Immune Responses. Arthritis Rheumatol. 2015 Sep;67(9):2343-53. doi: 10.1002/art.39192. http://www.ncbi.nlm.nih.gov/pubmed/25989191

Etanercept Biosimilars at the ACR 2015 Meeting in San Francisco

There has been one publication on SB4, an etanercept biosimilar, at the ACR 2015 Annual Meeting in San Francisco. SB4 has been developed by Samsung Bioepis. However, Hanwha Chemical’s HD203, also a biosimilar of etanercept, didn’t appear at the ACR 2015 Annual Meeting, which I think is strange as HD203 appeared at the ACR 2014 Annual Meeting with a phase 3 study.

Jiri Vencovsky and colleagues presented: “A Phase III, Randomized, Double-Blind Clinical Study Comparing SB4, an Etanercept Biosimilar, with Etanercept Reference Product (Enbrel®) in Patients with Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy (52-week Results)”. Conclusion: “Efficacy including radiographic progression and safety were comparable between SB4 and ETN [Enbrel] up to Week 52. The immunogenicity profile was lower in SB4 compared to ETN.”

SB4 will be marketed under the name of Benepali. What’s in a word: bene – good and the Tripitaka has been written in Pali. After the meeting the Committee for Medicinal Products for Human Use (CMPH) has recommended the European Medicines Agency (EMA) to approve Benepali. So, Samsung Bioepis now has the apply for approval. Benepali might be available in Europe in 2016. I did’t find anything on the status with the FDA.

References:

Vencovsky J, Sylwestrzak A, Leszczyñski P, Porawska W, Baranauskaite A, Tseluyko V, Zhdan V, Stasiuk B, Milasiene R, Barrera Rodriguez AA, Cheong SY, Ghil J, Emery P. A Phase III, Randomized, Double-Blind Clinical Study Comparing SB4, an Etanercept Biosimilar, with Etanercept Reference Product (Enbrel®) in Patients with Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy (52-week Results) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/a-phase-iii-randomized-double-blind-clinical-study-comparing-sb4-an-etanercept-biosimilar-with-etanercept-reference-product-enbrel-in-patients-with-moderate-to-severe-rheumatoid/. Accessed December 1, 2015.

Benepali and the Committee for Medicinal Products for Human Use - http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004007/WC500196736.pdf

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COVA322 and Bispecificity at the ACR Annual Meeting 2014 in Boston

Cova322 is a bispecific TNF/IL-17A inhibitor. Is this a new hype? Or are we going to see a change of view on combining biologics? To my knowledge there is no biologic agent, where a combination with another biologic agent is advocated. Some people combine biologics with denosumab, so the principle isn’t that new, but let’s say it isn’t accepted on a large scale. There had been studies combining anakinra and etanercept or abatacept and a TNF-alpha-inbibitor, so that remicade for instance dicidedly warns to be combined with other biologic agents. On the other hand we have ustekinumab, which is a monoclonal antibody against interleukins 12 and 23.

W. Lemke and colleagues presented the following paper [#1511]: “COVA322: A Clinical Stage Bispecific TNF/IL-17A Inhibitor for the Treatment of Inflammatory Diseases.” “COVA322 was analyzed for its cross-reactivity in a GLP study with human and Cynomolgus tissues.”  In “results” we’re told: “COVA322 showed no unexpected tissue cross-reactivity and no indication for the potential to cause a cytokine release syndrome.” Conclusions: “COVA322 is a unique bispecific TNF/IL-17A inhibitor, which was well tolerated in non-clinical safety studies. The non-clinical data package supports the planned dose range for the currently ongoing first in man, single dose escalation, tolerability, safety, PK and efficacy Phase Ib/IIa study in psoriasis.” It isn‘t a conclusion that COVA322 is a unique bispecific TNF/IL-17A inhibitor, that’s marketing! The only conclusions I see are cell studies, mouse arthritis model studies  and tests in Cynomolgus monkeys hadn’t raised safety concerns.

There is another study by D. Grabulovski and colleagues [#1491]: “Discovery and Characterization of COVA322, a Clinical Stage Bispecific TNF/IL-17A Inhibitor for the Treatment of Inflammatory Diseases.” I recomment to read the whole text as methods and results are really interesting to read.  Conclusion: “COVA322 is a unique bispecific TNF/IL-17A inhibitor with excellent biophysical properties. It is currently being tested in a first in man, single dose escalation, tolerability, safety, PK and efficacy Phase Ib/IIa study in psoriasis.” Too much marketing!

Let’s sum it up. Cova322 is a bispecific TNF/IL-17A inhibitor. It is a promising new agent, which could result in a new drug. It might be working in (at least) psoriasis and psoriatic arthritis. And maybe it will help us to find a safe way to combining biologic agents. Godspeed COVA322!

Link to ACR Abstracts: 

http://www.acrannualmeeting.org/abstracts/ 

Iguratimod at the ACR 2014 in Boston

I have already been interested in iguratimod (IGU) for a while. I’ve blogged on IGU for the first time 2 ½ years ago after the EULAR meeting in Berlin (2012). I had been a bit disappointed in 2013, when there had been only a Chinese cell study (Iguratimod inhibits RANKL-induced osteoclastogenesis in RAW264.7 cells) at the 2013 EULAR meeting in Madrid. Earlier this year at the EULAR meeting in Paris IGU returned with three posters/studies. Please see below. Iguratimod already has been approved for the Japanese market (2012); see below. It is marketed under the brand names Careram® and KOLBET®.

Y. Kanayama and colleagues presented the following study [#1488]: “Clinical Efficacy of Add-on Iguratimod Therapy in Patients with Active Rheumatoid Arthritis Despite of Methotrexate - a Multicenter Registry.” It#s hard to tell, what this study is. I think, the authors aggregated data from existing studies and looked at 51 patients, who fulfilled the ACR/EULAR criteria for RA and didn’t respond to MTX. DAS had been reduced from 4.67 to 3.32 after 24 weeks, CDAI from 16.9 to 7.9. Remission rates were 33.3% for DAS and 27.5% for CDAI. Conclusion: “This study suggested that the new combination therapy of add-on IGU with MTX was effective in patients with active RA with inadequate response to MTX.”

Y. Hirano and colleagues presented another study [#1489]: “Influences of Disease Activity at the Initiation of Iguratimod, a Small Molecule Antirheumatic Drug, on Efficacy of Iguratimod in Patients with Rheumatoid Arthritis –a Multicenter Registry Study”. They looked at 79 patients. The study period also had been 24 weeks. In results we find: “The mean DAS28-CRP at 0, 4, 8, 12 and 24w was 4.99, 4.49, 4.29, 3.70 and 3.58 in HG [high disease activity group] and 3.24, 3.16, 2.76, 2.62 and 2.56 in MLG [moderate and low disease activity group]. DAS28-CRP was significantly decreased after 4w in HG and after 8w in MLG.” Conclusion: “This study suggests that IGU is one of the options not only in RA patients with high disease activity treated with insufficient MTX.”

T. Kondo and colleagues presented a third study [#1497]: “Efficacy and Safety of Iguratimod for Rheumatoid Arthritis.” They looked at 62 patients, who received 25 mg iguratimod during the first month and who were changed to a dosage of 50 mg afterwards. “DAS28-ESR and SDAI decreased significantly from 4.49_1.33 to 3.09_1.12 and from 18.5_10.9 to 7.44_7.11 in 24 weeks respectively (P_0.01).” “Adverse events were digestive symptom (n=6), liver dysfunction (n=3), nasal hemorrhage (n=2) and so on. There’s no severe adverse event.”  Conclusion: Iguratimod was well tolerable and may have a good cost effectiveness. So iguratimod be a new useful option as small molecule DMARDs for RA patients in a manner similar to tofacitinib.”

Sorry, as much as I want a new DMARD to treat patients with RA, who can’t receive biologics, these studies aren’t convincing and won’t be sufficient to get an approval by FDA or EMEA for iguratimod. The studies didn’t define primary endpoints, consisted of aggregated data, weren’t blinded or placebo controlled. Kondo’s conclusions are far fetched: “may have a good cost effectiveness” (cost effectiveness hadn’t been tested), “similar to tofacitinib” (hadn’t been tested against tofacitinib). And were is data on radiographic progression? As tofacitinib has been mentioned – radiographic progression was one of the critical points for not having yet optained approval by EMEA.

I’m still in favour of iguratimod, but the company has to sponsor better powered and designed studies. These studies have to include data on radiographic progression.

Links:

http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html

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

http://rheumatologe.blogspot.de/2014/06/iguratimod-at-eular-2014-meeting-in.html

http://www.eisai.com/news/news201239.html