Levilimab, a novel Monoclonal Anti-IL-6 Receptor Antibody, at the 2020 EULAR Online Meeting

Levilimab is novel monoclonal anti-IL-6 receptor antibody. As tocilizumab and sarilumab are already approved drugs in rheumatology, and olokizumab [1] has been presented at the 2020 EULAR Online Meeting in a phase 3 study, I'm suprised seeing another actor on the IL-6 stage. And there are still others like monoclonal anti-il-6 receptor antibodies: clazakinumab, elsilimomab, sirukumab; and more in oncology like siltuximab.

V. Mazurov and colleagues presented 1-year results of the phase 2 AURORA study [2]. AURORA assessed efficacy and safety of two dosing regimens of levilimab in patients with active rheumatoid arthritis and inadequate response to methotrexate (primary endpoint). Secondary endpoints mentioned: ACR20/50/70, LDA, remission rates, and DAS28-CRP(4); more data collected. Levilimab plus MTX showed sustained efficacy with continuous clinical improvement. The safety profile of levilimab was consistent with other IL-6 receptor inhibitors.

Do we need more IL-6-Inhibitors? Levilimab, clazakinumab, elsilimomab, sirukumab as well as the established tocilizumab, sarilumab, and siltuximab? I guess no, but that's the luxury of a free market economy.

Links and References:

[1] https://rheumatologe.blogspot.com/2020/07/olokizumab-at-2020-eular-annual-online.html

[2] V. Mazurov1, E. Zotkin2, E. Ilivanova3, T. Kropotina4, T. Plaksina5, O. Nesmeyanova6, N. Soroka7, A. Kundzer8, A. Lutskii9, E. Dokukina9, A. Eremeeva9, A. Zinkina-Orihan9. FRI0114 EFFICACY OF LEVILIMAB, NOVEL MONOCLONAL ANTI-IL-6 RECEPTOR ANTIBODY, IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS: 1-YEAR RESULTS OF PHASE 2 AURORA STUDY. DOI: 10.1136/annrheumdis-2020-eular.5465

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Mavrilimumab at the 2020 EULAR Online Meeting

Mavrilimumab has my interest for about a decade now. There have been two studies at the 2020 EULAR Online Meeting. I am suprised! My last entry here on the blog concerning mavrilimumab dates back to January 17^th 2019 under the title: „Mavrilimumab discontinued“ [1].

Mavrilimumab is a human monoclonal antibody tht targets the GMCSF [Granulocyte macrophage colony stimulating factor] receptor and alpha-chain.

G. De Luca and colleagues presented the following study [2]: “CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION”. The study is single-center, non-randomized, open-label, single active arm intervention (N=13) with comparison to “contemporaneous patients (N=26) with similar baseline characteristics”. The patients in the active arm received a non-disclosed single dose of mavrilimumab. In “results” the authors tell us: “Death occurred in 0% (n=0/13)

of mavrilimumab recipients and 27% (n=7/26) of comparison-group patients (log rank p=0.046) during the 28-day follow-up. 100% (n=13) of mavrilimumab recipients and 65% (n=17) of comparison-group patients achieved clinical improvement (p=0.018) at Day 28, with earlier improvement (median 8.0 [IQR, 5.0–11.0] days vs 18.5 [11.0–NE] days) (p<0 -="" .001="" 1.0="" 14="" 61="" 7.0="" 91="" by="" compared="" comparison="" controls="" day="" days="" faster="" febrile="" fever="" group="" had="" in="" lang="en-US" mavrilimumab="" median="" n="11/18" ne="" of="" p="0・009)." patients="" recipients.="" recipients="" resolution="" resolved="" respectively="" span="" the="" to="" versus="" vs="" was="">was well tolerated in all patients.” The authors concluded: “Patients with severe COVID-19 pneumonia and systemic hyper-inflammation who received treatment with mavrilimumab had better clinical outcomes compared to patients receiving routine care. … Randomized controlled trials are warranted to confirm our findings.”

It is unclear, how patients were chosen to get mavrilimumab. Did the “26 contemporaneous patients with similar baseline characteristics” also showed “severe COVID-19 pneumonia (as evaluated by CT scanning), hypoxia (PaO2:FiO2 ratio ≤ 300 mmHg), and systemic hyper-inflammation (increased C-reactive protein [CRP] ≥ 100 mg/mL and/or ferritin ≥ 900 μg/L, increased lactate dehydrogenase [LDH])”?

In former studies the most common adverse event of mavrilimumab had been a decrease in CO diffusing capacity. So why choose an investigational drug instead of an IL-6-inhibitor already on the market in other indications?

The study by M. C. Cid and colleagues is a cell sttudy{3]: “CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION”. The authors looked at “expression of GM-CSF and GM-CSF-Rα proteins in temporal artery biopsies (TABs) from GCA and controls (patients with suspected but not confirmed GCA and a negative TAB).” The authors concluded: “Increased GM-CSF, GM-CSF-Rα, and downstream pathway-associated protein levels in GCA biopsies were consistent with previously-observed increased transcriptome signature. Expression of genes associated with inflammatory cells was suppressed by mavrilimumab in cultured GCA arteries. These data implicate the GM-CSF pathway in GCA pathophysiology and increase confidence in rationale for targeting the GM-CSF pathway in GCA.”

Adis Insight reports a phase II trial in B-cell lymphoma (Second-line therapy or greater, Combination therapy) in the second half of 2020 (17.06.2020) and phase II trial in Giant cell arteritis in Australia, Belgium, Croatia, Estonia, Germany, Italy, Ireland, Netherlands, New Zealand, Poland, Serbia, Slovenia, Spain, USA and United Kingdom (NCT03827018) (13.03.2020) [4].

I am still not convinced that mavrilimumab will become a drug in rheumatology. Kiniksa Pharmaceuticals should clarify how comparable the patients in the COVID-19 study were and why there hasn't been a randomization.

Links and References:

[1] http://rheumatologe.blogspot.com/2019/01/mavrilimumab-discontinued.html

[2] G. De Luca1,2, G. Cavalli1,2, C. Campochiaro1,2, E. Della Torre1,2, P. Angelillo1, A. Tomelleri1,2, N. Boffini1, S. Tentori1, F. Mette1,2, P. Rovere-Querini1,2, A. Ruggeri1, T. D’aliberti1, P. Scarpelllini1, G. Landoni1,2, F. De Cobelli1,2, J. F. Paolini3, A. Zangrillo1,2, M. Tresoldi1, B. C. Trapnell4, F. Ciceri1, L. Dagna1,2. CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION. DOI: 10.1136/annrheumdis-2020-eular.6858

[3] M. C. Cid1, S. Muralidharan2, M. Corbera-Bellalta1, G. Espigol-Frigole1, J. Marco Hernandez1, A. Denuc3, R. Rios-Garces1, N. Terrades-Garcia1, J.

F. Paolini2, A. D’andrea2. CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION. DOI: 10.1136/annrheumdis-2020-eular.4984

[4] https://adisinsight.springer.com/drugs/800014624

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Hydroxychloroquine and Colchicine in Hand Osteoarthritis at the 2020 EULAR Online Meeting

Hydroxychloroquine and colchicine in hand osteoarthritis isn't so far from the main stream of medicine. Hydroxychloroquine is important in the treatment of systemic lupus erythematodes. The current president of the U.S.A. has been advocating hydroxchloquine to fight covid-19 disease, though lacking scientific support. For colchicine there have been studies concerning osteoarthritis of weight bearing joints, mostly knee osteoarthritis.

For hydroxychloroquine and colchicine in hand osteoarthritis there have been two studies at the 2020 EULAR Online Meeting.

But let me start with a study by L.R Bryant and colleagues in 1995 [1]: „Hydroxychloroquine in the Treatment of Erosive Osteoarthritis“. The study had been underpowered (N=8). The authors concluded: „The use of hydroxychloroquine in patients with erosive OA unresponsive to NSAID appears promising. Prospective studies are needed to confirm our observations.“

C. Kedor and colleagues presented [2] at the 2020 EULAR Online Meeting: „OP0186 HYDROXYCHLOROQUINE IN PATIENTS WITH INFLAMMATORY AND EROSIVE OSTEOARTHRITIS OF THE HANDS: RESULTS OF A RANDOMIZED, DOUBLEBLIND, PLACEBO CONTROLLED, MULTI-CENTRE, INVESTIGATOR-INITIATED TRIAL (OA TREAT)“. The study originated in 2014. „The primary endpoint was AUSCAN for pain and hand disability at week 52 (W52). A secondary endpoint was radiographic progression from baseline (BL) to W52.“ „Of 156 patients 3 were excluded and 75 were randomized to HCQ and 78 to PBO.“ With only morning stiffness having been significantly reduced in the HCQ group, the authors had to conclude: „HCQ was no more effective than PBO for changes in pain, function and radiographic scores in the 52-week period.“

The study is congruent with a study that originated in 2013 and had been published earlier [3]: „Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial“. „The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months.“ The authors concluded: „Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis.“

So we now have two large randomized studies showing that hydroxychloroquine is ineffective in hand osteoarthritis.

C. Davis and colleagues presented [4]: „FRI0399 COLCHICINE IS NOT EFFECTIVE FOR REDUCING OSTEOARTHRITIC HAND PAIN COMPARED TO PLACEBO: A RANDOMISED, PLACEBO-CONTROLLED TRIAL (COLAH)“. Colchicine is effective as an anti-inflammatory agent in gouty arthritis, but has not been investigated before in hand osteoarthritis. The authors could evaluate 58 participants, who completed the study (N=27 colchicine, N=31 placebo). The authors concluded: „Colchicine 1mg daily for 12 weeks was not effective in improving pain, tender and swollen joint count or grip strength in symptomatic hand osteoarthritis patients. This study does not support colchicine for treatment of symptoms of hand osteoarthritis.“

It would have been nice to have drugs to prevent progression and treat symptoms of hand osteoarhritis, but hydroxychloroquine and colchicine are ineffective and should not be prescribed in patients with (erosive) hand osteoarthritis.

Links and References:

[1] Bryant LR, des Rosier KF, Carpenter MT. Hydroxychloroquine in the treatment of erosive osteoarthritis. J Rheumatol. 1995;22(8):1527-1531.

[2] C. Kedor1, J. Detert2, R. Rau3, S. Wassenberg3, J. Listing4, P. Klaus5, T. Braun1, W. Hermann6, S. Weiner7, M. Bohl-Buhler8, F. Buttgereit1, G. R. Burmester1. OP0186 HYDROXYCHLOROQUINE IN PATIENTS WITH INFLAMMATORY AND EROSIVE OSTEOARTHRITIS OF THE HANDS: RESULTS OF A RANDOMIZED, DOUBLEBLIND,

PLACEBO CONTROLLED, MULTI-CENTRE, INVESTIGATOR-INITIATED TRIAL (OA TREAT). DOI: 10.1136/annrheumdis-2020-eular.819

[3] Kingsbury SR, Tharmanathan P, Keding A, et al. Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial. Ann Intern Med. 2018;168(6):385-395. doi:10.7326/M17-1430

[4] C. Davis1,2, C. Ruediger1,2, K. Dyer2, S. Lester1,2, S. Graf3, F. P. B. Kroon4, S. Whittle2, C. Hill1,2. FRI0399 COLCHICINE IS NOT EFFECTIVE FOR REDUCING OSTEOARTHRITIC HAND PAIN COMPARED TO PLACEBO: A RANDOMISED, PLACEBO-CONTROLLED TRIAL (COLAH). DOI: 10.1136/annrheumdis-2020-eular.4040

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D-0120, a Novel Oral Selective Uric Acid Transporter Inhibitor, at the 2020 EULAR Online Meeting

It seems that we never have enough different drugs to lower hyperuricemia for the individual patient. Lesinurad is an oral selective uric acid transporter (URAT1) inhibitor, which has both FDA (2015) and EMA (2016) approval and is on the market under the brand name of Zurampic, but isn't sold in Germany for instance [1]. Now comes D-0120, a novel oral selective uric acid transporter (URAT1) inhibitor with one study at the 2020 EULAR Online Meeting. Will there be a market for such a drug?

L. Zhang presented the following study [2]: „OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT“. Daily oral D-0120, at dose levels from 2.5 mg/day to 20 mg/day in 32 healthy volunteers for 7 days was well tolerated. The pharmacokinetics profile demonstrated a dose proportional increase. There had been a significant reduction of serum uric acid levels.

Will there be a market for D-0120? D-0120 showed in a cell model a 150-fold more potent inhibitory activity than lesinurad, which might result in less side effects (hope and speculation!). This might be the pivotal point to go on studying D-0120. There will be patients needing an oral selective uric acid transporter (URAT1) inhibitor, but will there be enough patients to support the another drug of the kind that we already have?

Nevertheless I hope that studies go on and that D-0120 will come to market. That will take some years. In the mean time lesinurad should be available on the German market.

Links and References:

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

[2] L. Zhang1, D. Wyatt2, K. Stazzone1, Z. Shi1, Y. Wang1. OP0205 PHASE I STUDY OF D-0120, A NOVEL URAT1 INHIBITOR IN CLINICAL DEVELOPMENT FOR HYPERURICEMIA AND GOUT. DOI: 10.1136/annrheumdis-2020-eular.5107

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CR6086 at the 2020 EULAR Online Meeting

When I've checked for novel drug candidates, I've stumpled on CR6086. Somehow the number reminded me of Intel's 8086-series and others might associate Nokia's 6086-series. But CR6086 is an EP4 [a prostanoid receptor] receptor antagonist, which “may improve the response of tumours to immuno-oncology therapies, e.g. immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 drugs” [1]. CR6086 wouldn't be the first drug that proves useful not only in oncology but also in rheumatology.

There had been a study at the 2016 ACR/ARHP Annual Meeting [2], in which the authors concluded: "CR6086 was safe up to the maximum tested dose of 300 mg."

Adis Insight [3] has data up to March 28^th 2020 (“No recent reports of development identified for phase-I development in Rheumatoid-arthritis(In volunteers) in Italy (PO)”), and mentions two dates for study NCT03163966 in the Czech Republic (3^rd November 2017) and the preliminary data presented at the 2018 ACR/ARHP Annual Meeting as CREATIVE trial data [4]. Now there is data on study NCT03163966.

K. Pavelka and colleagues presented the following study [5] at the 2020 EULAR Online Meetin: „AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL“. The authors concluded: „There was no benefit demonstrated for CR6086 added to MTX in the study cohort as a whole. However, in a post-hoc analysis, enhanced responses were observed with CR6086 90mg bid added to MTX in patients >6 months disease duration. This generated the hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity, to be tested in further studies.“ There aren't any irregularities in methods and results. Even without post-hoc analysis there's a difference for MTX with or without CR6086. But 'll show you, why I habor doubts.

I've looked at a study by G. Caselli and colleagues [6]: „Pharmacological Characterisation of CR6086, a Potent Prostaglandin E2 Receptor 4 Antagonist, as a New Potential Disease-Modifying Anti-Rheumatic Drug“. In results the authors tell us: „ In models of human immune cells in culture, CR6086 reduced key cytokine players of RA (IL-6 and VEGF expression in macrophages, IL-23 release from dendritic cells, IL-17 release from Th17 cells). In the CIA model of RA in rats and mice, CR6086 significantly improved all features of arthritis: severity, histology, inflammation and pain. In rats, CR6086 was better than the selective cyclooxygenase-2 inhibitor rofecoxib and at least as effective as the Janus kinase inhibitor tofacitinib.“ But there's no hint to what happens to MTX if combined with CR6086.

J.M. Kremer and R.A. Hamilton published in 1995 [7]: „The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg“. So NSAIDs alter renal clearance of MTX at normal weekly maintenance doses. In a more recent study (2011) Yuichi Uwai and colleagues [8] showed in their meta-analysis „that NSAIDs increase blood levels of methotrexate by influencing renal excretion of the antifolate“.

Now, CR6086 isn't an NSAID, but it may (ot may not) effect the renal clearance of MTX.

K. Pavelka and colleagues stated the „hypothesis that addition of CR6086 90mg bid may benefit in RA patients initiating MTX after the window of opportunity“. I have my doubts, but I agree that this has to be tested in further studies. Hopefully, K. Pavelka and colleagues are right.

Links and References:

[1] http://www.rottapharmbiotech.com/cr6086-for-immuno-oncology/

[2] Persiani S, Manzotti C, Vitalini C, Giacovelli G, Girolami F, D'Amato M, Caselli G, Rovati LC. a First-in-Human Study of CR6086, a New Potent EP4 Prostanoid Receptor Antagonist, Demonstrates Good Safety and Tolerability at Therapeutically Relevant Exposures [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/a-first-in-human-study-of-cr6086-a-new-potent-ep4-prostanoid-receptor-antagonist-demonstrates-good-safety-and-tolerability-at-therapeutically-relevant-exposures/. Accessed July 2, 2020.

[3] https://adisinsight.springer.com/drugs/800048940

[4] Vitalini C, Barbetta B, Giacovelli G, Brambilla N, D'Amato M, Girolami F, Rovati LC. Acr Hybrid Analysis: Blinded Data from the Ongoing Phase IIb Trial with the EP4 Receptor Antagonist CR6086 in DMARD-Naïve Patients with Early Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/acr-hybrid-analysis-blinded-data-from-the-ongoing-phase-iib-trial-with-the-ep4-receptor-antagonist-cr6086-in-dmard-naive-patients-with-early-rheumatoid-arthritis/. Accessed July 3, 2020.

[5] K. Pavelka1, I. D. Delina2, M. Mazur3, M. D’amato4, G. Giacovelli4, F. Girolami4, M. Krogulec5, R. Ostgard6, A. R. Bihlet7, O. Kubassova8, L. Rovati4,9, P. C. Taylor10. AB0360 EFFICACY AND SAFETY OF THE PROSTAGLANDIN EP4 RECEPTOR ANTAGONIST CR6086 ADDED TO METHOTREXATE IN DMARD-NAIVE EARLY RA PATIENTS: A PHASE 2 RANDOMIZED CONTROLLED TRIAL. DOI: 10.1136/annrheumdis-2020-eular.5636

[6] Caselli G, Bonazzi A, Lanza M, et al. Pharmacological characterisation of CR6086, a potent prostaglandin E₂ receptor 4 antagonist, as a new potential disease-modifying anti-rheumatic drug. Arthritis Res Ther. 2018;20(1):39. Published 2018 Mar 1. doi:10.1186/s13075-018-1537-8

https://pubmed.ncbi.nlm.nih.gov/29490676/

[7] Kremer JM, Hamilton RA. The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg. J Rheumatol. 1995;22(11):2072-2077. https://pubmed.ncbi.nlm.nih.gov/8596147/

[8] Uwai Y, Suzuki R, Iwamoto K. Yakugaku Zasshi. 2011;131(5):853-861. doi:10.1248/yakushi.131.853 https://pubmed.ncbi.nlm.nih.gov/21532282/

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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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MBS2320 at the EULAR 2020 Online Meeting

MBS2320 might have escaped your attention. In 2019 there had been a poster at the EULAR Annual Meeting and this year there should have been an oral presentation.

MBS2320 is a novel selective modulator of immune metabolism. I haven't found much elucidation of what the compound selectively modulates [1]. The study I'll talk about here says: „MBS2320 is a selective modulator of immune metabolism displaying distinctive dual pharmacology: strong anti-inflammatory activity as well as a broader spectrum of osteoprotection than TNFα inhibition in preclinical models.“ [2] It is a reference to the poster presentation a year ago, both times L. Patel has been the first author. Adis Insight has as most recent event: „13 Aug 2019 / Modern Biosciences completes a phase IIa trial in Rheumatoid arthritis (Adjunctive treatment) in Moldova, Romania and Georgia (NCT03139136) (EudraCT2016-004038-24)“ [3]. So, we're really up to date.

L. Patel and colleagues presented the following study [2]: „OP0234 MBS2320, A NOVEL SELECTIVE MODULATOR OF IMMUNE METABOLISM, IN PATIENTS WITH SEVERE RHEUMATOID ARTHRITIS: SAFETY, TOLERABILITY AND EFFICACY RESULTS OF A PHASE 2 STUDY.“ It's a phase 2 study with dose escalation of MBS2320 after 4 weeks from 80mg to 120mg in patients, who tolerated 80 mg. The study lasted for 12 weeks. Of the 121 randomized patients only 96 completed the study; that's a loss of about 21%. The results show an increase of response rates in the verum group, but aren't comparable to other studies. Authors' conclusions: „MBS2320 was generally well tolerated for up to 12 weeks in this RA study population. Nausea was the most common TEAE, was generally mild in severity and resolved without treatment. In this population of patients with hardtotreat, severe, active, erosive disease MBS2320 showed evidence of a clinical benefit on both ACR20 responses and DAS28-CRP.“

I'm always happy if new novel mechanisms of action in anti-rheumatic drugs make it into phase 2 and 3 studies. Will there be a drug in coming years? Hard to tell as we lack precise information on the mode of action. I'd wish to have a comparator like a biologic agent or another small molecule like a JAK-inhibitor. I guess that there will be. Hopefully we don't have to wait too long.

Links and References:

[1] https://www.malacards.org/card/rheumatoid_arthritis?limit%5BClinicalTrial%5D=2464&limit%5Bde_genes%5D=117&showAll=False

[2] L. Patel1, L. Skillern1, M. Foster1, A. Gray1, R. Leff2, S. Williams1. 1Istesso Ltd,

London, United Kingdom; 2Richard Leff LLC, Philadelphia, United States of America. OP0234 MBS2320, A NOVEL SELECTIVE MODULATOR OF IMMUNE METABOLISM, IN PATIENTS WITH SEVERE RHEUMATOID ARTHRITIS: SAFETY, TOLERABILITY AND EFFICACY RESULTS OF A PHASE 2 STUDY. DOI: 10.1136/annrheumdis-2020-eular.3804.

[3] https://adisinsight.springer.com/drugs/800043721

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Iguratimod at the EULAR 2020 Online Meeting

Since 2012 I've been looking at iguratimod [1]. Iguratimod is a conventional synthetic disease modifying anti-rheumatic drug (csDMARD); chemical formula: N-(3-Formamido-4-oxo-6-phenoxy-4H-chromen-7-yl)-methanesulfonamide. Iguratimod is characterized by inhibitory effects on immunoglobulin production in B cells as well as inhibiting cytokine production. Its' mode of action comes by suppression of nuclear factor kappa B (NF-kB) activation and RANKL production.

There have been four studies presented at the EULAR 2020 Online Meeting and one publication in Clinical Rheumatology.

K. Katayama and colleagues presented [2]: „SAT0146 INHIBITION OF RADIOGRAPHIC PROGRESSION BY IGURATINOD IN 116 JAPANESE RHEUMATOID ARTHIRITIS PATIENTS DESPITE CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS THERAPY“. The study looked at 116 patients after one year of therapy; joint damage was evaluated by modified total Sharp scoring (mTSS) and RA activity was measured by DAS28-ESR. „Iguratimod suppressed not only clinical activities but also joint destruction in RA patients resistant to csDMARDs therapy.“

D. Kobayashi and colleagues presented the following study [3]: „SAT0147 EFFICACY AND SAFETY OF IGURATIMOD AS FIRSTLINE DISEASE-MODIFYING ANTIRHEUMATIC DRUG THERAPY FOR PATIENTS WITH RHEUMATOID ARTHRITIS“. The prospective single-center study aimed at efficacy and safety of iguratimod as a first-line DMARD in patients with rheumatoid arthritis. Conclusion: „Our study indicates IGU is safe and effective for DMARD naive RA patients. Starting treatment with IGU might be a new and effective strategy for RA

patients without previous use of a DMARD.“ Not much new information. The results are congruent with former studies.

T. Miyamoto and colleagues looked at RA patients with inadequate response to adalimumab [4]: „AB0350 EFFICACY OF ADDING IGURATIMOD THERAPY IN RHEUMATOID ARTHRITIS PATIENTS WHO HAD INADEQUATE RESPONSE TO BIOLOGIC DMARDS“. The authors looked at 107 RA patients receiving adalimumab plus methotrexate. The study is not blinded, no placebo arm. Results: „Mean DAS28-ESR, SDAI, CDAI were significantly decreased from the initiation of IGU treatment at 24 weeks (3.1→2.3, 7.1→2.7, 6.5→2.4), at 52 weeks (2.1, 2.4, 2.0). Remission rates of DAS28-ESR, SDAI, CDAI were 69.2%, 68.2%, 70.1% at 24 weeks, 74.8%, 78.5%, 79.4% at 52 weeks.“ I hab´ve problems with the statistics of this study. However the conclusion seems to be correct: „IGU might be a new RA treatment option for aiming remission in patients who had inadequate response to Bio.“

Y. Mochida and colleagues looked at 190 elderly patient [5]: „EFFICACY OF IGURATIMOD FOR RHEUMATOID ARTHRITIS IN ELDERLY PATIENTS“. Conclusion: „From the results of this study, the efficacy of IGU for elderly patients was confirmed and did not show differences with non-elderly people. IGU is an inexpensive drug with enough efficacy and thought to be possible substitute for cases with insufficient reaction with other DMARDs.“ Let's keep in mind: inexpensive drug.

And there is the study of S. Mizutani and colleagues in Clinical rheumatology [6]: „Clinical effectiveness of iguratimod based on real-world data of patients with rheumatoid arthritis“. „Disease activity scores in 177 RA patients treated using IGU were retrospectively evaluated“. The authors concluded, that iguratimod is effective for rheumatoid arthritis, especially with concomitant methotrexate. „Since all serious adverse events were in the elderly group in this study, sufficient monitoring for adverse events, especially for elderly RA patients, is needed during iguratimod therapy.“

Most if not all studies presented in this blogpost or the preceding ones would not meet the standards to apply for an approval by EMA or FDA, but iguratimod is an inexpensive csDMARD used successfully in Japan. So why isn't the drug made available in the rest of the world?

Links:

[1] Iguratimod at the EULAR Meeting 2012

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

Iguratimod at the EULAR Meeting 2013

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

Iguratimod at the ACR 2013 Meeting

http://rheumatologe.blogspot.de/2014/01/iguratimod-at-acr-2013-meeting-in-san.html

Iguratimod at the EULAR 2014 Meeting

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

Iguratimod at the ACR 2015 Meeting https://rheumatologe.blogspot.com/2015/11/iguratimod-at-acr-2015-meeting-in-san.html

Iguratimod at the EULAR 2017 Meeting

https://rheumatologe.blogspot.com/2017/06/iguratimod-at-2017-eular-annual-meeting.html

[2] K. Katayama1, T. Okubo1, K. Yujiro2, R. Fukai3, T. Sato1, M. Yuichi4, S. Abe4, H. Ito4. SAT0146 INHIBITION OF RADIOGRAPHIC PROGRESSION

BY IGURATINOD IN 116 JAPANESE RHEUMATOID ARTHIRITIS PATIENTS DESPITE CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS THERAPY. DOI: 10.1136/annrheumdis-2020-eular.1434

[3] D. Kobayashi1,2, E. Hasegawa2,3, Y. Wada4, S. Ito2, A. Abe2, K. Nakazono2, A. Murasawa2, I. Narita1, H. Ishikawa2. SAT0147 EFFICACY AND SAFETY OF IGURATIMOD AS FIRSTLINE DISEASE-MODIFYING ANTIRHEUMATIC DRUG THERAPY FOR PATIENTS WITH RHEUMATOID ARTHRITIS. DOI: 10.1136/annrheumdis-2020-eular.2691

[4] T. Miyamoto1,2, K. Yamazaki1. AB0350 EFFICACY OF ADDING IGURATIMOD THERAPY IN RHEUMATOID ARTHRITIS PATIENTS WHO HAD INADEQUATE RESPONSE TO BIOLOGIC DMARDS. DOI: 10.1136/annrheumdis-2020-eular.459

[5] Y. Mochida1, K. Harigane1, T. Shimazaki1, Y. Inaba2, A. Nagaoka2. AB0351 EFFICACY OF IGURATIMOD FOR RHEUMATOID

ARTHRITIS IN ELDERLY PATIENTS. DOI: 10.1136/annrheumdis-2020-eular.2639

[6] Mizutani S, Kodera H, Sato Y, Nanki T, Yoshida S, Yasuoka H. Clinical effectiveness of iguratimod based on real-world data of patients with rheumatoid arthritis [published online ahead of print, 2020 Jun 6]. Clin Rheumatol. 2020;10.1007/s10067-020-05208-y. doi:10.1007/s10067-020-05208-y https://pubmed.ncbi.nlm.nih.gov/32506311/

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