Methotrexate (MTX) and Caffeine

 

Recently I had written a blog post on Methotrexate (MTX) and Caffeine in German [1]. This is an offspring and not merely a translation of this article.

Klaus Krüger, a German Professor of Rheumatology based in Munich, told in an interview for BDI aktuell [a publication of the BDI, which stands for Berufsverband Deutscher Internisten - Professional Association of German Internists], that even though MTX is generally well tolerated, nausea is a common side effect. He mentioned coffee being able to alleviate this side effect.

As I've known Dr. Krüger for at least 15 years, I thought to look for the study not mentioned in BDI aktuell. He monitores, condenses and lectures on studies and won't give this kind of information without having read a study. And I've found a likely study by Dr. Anand Narayan Malaviya [2].

In his study, A.N. Malaviya examined the effect of caffeine on the symptoms of methotrexate intolerance in patients with rheumatoid arthritis. Caffeine (coffee / dark chocolate) relieved the symptoms of MTX intolerance in the majority of patients.

Let's look at some details of this study, which looked at 855 patients treated with methotrexate. 313 patiens did not have any MTX intolerance, leaving 542 patients with some degree of MTX intolerance. In 422 patients MTX intolerance did not require any intervention. 120 (14 % of the initial 855) patients had 'moderate' or 'severe' MTX intolerance. “Among these, 55 % had complete relief of symptoms and were able to continue taking the advised dose of MTX; 13.3 % had partial improvement and continued taking MTX but only with antiemetics; 7.5 % were minimally better but were somehow managing; 10 % were complete caffeine failure without any relief; 14.2 % did not like caffeine (coffee or dark chocolate) and did not want to take it.” Tea, not coffee is mostly drunk in the northern part of India.

I myself like coffee and dark chocolate, but I would have no hesitation in recommending tea drinkers to give it a try; however, precisely that was not tested. Dark chocolate and coffee contain slightly more caffeine when compared to tea. However, it is more important that the polyphenols in tea (e.g. epigallocatechin gallate) bind the caffeine and only release it in the intestine, which renders the kinetics different from those of coffee, for example. It may well be the case that the faster absorption of caffeine from coffee is more effective at preventing methotrexate nausea.

I've always been concerned about strategies to keep patients on MTX as it is very effective in itself or as a co-medication [3]. Give coffee a chance!


Links and annotations:
[1] https://rheumatologe.blogspot.com/2021/07/methotrexat-mtx-und-kaffee.html – more annotations and links to texts in German there
[2] Malaviya AN. Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): effect of adding caffeine to the management regimen. Clin Rheumatol. 2017 Feb;36(2):279-285. doi: 10.1007/s10067-016-3398-3. Epub 2016 Sep 6. PMID: 27596742.  https://pubmed.ncbi.nlm.nih.gov/27596742/
[3] https://rheumatologe.blogspot.com/2015/05/methotrexate-and-hydrating.html

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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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BTK-Inhibitors at the 2019 EULAR Meeting in Madrid

Again there is a hype on small molecules as JAK-inhibitors are on the market and the drug are sold at exorbitant prices – for a small, less complex molecules as compared to large, complex molecules like MABs with much higher production costs. So it is understandable that companies try to come to the market with such drugs. Filgotinib is presented in 10 studies at the 2019 EULAR Meeting in Madrid; as tofacitinib and as baricitinib.

Bruton’s tyrosine kinase (BTK) plays an essential role in B cell development and is thought to be involved in the pathogenesis of RA. There are 5 studies on different BTK-inhibitors at the 2019 EULAR Meeting.

I’ve had a discussion on twitter with friend and colleague Dr Irwin Lim (@_connectedcare) on Twitter yesterday [1]. So I looked deeper into BTK-inhibitors.

Acalabrutinib (Calquence®)

Acalabrutinib (Calquence®) by AstraZeneca: study completed, but no published data on outcome (DAS28) in April 2015. Nothing at the 2019 EULAR Meeting. Calquence® has been approved by the FDA and the EMA for the treatment of mantle cell lymphoma (MCL).

AC0058

AC0058 by ACEA has an ungoing study on systemic lupus erythematodes (NCT03878303), which is still recruiting. I haven't found a study on rheumatoid arthritis.

BMS-986142

BMS-986142 by Bristol-Myers Squibb: study completed, but no published data on outcome (ACR20, ACR70) in Feb. 2016. Nothing at the 2019 EULAR Meeting.

Evobrutinib

Evobrutinib by Merck: study ongoing (ACR20) in Jul. 2017. Nothing at the 2019 EULAR Meeting.

Fenebrutinib

Fenebrutinib by Roche/Genentech: study completed (ACR50) in Sep. 2016. There are two studies. St. Cohen and colleagues concluded in phase 2 study: “FEN [Fenebrutinib] demonstrated higher efficacy rates than PBO [placebo] for ACR50 at W12 in both MTX-IR and TNF-IR [inadequate response] populations, and was similar to ADA [adalimumab] in MTX-IR pts. The overall safety profile of FEN was acceptable.“ [2] The other study is a cell study (THE BTK INHIBITOR, FENEBRUTINIB, EFFECTIVELY MODULATES B AND MYELOID CELL BIOLOGY IN RHEUMATOID ARTHRITIS PATIENTS).

Poseltinib

Poseltinib (LY3337641) by Eli Lilly: study terminated because of lack of efficacy (ACR20) in Aug. 2016. Early in 2018 Eli Lilly has halted a phase 2 trial on rheumatoid arthritis after looking at the mid-study data. Probably the efficacy goal wasn’t likely to be met (ACR20). [3] These study results will be discussed at the 2019 EULAR Meeting on Saturday.

Spebrutinib

Spebrutinib by Celgene failed to meet primary outcome (ACR20) in Oct. 2013. Nothing at the 2019 EULAR Meeting.

TAS 5315

TAS 5315 is a BTK inhibitor by Taiho. There are two animal studies at the 2019 EULAR Meeting.

Tirabrutinib

Tirabrutinib (ONO-4059) by Ono Pharmaceutical/Gilead Sciences: there had been some efficacy in a CIA study, but nothing more than a phase 1 study for rheumatoid arthritis so far.

Irwin, you’ve written: Fenebrutinib in RA - some promise #eular2019, and I have to admit, I come to the same conclusion. I had answered: BTK inhibitor? There have been posters for a long time. Is the small molecule hype back? #EULAR2019 #Fenebrutinib. There is some promise as fenebrutinib showed a similar response like adalimumab. Now, we’ll have to wait for a phase 3 study and of course the approval by FDA, EMA and other countries’ boards. Hopefully, the price level will be lower than it is now with other small molecules.

Links:

[1] Orininal Tweet by Dr Lim: https://twitter.com/_connectedcare/status/1138821551229493250

[2] St. Cohen and colleagues: Ann Rheum Dis, volume 78, supplement 2, year 2019, page A80 http://scientific.sparx-ip.net/archiveeular/?view=1&c=a&searchfor=Bruton%E2%80%99s%20tyrosine%20kinase%20&item=2019OP0025

[3] https://www.fiercebiotech.com/biotech/lilly-scraps-rheumatoid-arthritis-trial-after-interim-review

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