Carpe Diem Haiku No. 869 Tavn Bogd

Islam’s five pillars

Five precepts of Buddhism

Only four seasons

The seasons go round

And prayers leave prayer wheels

Practice on pillars

Profession of faith, prayer, fasting, alms, pilgrimage.

Abstain from killing (1), taking what is not given. (2), avoiding sexual misconduct (3), abstain from false speech (4), fermented drink that causes heedlessness.

Souls may be leaving

Spirits inhabit mountains

But ah, the beauty

Near the mountains’ ice

Only the conifers thrive

Shelter for shamans

Calving of glaciers

Shaman’s drumming and singing

Different but one

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-869-tavn-bogd.html

Carpe Diem Special Haiku No. 184 Ese's fifth "still beautiful"

Shivering elm trees

While the leaves rod on the ground

Moon still beautiful

Spring opening meadows

But still carrying white caps

The distant mountains

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-special-184-eses-fifth-still.html

Carpe Diem No. 868 Stag Beetle / Flying Deer

Images on rocks

Dark clouds ruling sky and mind

Flying Deer lifts up

The deer come and go

As the wind howls and whispers

Steady Flying Deer

The deer disappeared

And Tuvans live in cities

Flying Deer on rock

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-868-stag-beetle.html

I’ve found my pictures, but still I don’t have them here. I’ll supply the pictures after the weekend.

Rubax, natürliches Arzneimittel auf dem Vormarsch?

Ich lese gerade die doppelseitige Anzeige mit dem Titel: „Natürliches Arzneimittel auf dem Vormarsch – Schwerpunkt Rücken- und Gelenkschmerzen“. Über der Anzeige steht ganz groß GESUNDHEIT und zwar so gesetzt wie ein redaktioneller Artikel. Versteckt im Haar eines schmerzverzerrten Mannes kann man auch das Wort ANZEIGE entdecken. In den Blick fällt auch schnell das Brustbild eines weiteren Mannes unter „Unser Experte erklärt“. Wer oder was dieser junge Mann ist, wird allerdings nicht gesagt.

Wir erfahren, dass „10 Millionen Menschen in Deutschland“ „Schmerzen im Bewegungsapparat“ haben. Ja, Sie haben richtig gelesen IM Bewegungsapparat. Vielleicht denkt sich der Schreiber, unter Bewegungsapparat würde man ein kleines Maschinchen verstehen.

„Natürliches Arzneimittel erweist sich als wirksam und gut verträglich“. Ja, tut es das wirklich? Das Mittel heißt Rubax und „verheißt Hoffnung“ – Hoffnung verheißen kenne ich aus der Bibel. Vielleicht, weil Homöopathie Glaubensmedizin ist? Es wird auf Studien hingewiesen, aber zitiert wird nur eine Studie an Ratten (Patil et al.: Modulation of arthritis in rats by Toxicodendronpubescens and its homeopathic dilutions). „The maximum protective effect was evident in the crude form at 10mg/kg/day, by mouth.” Das heißt, nicht in den Verdünnungen sondern bei 10 mg pro kg Körpergewicht pro Tag hat man Effekte bei Ratten gesehen. Der vollständige Text lag mir leider nicht vor. Abstract: http://www.ncbi.nlm.nih.gov/pubmed/21784329

Andererseits gibt es zwei Studien am Menschen. D. Pach und Kollegen untersuchten: „Efficacy of injections with Disci/Rhus toxicodendron compositum for chronic low back pain--a randomized placebo-controlled trial.” 150 Personen wurden untersucht, 51 erhielten das Verum, 48 Placebo and 51 keine Behandlung. Toxicodendron war nicht effektiver als Placebo. Vollständige Studie: http://www.ncbi.nlm.nih.gov/pubmed/21784329.

M. Shipley und Kollegen führten diese Studie durch: „Controlled trial of homoeopathic treatment of osteoarthritis.” Sie konnten zeigen (und das schon 1983), dass eine homöopathische Zubereitung von Rhus toxicodendron nicht wirksam gegen Kniegelenks- oder Hüftgelenksarthrose war. Man hatte nicht nur gegen Placebo sondern auch gegen Fenoprofen, einem nicht-steroidalen, entzündungshemmenden Schmerzmittel (NSAID), getestet. Link: http://www.ncbi.nlm.nih.gov/pubmed/6129459.

Was kostet der Spaß? 10 ml der Tropfen kosten zwischen 13 € und 20 €. Wenn man nicht mehr als 15 Tropfen täglich einnimmt, reicht das Fläschchen weniger als zwei Wochen. Bei täglichem Gebrauch sind das Jahreskosten von 462 €. Angesichts der Studienlage wäre mir das zu viel.
Rubax, natürliches Arzneimittel auf dem Vormarsch - hoffentlich nicht.

04.12.2015:
Heute sehe ich die Anzeige zu Rubax mit dem Titel: "Was tun bei Rückenschmerzen". Die Zwischenüberschrift "So wirksam wie harte Chemie, dabei aber gut verträglich" verweist auf eine Fußnote, in der als Nachweis dieser Behauptung die o.g. homöopathische Studie an Ratten herangezogen wird. Das sollte man nicht als Wissenschaft bezeichnen.

11.02.2016:
Gerade bekomme ich ein Fläschlein Rubax gezeigt. Es ist apothekenpflichtig!!! Vielleicht, weil es 51% Alkohol enthält. Andererseits könnte es sich auch um eine verkaufsfördernde Maßnahme handeln. Und kostet € 10,99! 10 ml!

Carpe Diem Haiku No. 867 Tuvan People

The small waterfall

Murmurs into winter’s world

Wadded by white snow

The small waterfall

And a light breeze through meadows

Calling a new spring

The small waterfall

Dripping softly all summer

Ready refreshment

The small waterfall

Bears farewell to the cattle

As autumn is back

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-867-tuvan-people.html

I had been intrigued by the words: "An example of this is the Mongolian story of the waterfall above the Buyan Gol (Deer River), where mysterious harmonic sounds are said to have attracted deer to bask in the waters, ..."

Carpe Diem Haiku No. 866 Shevet Uul (or the valley of Shiveet Khairhan Mountain)

 

Glaring sun and wind

Try to erase old stories

Still eons to go

 

Gazing

Grazing cattle

Carving

 

Around the campfire

The dancers are in a trance

Howling to the moon

 

Across the flat lands

Dust rising behind the beasts

Not carved for trophy

 

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-866-shevet-uul-or-valley-of.html

 

PS. I might change the pictures. I didn't find the originals on my backup external HHD, which makes me nervous!

Buenos Aires at Night

I’ve reached Buenos Aires after nightfall and despite the advice not to wander through the night, I did so being the more adventurous type of traveller. Colours are different and you see the city in other light, also dark corners, which are bleached by the sun during the day.

The inner city of Buenos Aires is home for about 3 to 3.5 million people. Counting together with the province (Greater Buenos Aires) you will have more than 15 million inhabitants. History of the city reaches back to 1541, though the very first Spanish settlement had to be abandoned and the second (and permanent) settlement had been established in 1580 under the orinal name: Ciudad de la Santísima Trinidad y Puerto de Santa María del Buen Aire, which was shortened later to Buenos Aires.

The Obelisk – a landmark 

(Avenida 9 de Junio / Plaza de la República)

A rally of Scioli supporters (first part of the elections)

Cristina Fernández de Kirchner wanted the Palace to be illuminated in pink – 

the new president (Macri) might change that

Nightscene – quite near to my hotel on the way back

Carpe Diem Haiku Writing Techniques No. 20 Paradox

Eyes shut

The monk sees the whole world

Mere nothing

The dry cleaner

Delivering clothes

Through the rain

November

Sunshine falls in

Snowflakes

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-haiku-writing-techniques-20.html

PS.
Just found an old Haiku that might fit in:

This night 

Too cold 

For leaves to tremble

Carpe Diem Haiku No. 865 torn apart book (reading nature)

A burst of colours

Autumn blows the feast trumpets

Before the long sleep

Colours are fading

From red and yellow to grey

And then black and white

White clouds on black sky

Below black trees in white snow

Gravedigger’s red nose

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-865-torn-apart-book-reading.html

Carpe Diem Haiku No. 864 Juniper

“holy smoke rises”

From the steppes and the cities

Prayer flags flutter

“holy smoke rises”

The ardent prostrate themselves

As pilgrims wander

“holy smoke rises”

From the holy city out

Into the steppes

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-864-juniper.html

Carpe Diem Haiku Special No.183 Ese's fourth "inevitable"

Inevitable

The blur after the booze

And the head after

Inebriety

And an empty jar

Winter covers with snow

Inevitable

With so many fallen leaves

Leaf blower man

Irresistible

In defoliated woods

The smell of decay

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-special-183-eses-fourth.html

PS. I’ve put Evita in inevitable. Reminiscing Argentina.

Coffee - a Remarkable Experience in Argentina

A couple of months ago we had a discussion on Twitter at the German speaking corner on what to do, if you run out of paper filters for the drip. There are instant coffee, coffee pads, French press, Nespresso (actually I don’t consider this as coffee), and more - but you might not have this at home, because you believe in the coffee drip (e.g. flat bottom filter, syphon, clever dripper). You have coffee, but you lack the filters. And you don't have a French press down device. One solution could be paper towels, which one folds to make a filter. We came up with using tea filter bags, which you fill with coffee instead of tea. We thought we were inventive.

I still think we were and I've used this method, when I only wanted to brew a single cup of coffee. But have a look at what I've found in a hotel in Mendoza, Argentina. On a dim day I wanted to brew a coffee or a tea. I didn't see the usual instant coffee and thought I had to make tea, when I found this:

... café en saquitos - and how to make the coffee.

Filgotinib at the ACR 2015 Meeting in San Francisco

There have been seven publications on Filgotinib at the ACR 2015 Annual Meeting in San Francisco. Filgotinib (already known as: GLPG0634) is a novel oral, potent and selective JAK1 inhibitor.

R Westhovens and colleagues presented results from a phase 2B dose ranging study over 12 weeks. Conclusion: "Over 12 weeks, filgotinib in combination with MTX demonstrated consistent efficacy on signs and symptoms of active RA with a rapid onset of action. [...]"

Arthur Kavanaugh et al. also looked at results from a phase 2B dose ranging study over 12 weeks. The reported on filgotinib as monotherapy. Conclusion: "Over 12 weeks, filgotinib as monotherapy demonstrated clear efficacy in treating the signs and symptoms of active RA with a rapid onset of action. Overall safety profile was favorable and consistent with previous studies conducted in RA with filgotinib."

Namour Florence and colleagues presented data in the influende of age and renal impairment from phase 1 studies. Conclusion: "Higher age and mild to moderate impairment of renal function has a limited impact on the PK [pharmacokinetics] of filgotinib. In severe renal impairment, the exposure to filgotinib’s active metabolite is elevated, consistent with its renal elimination pathway. This was not associated with safety signals in these Phase 1 studies."

There were of course more studies: René Galien and colleagues (filgotinib) decreases plasma markers of inflammation and joint damage), René Galien and another team (filgotinib changes lipid profile with a preferential increase in HDL), Namour Florence et al. (filgotinib shows similar pharmacokinetics and pharmacodynamics profiles in Japanese and Caucasian healthy volunteers), and René Galien and colleagues (further evidence for the JAK1 selectivity of filgotinib).

All in all, filgotinib has presented data up to 12 weeks. We have to wait for a phase 3 study ... and much longer for data on radiographic progression.

References:

Westhovens R, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-an-oral-jak1-selective-inhibitor-is-effective-in-combination-with-methotrexate-in-patients-with-active-rheumatoid-arthritis-results-from-a-phase-2b-dose-ranging-study/. Accessed November 18, 2015.

Kavanaugh A, Ponce L, Cseuz R, Reshetko O, Stanislavchuk MA, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective As Monotherapy in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-an-oral-jak1-selective-inhibitor-is-effective-as-monotherapy-in-patients-with-active-rheumatoid-arthritis-results-from-a-phase-2b-dose-ranging-study/. Accessed November 18, 2015.

Florence N, Fagard L, Van der Aa A, Goss S, Harrison P, Tasset C. Influence of Age and Renal Impairment on Pharmacokinetics of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/influence-of-age-and-renal-impairment-on-pharmacokinetics-of-filgotinib-glpg0634-a-selective-jak1-inhibitor/. Accessed November 18, 2015.

Galien R, Van der Aa A, Blanque R, Darquenne S, Harrison P, Tasset C. Selective JAK1 Inhibition with Filgotinib (GLPG0634) Decreases Plasma Markers of Inflammation and Joint Damage in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/selective-jak1-inhibition-with-filgotinib-glpg0634-decreases-plasma-markers-of-inflammation-and-joint-damage-in-patients-with-rheumatoid-arthritis/. Accessed November 18, 2015.

Galien R, Harrison P, Brys R, Van der Aa A, van 't Klooster G, Tasset C. 4-Week Treatment of Rheumatoid Arthritis Patients with the JAK1-Selective Inhibitor Filgotinib (GLPG0634) Changes Lipid Profile with a Preferential Increase in HDL [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/4-week-treatment-of-rheumatoid-arthritis-patients-with-the-jak1-selective-inhibitor-filgotinib-glpg0634-changes-lipid-profile-with-a-preferential-increase-in-hdl/. Accessed November 18, 2015.

Florence N, Vayssière B, Galien R, Fagard L, Van der Aa A, Goss S, Harrison P, Tasset C. Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, Shows Similar Pharmacokinetics and Pharmacodynamics Profiles in Japanese and Caucasian Healthy Volunteers [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-a-selective-jak1-inhibitor-shows-similar-pharmacokinetics-and-pharmacodynamics-profiles-in-japanese-and-caucasian-healthy-volunteers/. Accessed November 18, 2015.

Galien R, Brys R, Van der Aa A, Harrison P, Tasset C. Absence of Effects of Filgotinib on Erythrocytes, CD8+ and NK Cells in Rheumatoid Arthritis Patients Brings Further Evidence for the JAK1 Selectivity of Filgotinib [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/absence-of-effects-of-filgotinib-on-erythrocytes-cd8-and-nk-cells-in-rheumatoid-arthritis-patients-brings-further-evidence-for-the-jak1-selectivity-of-filgotinib/. Accessed November 18, 2015.

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Baricitinib at the ACR 2015 Meeting in San Francisco

There have been seven publications on Baricitinib at the ACR 2015 Annual Meeting in San Francisco. Baricitinib is an oral inhibitor of Janus kinases selective for JAK 1 and 2.

The first study is a three arm study: baricitinib versus placebo or adalimumab. The study was published as a late breaking abstract. Peter C. Taylor and colleagues presented the results of a phase 3 study. In methods we read: "Pts with active RA (TJC≥6 & SJC≥6 & hsCRP≥6 mg/L) despite stable background MTX were randomized 3:3:2 to PBO, bari 4 mg once daily (QD), or adalimumab (ADA) 40 mg biweekly (Q2W), stratified by region and baseline joint erosion status. [...]" Conclusion: "In pts with active RA despite background MTX, once-daily oral bari was associated with significant clinical improvements compared to PBO and to ADA, with an acceptable safety and tolerability profile." There seems to be a slight advantage of baricitinib compared to adaliimumab.

Xin Zhang and colleagues worked on: "Evaluate the Dose Efficacy Response Relationship of Baricitinib in Patients with Rheumatoid Arthritis". The authors identified 4 mg QD identified as the preferred phase 3 dose, "splitting the dose into a BID regimen does not provide any advantage over QD dosing for any of the efficacy endpoints."

Roy Fleischmann and colleagues looked at: "Baricitinib, Methotrexate, or Baricitinib Plus Methotrexate in Patients with Early Rheumatoid Arthritis Who Had Received Limited or No Treatment with Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Phase 3 Trial Results". Study over 24 weeks. Conclusion: "In pts with early RA, all treatment groups experienced improvements in disease activity with bari 4 mg monotherapy producing significantly larger and more rapid improvements and higher rates of clinical remission compared to MTX monotherapy, with a satisfactory safety profile. MTX addition to bari 4 mg did not increase the benefit observed with bari monotherapy, while it appeared to increase the frequency of laboratory abnormalities." As methotrexate isn't tolerated by all patients, this could make baricitinib interesting.

Mark C. Genovese and colleagues presented: "Previous Biologic Disease-Modifying Antirheumatic Drug (bDMARD) Exposure and Efficacy and Safety Analysis from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitors". This post hoc analysis didn't reveal any "evidence of a qualitative interaction".

There were three more studies: Paul Emery and colleagues (Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients), Joel Kremer et al. (Response to Baricitinib at 4 Weeks Predicts Response at 12 and 24 Weeks), and Paul Emery and colleagues (Patient-Reported Outcomes from a Phase 3 Study of Baricitinib). Please see below for access to these studies.

Lots of interesting data! A new drug against rheumatoid arthritis has appeared on the horizon. But ... the evaluated and published data ends after 24 weeks. And there's no data yet on how successful baricitinb is concerning minimizing radiographic progression. Still some time needed before approval as a drug may be discussed. Anyway: good luck, baricitinib!

References:

Taylor PC, Keystone EC, van der Heijde D, Tanaka Y, Ishii T, Emoto K, Yang L, Arora V, Gaich CL, Rooney T, Schlichting DE, Macias W, de Bono S, Weinblatt ME. Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy: Results of a Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/baricitinib-versus-placebo-or-adalimumab-in-patients-with-active-rheumatoid-arthritis-ra-and-an-inadequate-response-to-background-methotrexate-therapy-results-of-a-phase-3-study/. Accessed November 20, 2015.

Zhang X, Chua L, Ernest CS II, Macias W, Rooney T, Tham LS. Evaluate the Dose Efficacy Response Relationship of Baricitinib in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/evaluate-the-dose-efficacy-response-relationship-of-baricitinib-in-patients-with-rheumatoid-arthritis/. Accessed November 20, 2015.

Fleischmann R, Takeuchi T, Schlichting DE, Macias WL, Rooney T, Gurbuz S, Stoykov I, Beattie SD, Kuo WL, Schiff M. Baricitinib, Methotrexate, or Baricitinib Plus Methotrexate in Patients with Early Rheumatoid Arthritis Who Had Received Limited or No Treatment with Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Phase 3 Trial Results [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/baricitinib-methotrexate-or-baricitinib-plus-methotrexate-in-patients-with-early-rheumatoid-arthritis-who-had-received-limited-or-no-treatment-with-disease-modifying-anti-rheumatic-drugs-dmards-p/. Accessed November 20, 2015.

Genovese MC, Kremer JM, Kartman C, Schlichting DE, Xie L, Carmack T, Macias WL, Smolen JS. Previous Biologic Disease-Modifying Antirheumatic Drug (bDMARD) Exposure and Efficacy and Safety Analysis from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitors [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/previous-biologic-disease-modifying-antirheumatic-drug-bdmard-exposure-and-efficacy-and-safety-analysis-from-a-phase-3-study-of-baricitinib-in-patients-with-rheumatoid-arthritis-and-an-inadequate-re/. Accessed November 20, 2015.

Emery P, McInnes I, Genovese MC, Smolen JS, Kremer J, Dougados M, Schlichting DE, Rooney T, Issa M, de Bono S, Macias WL, Rogai V, Zuckerman SH, Taylor PC. Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients with Rheumatoid Arthritis in Two Phase 3 Studies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/characterization-of-changes-in-lymphocyte-subsets-in-baricitinib-treated-patients-with-rheumatoid-arthritis-in-two-phase-3-studies/. Accessed November 20, 2015.

Emery P, McInnes I, Genovese MC, Smolen JS, Kremer J, Dougados M, Schlichting DE, Rooney T, Issa M, de Bono S, Macias WL, Rogai V, Zuckerman SH, Taylor PC. Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients with Rheumatoid Arthritis in Two Phase 3 Studies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/characterization-of-changes-in-lymphocyte-subsets-in-baricitinib-treated-patients-with-rheumatoid-arthritis-in-two-phase-3-studies/. Accessed November 20, 2015.

Kremer J, Dougados M, Genovese MC, Emery P, Yang L, de Bono S, Holzkaemper T, Iikuni N, Schlichting DE, Smolen JS. Response to Baricitinib at 4 Weeks Predicts Response at 12 and 24 Weeks in Patients with Rheumatoid Arthritis: Results from Two Phase 3 Studies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/response-to-baricitinib-at-4-weeks-predicts-response-at-12-and-24-weeks-in-patients-with-rheumatoid-arthritis-results-from-two-phase-3-studies/. Accessed November 20, 2015.

Emery P, Gaich CL, DeLozier AM, de Bono S, Liu J, Chang C, Dougados M. Patient-Reported Outcomes from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis with Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/patient-reported-outcomes-from-a-phase-3-study-of-baricitinib-in-patients-with-rheumatoid-arthritis-with-inadequate-response-to-conventional-synthetic-disease-modifying-antirheumatic-drugs/. Accessed November 20, 2015.

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Protein Kinase Inhibitors after the ACR 2015 Meeting in San Francisco – how much Hype is left?

I have already written about hype or hope in protein kinase inhibitors. Now, after the ACR 2015 Annual Meeting in San Francisco it’s time to ask: how much hype is left?

Here a chart, I’ve prepared only a year ago:

Xeljanz (tofacitinib) is on the market in the US for the treatment of rheumatoid arthritis, but still lacks approval in Europe.

Otezla (apremilast) has been approved in the US and later in Europe for the treatment of psoriatic arthritis.

One study on fostamatinib came up, but only on bovine cartilage cells – but still unexpected for me; see: links.

Baricitinib had been discussed in several studies, posters, talks at the meeting; I’ll write on the studies in detail, soon.

Addendum: somehow I've left out filgotinib. Filgotinib is still in the race. Please look for more details under links.

This list above is incomplete, I know, but it shows how many hopes we had. I think that too many pharmaceutical companies tried to run for a small molecule, which is easier to produce, but might be sold at a high price. This mass of different molecules with facets of different effects was fuelling the hype, which peaked, when Xeljanz got the FDA approval. But I assure you: the hype is gone. Xeljanz is struggling for EMEA approval. Fostamatinib like most others have been abandoned as potential drugs. Otezla is approved in Germany, but will hardly be used because of failure of obtain a positive GBA ruling. The GBA (Federal Joint Committee) “exerts a direct influence on the healthcare provisions”; for further details look at Wikipedia, you can use the link below. And I think that Baricitinib will reach approval, too.

I hope that the pharmaceutical industry is prudent enough not to overprice small molecules, so that our patient's needs are addressed.

Links:

http://rheumatologe.blogspot.de/2013/06/protein-kinase-inhibitors-hype-or-hope.html

http://rheumatologe.blogspot.de/2014/01/protein-kinase-inhibitors-where-do-we.html

http://rheumatologe.blogspot.de/2014/06/protein-kinase-inhibitors-at-eular-2014.html

http://rheumatologe.blogspot.de/2015/11/fostamatinib-at-acr-2015-meeting-in-san.html

https://en.wikipedia.org/wiki/Federal_Joint_Committee_(Germany)
http://rheumatologe.blogspot.de/2015/11/filgotinib-at-acr-2015-meeting-in-san.html

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Carpe Diem Haiku No. 862 Vistas

  

Snow fallen on peaks

Resting for a while, then melt

Monk is resting, too

Camels are ready

To move down from the mountains

Seasons guide nomads

Sharp ridges on top

Rounded base holds man and rock

Nature is yin-yang

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-862-vistas.html

Fostamatinib at the ACR 2015 Meeting in San Francisco

There has been one publication on Fostamatinib at the ACR 2015 Annual Meeting in San Francisco. After reading the study by M. Genovese and colleagues last year, I thought I’d never hear anything on fostamatinib again; follow the link below for the whole story. Let’s look at the study, I’ve found in the wake of this year’s ACR Meeting.

Cecilie F. Kjelgaard-Petersen and colleagues presented: “The Active Metabolite of Fostamatinib, R406, Only Decreases the Inflammation-Driven Extracellular Matrix Turnover of the Joint at High Concentrations Ex Vivo”. Background/Purpose: “Osteoarthritis (OA) and rheumatoid arthritis are degenerative diseases of the whole joint. […]” I wouldn’t classify RA as a degenerative disease, though mutilations might lead to further degeneration, also after successful therapy and in the absence of autoimmune inflammation. But let’s move on. “Fostamatinib has been tested in both phase II and phase III clinical trials with mixed results.” Well, I'd call this statement euphemistic, but this view is possible. Methods: ”Cartilage turnover was investigated using a bovine cartilage explant (BEX) model. […]” Conclusion: “These data show that R406 can inhibit pro-inflammatory ECM joint degradation at concentrations higher than 0.5 μM, but at 0.5 μM or lower R406 increased the inflammatory degradation of collagen type III and had no effect on aggrecan degradation. In contrast, the p38 inhibitor SB203580 had no effect on synovial ECM turnover or aggrecan degradation, underlining the importance of understanding the differences between inhibitors of pro-inflammatory mediators and their effect on the joint tissue.”

I think , we best sum it up this way: good study to know more about “differences between inhibitors of pro-inflammatory mediators and their effect on the joint tissue”, but I don’t see anything, that could lead to putting fostamatinib back on the agenda concerning rheumatoid arthritis.

References:

Kjelgaard-Petersen CF, Thudium CS, Siebuhr AS, Christiansen TG, Karsdal MA, Hägglund P, Bay-Jensen AC. The Active Metabolite of Fostamatinib, R406, Only Decreases the Inflammation-Driven Extracellular Matrix Turnover of the Joint at High Concentrations Ex Vivo [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/the-active-metabolite-of-fostamatinib-r406-only-decreases-the-inflammation-driven-extracellular-matrix-turnover-of-the-joint-at-high-concentrations-ex-vivo/. Accessed November 20, 2015.

Fostamatinib in Rheumatoid Arthritis

http://rheumatologe.blogspot.de/2014/10/fostamatinib-in-rheumatoid-arthritis.html

04.12.2015
Today I've read in the "Annals of the Rheumatic Diseases / The EULAR Journal" an article by P.C. Taylor and colleagues: "OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy". Conclusions: "Fostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24." "The modest clinical resulta in all of the phase III studies have let to a decision by the companies developing fostamatinib to not submit a regulatoty filing for its use in RA." "The relevance of these findings for other more selective SYK inhibitors remains to be seen.

Link:
http://ard.bmj.com/content/early/2014/07/29/annrheumdis-2014-205361.short?rss=1 

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ERAP1 at the ACR 2015 Meeting in San Francisco

There has been one publication on ERAP1 at the ACR 2015 Annual Meeting in San Francisco. ERAP1 (endoplasmic reticulum aminopeptidase 1) has a strong genetic association of with ankylosing spondylitis, which is restricted to HLA-B27 positive cases. I’ve become interested while being at the 2014 EULAR Meeting in Paris. And now we have a new tiny piece of evidence that there might be a drug in the far future.

Tri M. Tran and colleagues presented: “ERAP1 Deficiency Protects HLA-B27 Transgenic Rats from Arthritis”. Conclusion: “Complete absence of ERAP1 protected B27-TG rats from arthritis, but led to an increase in gut inflammation, suggesting different effects on pathogenic mechanisms involved in arthritis and colitis. B27-TG rats heterologous for ERAP1 exhibited higher incidence of arthritis concomitant with lower inflammation in the gut as compared to ERAP1-/- .This novel model provides an opportunity to better understand the mechanism(s) by which HLA-B27 contributes to SpA pathogenesis”.

Protection from arthritis, but increase in gut inflammation. What goes through my mind now? Far future, individually tailored therapy, basic science … Yes, and far too early to speculate on a new drug.

References:

Tran TM, Hong S, Gill T, Bennett J, Sikora K, Colbert RA. ERAP1 Deficiency Protects HLA-B27 Transgenic Rats from Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/erap1-deficiency-protects-hla-b27-transgenic-rats-from-arthritis/. Accessed November 20, 2015.

ERAP1 at the EULAR 2014 Meeting in Paris http://rheumatologe.blogspot.de/2014/07/erap1-at-eular-2014-meeting-in-paris.html