Friday, December 28, 2012

Anakinra at the ACR 2012 in Washington

There have been 8 studies at the ACR 2012 in Washington mentioning anakinra (IL-1Ra-Receptor antagonist).

Pascal Zufferey and colleagues presented a study on rotator cuff calcifications (Abstract No. 135): “A Pilot Study of the Efficacy of IL1 Blockade by Anakinra in Acute Calcific Periarthritis of the Rotator Cuff”. Conclusion: This pilot open study suggests that IL-1Ra inhibition may be an interesting therapeutic approach in acute calcific periarthritis, especially in patients who have not responded adequately to NSAIDs.” The debate will be opened if anakinra is better than steroid injection, which has a clear cost advantage.

Mary Bach and colleagues looked at gouty arthritis (Abstract No. 146): “The Treatment of Acute Gouty Arthritis in Complex Hospitalized Patients with Anakinra”. Conclusion: “Anakinra is an effective and safe alternative treatment for acute gouty arthritis in medically complex patients who fail or cannot undergo more conventional therapy.” Up to now I didn’t have a patient, who “cannot undergo a more conventional therapy”. We should focus on how to decide which patients fit into such a categogy.

Other studies looked at TRAPs, FMF, and other fever syndroms as well as juvenile idiopathic arthritis (Abstracts No. 179, 190 [Schnitzler’s Syndrome], 275 [Juvenile Dermatomyositis], 747, 762, 1142, 2021).

Anakinra is mentioned in a poster on relapsing polychondritis (No. 1923). Two patients were treated with anakinra, but the treatment has been inefficient.

Anakinra and pseudo gout (calcium pyrophosphate crystal arthritis) - what has changed since the EULAR 2012? In abstract No. 146 two case reports on pseudo gout and anakinra are mentioned.

Link to the EULAR evaluation:  

Thursday, December 27, 2012

Carpe Diem Haiku Nearly Spring (haru chikashi)

At St. Pancraz’ cross
Frail pansies resist
An ice-cold wind

Old green
Smelling like spring
While snow’s just melting


Melting snow
Rising rivulets
Dingle-dangles call

Carpe Diem Haiku Winter Moon (fuyu no tsuki)


Winter moon
Don't hide under my quilt
Rather shine above

Winter moon
Clatters with his teeth
Running for the clouds

Wind tried hard
To blow out the moon
Snow storm does

Clear sky
Frosty winter night
Where is the moon hiding?

Winter passing on
The cheeks of the moon
Are white with snow

Winter Moon
Not too late for romance
With all your diamonds

Psoriatic Arthritis at the ACR 2012 in Washington

Non-anti-TNF Biologics in Psoriatic Arthritis at EULAR 2011. I hope for new results on new drugs as therapy for psoriatic arthritis still lags behind.

Actually I’ve found only data on one drug: apremilast. Apremilast is a small molecule – a phospodiesterase 4 inhibitor. About a year ago, I’ve mentioned apremilast in ankylosing spondylitis:

Juergen Rech and colleagues presented (Abstract No 272): “Interim Safety Analysis of a Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy Study of Apremilast (CC10004) in Subjects with Erosive Hand Osteoarthritis.” Conclusion: “ … we conclude that apremilast may also be well tolerated in patients with EHOA [erosive hand arthritis]. Apremilast, if proven to be efficacious in ongoing investigations, will be an interesting treatment option for patients with EHOA.”

There has been a second study by Arthur Kavanaugh and colleagues (Abstract No. L13): “Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Results of a Phase 3, Randomized, Controlled Trial”. Conclusion: “Apremilast significantly improved signs and symptoms of PsA and resulted in statistically and clinically meaningful improvements in physical function. Apremilast was generally well tolerated and no new safety or laboratory signals were detected.” Lets look at some side effects: diarrhea (placebo: 2.4%; apremilast 20 mg BID: 11.3%; and apremilast 30 mg BID, 19.0%), nausea (high dose: 18.5%), headache (10.1%, and 10.7%), and more.

There are still some hurdles to be taken by apremilast!

There’s another study of Bremander on smoking. B. I. Bremander and colleagues presented: "Smoking Is Associated with Worse and More Widespread Pain, Worse Fatigue, General Health and Quality of Life in a Swedish Population Based Cohort of Patients with Psoriatic Arthritis" (Abstract No. 1828). Conclusion: In this population based PsA cohort, patients who were ever smokers reported worse clinical outcomes compared with never smokers. ..."

I think the message is clear. Stop smoking!

Studies on ustekinumab are here:

ARRY-797 at the ACR2012 in Washington

There has been a late breaking abstract on ... osteoarthritis.

ARRY-371797 / ARRY-797 is a p38 inhibitor (P38 mitogen-activated protein kinases [MAPK]). There were some studies on the way:
• A Study of ARRY-371797 in Patients With Rheumatoid Arthritis
• A Study of ARRY-371797 in Patients With Active Ankylosing Spondylitis
• A Study of ARRY-371797 in Patients With Osteoarthritis of the Knee

All three studies have been completed by July 2012, but nothing has been published at the EULAR 2012 meeting in Berlin and I haven’t seen any results the ACR 2012 in Washington. What does it mean? My guess is that p38 inhibition isn’t working in RA and AS, but the producer (Array BioPharma) is looking desperately for an indication to launch the drug on the market.
Alan J. Kivitz and colleagues presented a study (Abstract No. L1): “A Randomized, Placebo-Controlled Phase 2 Study of ARRY-797 in Patients with Osteoarthritis Pain Refractory to NSAID Treatment Showed Statistically Significant Improvements in WOMAC Pain and in Biomarkers of Bone and Cartilage Degradation”. Conclusion: “ARRY-797 treatment resulted in durable, statistically significant improvement in OA pain and in reduction of circulating biomarkers of both cartilage and bone degradation in this 4-week study.” That’s quickly said! ARRY-797 only showed a significant WOMAC pain reduction at weeks 1 and 4 at p>/= 0.05

Is this a meaningful reduction of pain? My guess is it isn’t, otherwise one would have said so.
Please have a look at my more elaborate evaluation under: 

MOR103 at the ACR 2012 in Washington

Target GM-CSF, there had been some interesting data, but only published by MorphoSys:

There has been a late breaking poster on MOR103. Frank Behrens and colleagues presented a poster with the title (Abstract No. L11): “First in Patient Study of Anti-GM-CSF Monoclonal Antibody (MOR103) in Active Rheumatoid Arthritis: Results of a Phase 1b/2a Randomized, Double-Blind, Placebo-Controlled Trial”. Conclusion: “MOR103 demonstrated rapid and significant clinical activity compared to placebo, most pronounced at the 1.0 mg/kg dosage in this study. Short-term safety and tolerability remained in the range of placebo. …”. So far, so good. But in “results” I’ve found: “Most frequent AEs in the MOR103 group were nasopharyngitis and worsening of RA (in all but one patient in post-treatment follow-up).” We can handle nasopharyngitis, but what does “worsening of RA” stand for? How bad would it be?

MorphoSys seems to be happy with their new child. The German review “Rheuma Management” speaks of promising data. Unless there’s data from a larger study I refrain from taking the same line.

Secukinumab at the ACR 2012 in Washington

Secukinumab is an Anti-Il17a Monoclonal Antibody.  

X. Baraliakos and colleagues tested secukinumab (IL-17A inhibition) in a proof-of-concept (PoC) trial and showed via MRI, that secukinumab may reduce spinal inflammation (Abstract No. 574). Conclusion: “This exploratory MRI analysis shows that the IL-17 inhibitor secukinumab may reduce spinal inflammation and this effect may be sustained for up to 24 months using a lower dose in the maintenance compared to induction phase. …”.

D. L. Baeten and colleagues presented another study on secukinumab in ankylosing spondylitis (Abstract No. 2225): “Improvement in Signs and Symptoms of Active Ankylosing Spondylitis Following Treatment with Anti-Interleukin (IL)-17A Monoclonal Antibody Secukinumab Are Paralleled by Reductions in Acute Phase Markers and Inflammatory Markers S100A8 and A9 (Calgranulin A and B)”. It’s a dose finding study with only 30 patients in a multicenter setting. Conclusion: “In this trial of secukinumab in AS, exploratory analyses of selected inflammatory markers suggest that secukinumab reduces CRP, S100A8 and S100A9, but only S100A8/9 reductions appear to correlate with clinical responses at Wk 6. …”.

There are some promising results, but secukinumab still has a long way to go.

Wednesday, December 26, 2012

Auferstehungskirche (Köln-Buchforst)

Am heiligen Abend hatte meine Mutter die Idee, mit Gatten und Söhnen in die Kirche zu gehen. Nun das haben wir getan und gerade noch einen Platz bekommen.

Pfarrer Licht erkannte zumindest meinen jüngsten Bruder, da er ihn konfirmiert hatte. Wir beiden, älteren Brüder gingen noch bei seinem Vorgänger zur Konfirmation.

Die Auferstehungskirche wurde im März 1968 eingeweiht und kurz darauf wurde ich konfirmiert. Vorbei waren die Jahre mit Gottesdiensten in der evangelischen Volksschule in Köln-Buchforst oder im Andreae-Haus in Köln-Mülheim. Die Kirche stellt ein untergehendes Schiff dar – alles andere ist geschummelt. 1992 stellte man die Kirche unter Denkmalschutz. Dennoch wurde sie 2005 als regelmäßiger Ort für Gottesdienste aufgegeben, aber wird im Rahmen eines Modellprojektes weiter genutzt. Wer sich für solche und weitere Einzelheiten interessiert, der schaue hier nach:

Warum wurde die Kirche aufgegeben. Nun, von den Alten leben nicht mehr viele, die mittlere Generation ist fortgezogen, die neue Generation hat es teilweise nicht so mit der Kirche und andererseits stehen auf den Mülltonnen die Bezeichnungen neben Deutsch noch in Türkisch und Russisch (Restmüll, Kunststoffe, Papier/Pappe - Çöp, Plastik, Kağıt/Karton - Мусор, Пластмасса, бумага/Картон).

Wenn man spät kommt, sitzt man vorne, aber mir war früher die Kirche nicht so klein vorgekommen, aber durch die dreieckige Grundfläche wird es zum Altar hin eng. Das Innere ist roh, man kann die Verschalung vom Beton sehen. Außen ist die Kirche nun gestrichen worden, was einen meiner Brüder sehr aufgebracht hatte, allerdings meinte mein Vater (damals Mitglied des Bauausschusses, Dipl.-Ing.), dass der Beton nicht sehr gut war und sonst die Witterung ihm zu sehr zusetzen würde. Bei der Zumthor Kapelle in Wachendorf (Eifel) kann man innen auch die Verschalung erkennen, dort wurde ein Witterungsschutz durch Russ geschaffen:

Und mir fiel auf, wie doch Verknappung die Nachfrage anheizt. So voll war die Auferstehungskirche zu den besten Zeiten nicht gewesen.

Juli 2014:
Die GAG bewirbt die Kulturkirche u.a. mit diesen Worten:

"... seit der Wiedereröffnung im Oktober 2012 auch als kulturellen Treffpunkt mit abwechslungsreichen Veranstaltungen etabliert. Ein Treffpunkt, der mittlerweile über die Grenzen des Stadtteils hinaus Beachtung findet: Die Kulturkirche Buchforst – ein Leuchtturm mit Strahlkraft im Kulturquartier Buchforst."

Unter dem Link findet sich auch der Terminkalender: 

Ich gebe zu, dass ich nicht in der Ausstellung war. 

Aber es gibt einen Katalog zur Ausstellung für 8 €.

Ausstellungsdauer: 07.07. - 18.07.2014

Hier sieht man den Glockenstuhl.

... und so wird vor der Kulturkirche geworben

Und hier ist noch mehr sehen:

Und eine weitere Ankündigung. Übrigens findet der Gottesdienst, leider nicht wöchentlich, auch dort statt. Da kann man sich die Ausstellung auch ansehen.

Und wieder habe ich einen Hinweis auf eine Ausstellung gefunden, als ich durch das abendliche Buchforst schlenderte.

Marit Mertin und Ursula Radermacher haben abgelegte Kleidungsstücke und Geschichten in Buchforst gesammelt. Am 21.09. können Interessierte noch mitwirken (15:00 bis 18:00 Uhr). Die Vernissage findet am 26.09. ab 19:00 Uhr statt. Danach kann man sich das fertige Raumbild mit Kleidern und Texten bis zum 01.10. täglich von 17:00 bis 20:00 Uhr ansehen. Link:

Hier sind noch ein paar neue Bilder und das Programm.

Auch aktuell tut sich wieder etwas in der Kulturkirche/Auferstehungskirche in Köln-Buchforst.

Diese Hommage à Heinrich Böll kommt nicht von ungefähr, denn der Nobelpreisträger ist am 16.07.1985 gestorben. Ich nehme an, dass am 16. Juli die Kirche ziemlich voll sein wird, insbesondere da Elke Heidenreich liest.

Der Eid des Hippokrates

Geschichte ist schön und man kann daraus lernen, aber was vor über 2000 Jahren Gültigkeit hatte, muss man nicht heute eins zu eins übernehmen können. Es kommt zu einem Familientreffen und schon spricht mich irgendjemand auf den Eid des Hippokrates an; einer meiner Brüder pflegt, Eid des Hypochonders zu sagen. Ich habe den nicht geleistet! Nun ist es heraus.

Hippokrates von Kos formulierte mit seinem Eid vor ca. 2400 Jahren erstmals eine ärztliche Ethik. Aber diese muss weiterentwickelt werden. Diese Ethik muss anderen gesellschaftlichen Bedingungen angepasst werden. Andererseits stehen in diesem Eid Aussagen, die fortgeführt werden sollten. Da ist von der Schweigepflicht die Rede oder vom Gebot, dem Kranken nicht zu schaden.

So heißt es etwa: „Ich rufe ... alle Götter und Göttinnen als Zeugen an ...“ – was ist mit den Christen oder Muslimen unter uns? Rufen wir alle Götter und Göttinnen an?

Auch die Beschränkung des Unterrichts auf bestimmte Personen, wie z.B. „nach der ärztlichen Sitte vereidigten Schüler ..., sonst aber niemanden“, zeigt Ausschlusskriterien auf, die wahrscheinlich nicht zeitgemäß sind. Oder zumindest einer zeitgemäßen Definition bedürfen.

Weiter ist vom „Nutzen der Kranken“ und nicht „zum Schaden und in unrechter Weise“ die Rede – da steige ich wiederum voll drauf ein. Mir geht der Bauchladen der Leistungen, die für Geld angeboten und nicht von der gesetzlichen Krankenkasse übernommen werden (IGeL), auf den ethischen Nerv.

„Auch werde ich niemandem ein tödliches Gift geben, auch nicht, wenn ich darum gebeten werde“ – darunter fällt unter Umständen die Hilfe zur Selbsttötung. Hätte ich auch nichts dagegen, denn ich sehe in der Aufgabe des Arztes, Leiden zu linden, aber nicht das Leben zu beenden.

„... auch werde ich keiner Frau ein Abtreibungsmittel geben“ – ich arbeite in einem katholischen Krankenhaus, da ist das umgesetzt, wie aber ist das mit jemandem, der in einem städtischen Krankenhaus arbeitet? Und ist es, auf alle Ärzte angewendet, in unserer Gesellschaft erwünscht?

„Rein und fromm“ geht es weiter – der deutsche Turnerbund hat auch noch „frisch, fromm, fröhlich, frei“. Zeitgemäß? Also ich kann damit leben ...

Es folgt der Satz, dass man als Arzt nicht schneiden wird, denn die heutige Chirurgie oder operative Medizin gehörte damals nicht zur ärztlichen Tätigkeit. Gut, als Internist ist man geneigt, das gutzuheißen ... aber ich bleibe bei der Wahrheit, die moderne Medizin benötigt konservative und operative Medizin.

Es gibt noch weitere Aspekte, wie eine erste soziale Absicherung im Fall der Berufsunfähigkeit, aber das liest sich alles besser in dem Artikel von Wikipedia, aus dem ich auch teilweise den Eid zitiert habe:  

Wenn der Hinweis auf den Eid des Hippokrates geschichtlich gemeint ist, bin ich dabei, aber sonst bleiben wir bitte bei den Regelungen, die von den Ärztekammern bestimmt werden und mit der Approbation verpflichtend sind. Hier im Bezirk Nordrhein ist dies „Berufsordnung für die nordrheinischen Ärztinnen und Ärzte“ – Link: Das Gelöbnis kann hier eingesehen und auch angehört werden:

Ustekinumab at the ACR 2012 in Washington

I restrict this blogpost to Ustekinumab. Link for EULAR 2012: (Stelara) is a human monoclonal antibody against IL-12 and IL-23. Adverse events include an increased risk of infections (tuberculosis and others) and cancer.

A. Kavanaugh and colleagues presented: "Ustekinumab Improves Arthritis-Related and Skin-Related Quality of Life in Patients with Active Psoriatic Arthritis: Patient Reported Outcomes From Randomized and Double Blinded Phase III Psummit I Trial" (Abstract No. 569). Conclusion: "Ustekinumab improves general as well as arthritis and skin-related quality of life, and reduces the impact of disease on work productivity in patients with active PsA." There is not much on arthritis in this part of the study.

Ch. T. Ritchlin and colleagues presented: "Ustekinumab in Active Psoriatic Arthritis Including Patients Previously Treated with Anti-TNF Agents: Results of a Phase 3, Multicenter, Double-Blind, Placebo-Controlled Study" (Abstract No. 2557). The conclusion looked like this: "UST reduced signs & symptoms, improved physical fxn, enthesitis & improved plaque PsO. Safety profiles were similar between UST & PBO." - Welcome to twitter! (UST, PsO &b PBO) The presentation of results is very eloquent, whereas it is very laconic on the DAS28 response.

Another study (actually all are the same) by A. Kavanaugh and colleagues: " Ustekinumab in Patients with Active Psoriatic Arthritis: Results of the Phase 3, Multicenter, Double-Blind, Placebo-Controlled Psummit I Study" (Abstract No. 2562). Here we have DAS28-CRP responses: 34.5% for placebo, 65.9% for 45 mg, and 67.6% for 90 mg. Conclusion: "In pts with active PsA, UST significantly reduced the signs and symptoms of arthritis, improved physical function, enthesitis and dactylitis, and improved plaque psoriasis vs PBO-treated pts at wk24. Safety profiles were similar between UST-and PBO-treated pts."

And there has been the late breaking poster (Abstract No. L4): Continued Improvement of Signs and Symptoms in Patients with Active Psoriatic Arthritis: Week 52 Results of a Phase 3, Multicenter, Double-Blind,Placebo-Controlled Study." Here we have DAS28-CRP responses: none for placebo, as these patients changed to ustekinumab, 72,7% for 45 mg, and 74,6% for 90 mg. Conclusion has been much the same like above.

Do we have the solution of our problems in psoriatic arthritis? I fear we haven't, but we get a new option to treat at least some of our patients better than before.

Ruxolitinib at the ACR 2012 in Washington

Ruxolitinib is a JAK1/JAK2 inhibitor, which could be useful to treat rheumatoid arthritis. There has been a study being presented at the 2008 ACR meeting, here’s an article referring to this study. Nothing new at the EULAR 2012 meeting in Berlin. And ruxolitinib hasn't been a hot topic at the ACR 2012. But there has been a study mentioning the drug (Abstract No. 1807). Anna Yarilina and colleagues looked at: "Regulation of Inflammatory Responses in Tumor Necrosis Factor-Activated and Rheumatoid Arthritis Synovial Macrophages by Janus Kinase Inhibitors". Conclusion: "Taken together, our data demonstrate that JAK inhibitors suppress inflammatory functions of macrophages, in part by altering cell responses to the key pathogenic cytokine TNF. These findings suggest that suppression of macrophages and innate immunity may contribute to the therapeutic efficacy of JAK inhibitors in RA." There are differences between these two JAK inhibitors: tofacitinib "significantly decreased IL6 expression in RA synovial macrophages", both ruxolitinib and tofacitinib increased formation of osteoclast-like cells, but only tofacitinib "dramatically increased resorptive activity of these cells".

Strange that we havn't heard more about ruxolitinib, yet. Baricitinib seems to be doing much better. As the first study has been presented 2008 and nothing followed, it might mean that ruxolitinib has been abandoned because of mercantile rather than medical reasons. I'll stay on the look-out during 2013.

PRTX-100 (Staphylococcal Protein A)

E. Bernton et al. presented: "A Phase 1, Randomized, Double-Blind, Placebo-Controlled Multiple-Dose Study of Intravenous Staphylococcal Protein A in Patients with Active Rheumatoid Arthritis On Methotrexate: Safety, Pharmacokinetics and Efficacy" (Abstract No. 833). "Results of this pilot study support further clinical trials of PRTX-100 at doses of 1.5 _g/kg and higher." "The primary disease activity response endpoint was the number of patients with a DAS28-CRP _3.2 at Week 6" - and this endpoint was "met by 3/29 PRTX-100 and 0/8 placebo patients". "PRTX-100 elicited anti-drug antibodies (ADAs) in the majority of patients but the incidence or titer of ADAs was not dose-dependent."

As I had been part in testing immunoadsorption, I'm not too confident in PRTX-100. Anti-drug antibodies in the majority of patients and a small effect on 10% of the patients make it hard to believe that we'll see a working drug added to existing drugs. But maybe it's still too early for skepticism.

Pioglitazone at the ACR 2012 in Washington

Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, prescribed in diabetes usually, now has been tested in rheumatoid arthritis.

Michelle J. Ormseth and colleagues presented a study: "A Proof-of-Concept Randomized Controlled Trial" (Abstract No. 832). Conclusion by the authors: Pioglitazone "modestly reduces RA disease activity measured by DAS28 CRP and CRP levels". Results speak another language: no significant reduction in swollen or tender joint count, no significant change in ESR or DAS28 ESR, and a non-significant trend toward decreased patient reported disease activity. But lower extremity edema was more common in patients receiving pioglitazone (16%) than placebo (0%).

Wenpu Zhao and colleagues looked into effects of pioglitazone in lupus: "The Peroxisome-Proliferator Activated Receptor-Agonist Pioglitazone Modulates Aberrant T-Cell Responses in Systemic Lupus Erythematosus" (Abstract No. 2499). RNA from treated or untreated SLE patients and controls was extracted and processed on microarrays. In conclusion the authors interpreted their results as indication that peroxisome-proliferator activated receptor-agonist selectively modulate T cell function in SLE.

But in RA patients joints stay tender and swollen, effect is limited to CRP, a reasonable number of patients develops lower extremity edema. Though I can see a rational for testing pioglitazone, I see a possible use for this drug only in patients who suffer from rheumatoid arthritis and diabetes at the same time. Maybe scientific knowledge gains more by messenger RNA testing of T-cell responses than patients or clinicians gain directly. I'll keep it on my list for the next year, but there should be more than just a reduction of CRP.

Addendum 06.03.2013:
France had withdrawn the approval of pioglitazone because of the increased incidence of bladder cancer. Another problem is the increase of bone loss. This might reduce even more the handiness in treating patients who are already at a risk for bone loss.
I'll keep it on my list, though I think that Takeda is looking for a new playground for pioglitazone.

Tuesday, December 25, 2012

Carpe Diem Haiku Frost (shino)

Fog and frost
Up in the mountains
White on white

Out in the open
Frost biting the wanderer
Steps in snow

Out of a frosty sky
Sun ventures into a forest
Shadows and light 

Ozoralizumab (ATN-103) at the ACR 2012 in Washington

“Ozoralizumab (ATN-103), a novel TNF-alpha inhibitor, is a trivalent, bispecific NanobodyR that potently neutralises TNF and binds to human serum albumin to increase its in vivo half-life.”

R. M. Fleischmann and colleagues presented: "A Novel Individualized Treatment Approach in Open-Label Extension Study of Ozoralizumab (ATN-103) in Subjects with Rheumatoid Arthritis On a Background of Methotrexate" (No. 1311). The study is a extension of the study, I’ve written about a year ago:  Results: " ... EULAR good/moderate response rate was 97% ...". Conclusions: " ... This treatment approach could prove beneficial to patients and minimize treatment costs."

Interestingly the results had already been presented by Ablynx prior to the ACR 2012:  (“ABLYNX ANNOUNCES NEW COMPELLING RESULTS ON OZORALIZUMAB (ATN-103) IN RHEUMATOID ARTHRITIS.”). I think that’s premature. Please show some larger trials that have data on long term use and adverse events. And it is unclear, why this drug should be minimizing treatment costs. I’d call it wishful thinking at this stage of development. And I'd like to see more commitment by Ablynx - one study in 2011 and an extension of this study in 2012 isn't impressing.

Olokizumab at the ACR 2012 in Washington

Olokizumab targets interleukin-6 (IL-6). So it would be much like tocilizumab (Actemra). I hadn’t seen any study at the EULAR 2012 meeting in Berlin. But I have seen some results on olokizumab at the ACR 2012.

R. Fleischmann and colleagues presented: "A Pilot Study Investigating the Tolerability and Pharmacodynamic Effect of Single Intravenous / Subcutaneous Doses of Olokizumab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Rheumatoid Arthritis (Abstract No. 1339). They concluded: "These results provided the rationale for a further study to investigate the clinical efficacy of olokizumab in RA."

The study only looked at CRP levels and not at any change in DAS etc. CRP dropped rapidly and the suppression lasted in most dose groups; only the 0.1 mg/kg iv group showed some recovery after 28 days. Uwe Fuhr, one of the authors, of the University of Cologne (Köln, Germany) isn’t known to me (most rheumatologists in Germany know each other); so I looked him up, he is working the field of clinical pharmacology. Back to olokizumab. Too young, too fresh! Let’s wait for more results, and please let’s have some DAS28 and ACR responses. Until then we’ll keep olokizumab on the screen.

You'll find some more here:

Sunday, December 23, 2012

Carpe Diem Haiku Icicles (tsurara) 氷柱

Icicle, icicle
I want to ride my icicle
I want to my fly my kite

(sorry, I couldn’t help myself – I had to write it! )

Snow and rain
Thawing and frost again
Weeping icicles

Carved into icicles
Watching intimate wishes
To melt into oblivion

Ocaratuzumab at the ACR 2012 in Washington

Ocaratuzumab is a Fc- and Fab engineered anti-CD20 antibody.

Adrienne O'Reilly and colleagues presented a study (Abstract No. 835): "Low Doses of Ocaratuzumab, a Fc- and Fab-Engineered Anti-CD20 Antibody, Result in Rapid and Sustained Depletion of Circulating B-Cells in Rheumatoid Arthritis Patients". Conclusion: "Even when administered at doses that are less than 100 fold that of rituximab, ocaratuzumab demonstrates rapid and prolonged B-cell depletion in RA patients. ... Furthermore, ocaratuzumab can potentially be given at doses much smaller than that of the conventional antibodies, possibly permitting subcutaneous administration."

If ocaratuzumab comes as a subcutaneously administered B-cell depleting agent, then it could a great success. I know that my colleagues in private practice don't like the idea of infusing rituximab for long hours. And even clinics run short of capacity for infusion patients. But still a long way to go!

NNC0109-0012 at the ACR 2012 in Washington

Discussion of studies presented at the EULAR 2013 meeting in Madrid:

"NNC0109-0012 (anti-IL-20 mAb) is a novel human monoclonal IgG4 antibody which binds to and neutralizes the activity of IL-20."

L. SEnolt and colleagues presented: "Clinical Responses and Patient Reported Outcomes to NNC0109-0012 (anti-IL-20 mAb) in Rheumatoid Arthritis (RA) Patients Following 12-Weeks Dosing and 13 Weeks Follow up: Results From a Phase 2a Trial" (Abstract No. 836). Conclusion included: "The data from this trial support further clinical development of NNC0109-0012 (anti-IL-20 mAb) in RA." It seems that the effect is more pronounced for the sub-group of RF/anti-CCP-positive patients.
Amanda L. Blasius and colleagues presented a cell study of NNC0109-0012 (Abstract No. 1796): Anti-IL-20 Targets Local Tissue Inflammation As Opposed to Systemic Inflammation." Conclusion: "..., these data suggest that IL-20 is restricted to acting locally on inflamed synovium in patients with RA."
Christina Andersson and colleagues presented a study on mouse CIA (Abstract No. 2080): "IL-20 Is Not Involved in Mouse Collagen Induced Arthritis." Conclusion: " ..., our findings indicate that IL-20 does not play a pathogenic role in the mouse CIA arthritis model." That`s also very interesting, but doesn´t bring us closer to a new drug.

If there is a clear advantage for the sub-group of RF/anti-CCP-positive patients, then NNC0109-0012 might successful as a personalized drug. And Nordisk - how about naming the child? Would make discussions easier and show commitment.

Saturday, December 22, 2012

NNC0114-0005 at the ACR 2012 in Washington

NNC0114-0005 is a recombinant anti-IL-21 monoclonal antibody. IL-21 is produced by activated T-cells. The receptor is expressed on T-cells, B-cells, natural killer cells. An up regulation of IL-21 and the IL-21 receptor has been shown in patients with rheumatoid arthritis. If you look at the Wikipedia article on IL-21, you don’t find rheumatoid arthritis there:

St. Ignatenko and colleagues presented: "First in Human Study with Recombinant Anti-IL-21 Monoclonal Antibody in Healthy Subjects and Patients with Rheumatoid Arthritis" (Abstract No. 1279). Results showed: “In total, 55 AEs were reported in 31/64 (48%) subjects: 32 AEs in 16/32 HS on i.v. treatment; 16 AEs in 10/20 RA patients on i.v. treatment; and 7 AEs in 5/12 HS on s.c. treatment.” About 50% adverse events seems high to me! And: “The reduction in DAS28-CRP was numerically favorable (but not statistically significant) for patients with RA treated with 25 mg/kg NNC0114-0005 compared to placebo.” OK, it’s a phase 1 study; but it isn’t convincing. Conclusions included: "The improvements in DAS28-CRP for patients with RA at the highest dose level may suggest biologic and clinical activity of NNC0114-0005."

“May suggest” – OK I’ll be patient for the next two years!

NKG2A at the ACR 2012 in Washington

NKG2A / NNC141-0100 at the EULAR 2012 Link:  

But what is it all about? Wikipedia gives a hint: “The CD94/NKG2 complex, on the surface of natural killer cells interacts with Human Leukocyte Antigen (HLA)-E on target cells.” The principle is to block the NKG2A HLA-E interaction on peripheral NK cells. NNC141-0100 is an Anti-NKG2A MAB, which blocks natural killer cell activation. But natural killer cells haven’t been in the focus of treatment so far. If the drug does, what it is intended to do, it doesn’t mean that it treats rheumatoid arthritis.

J. Wahle and colleagues presented an in vitro study with the title "Effect of Anti-NKG2A Antibody Treatment On NK Cell Receptor Expression in Rheumatoid Arthritis Patients" (Abstract No. 1080). In results we find: “Finally the effect was specific to RA patients as similar changes were not seen in normal donors.”

I must admit that I don’t know enough of the weight of natural killer cells in contrast to other cells in the inflammation concert of rheumatoid arthritis. I won’t rule out that this principle might be effective, but allow me some scepticism until further results are presented.

GLPG0634 at the ACR 2012 in Washington

New data from the EULAR 29013 in Madrid:

GLPG0634 is selective inhibitor of Janus kinase 1 (JAK-1). If you look at the development of NSAIDs you see a similar phenomenon: non-selective NSAIDs that also block COX-1 have certain side effects, whereas COX-2 selective NSAIDs don’t have these side effects. With JAK-inhibitors it seems that JAK-2-driven side effects limit the use of non-selective JAK-inhibitors. GLPG0634 has a 30-fold selectivity for JAK-1 over JAK-2 in human whole blood.

F. Namour and colleagues presented: "Once Daily High Dose Regimens of GLPG0634 in Healthy Volunteers Are Safe and Provide Continuous Inhibition of JAK1 but Not JAK2." (Abstract No. 1331). Conclusion: “At high doses, exceeding those showing high level efficacy in a 4-week RA patient study, GLPG0634 was well tolerated and safe in healthy volunteers. No safety signals were found with GLPG0634; …”

F. Vanhoutte and colleagues presented: "Selective JAK1 Inhibition in the Treatment of Rheumatoid Arthritis: Proof of Concept with GLPG0634" (Abstract No. 2489). Results included: “GLPG0634 met the primary endpoint of significant improvement in ACR20 response rate.” Conclusions included: "These early clinical results are the first to demonstrate that selective inhibition of JAK1 is efficacious and safe for the treatment of RA. Consistent with the lack of inhibition of JAK2, no anemia was observed. ..."

Let´s see if this compound by Galapagos NC is going to make it. If it shows the same efficacy as tofacitinib and has less side effects because of JAK-1 selectivity, well then … but let’s not dream and wait for results of further studies. Of course, we wait eagerly! Good luck, Galapagos!

Friday, December 21, 2012

Carpe Diem Haiku Quilt (futon)

Shattered windows
Just at the quilt’s rim
A red nose

Broken shoji
The cockroaches come closer
To the futon

Grey fog
White landscape
Colours of the quilt

Fostamatinib at the ACR 2012 in Washington

New data from the EULAR 2013 at:

Concerning fostamatinib (a SYK inhibitor), how far have we come during the time since EULAR 2012? Any date for launching the drug? Look for details already presented at the EULAR 2012:

I was quite surprised seeing a rat CIA study on fostamatinib by Polly Pine et al. (Abstract No. 329): “The SYK Inhibitor, Fostamatinib, Administered Alone or in Combination with Methotrexate in Rat Collagen-Induced Arthritis, Reduces Bone Erosions, Biomarkers of Cartilage/Bone Destruction, and Synovial Osteoclastogenic Cytokines.” Conclusion: “Fostamatinib significantly reduced the severity of established rat CIA, had modest additional improvement [my italics] with co-administered MTX, and was superior to MTX alone. These results indicate that fostamatinib may have potential therapeutic benefits for both the inflammatory synovitis and bone erosions of CIA. Fostamatinib is currently in Phase III trials for RA.” This doesn’t sound convincing and if it isn’t convincing in rats, what about humans? I had already voiced my suspicions before, though there’s nothing wrong with this study, it doesn’t convince me of the drug.

And there has been nothing more at the ACR 2012 meeting! Perhaps asking for a date, when fostamatinib is to be launched, was a bit premature. I ask myself if there really is any drug in sight!

Dekavil at the ACR 2012 in Washington

Dekavil - fibronectin-A-chain connected to IL-10 or as it is said in the abstract below: “F8-IL10 is a fusion protein in which the cytokine is fused with the antibody F8 specific to the alternatively-spliced EDA domain of fibronectin, a marker of angiogenesis.” Link to my blog post on the drug at the EULAR 2012:  

The poster says it’s dekavil, but the name isn’t mentioned in the abstract! M. Galeazzi and colleagues presented: "A Phase Ib Clinical Trial with F8-IL10, an Anti-Inflammatory Immunocytokine for the Treatment of Rheumatoid Arthritis (RA), Used in Combination with Methotrexate (MTX)" (AbstractNo.1291). In this ongoing dose finding study, results are only clear for the low dosages (6 mg and 15 mg/kg body weight). On the poster achievements of ACR50 in 2 patients and ACR70 in 1 patient are shown. Maybe the drug is ao powerful, but maybe it’s simply an effect due to an unblinded study design. Conclusion: “These results also warrant future developments of the product in randomized clinical trials, which are currently in planning.”

Maybe we have to wait for a couple of years to evaluate dekavil. If the results are as good as shown in the abstract, then it could develop into a block buster. Philogen S.p.A. hasn’t rushed yet to large scale international multicenter studies and I interpret this as a hint, that the potential of this drug isn’t as high as the study of M. Galeazzi wants us to believe.

Cetrorelix at the ACR 2012 in Washington

Cetrorelix is a gonadotropin-releasing hormone antagonist (GnRH antagonist). I expected some new results. Older results here:

And there are new results! A. Kass and colleagues looked at cetrorelix in a proof-of concept study and it demonstrates efficacy in patients with active rheumatoid arthritis (Abstract No. 834). Their results showed that “more patients on cetrorelix achieved ACR20 responses (40% vs 18%; p_0.015)”. Nothing that makes drop off your chair, but at least a result to work on. Conclusions included: “Larger, long-term studies on the efficacy and safety of GnRH antagonists in RA patients are warranted.”

No other abstract on cetrorelix! It doesn’t sound like a success story, but it’s interesting enough to be followed. We’ll just have to wait for further results.
Nothing at the EULAR 2013 Meeting in Madrid.

Brodalumab at the ACR 2012 in Washington

More on brodalumab and the EULAR 2013 at:

Brodalumab targets interleukin-17 (IL-17) and is therefore much like ixekizumab, which hasn’t been presented at the 2012 ACR meeting. Ixekizumab is studied in chronic plaque psoriasis as shown in this article of the New England Journal of Medicine: Back to brodalumab.

Karel Pavelka and collaegues looked at safety, tolerability, and efficacy of brodalumab (AMG 827) in rheumatoid arthritis and an inadequate response to Methotrexate (Abstract No. 831), but the preliminary results do not support further evaluation of brodalumab as a treatment for RA.

M.A. Curchill and collaegues presented "A Phase Ib Multiple Ascending Dose Study Evaluating Safety, Pharmacokinetics, and Early Clinical Response of Brodalumab (AMG 827), a Human Anti-Interleukin 17 Receptor (IL-17R) Antibody, in Rheumatoid Arthritis" (Abstract No. 1294). “Conclusions about efficacy cannot be reached given the study design.”

I think brodalumab is a dead end for rheumatoid arthritis though it might be useful in other diseases.

ASP015K at the ACR 2012 in Washington

I've just written a blogpost concerning the data from EULAR 2013, which isn't as positive as the one below:

"ASP015K is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3 in development for treatment of rheumatoid arthritis (RA) and other autoimmune diseases."

T. Zhu et al. presented: "Coadministration of ASP015K, a Novel Janus Kinase Inhibitor with Methotrexate Demonstrates Tolerability and Lack of Pharmacokinetic Interactions in Patients with Rheumatoid Arthritis" (Abstract No. 1322). The study had two parts: 1. In vitro experiments on the “inhibitory potency of ASP015K on human multidrug resistance-associated protein 2/4 (MRP2/4) and organic anion transporter 1/3 (OAT1/3).” And a phase 1 study, which was open-labeled and single-sequenced, “to confirm the in vivo effect of ASP015K on the PK of MTX, a substrate of MRP2/4 and OAT1/3.” Conclusions: " Coadministration of ASP015K and MTX was well tolerated in this short-term study exhibiting no clinically significant effect on the PK profile of either drug. Efficacy and safety of ASP015K/MTX combination therapy is being assessed in ongoing phase 2 trials in RA patients."
According to the design of the study there wasn’t more to be expected.

Shunji Yamazaki and colleagues presented a seond study (Abstract No. 2084): “ASP015K: A Novel JAK Inhibitor Demonstrated Potent Efficacy in Adjuvant-Induced Arthritis Model in Rats.” They could show in this rat model, that ASP015K “potently inhibits human JAK enzymes with moderate selectivity against JAK1/3 over JAK2/2, which may translate to less hematological side effects observed in the clinic such as anemia.” Further conclusions: “The data suggests that ASP015K has the potential to reduce clinical signs and symptoms as well as prevent disease progression in RA patients warranting further clinical investigation.”

ASP015K is an interesting small molecule as it may be efficacious against rheumatoid arthritis with less adverse events when compared to other small molecules. The data is preliminary and there’s still a long way to go. It would be nice, if Astellas Pharma could give the compound a name. Good luck from my side!