Wednesday, July 18, 2012

Mavrilimumab at the EULAR 2012


New data from the EULAR 2014 Meeting in Paris:




New blogpost with data from ACR 2013:

http://rheumatologe.blogspot.de/2013/11/mavrilimumab-at-acr-2013-meeting-in-san.html


Blogpost with data from EULAR 2013:

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



Mavrilimumab is a human MAB for the treatment of rheumatoid arthritis. It targets the GMCSF receptor and alpha-chain. More at: http://en.wikipedia.org/wiki/Mavrilimumab  

There have been three studies at the EULAR 2012 in Berlin.

C.-Y. Wu and colleagues looked at pharmacokinetics and immunogenicity of mavrilimumab. The average half-life was approximately 13 days for the 100 mg dose of mavrilimumab. They found anti-drug antibodies in 13% of mavrilimumab-treated subjects but only 3.8% in the placebo group. The authors concluded that the study supports “further clinical development of mavrilimumab for the treatment of RA.” I'd like to point out the high number of patients developing anti-drug antibodies. But maybe this will be irrelevant if patients need to be treated with methotrexate at the same time.

[FRI0182] PHARMACOKINETICS AND IMMUNOGENICITY OF MAVRILIMUMAB ADMINISTERED SUBCUTANEOUSLY IN SUBJECTS WITH RHEUMATOID ARTHRITIS
C.-Y. Wu1, X. Chen1, H. Lu1, E. Esfandiari2, F. Magrini2, A. Godwood3, P. Ryan4, C. Kane5, L. Roskos1, B. Wang1. 1Clinical Pharmacology & D M P K, Medimmune, Hayward, United States; 2Clinical; 3Clinical/Biostatistics, Medimmune, Cambridge, United Kingdom; 4Research - Cell Biology; 5Toxicology, Medimmune, Gaithersburg, United States
Conclusions: The observed mavrilimumab PK profiles in this Phase 2a study were consistent with prior projections from a mechanistic population model1. The PK parameters of mavrilimumab following SC dosing are typical of a monoclonal antibody with target-mediated disposition. The PK and immunogenicity properties of mavrilimumab, and the direct exposure-response relationship support further clinical development of mavrilimumab for the treatment of RA.

The next study is a double-blind, placebo controlled phase 2 study. G. Burmester and colleagues presented a study on “efficacy and safety of 3-month treatment with ascending doses (10–100 mg q2w) of mavrilimumab in adult subjects with RA in combination with methotrexate.” There is the need of methotrexate! Onset of response has been two weeks after the first dose. Primary endpoint has been a DAS28-CRP decrease ≥1.2 from baseline. Mavrilimumab did better than placebo, but the effect didn't last as long as the follow-up period after stopping the drug. The most common adverse events has been a decrease in CO diffusing capacity. Did any reader, who worked on studies, ever have to monitor CO diffusing capacity? As I haven't, this point leaves me a little bit uneasy.

[THU0096] MAVRILIMUMAB IN RHEUMATOID ARTHRITIS: RESULTS OF A PHASE 2 DOUBLE-BLIND, PLACEBO CONTROLLED STUDY
G. Burmester1, M. Weinblatt2, I. McInnes3, O. Barbarash4, E. Esfandieri5, M. Sleeman5, A. Godwood5, F. Magrini5, and EARTH Study Group. 1Charité - University Medicine, Berlin, Germany; 2Brigham and Women's Hospital, Boston, United States; 3University of Glasgow, Glasgow, United Kingdom; 4SIH Kemerovo Regional Clinical Hospital, Kemerovo, Russian Federation; 5Medimmune, Ltd, Cambridge, United Kingdom
Conclusions: Mavrilimumab showed a rapid (within 2 wks) and significant clinical effect vs PBO, especially in the higher (100 mg) dose cohort. DAS28 response and ACR20 was maintained for 12 wks after cessation of mavrilimumab 100 mg. The sustained clinical activity along with an acceptable safety profile supports further clinical development of this new anti-GM-CSFRα mAb.

The next study makes my feelings even worse. S. Spitz and colleagues evaluated surfactant proteins as potential pumonary safety markers. KL-6, that is „Krebs von den Lungen“, which means cancer from the lungs. “No clinical significant lung problem was detected for DLCO deterioration cases assessed by the pulmonologists.” But as the saying goes: no smoke without a fire.

[AB0576] EVALUATION OF SURFACTANT PROTEIN-D AND KL-6 AS POTENTIAL PULMONARY SAFETY BIOMARKERS DURING MAVRILIMUMAB TREATMENT
S. Spitz1, D. Wilkins1, E. Esfandiari2, A. Godwood2, L. Roskos1, P. Ryan1, F. Magrini2. 1Translational Sciences, MedImmune, LLC, Gaithersburg, United States; 2Clinical Development, MedImmune, LLC, Cambridge, United Kingdom
Conclusions: These findings indicate that no changes in serum levels of two potential pulmonary safety biomarkers, SP-D and KL-6, that have been reported to be associated with pulmonary diseases, could be detected over the 12 week treatment period with mavrilimumab in the Phase 2 clinical study EARTH.
EARTH = rhEumatoid ARTHritis

My opinion: this doesn't seem to be the start of a success story. But still, as we need new drugs: All the best, Mavrilimumab!

A quick an dirty translation of the commentaries below:
1. What do you say to the findings of scientists, that GM-CSF plays a key role in the development of autoimmune diseases? http://www.mediadesk.Uzh.ch/articles/2011/GM-CSF.html  

2. Why do you see a problem with KL-6? The abstract explicitly says that no increased values have been found. Being cancerogenes is a problem with all drugs that intervene in the immune system, even the blockbusters like the anti-TNF alphas or the anti-ILx but for.
3. How appreciate a reduced CO diffusing capacity? Is it medically handable?
4. Do you see the program of MorphoSys MOR103, which as a target also GM-CSF, however has the ligand, not the receptor, also as critical?

To 1. It is the communication of the University on their research and of a researcher on his special subject. Research requires funds, the importance of the topic is pointed out (examples from the text). In addition, GM-CSF is covered here on multiple sclerosis, rheumatoid arthritis is mentioned only in one sentence. It is quite possible that GM-CSF plays a key role, but then this may be source for a wide range of adverse effects. (http://www.mediadesk.uzh.ch/articles/2011/gm-csf.html)
To. 2. It isn’t cancer but the surfactant. http://de.wikipedia.org/wiki/Surfactant I don’t know any biologic, where this has been discussed.
To 3. That will have to be shown. It involves monitoring. I cannot measure CO diffusion capacity in my clinic; I would have to send patients to the pulmonologist.
To 4. Probably yes, but MorphoSys hasn’t published anything on MOR103 at the EULAR 2012 in Berlin, most probably the company will publish data at the ACR 2012 meeting in Washington.

29.08.2012



Ville731. August 2012 13: 15
Hello Rheumatologe,
I would want to check off the results of the research group not just as in this way ("you need results to get research money"), not only the Becher and the Suter group of the University of Zurich, which have among other things also very interesting mouse studies, but other universities such as the University of Melbourne (Prof. Hamilton) also have identified GM-CSF as one of the key cytkins in autoimmune diseases.
GM-CSF could be a future important target was detected just over years not a cytokine and has regarded rather as a growth factor. Meanwhile the understanding has changed slightly.
http://www.amsel.de/multiple-sklerose-news/medizin/index.php?w3pid=news&kategorie=medizin&anr=3620  http://www.ncbi.NLM.NIH.gov/PubMed/12133803
Kalo BIOS has a nice list of literature to this target: http://kalobios.com/product-pipeline/kb002003/references/
You may be curious to see what will bear this target and whether it really will be so problematic in the side effects (cancer auslösend). It was thought that Blockbuster-anti-TNF alpha in the 1990s by the now also.
04.10.2012


OK. What's new after the 2012 ACR Meeting in Washington? Nothing. No abstract or poster appeared on mavrilimumab. It doesn't surprise me and I still think that mavrilimumab isn't a success story.
23.11.2012

Just now I received an email "Dr. Kirsch . 2 things you need to know" - one is a study on mavrilimumab. Here's the link: http://www.ncbi.nlm.nih.gov/pubmed/23234647. That isn't much more than the results published at the EULAR 2012. I'm getting concerned about the missing progress in proving the drug's capabilities.
14.01.2013

10 comments:

  1. Hallo Herr Dr. Hirsch

    Danke für ihre Meinung bzgl. mavrilimumab.

    Ein paar Fragen:

    1. Was sagen Sie zu den Erkenntnissen der Wissenschaftler, dass GM-CSF eine Schlüsselrolle bei der Entwicklung von Autoimmunerkrankungen spielt?

    http://www.mediadesk.uzh.ch/articles/2011/gm-csf.html

    2. Wieso sehen sie ein Problem mit KL-6? Der abstract sagt doch explizit aus, dass keine erhöhten Werte gefunden wurden. Ein cancerogenes Problem besteht doch bei allen Medikamenten, die in das Immunsystem eingreifen, selbst den Blockbustern der anti-TNF-alphas oder den anti-ILx.

    3. Wie schätzen Sie die verminderte CO diffusing capacity ein? Ist das medizinisch handlebar?

    4. Sehen Sie das Programm von Morphosys MOR103, welches als Target ebenfalls GM-CSF, allerdings den Ligand, nicht den Rezeptor hat, ebenso kritisch an?

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  2. Kirsch natürlich, nicht Hirsch..

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  3. Zu 1. Es handelt sich um die Mitteilung der Universität zu Ihrer Forschung und eines Forschers zu seinem Spezialthema. Da Forschung Gelder benötigt, muss die Wichtigkeit hervorgehoben werden („wurden sie endlich fündig“, «GM-CSF ist demnach das erste T-Zell-Zytokin, das für die Entzündungsentstehung von absoluter Notwendigkeit ist», sagt Becher.). Außerdem wird hier GM-CSF in Bezug auf die Multiple Sklerose behandelt, die rheumatoide Arthritis wird nur in einem Satz erwähnt. Es ist durchaus möglich, dass GM-CSF eine Schlüsselrolle spielt, aber dann kann dies auch die Quelle für eine Vielzahl von unerwünschten Arzneimittelwirkungen sein. (http://www.mediadesk.uzh.ch/articles/2011/gm-csf.html)
    Zu. 2. Es geht dabei nicht um Krebs sondern um den Surfactant http://de.wikipedia.org/wiki/Surfactant. Mir ist kein Biologikum bekannt, bei dem dies thematisiert wurde.
    Zu 3. Das wird sich zeigen. Es geht um Monitoring. CO Diffusionskapaziät kann ich in hier nicht messen; ich müsste Patienten extra zum Pulmonologen schicken.
    Zu 4. Wahrscheinlich ja, aber Morphosys hat zu MOR103 auf dem EULAR 2012 in Berlin nichts veröffentlicht, wahrscheinlich wird die Firma Daten beim ACR 2012 in Washington veröffentlichen.

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  4. Hallo Rheumatologe,

    ich würde die Ergebnisse der Forschergruppe nicht einfach so auf diese Art ("die brauchen Ergebnisse um Forschungsgelder zu bekommen") abhaken wollen, denn nicht nur die Becher- und die Suter-Gruppe der Universität Zürich, die u.a. auch sehr interessante Mausstudien vorweisen können, sondern auch andere Universitäten wie die Universität Melbourne (Prof. Hamilton) haben GM-CSF als eines der Schlüsselzytokine bei Autoimmunerkrankungen ausgemacht.

    GM-CSF könnte ein künftig wichtiges Target sein, das man eben über Jahre hinweg nicht als Zytokin erkannt wurde und eher als growth factor angesehen hat. Inzwischen hat sich das Verständnis etwas verändert.

    http://www.amsel.de/multiple-sklerose-news/medizin/index.php?w3pid=news&kategorie=medizin&anr=3620

    http://www.ncbi.nlm.nih.gov/pubmed/12133803

    Kalobios hat eine nette Literaturliste zu diesem Target: http://kalobios.com/product-pipeline/kb002003/references/

    Man darf gespannt sein, was dieses Target hergibt und ob es wirklich in den Nebenwirkungen so problematisch sein wird (krebsauslösend). Das dachte man in den 90er Jahren von den inzwischen Blockbuster-anti-TNF-alphas auch.

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  5. Concerning http://www.amsel.de/multiple-sklerose-news/medizin/index.php?w3pid=news&kategorie=medizin&anr=3620 - This article is on multiple sclerosis and the article bears a question mark in the title. (“Botenstoff GM-CSF: Doppelrolle bei Multipler Sklerose?“)
    Concerning http://www.ncbi.NLM.NIH.gov/PubMed/12133803 - The first sentence of the abstract is: “Granulocyte macrophage-colony stimulating factor (GM-CSF) is now best viewed as a major regulator governing the functions of granulocyte and macrophage lineage populations at all stages of maturation.” The article discusses animal models.
    Concerning http://kalobios.com/product-pipeline/kb002003/references/ - this list mostly shows old articles, 25 years is a long time in medicine. So my enthusiasm towards mavrilimumab still is very fragile.

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  6. I'll change this blogpost soon, adding news from the EULAR 2013 - if there is anything as I haven't seen anything new so far, but we've still got two days.

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    1. Sorry, I just found out, that there were three spam posts. I've deleted these posts.

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