Mavrilimumab at the EULAR 2012

New data from the EULAR 2014 Meeting in Paris:

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

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