Strontium ranelate in Knee Osteoarthritis at the EULAR 2012

Strontium ranelate in knee osteoarthritis has also been advocated at the EULAR 2012 in Berlin. It has been the Cooper/ Reginster study that had been discussed at the IOF-ECCEO12 Congress at Bordeaux earlier this year (http://www.ncbi.nlm.nih.gov/pubmed/22148897). In April this year I've received a Red Hand Letter concerning strontium ranelate (Link to the German text: http://www.bfarm.de/DE/Pharmakovigilanz/risikoinfo/2012/rhb-protelos.html). EMEA and the German Bundesinstitut für Arzneimittel und Medizinprodukte had Servier to inform all physicians in Germany about new risks concerning strontium ranelate. There is a contraindication for patients with acute venous thrombembolism, phlebothrombosis, or pulmonary embolism. Also immobilized patients aren't allowed to take strontium ranelate. Reason for this information is a study that has been published in France. More about risks at: http://www.netdoctor.co.uk/seniors-health/medicines/protelos.html.

C. Cooper and colleagues looked at efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis. The text on “objectives” doesn’t give a clue to an endpoint of the study. In “results” we are given characteristics in mean values of the patients that were assigned to the study in 113 centres. No result whatsoever! In “conclusions” we are given wishful thinking instead of conclusions drawn from results.

[AB0962] EFFICACY AND SAFETY OF STRONTIUM RANELATE IN THE TREATMENT OF KNEE OSTEOARTHRITIS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED INTERNATIONAL TRIAL
C. Cooper1, R. Chapurlat2, C. Christiansen3, H. Genant4, N. Bellamy5, W. Bensen6, F. Navarro7, J. Badurski8, E. Nasonov9, X. Chevalier10, P. Sambrook11, T. Spector12, J.-Y. Reginster13. 1MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, United Kingdom; 2INSERM UMR 1033 and Université de Lyon, Hôpital Edouard Herriot, Lyon, France; 3CCBR Ballerup, Ballerup, Denmark; 4Radiology, Medicine and Orthopaedic Surgery University of California San Francisco, and Synarc, San Francisco, United States; 5University of Queensland, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; 6McMaster University Hamilton, Ontario, Canada; 7H. Clinico Virgen de la Macarena Servicio de Reumatologia, Sevilla, Spain; 8Centre of Osteoporosis and Osteo– articular Diseases, Bialystock, Poland; 9State Institute of Rheumatology, the Russian Academy of Medical Sciences, Moscow, Russian Federation; 10Hôpital Henri Mondor, Créteil, France; 11Royal North Shore Hospital, St. Leonards NSW, Australia; 12Kings College London, St Thomas' Campus, London, United Kingdom; 13University of Liège, Liège, Belgium
Conclusions: This large randomised placebo-controlled study will establish the long-term efficacyof SrRan on structure and symptoms in patients with knee osteoarthritis.


Strontium ranelate isn’t a goal getter in osteoporosis therapy. It has a very low persistence in patients, link: http://www.ncbi.nlm.nih.gov/pubmed/22541835. I don’t think that strontium ranelate will be a goal getter as a drug against knee osteoarthritis. I think Servier is desperately seeking a new indication to sell strontium ranelate.

Addition at 20. February 2013:
There's an editorial in this month's isssue of the Annals of the Rheumatic Diseases (Ann Rheum Dis 2013;72:157-161 doi:10.1136/annrheumdis-2012-202453) by  Floris PJG Lafeber and Jacob M va Laar: "Strontium ranelate: ready for clinical use as a disease-modifying osteoarthritis drug?" In this editorial they also discussed cindunistat and statins, but had to conclude: "Clearly, none of the three drugs presented is ready for use as a DMOAD [Disease Modyfying Osteoarthritis Drug] in clinical practice." 

Another addendum 10.05.2013:
Strontium ranelate (Protelos®; Osseor®) ist in the discussion at the EMA. 2011 a French study showed 199 severe adverse events, 52% cardiovascular events [4.Jonville-Bera AP, et al: Presse Med. 2011: 40(10): e453-e462. http://dx.doi.org/10.1016/j.lpm.2011.07.010 as cited by Medscape Germany]. 2012 the Committee for Medicinal Products for Human Use (CHMP) added deep vein thrombosis and pulmonary embolism as contraindications. As there are more safety issues, EMA might further restrict the use of strontium ranelate.
Considering this, one would be well advised not to use strontium ranelate off-label, which would be prescribing the drug in osteoarthritis patients.

Safety of different small molecules / protein kinase inhibitors

Salgado and colleagues looked at the safety profiles of 18 protein kinase inhibitors (AMG-548, ARRY-371797, BMS-582949, dilmapimod, doramapimod, pamapimod, PH-797804, SCIO-323, talmapimod, VX-702, VX-745, LY3009104, tofacitinib, ruxolitinib, fostamatinib disodium, imatinib mesylate, masitinib and ARRY-438162) in clinical trials in rheumatoid arthritis. Most interesting for the being are tofacitinib and fostamatinib, of course. Tofacitinib is closer to being launched than fostamatinib. Tofacitinib shows higher rates of adverse events concerning cholesterol, headaches, and renal impairment. LY3009104, another Jak inhibitor also has higher rates of adverse events for cholesterol and headaches. Fostmatinib showed higher rates af adverse events for mild increase of transaminases, hypertension, and diarrhea. I’ll come back to this excellent review, when other small molecules mentioned here surface with relevant studies in rheumatoid arthritis.

[THU0097] SYSTEMATIC REVIEW OF THE SAFETY OF PROTEIN KINASE INHIBITORS IN CLINICAL TRIALS IN RHEUMATOID ARTHRITIS - POSTER TOURS
E. Salgado1, J.R. Maneiro1, L. Carmona1,2, J.J. Gomez-Reino1,3. 1Hospital Clinico Universitario De Santiago, Santiago de Compostela; 2Universidad Camilo José Cela, Madrid; 3Universidad de Santiago de Compostela, Santiago de Compostela, Spain
Conclusions: In RA, a unique safety profile seems related to the different PK inhibitors. Dizziness, rash and neutrophilia are related with p38 inhibition; cholesterol increase with JAK inhibition; mild transaminases increase, hypertension and diarrhea with Syk inhibition; and headache, rash, peripheral edema, nausea, vomiting and diarrhea with cKit inhibition.

Back from EULAR 2012 in Berlin – refocussing

I’m back from the 2012 EULAR Meeting in Berlin. Here is some information on the topics I had been looking for:


1. Biosimilars
How far have we come? What will be on the market as alternative to existing products?
Celltrion will most probably launch an infliximab biosimilar in 2013.

http://rheumatologe.blogspot.de/2012/06/biosimilars.html

2. Anti-CD-20 Monoclonal Antibody (like Rituximab)
Is ofatumumab still in the race? Unclear, I’ve seen no poster.

How about ocrelizumab? Unclear, I’ve seen no poster.

Both have been analyzed in:
[AB0572] META-ANALYSIS OF THE KEY RHEUMATOID ARTHRITIS (RA) DISEASE ACTIVITY ENDPOINTS IN PATIENTS TREATED WITH B-CELL DEPLETING THERAPIES
S. Menon, K. Barker, E. Peeva, I. Gourley, A. Heatherington. Research and Development, Pfizer Inc, Cambridge, United States

And veltuzumab? Unclear, I’ve seen no poster.

http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html 

3. Co-Stimulation-Inhibition
Subcutaneous abatacept, when will it be available?
I have an idea about this.


4. Anti-Interleukin-6 Monoclonal Antibody (like Tocilizumab)
How far has BMS-945429 (ALD518), an anti-IL-6 monoclonal antibody, come? An alternative to tocilizumab? Can’t find an abstract!


And CDP6038, another anti-IL-6 monoclonal antibody? Can’t find an abstract!


Sarilumab, another anti-IL-6 monoclonal antibody, has already been in a phase 2 study last year, what’s new?
There are two studies:
[OP0023] SARILUMAB FOR THE TREATMENT OF MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS: RESULTS OF A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, INTERNATIONAL STUDY
[OP0169] SARILUMAB FOR THE TREATMENT OF ANKYLOSING SPONDYLITIS: RESULTS OF A PHASE 2, RANDOMIZED. DOUBLE-BLIND, PLACEBO-CONTROLLED, INTERNATIONAL STUDY (ALIGN)
http://rheumatologe.blogspot.de/2012/06/sarilumab-news-from-eular-2012.html



Will still take a while. Here’s one of the studies:
[FRI0180] THE MUSASHI STUDY: COMPARISON OF SUBCUTANEOUS TOCILIZUMAB MONOTHERAPY VERSUS INTRAVENOUS TOCILIZUMAB MONOTHERAPY: RESULTS FROM A DOUBLE-BLIND, PARALLEL-GROUP, COMPARATIVE PHASE III NON-INFERIORITY STUDY IN JAPANESE PATIENTS WITH RHEUMATOID ARTHRITIS
http://rheumatologe.blogspot.de/2012/06/tocilizumab-at-eular-2012.html



Has LY2127399 (an anti-BAFF monoclonal antibody) been studied further? Didn’t find an abstract.
I did so later:

Has atacicept [works on BLys(B-lymphocyte stimulator) and APRIL (A PRoliferation Inducing Ligand)] shown new efficacy? There is a study on atacicept:
[THU0090] SAFETY AND EFFICACY OF ATACICEPT IN COMBINATION WITH RITUXIMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS FROM THE ATACICEPT FOR REDUCTION OF SIGNS AND SYMPTOMS IN RHEUMATOID ARTHRITIS TRIAL (III)

http://rheumatologe.blogspot.de/2012/06/atacicept.html

6. Anti-Lymphotoxin-alpha Monoclonal Antibody
Is MLTA3698A, an anti-lymphotoxin-alpha monoclonal antibody, still studied? Didn’t find an abstract.
I did so later.


7. Secukinumab (an Anti-Il17a Monoclonal Antibody)
Is secukinumab (AIN457), an anti-IL17A monoclonal antibody, still under study? There are 8 abstracts, here is one:
[THU0111] SECUKINUMAB TREATMENT IMPROVES ACR50, HAQ-DI AND EULAR REMISSION RATES IN PATIENTS WITH RHEUMATOID ARTHRITIS

http://rheumatologe.blogspot.de/2012/06/secukinumab-anti-il17a-monoclonal.html

8. Oral JAK-Inhibitor, “small molecules”, SYK-Inhibitor and others
The oral jak inhibitor tofacitinib (CP-690,550) will most probably attract most attention. When will the drug be available? There are 16 studies like:
[THU0152] HOW SHOULD THE PRIMARY ENDPOINT BE ANALYSED IN RHEUMATOID ARTHRITIS TRIALS WHICH MANDATE RESCUE PRIOR TO THE CLINICAL ENDPOINT? ANALYSIS OF THREE PHASE 3 TRIALS OF TOFACITINIB


GLPG0259, a MAPKAPK5 inhibitor, should be abandoned. Didn’t find an abstract.
Has AMAP102, an orally available 5-HT2 receptor antagonist been studied further in a phase 2 study as planned? Didn’t find an abstract.




Concerning fostamatinib (a SYK inhibitor), how far have we come during the past year?, pain, fatigue, and overall physical health status. There are three abstracts:
[THU0139] PHARMACOKINETICS OF FOSTAMATINIB IN PATIENTS WITH IMPAIRED HEPATIC FUNCTION: A PHASE I STUDY


Do we have new data on the oral S1P lyase inhibitor LX3305 (LX2931)? Didn’t find an abstract.

A study small molecules / protein kinase inhibitors (PKI)

http://rheumatologe.blogspot.de/2012/06/safety-of-different-small-molecules.html

9. IL-1Ra-Receptor antagonist
New developments concerning anakinra?
There are 40 abstracts – I haven’t read one, yet!


10. Some further ideas after today's preliminary session (06.06.2012)
* SBI-087 is a SMIP (= small molecule immune pharmaceutical) binding to CD-20 – here is one study
[OP0024] SAFETY AND EFFICACY OF SBI-087 IN SUBJECTS WITH ACTIVE RHEUMATOID ARTHRITIS IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY

* Sirukumab MAB against IL-6 – has 4 abstracts:
[FRI0181] SIRUKUMAB, A HUMAN ANTI-IL-6 MONOCLONAL ANTIBODY, IMPROVES PHYSICAL FUNCTION IN PATIENTS WITH ACTIVE RA DESPITE METHOTREXATE THERAPY: RESULTS FROM A 2-PART, PROOF-OF-CONCEPT, DOSE-RANGING, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 2 STUDY


* Mavrilimumab MAB against GM-CSF has four abstracts:
[FRI0182] PHARMACOKINETICS AND IMMUNOGENICITY OF MAVRILIMUMAB
ADMINISTERED SUBCUTANEOUSLY IN SUBJECTS WITH RHEUMATOID ARTHRITIS


* NKG2a - negative regulator of cell activation has seven abstracts:
[AB0071] CHARACTERIZATION OF NNC141-0100, A THERAPEUTIC ANTIBODY TARGETING INHIBITORY CD94/NKG2A RECEPTORS EXPRESSED IN INFLAMED JOINTS OF RHEUMATOID ARTHRITIS PATIENTS


* Cetrorelix - GnRH-antagonist one abstract:
[OP0202] CETRORELIX, A GONADOTROPIN-RELEASING HORMONE ANTAGONIST, SIGNIFICANTLY REDUCES TNF-ALPHA AND DEMONSTRATES EFFICACY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: A PROOF-OF-CONCEPT, DOUBLE-BLIND RANDOMISED TRIAL


* CCX354-C and CCX168, which are chemokin-inhibitors. CCX354-C better than expected, one abstract:
[OP0203] ORALLY-ADMINISTERED CCR1 ANTAGONIST CCX354-C IN A PHASE 2 RHEUMATOID ARTHRITIS STUDY
Also something on CCX168, one abstract:
[OP0204] CHARACTERIZATION OF THE NOVEL C5AR ANTAGONIST CCX168, A POTENTIAL THERAPEUTIC FOR ANCA-VASCULITIS, RHEUMATOID ARTHRITIS, AND OTHER AUTOIMMUNE DISORDERS


* Dekavil - fibronectin-A-chain connected to IL-10
One abstract:
[FRI0194] A PHASE IB CLINICAL TRIAL WITH DEKAVIL (F8-IL10), AN ANTI-INFLAMMATORY IMMUNOCYTOKINE FOR THE TREATMENT OF RHEUMATOID ARTHRITIS, USED IN COMBINATION WITH METHOTREXATE


* GLPG0634 - JAK1 inhibitor also one study:
[OP0263] EFFICACY AND SAFETY OF GLPG0634, A SELECTIVE JAK1 INHIBITOR, AFTER SHORT-TERM TREATMENT OF RHEUMATOID ARTHRITIS; RESULTS OF A PHASE IIA TRIAL


* A new DMARD is under way from Japan:

http://rheumatologe.blogspot.de/2012/06/iguratimod-at-eular-2012.html

* On modified release prednisolone:

http://rheumatologe.blogspot.de/2012/06/modified-release-prednisone.html  

* Acronyms of studies in rheumatology:
http://rheumatologe.blogspot.de/2012/06/acronyms-of-studies-in-rheumatoid.html



I hope you liked this teaser – it will take a couple of weeks to work through this.

http://rheumatologe.blogspot.de/2012/06/pateclizumab-anti-lymphotoxin-alpha.html

http://rheumatologe.blogspot.de/2012/06/tabalumab-ly2127399-anti-baff.html

5. Anti-BAFF Monoclonal AntibodyHow about subcutaneous tocilizumab?

Tweetup EULAR 2012 - social event

Our social event has been a great success. People didn't have problems showing up in a restaurant in one of Berlin's nice quarters. Nice restaurant, nice atmosphere, great talks. Needs to be repeated at the next meeetings. Somehow I wonder, how Ronan guessed the right number of participants.
Here's the link to the picture Ronan just has put on Twitpic:
https://twitter.com/RonanTKavanagh/status/210661744723509248/photo/1 
He removed the flag from my face - I wonder how he did it! :-)

And here is one more by Michiel @zandbelt: http://twitpic.com/9uy7wd 

Great Post on his blog! Irwin ‏@_connectedcare on his Berlin rheumination
http://bjcconnectedcare.com/2012/06/eular-2012-my-berlin-rheumination/


Another picture supplied by Francis Berenbaum ‏@Larhumato

https://twitter.com/Larhumato/status/214807655166902272/photo/1

And Chetan Narshi ‏@rheumi_  shared the following picture:

https://twitter.com/rheumi_/status/214793895349993474/photo/1 

Will be continued as time goes by.