Gout at the EULAR 2013 Meeting in Madrid

There were far too many posters, talks, abstracts, etc. at the EULAR 2013 Meeting in Madrid than to comment on everything. So I select my personal highlights and updates.

B. Manger [SP0006] talked on “Visualising crystals: DECT and more”. “Dual energy computed tomography (DECT) is an imaging method, which uses X-ray beams of two different energies to differentiate solid sodium urate deposits from connective tissues and from calcium containing structures by their absorption properties.” “…,DECT may not only be a very helpful imaging method for tophus assessment and follow-up in clinical trials and during urate lowering therapy in patients with the established diagnosis of chronic gout. It may also be valuable as differential diagnostic tool in patients with “unclassified” acute or relapsing arthritides, when aspiration of synovial fluid is not possible or not successful.“

I haven’t used DECT yet and also don’t know, where to look for someone, who is experienced in this method, here in the vicinity.

S.-J. Kee and colleagues studied [OP0002]: “Pathomechanism of bone destruction in chronic gouty arthritis”. “MSU [monosodium urate monohydrate] crystals induced the expressions of IL-1, IL-6, TNF-alpha and RANKL in PBMCs [peripheral blood mononuclear cells], but inhibited OPG [osteoprotegerin] expression.” Conclusions: “ …, our data show that MSU crystals have the potential to induce pro-resorptive cytokines, and T cells are involved in osteoclastogenesis in chronic gout.” Good basic research, which might lead to understand, why erosive lesions look different in gout and RA for instance.

T. Cooper and colleagues presented a study [FRI0568-PC]: “Gout: are we getting it right in primary care? An audit of serum uric acid level measurement and monitoring.” Methods: “This study audited one general practice in the UK.” Results: “A total of 125 patients had received allopurinol in the 3 year period. 76 patients (60.8%) had not had their SUA level measured, leaving only 49 (39.2%) who had their SUA levels checked. …”. Conclusions: “Clearly the majority of patients receiving allopurinol in this general practice were not having their SUA levels measured, being treated to target or monitored annually. If these simple tests and management strategies were performed in primary care then a large number of hospital admissions for attacks of gout could be avoided, with the accompanying save in expenditure. …”

So, it’s important to have revisits by the patient, who have been presented to rheumatologists in order to help our colleagues in primary care, once we’ve seen these gout patients as I presume they suffer from more severe or complicated forms of gout.

D. Chandrasekaran and colleagues presented [SAT0363]: “Evaluation of the use of colchicine in the management of chronic gout.” The authors looked at 515 patients taking colchicines. Conclusions: “… a significant percentage of gout patients are inappropriately on long-term colchicine with only 26% having serum uric acid levels at or below the target level of 6 mg/dl.”

I may add that some GPs don’t read the letters, maybe because the patients don’t show up or maybe because they think that the gout problem has been solved, once the arthritis has been treated. With us rheumatologists there rests an educational responsibility – we have to both educate our referring colleagues as well as our gout patients, whom we normally see only sporadically.  

D. Khanna and colleagues looked at [SAT0384]: “Patients that continue to flare despite reaching EULAR/ ACR recommended serum urate target.” Conclusions: “Less than 50% of patients treated with a XOI inhibitor alone reached sUA target. Of the patients achieving a sUA level of < 6 mg/dL, over a third reported 2 or more flares in a 12-month period.”

Can you see gout patients, who do not flare? I can’t as our outpatient department is only allowed to see patients suffering from severe auto inflammatory diseases. How can we help then? Wait till the poor patients flares again? I don’t have an easy answer.

Gout is a topic that lots of colleagues outside the rheumatologic world feel fit in, but there are still gaps to be filled. I read out of the above studies, that we as rheumatologists have an educational responsibility owards colleagues in primary care and patients as well.

More on gout:

ACR2012 Abstracts on Gout without drug studies http://rheumatologe.blogspot.de/2012/12/acr2012-abstracts-on-gout-without-drug.html

Gout and other crystal diseases at the EULAR 2012 http://rheumatologe.blogspot.de/2012/07/gout-and-other-crystal-diseases-at.html

Some Ideas on Gout http://rheumatologe.blogspot.de/2012/05/some-ideas-on-gout.html

An expedition into the world of gout http://rheumatologe.blogspot.de/2012/04/expedition-into-world-of-gout_27.html

Gout / subcutaneous depots of uric acid http://twitpic.com/4q61mh

Sarilumab at the EULAR 2013 Meeting

I had been wondering, if there is some news on sarilumb as there hadn’t been too much at the ACR 2012 Meeting; see link below.

L.-H. Wang and colleagues presented [FRI0020]: “Preclinical development of sarilumab, the first fully human monoclonal antibody (MAB) against IL-6R alpha: utilization and value of double humanized animal model.” Conclusions: “These results show that sarilumab was biologically active in a humanized mouse model of acute inflammation and achieved a dose‑dependent reduction in SAA following turpentine injection, …”
??? I’m a bit confused and disappointed. I thought we were already past the animal studies.

M. C. Genovese and colleagues presented a post hoc analysis of the MOBILITY study [SAT0117]: “Sarilumab, a subcutaneously-administered, fully-human monoclonal antibody inhibitor of the IL-6 receptor: relationship between EULAR responses and change from baseline of selected clinical parameters.” Conclusions: “Sarilumab doses studied in Phase 3 resulted in a significantly higher proportion of RA patients with improved Hb, hsCRP and EULAR good responses compared to placebo. This preliminary evaluation of a subset of PROs in MOBILITY Part A shows improvements in FACIT and sleep VAS scores that correlated with achievement of a EULAR good response.”
It’s like eight months ago. We only get some preliminary results from a phase 3 study.

R. Fleischmann and colleagues also presented a piece of cake from the MOBILITY study [SAT0136]: “Sarilumab, a fully human MAB against IL-6R alpha, subcutaneously-administered shows significant improvement in RA patients as early as 2 weeks: a time to event analysis for ACR50 and EULAR good response.” Conclusions: “The effect of SAR in reducing signs and symptoms by the ACR50 response and EULAR good and good+moderate criteria was seen early. Pts treated with 150 or 200mg q2w or 100 or 150mg qw were >2 times as likely as Pbo to achieve ACR50 response after 12 wks. A significant improvement in the proportion of EULAR responders was also observed for 4 SAR groups starting at wk 2. These proportional hazard methods support Phase 3 study of 150 and 200mg q2w regimens that provide high hurdle ACR and EULAR clinical responses.”
It doesn’t exceed very much the data, which has been published at the 2012 EULAR Meeting.

And finally let’s look at the study by A. Rafique and colleagues [AB0037]: “Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human IL-6 receptor (IL-6R) alpha.” Conclusions: “Based on these in vitro assay data, sarilumab has both a higher relative binding affinity for IL-6Rα, blocks IL-6Rα activation, and inhibits IL-6-induced cellular responses such as cell proliferation at lower concentrations than tocilizumab.”
So, sarilumab might have an edge against tocilizumab.

It might well be that sarilumab would work in lower concentrations, but as tocilizumab has already been evaluated for subcutaneous injection, how big could be an advantage? We've seen two studies, which would be expected before going into phase 2 and 3, and two tidbids from a phase 3 study, which hasn’t been fully evaluated. What are these facts telling us? There must be a strategy included – and I’m not too sure about sarilumab’s future.

Links:
ACR 2012: http://rheumatologe.blogspot.de/2012/12/sarilumab-at-acr-2012-in-washington.html  
EULAR 2012: http://rheumatologe.blogspot.de/2012/06/sarilumab-news-from-eular-2012.html  

IL-33 at the EULAR 2013

IL-33 is an interesting cytokine. XU W.D. and colleagues published a paper recently, which looked at the potential role of IL-33, a member of the IL-1 family, in rheumatoid arthritis and experimental inflammatory arthritis. The authors think that inhibition of IL-33 could be a potential therapeutic approach. Link: http://www.ncbi.nlm.nih.gov/pubmed/23800433

There were several papers at the EULAR 2013 Meeting in Madrid, I’ll only refer to the study concerning rheumatoid arthritis. The other studies are on tendinopathy, systemic sclerosis, and lupus. Conclusions: “Serum IL33 level is increased in RA pts with anti-CCP and/or RF. Moreover, we confirm our transcriptomic analysis and demonstrate for the first time that serum IL-33 level represents a novel simple useful biomarker predicting clinical response to RTX, independently of auto-antibodies status, which usually displays a strong impact on rituximab response. The role of the IL-33/ST2 axis in B-cell immunopathology in RA needs to be further addressed.” Roche already tried to establish the rheumatoid factor as a marker for response to rituximab. IL-33 seems to be a better candidate.

I’ll look for more studies in the future, as IL-33 might get more attention both for diagnostic/prognostic and therapeutic reasons.

Biosimilars after the EULAR 2013

EMEA's Committee for Medicinal Products for Human Use (CMHP) recommended biosimilars of infliximab by Celltrion and Hospira to be granted the same indications as Remicade®. For more on this recent information (post EULAR!) please look under links for Forbes.
I don't think that biosimilars are a panacea to reduce costs; nevertheless it's worth a try. Some biosimilars are already marketed though not in the US, Japan, Australia, or the EU.

Already approved
There are some biosimilars already approved and in use.
Biosimilars of etanercept are marketed by Shanghai CP Goujian Pharmaceutical Co. in China and Colombia, as Yisaipu (益赛普) and Etanar®.
There are two biosimilars of rituximab; Reditux® is marketed by Dr Reddy's Laboratories in Bolivia, Chile, India and Peru, Kikuzubam® is marketed by Probiomed in Bolivia, Chile, Mexico, and Peru. More information can be looked up under the link for Morton, but mind that the data on study progress has been collected more than a year ago. So the list might need to be updated.

Some more preliminary information
Boehringer works on adalimumab. Avesthagen (India) works on etanercept. Sandoz, Celltrion, and Pfizer work on rituximab.
Celltrion will name its infliximab Remsima®.
"BioXpress Therapeutics S. A. (Switzerland) is currently developing biosimilars for abatacept, adalimumab, etanercept, golimumab, infliximab, and tocilizumab." (See: A. Morton et al)

Studies presented at the EULAR 2013
Three studies on CT-P13 (infliximab biosimilar):
D. H. Yoo and colleagues presented [OP0068]: "A phase 3 randomised controlled trial to compare CT-P13 with infliximab in patients with active rheumatoid arthritis: 54 week results from the PLANETRA study." Conclusions: "CT-P13 showed comparable efficacy and PKs to those of INX up to week 54. CT-P13 was well tolerated with a safety profile comparable to that of INX up to week 54."

D. H. Yoo and colleagues presented a secon study [FRI0164]: "Local tuberculosis incidence affects the rate of positive conversion in the Quantiferon®-TB gold test among patients receiving infliximab or CT-P13 therapy." Conclusions: "To reduce TB incidence in patients treated with anti-TNF agents, serial testing using QTF in the first year of anti-TNF treatment could be helpful in detecting LTBI patients who had a false negative result at baseline, especially in countries with intermediate or high incidence of TB."
Same risk profile for biosimilars!

W. Park and colleagues presented [FRI0421]: "A randomised, double-blind, parallelgroup, phase 1 study comparing the pharmacokinetics, safety and efficacy of CT-P13 and infliximab in patients with active ankylosing spondylitis: 54 week results from the PLANETAS study." Conclusions: "CT-P13 has similar PK values and a clinical efficacy comparable to INX up to week 54. CT-P13 was well tolerated with a safety profile comparable to that of INX up to 54 weeks. ADAs seem to diminish the clinical response to both agents in some patients."
Nothing unexpected.

One study on a rituximab biosimilar:
S. I. Hurst and colleagues presented [THU0104]: "Nonclinical assessments demonstrating the similarity of the proposed biosimilar PF-05280586 and rituximab." PF stands for Pfizer. Methods: "Structural similarity was determined by peptide mapping. Functional similarity was confirmed using an in vitro complement-dependent cytotoxicity (CDC) assay using Ramos cells." I don't like to go on, but in methods we're told about the necropsied cynomolgus monkeys. Let's swiftly switch to conclusions: "PF-05280586 showed structural, functional, PK, PD, and ADA similarity to rituximab-EU. Both drugs were well tolerated. The results support the development of PF-05280586 as a proposed biosimilar to rituximab."
I don't know how far Celltrion has come, but Sandoz and Teva (Israel) seem to be nearer to the goal than both Pfizer and Celltrion.

One study on Infinitam® (etanercept):
J. F. Moctezuma and colleagues presented [THU0208]: "Comparative, randomized, simple blind to evaluate efficacy and safety of Infinitam® (etanercept), associated with methotrexate compared with Enbrel® (etanercept) associated with methotrexate in patients with modeate and severe rheumatoid arthritis". Conclusions: "Clinical response, procedures and observations at the end of treatment was as expected in all group of patients. Study drug safety was similar for both drugs. All patients improved DAS28 evaluations."
It's a preliminary study!

If we put all together, there's only one biosimilar, which might make it to the market in the next 12-18 months and that's Celltrion's Remsima® (infliximab).

Links:
Forbes: http://www.forbes.com/sites/edsilverman/2013/06/28/a-landmark-for-biosimilars-eu-endorses-copies-of-a-jj-drug/  
Morton: http://www.nature.com/nrrheum/journal/v8/n7/fig_tab/nrrheum.2012.84_T1.html  

03.07.2013:


What are biosimilars good for, anyway? Someone else wants to make a profit, too. And with biologics being very expensive, biosimilars are good to make money. Could biosimilars replace biologics? I don’t think so as the pharmaceutical companies have to invest in the development and production of biosimilars. It’s my guess that the companies, who developed original biologics will stand a price fight much better as they are well past the amortisation of their investments. And biosimilars aren’t offering a new concept, they offer what we already have.

In Spain the annual cost for biologics is fixed at 9000 € (not my own research), in German we pay above 20,000 €. Why is there such a discrepancy within the EU. It means that we pay too much. Biosimilars could help to reduce this. But I doubt that there will be a breakthrough.

If Sandoz, Teva, Pfizer start developing a rituximab biosimilar, there might be more behind it than just getting a piece of the cake. I think there are other strategies involved like safeguarding against a hostile takeover.

Would I switch over patients to biosimilars? No! I would start new patients on biosimilars, however. It’s the same reasoning like I won’t switch between TNF-inhibitors, if there isn’t a reason like secondary failure or side effects. The real chance of biosimilars could only be the price.

04.01.2016:
Yisaipu (益赛普) / Etanar® and Kikuzubam® fall in the category of biomimics!

New Rheumatoid Arthritis Guidelines at the EULAR 2013 Meeting

Too bad, I’ve missed the session, in which the new guidelines were presented. The guidelines will be published soon to replace the 2010 guidelines. I’ll look through the guidelines as soon as possible, but can rely for the time being on an article by Alice Goodman.

According to Josef Smolen, MD, "the 2013 EULAR guidelines will avoid the overtreatment of 20% to 30% of patients with rheumatoid arthritis".
Tocilizumab will get special attention as monotherapy, while TNF-inhibitors and other biologics should be used in combination with methotrexate.
Methotrexate is the first line drug of choice. One can substitute MTX for leflunomide or sulphasalazine, if MTX isn’t tolerated. Gold isn’t available at all places and is therefore omitted, but still has a mention in the German guidelines for instance.
After DMARD failure (not reaching the target) therapies should be stratified to DMARDs in combination or biologics according to individual prognosis.
Biosimilars are mentioned in the text and we’ll have to wait and see, what Celltrion and Hospira are going to do. Inflectra and Remsima have a positive opinion in the EU, but EMEA hasn’t approved yet. “Johnson & Johnson and partner Merck & Co. may initiate a patent infringement case against Celltrion and Hospira if they launch their products in Europe.” Link: http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5794  
Tofacitinib already has a place in the EULAR guidelines, but EMEA isn’t near approval. I think that including tofacitinib is premature, but we’ll have to look at the text, when it will have been published. Needless to say, but I say it: I’m also desperately waiting for tofacitinib’s approval because we already have patients, who need a new drug as they have been through with all the established drugs.
Initial low dose glucocorticoids lead to better result. High dosage and long duration on steroids should be avoided.

All and all, it’s a good idea to update guidelines as quickly as science changes, but the guidelines shouldn’t run ahead.

PS. Consider my word preliminary as I wait for the full text of the EULAR Rheumatoid Arthritis Guidelines to be released.

Ustekinumab at the EULAR 2013 Meeting

Ustekinumab (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. There were a couple of studies on Ustekinumab and I've been eager to know, whether these studies confirmed the positive impressions, the drug had made last year. I didn’t see the solution of problems treating psoriatic arthritis in ustekinumab, but thought of getting a new option to treat at least some patients with psoriatic arthritis better than before (ACR 2012). Now let’s switch to the newer studies or new results.

P. Rahman an colleagues presented a study [SAT0264]: "Ustekinumab [UST] improves physical function, quality of life and work productivity of patients with active psoriatic arthritis who were naïve to MTX, despite MTX therapy or previously treated with anti-TNFα: results from PSUMMIT I and PSUMMIT II". Conclusions: "UST improves physical function, improves general, arthritis and skin-related quality of life, and reduces the impact of disease on work productivity in patients with active PsA regardless of current or prior MTX use or prior anti-TNF experience." If you expected differences in patients naïve to anti-TNFα, your're right. In results we find: " In the anti-TNF naïve population, statistically significantly greater improvement in SF-36 MCS was observed in the combined UST 45mg and 90mg group vs PBO."

I. McInnes and colleagues presented [SAT0267]: "Safety of ustekinumab from the placebocontrolled periods of psoriatic arthritis and psoriasis clinical developmental programs". The conclusions as expected: " During the PBO-controlled portion, UST was well-tolerated. Overall safety were consistent between populations & safety event rates were generally comparable between pts receiving PBO & UST within each population."

K. Papp and colleagues looked at long-term safety [SAT0287]: "Long-term safety of ustekinumab: 5 years of follow-up from the psoriasis clinical development program including patients with psoriatic arthritis". Conclusions: "With continuous UST exposure for up to 5yrs and approximately 9000 pt-years of follow-up in the PsO development program, long-term safety in the Overall Population were consistent with previous reports at earlier follow-up and event rates were generally comparable to other currently approved biologic agents. Long-term safety in the sub-group of PsO patients with a history of PsA at baseline were generally comparable to those in the overall study population." Nothing unexpected, but this look on safety makes one feel safe to prescribe the drug later.

C. Ritchlin and colleagues presented the following study [OP0001]: "Maintenance of efficacy and safety of ustekinumab in patients with active psoriatic arthritis despite prior conventional nonbiologic and anti-TNF biologic therapy: 1 yr results of the PSUMMIT 2 trial". The highest ACR70 was reached in the 90 mgs group at 17.9%. Conclusions: "Both UST doses (45/90 mg q12w) yielded significant and sustained improvements in PsA signs/symptoms with favorable and comparable safety profiles. UST was effective in both anti-TNF-naïve and anti-TNF-experienced pts, with greater efficacy in anti-TNF naïve pts and anti-TNFexperienced pts previously treated with 1 or 2 anti-TNF agents."

It seems we're getting a new drug to treat psoriatic arthritis - now let's wait for if and when FDA and EMEA approve ustekinumab.


Link:
ACR 2012 in Washington http://rheumatologe.blogspot.de/2012/12/ustekinumab-at-acr-2012-in-washington.html

VX-509 at the EULAR 2013 Meeting

No, VX-509 isn’t a motor oil, it’s a JAK3 inhibitor. There hadn’t been much at the EULAR 2012 Meeting and nothing at the ACR 2012 Meeting. Link. http://rheumatologe.blogspot.de/2012/07/vx-509-and-eular-2012.html. But VX-509 was sighted again at the EULAR 2013 Meeting.

I. M. Catlett and colleagues presented [THU0160]: “The effect of VX-509, a selective oral JAK3 inhibitor, on plasma biomarkers of disease activity in patients with rheumatoid arthritis.” Conclusions: “VX-509 treatment modulated biomarkers of RA associated with inflammation (IL-6, CD25, and CCL18) and bone erosion (MMP-3). These changes are consistent with the efficacy of VX-509 in improving RA signs and symptoms.” – and then I had a strange feeling … I accessed: http://www.abstracts2view.com/eular/view.php?nu=EULAR13L_THU0160 … and I found the same abstract in the archives of EULAR 2012!

We should ask Vertex if they still want to bring VX-509 to the market. Maybe they should change the motor oil name into a pharmaceutical name. Or maybe it’s also bye-bye VX-509.

Secukinumab at the EULAR 2013 Meeting

I’ve already written on secukinumab: http://rheumatologe.blogspot.de/2013/06/targeting-interleukin-17-in-patients.html. Here’s more on this drug.

X. Baraliakos and colleagues presented [FRI0420]: “Long term inhibition of IL-17a with secukinumab reduces spinal inflammation but has no influence on fatty lesions as assessed by magnetic resonance imaging in patients with ankylosing spondylitis.” Quo usque tandem abutere, Catilina, patientia nostra? No, that’s a bit too hard, but it’s the same study as presented in Washington.

O.K. We’ve still got another study. U. Klein and colleagues presented [SAT0142]: “Immunogenicity of the novel anti-IL-17a antibody, secukinumab, with intravenous and subcutaneous dosing regimens in healthy subjects and patients.” Conclusions: “Based on the available data, secukinumab appears to carry a low risk of immunogenicity. In the very few transient immunogenicity positive patients identified so far, there has been no indication of altered pharmacokinetics or loss of efficacy, and no adverse event that could be linked to immunogenicity has been detected. More data from the ongoing phase 3 studies are required to strengthen this encouraging finding in a larger patient population.”

The more I read on secukinumab the surer I get. We won’t here much on RA and secukinumab.

Tabalumab at the EULAR 2013 Meeting

I had been disappointed about tabalumab at the ACR 2012 Meeting. Even as there had been four studies in Washington. The reasons for my disappointment are here: http://rheumatologe.blogspot.de/2012/12/tabalumab-at-acr-2012-in-washington.html How about Madrid?

E. R. Dow and colleagues presented [SAT0005]: “Human C-type lectin domain family 4, member C gene expression level helps predict future clinical response to tabalumab blockade of BAFF in rheumatoid arthritis”. In German we have the idiom “BAFF erstaunt sein”, which means to be flabbergasted. That’s describes my feelings. Only one study at the EULAR and … it’s an abstract, which had already been presented at the ACR 2012 Meeting.

Bye bye tabalumab.

Drugs that didn't show up at the EULAR 2013 Meeting in Madrid

Prior to the EULAR 2013 Meeting in Madrid I had published my list of topics, I'm interested in. I was just going through my list and found out that there are a lot of drugs that didn't have any publication at the EULAR 2013. It may mean that these drugs won't be studied anymore because the drug companies don't see any profit. But this can't be 100%, maybe some drugs need more time for the next publications.

ARRY-371797 / ARRY-797
Nothing!
Link for last ACR meeting: http://rheumatologe.blogspot.de/2012/12/arry-797-at-acr2012-in-washington.html

BT061
Nothing!
Estimated Study Completion Date: December 2013. http://clinicaltrials.gov/ct2/show/NCT01481493 So, unless there is some other information we should wait until the ACR2014.

CCX354-C
Nothing!
I'm not expecting too much in the furture.
For EULAR 2012 look at: http://rheumatologe.blogspot.de/2012/07/ccx-354-c-at-eular-2012.html

Cetrorelix
Nothing!
I have already had my reservations against this gonadotropin-releasing hormone antagonist (GnRH antagonist): http://rheumatologe.blogspot.de/2012/07/cetrorelix-at-eular-2012.html http://rheumatologe.blogspot.de/2012/12/cetrorelix-at-acr-2012-in-washington.html  

MOR103
Nothing!
After the stunt with the late breaking poster at the ACR 2013 this is disappointing, but I'd thought that the paper left open lots of questions.
Link: http://rheumatologe.blogspot.de/2012/12/mor103-at-acr-2012-in-washington.html  

NKG2a
Nothing!
Links to the previous meetings, if you're still interested: http://rheumatologe.blogspot.de/2012/07/nkg2a-nnc141-0100-at-eular-2012.html and http://rheumatologe.blogspot.de/2012/12/nkg2a-at-acr-2012-in-washington.html  

NNC0114-0005
Nothing!
NNC0114-0005 is a recombinant anti-IL-21 monoclonal antibody. I had my doubts, as one paper ended in the conclusion: "The improvements in DAS28-CRP for patients with RA at the highest dose level may suggest biologic and clinical activity of NNC0114-0005." Link: http://rheumatologe.blogspot.de/2012/12/nnc0114-0005-at-acr-2012-in-washington.html  

Ocaratuzumab
Nothing!
As ocaratuzumab showed rapid and sustained depletion of circulating B-cells in rheumatoid arthritis patients, I was surprised. Link to more information: http://rheumatologe.blogspot.de/2012/12/ocaratuzumab-at-acr-2012-in-washington.html  

Ocrelizumab
Nothing!
I didn't expect to hear more from this anti-CD20 MAB.
Link: http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html  

Olokizumab
Nothing!
Very strange as olokizumab targets interleukin-6 (IL-6). Link to more information from the ACR 2012: http://rheumatologe.blogspot.de/2012/12/olokizumab-at-acr-2012-in-washington.html  
Postponed or abandoned?

Ozoralizumab (ATN-103)
Nothing!
It had been presented as "a trivalent, bispecific nanobody that potently neutralises TNF". Link: http://rheumatologe.blogspot.de/2012/12/ozoralizumab-atn-103-at-acr-2012-in.html
If I hear nano, I think of hype; an if new drugs don't show up at the next meeting, it makes me even more skeptical.

Pioglitazone
Nothing!
Doesn't come as a surprise, please look here:
http://rheumatologe.blogspot.de/2012/12/pioglitazone-at-acr-2012-in-washington.html 

PRTX-100 (Staphylococcal Protein A)
Nothing!
As I had been part in testing immunoadsorption, I´m not too confident in PRTX-100. But it´s still early for skepticism.You find more here: http://rheumatologe.blogspot.de/2012/12/prtx-100-staphylococcal-protein-a.html
I thought that he EULAR 2013 might still be too early. So I'll be watching, if something comes to surface at the ACR 2013.

SBI-087
Nothing!
SBI-087 is a SMIP (= small molecule immune pharmaceutical) binding to CD-20 http://rheumatologe.blogspot.de/2012/07/sbi-087-at-eular-2012.html  
Guess it's abandoned.

Synavive
Nothing!
Synavive, a combination of 2 mgs of prednisolone and 200 mgs of dipyramidole: http://rheumatologe.blogspot.de/2012/07/synavive-crx-102-at-eular-2012.html.
Should be abandoned.

Veltuzumab
Nothing!
Please check: http://rheumatologe.blogspot.de/2012/06/anti-cd-20-monoclonal-antibody.html  
A year without results? Better forget this drug.

VX-702
Nothing!
There hasn't been anything new on VX-702, a novel p38 MAPK inhibitor, since 2011. My guess: p38 MAPK inhibitors don't work.

Modified Release Prednisone at the EULAR 2013

I have already published my concerns about modified release prednisone severeal times; please look for the links below.

At the EULAR 2012 Meeting there had been four studies: "To sum up these studies: Lodotra (modified-release prednisone) failed to show a clear advantage over conventional immediate-release prednisone in the studies presented at the 2012 EULAR meeting. One study failed to look at 1733 of 2661 patients, while another study only presented data on 950 of 1928 patients."

At the EULAR 2013 Meeting we could see two studies on modified release prednisone.

M. Benucci and colleagues presented [SAT0152]: "Polymyalgia rheumatica: a comparative study of methylprednisolone and the modified release prednisone". The study is non-blinded, non-randomized and looks only at N=42 in two groups. The endpoint is unclear. The objective is to " compare changes in inflammation markers and their correlations with cortisol levels ...". Conclusions: " In this non-randomized prospective observational study the response of inflammation markers to low-dose GC was similar in patients with PM treated with 6-MP or MR-P, and morning cortisol levels were unaffected. However, the patients treated with MR-P showed a greater decrease in IL-6 levels after the first month."
Does anyone treat IL-6 levels after the first month in patients with polymyalgia rheumatica? I don't! So this study rather convinces me to not use Lodotra.

D. Sola and colleagues presented a study [AB0346]: "Safety and efficacy of rheumatoid arthritis treatment with modified-release prednisone (MR-PDN), experience in “real life”". The study is retrospective! Objectives: "To assess in “real life” adherence to treatment and efficacy (morning stiffness, DAS28 score and steroid dose reduction) in RA patients who initiated treatment with MR-PDN,". "64 RA patients who initiated RM-PDN completed a 12 weeks (W) follow-up, 49 completed 24 W and 33 48W." So the study lost about 50% of it's initial patients to follow up after 48 weeks or is incomplete. "In 19 patients this was the first steroid treatment, 45 received MR-PDN after a switch from one other steroid (in this case 1 month bridging with traditional steroid was performed)." So, in about 33% of the patients we look at prednisone naive and in 66% at pretreated patients. At week 48 only 64% stayed on treatment. "The efficacy analysis was limited only to patients with DMARDs or biological therapies stable for the whole period of observation." But we don't know how many patients had been on which therapy. And in the end we look at patients, who have been doing better and measure the success. Conclusions: "In RA patients in “real life” the use of MR-PDN showed good safety profile and adherence to treatment also after switch from prolonged traditional steroid treatment. We observed a reduction in morning stiffness and disease activity similarly to that described in clinical trial. The greatest improvement occurs within the first 12 weeks confirmed by further modest improvement up to 48 weeks. Finally the use of the MR-PDN permitted a lower consumption of steroid in these patients with obvious long term benefits."
The study is a catastrophe. It looks retrospectively at a heterogenous group of patients (pretreated with steroids of steroid naive, on traditional DMARDs or on different biologics) without a well defined endpoint. Is it desirable to stay on prednisone after 48 weeks? Is the reduction of morning stiffness and disease activity due to modified release prednisone or DMARDs/biologics? What is the idea of the authors behind: lower consumption of steroid? Lower than at the beginning? That would mean modified release prednisone could be tapered like any other steroid. What are the "obvious long term benefits"?

These two studies convince me even more that modified release prednisone (Lodotra) won't be my drug of choice.

Links:
http://rheumatologe.blogspot.de/2012/11/lodotra-auf-dem-kongress-der.html (Text in German)
http://rheumatologe.blogspot.de/2012/06/modified-release-prednisone.html
http://rheumatologe.blogspot.de/2010/06/lodotra-my-problems-with-new-miracle.html

Protein kinase inhibitors - hype or hope?

As we've seen quite a lot of compounts being studied during the past two years, I think it's to look how much hype or hope there is. Where do we stand after the EULAR 2013 Meeting?

This list is incomplete, I know, but it shows that our hopes are mixed with lots of hype. And this list is my personal interpretation; someone might disagree and should do so in the commentary part. Red stands for problems ot that I don't think it will develop into a drug on the market. Yellow stands for might develop into a drug, still to early. One could argue, if VX-509, ARRY-797, ASP015K, and Ruxolitinib still belong to this group. And only one in the green group.

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.

I hope that we'll get these drug in the future, though well tested, safe, and not at the top pricing drug companies expect.

Xeljanz right now stands alone on the U.S. market. The European market will have to wait. Even if there is much hype, I hope for Xeljanz at least to make it to the European market.

ASP015K at the EULAR 2013 Meeting

I thought very positively about ASP015K after the ACR 2013 meeting in Washington:
“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!”
http://rheumatologe.blogspot.de/2012/12/asp015k-at-acr-2012-in-washington.html

Could ASP015K keep up with its’ aspirations at the EULAR 2013 meeting?

S. Yamazaki and colleagues presented a study [THU0101]: “ASP015K: a novel JAK inhibitor demonstrated potent efficacy in adjuvant-induced arthritis model in rats”. As I had already seen this study in Washington, I don’t want to comment on it again; please look up the above link.

J. Garg and colleagues presented a new phase 1 and 2 study [THU0227]: “Pooled analysis of clinical safety data for ASP015K, a novel JAK inhibitor in development for treatment of autoimmune diseases”. Conclusions: “ASP015K administered as single or multiple doses for up to 42 days was safe and well tolerated in HVs/pts in 13 phase 1 and 2 studies.”

T. Zhu and colleagues presented the following study [THU0256]: “Pharmacodynamics of ASP015K, a novel janus kinase inhibitor, in healthy volunteers.” Conclusions: “ASP015K showed dose- and concentration-dependent inhibition of STAT5-P. Total lymphocyte count showed no dose-dependent changes. A dose-dependent reduction in NK cells was seen with multiple doses. These results are consistent with the pharmacologic effect of JAK1/3 inhibition by ASP015K.” I’m a bit surprised that this study is presented now – I would have expected it at the ACR 2012, half a year ago.

T. Zhu and colleagues presented [AB0363]: “Coadministration of ASP015K, a novel janus kinase inhibitor, with methotrexate demonstrates tolerability and lack of pharmacokinetic interactions in patients with rheumatoid arthritis”. Please look it up on the ACR 2012 blogpost, mentioned above.

My positive impression dwindles considerably! I hope we’ll see results from a phase 2b study later this year. And if ASP015K doesn’t have a name by then, it might never get a name.

GLPG0634 at the EULAR 2013

GLPG0634 is selective inhibitor of Janus kinase 1 (JAK-1). And I had been quite thrilled by this new drug at the ACR 2012 in Washington. Now, I was eager to see, what new developments would be presented at the EULAR 2013 in Madrid.

B. Vayssiere and colleagues presented a rodent study [THU0116]: “Biological effects of the jak1 selective inhibitor GLPG0634 on inflammation markers in arthritic mice”. Conclusions: “ … These data establish that selective JAK1 inhibition by GLPG0634 is sufficient to mediate strong efficacy in an established arthritis model …”. That wasn’t so thrilling.

F. P. Vanhoutte and colleagues presented [THU0229]: “Safety and efficacy of GLPG0634, a selective JAK1 inhibitor in patients with rheumatoid arthritis: results of a 4-week phase II a dose ranging, multi-center trial”. Conclusions: “These early clinical results demonstrate that selective inhibition of JAK1 by once-daily dosing of GLPG0634 from 75 mg to 300 mg is efficacious and generally well tolerated for 4-weeks treatment of RA, and confirm data from a previous study at a 200 mg daily dose. A dose of 30 mg QD was suboptimal for efficacy. Larger, longer term studies in RA are being initiated to evaluate optimal doses for efficacy and safety.” I looked into the results and agree with the authors’ conclusions.

F. Namour and colleagues presented a third study [THU0236]: “Once-daily dosing of GLPG0634, a selective JAK1 inhibitor, is supported by its active metabolite“. Conclusions: “The results of these studies indicate that an active metabolite supports the activity of GLPG0634. The long half-life of this metabolite provides a lasting effect, though at a lower level of JAK1 inhibition than GLPG0634. …”.

As EMEA seems to be reluctant to approve tofacitinib, maybe GLPG0634 has a better chance. With two PK inhibitors prices might come down to level, where it’s affordable for society. So I wish both drugs good luck!

Link:
http://rheumatologe.blogspot.de/2012/12/glpg0634-at-acr-2012-in-washington.html

Dekavil at the EULAR 2013

I’ve seen a poster on dekavil at the EULAR 2013 meeting. Let’s return to the ACR 2012 meeting for a moment. I’d written:
“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.”

M. Galeazzi and colleagues presented [SAT0108]: Dekavil (F8-IL10): a novel anti-inflammatory immunocytokine for the treatment of rheumathoid arthritis”. Conclusions: “The promising safety data regarding the clinical use of F8-IL10, together with preliminary positive signs of activity, suggest that the targeted delivery of IL10 to the site of inflammation may be beneficial to patients with RA. These results also warrant future developments of the product in randomized clinical trials. An update of clinical data will be presented.”

That’s not so different from the text presented at the ACR 2012: “The promising safety data regarding the clinical use of F8-IL10, together with preliminary positive signs of activity may be favored by the targeted delivery of IL10 to the site of inflammation. These results also warrant future developments of the product in randomized clinical trials, which are currently in planning. An update of clinical data will be presented at the ACR meeting.”
Please promise to publish more than promising data at the ACR 2013 at the next ACR meeting.

Links:

http://rheumatologe.blogspot.de/2012/12/dekavil-at-acr-2012-in-washington.html
http://rheumatologe.blogspot.de/2012/07/dekavil-at-eular-2012.html

Fostamatinib at the EULAR 2013

Concerning fostamatinib I had grown suspicious if it will come to market at all.

EULAR 2012: “It looks a bit too good not to cause suspicion, not in the results but in the relevance. I think we should look careful at the results of the studies that are to come in the next two years. Larger numbers of patients in phase 2 studies would make me more confident that fostamatinib may become a useful drug in the treatment of rheumatoid arthritis.”
ACR 2012, after I had to look at a rodent study: “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!”

Any new developments at the EULAR 2013 to get less suspicious?

There has been a study, one study. P. C. Taylor and colleagues presented [OP0048]: “OSKIRA-4: a phase IIb randomised, placebocontrolled study of the efficacy and safety of fostamatinib monotherapy”. Objectives were the efficacy of fostamatinib monotherapy compared with placebo and the assessment of non-inferiority of fostamatinib to Adalimumab. Two study arms of fostamatinib were superior to placebo, but one wasn’t. All three fostamatinib arms were inferior to adalimumab. The authors argue: “However, the performance of ADA monotherapy in this trial was at the upper end of that observed in previous studies. Fosta is being evaluated in combination with DMARDs in the ongoing Phase III programme.” If I choose to run a 100 m sprint against Donovan Bailey and loose, I can’t argue that he was exceptional quick this day.

The suspicion reaches maximum proportions. We must ask the people in charge if it’s still ethical to continue the phase III study as up to 27% diarrhoea as well as other adverse events may harm the patients, who take part in the trial. I don’t think that FDA or EMEA will approve a drug with such a weak effect and side effects nowadays.

PS. OT: I wouldn’t have approved anakinra for the indication rheumatoid arthritis!

Links:
http://rheumatologe.blogspot.de/2012/07/fostamatinib-at-eular-2012.html
http://rheumatologe.blogspot.de/2012/12/fostamatinib-at-acr-2012-in-washington.html

PPS. Just got a post on Twitter by Philip Gardiner ‏@PhilipGardiner : AstraZeneca has already dropped the fostacitinib! http://www.pmlive.com/pharma_news/astrazeneca_drops_arthritis_candidate_fostamatinib_481092

NNC0109-0012 (anti-IL-20 MAB) at the EULAR 2013

I had written about the novel anti-IL-20 MAB (NNC0109-0012) coming from last year’s ACR in Washington. NNC0109-0012 is a novel human monoclonal IgG4 antibody which binds to IL-20. Here’s the old story: http://rheumatologe.blogspot.de/2012/12/nnc0109-0012-at-acr-2012-in-washington.html.

Let’s switch to the 2013 meeting of EULAR in Madrid. There have been two posters/abstracts.

A. L. Blasius and colleagues, all working for Nordisk, published a study [AB0036]: “IL-20 targets local tissue inflammation as opposed to systemic inflammation”. Conclusions: “Using a variety of methods, no evidence could be found in support of a role for IL-20 in systemic immune responses. This is consistent with the hypothesis that IL-20 acts predominantly at local sites of inflammation.”

L. Senolt and colleagues presented a study [SAT0112]: “Improvements in patient-reported physical function, pain and global disease activity in patients with rheumatoid arthritis after treatment with NNC0109-0012 (anti-IL-20 MAB) in a phase 2a trial”. Conclusions: “12-weeks treatment with 3 mg/kg NNC0109-0012 effectively improved physical function, pain and global disease activity in RF- and ACPA positive patients with RA on stable MTX. These improvements were clinically relevant and sustained when measured at the end of the 13 weeks follow-up.”
Let’s compare this study and the study presented at the ACR.
Methods (EULAR 2013): “67 patients with active RA and inadequate responses to MTX were randomised to 12 once-weekly doses of 3mg/kg NNC0109-0012 (n=45) or placebo (n=22) and stable background MTX, and then followed for an additional 13 weeks. Of the 67 randomised patients 43 were Rheumatoid Factor [RF]- and anti-citrullinated peptide antibody [ACPA]-positive.”
Methods (ACR 2012): “A total of 67 RA patients (51 females:16 males) with active disease (DAS28 (CRP) _4.5, _5 swollen and _5 tender joints) were randomized in a 2:1 ratio (45 NNC0109-0012: 22 placebo) in a multicenter, double-blind, placebo-controlled, parallel group trial.”

If we see the same study again next ACR in newer evaluation and wording, it should be clear that “something is rotten in the state of Denmark” – sorry Nordisk, I couldn’t resist!

I’m less optimistic about NNC0109-0012 than I had been post ACR 2012. And I repeat: Nordisk - how about naming the child? It would make discussions easier and show commitment.

Brodalumab at the EULAR 2013

If I look at what I’ve written half a year ago concerning brodalumab, I guess, I’ve been quite right: http://rheumatologe.blogspot.de/2012/12/brodalumab-at-acr-2012-in-washington.html. “I think brodalumab is a dead end for rheumatoid arthritis though it might be useful in other diseases.” There has been just one study on brodalumab in the treatment of psoriatic arthritis as it targets IL-17, which plays a role "in the pathogenesis and ongoing inflammation of psoriatic disease".

P. J. Mease and colleagues presented the following study [OP0103]: “Efficacy of brodalumab, an anti-il-17r antibody, in subjects with psoriatic arthritis”. In results we read: “ACR20 was achieved at week 12 by 37% and 39% of subjects in the 140- and 280-mg brodalumab groups, respectively, compared with 18% of subjects in the pbo group (p < .05).” Conclusions: “Brodalumab treatment was associated with significant clinical response and acceptable safety profile in subjects with PsA.”

The ACR20 response isn’t very high, but nevertheless there’s a significant difference between placebo and brodalumab in both dosings. So I agree with the authors, that brodalumab warrants further evaluation for treatment of psoriatic arthritis.

ALX-0061 / ANTI-IL-6 RECEPTOR NANOBODY® at the EULAR 2013

Two studies on the novel anti-IL-6 receptor nanobody® (ALX-0061) had been presented at the ACR 2012 meeting in Washington; http://rheumatologe.blogspot.de/2012/12/alx-0061-at-acr-annual-meeting-2012-in.html. At the EULAR meeting 2013 in Madrid we’ll get two more studies to discuss.

J.-B. Holz and colleagues presented a study [OP0043]: “Twenty-four weeks of treatment with a novel anti-il-6 receptor nanobody® (ALX-0061) resulted in 84% ACR20 improvement and 58% DAS28 remission in a phase I/II study in RA”. Conclusions: “In patients with active RA, rapid and strong effects on the IL-6 pathway were observed and associated with a strong clinical response. Clinically significant improvement of disease activity occurred fast and almost 60% of patients achieved state of remission at the end of 24 weeks. The treatment was well tolerated at all doses …”. ACR20 84%, ACR50 68%, ACR70 52% sounds too good. The AMBITION study resulted in: ACR20 70%, ACR50 44%, ACR70 28%. I think future results for ALX-0061 will look more realistic to be comparable to real life.

M. Van Roy and colleagues presented the following study [FRI0021]: “ALX-0061, an anti-IL-6R nanobody® for therapeutic use in rheumatoid arthritis, demonstrates in vitro a differential biological activity profile as compared to tocilizumab“. Conclusions: “ALX-0061 demonstrates in vitro a preferential biological activity profile for sIL-6R with a lesser activity for mIL-6R, while TCZ has a higher preference for mIL-6R. Preferential inhibition of sIL-6R trans-signalling by ALX-0061 could provide superior therapeutic efficacy with a better side effect profile than TCZ.”

There seems to be a lot of optimism within the research teams! But compared with the results of some small molecules I’m tempted to share this optimism. I’m looking forward to see larger studies on ALX-0061!

Pateclizumab at the EULAR 2013

Pateclizumab is an anti-lymphotoxin-alpha monoclonal antibody (the artist formely known as MLTA3698A). I hadn’t seen anything at the EULAR 2012 in Berlin. As I hadn't seen anything at the ACR 2012 in Washington, I thought to wait until the EULAR 2013 before I'd erase pateclizumab from my list of interests.
Now there have been two studies on Pateclizumab at the EULAR 2013 in Madrid.

A. E. Herman and colleagues presented a study [FRI0170]: "Pharmacodynamic biomarkers demonstrate overlapping and distinct biological pathways for lymphotoxin-αlpha and tumor necrosis factor-alpha in patients with rheumatoid arthritis". Within their conclusion you find this sentence: "LTα blockade demonstrated significant reduction in levels of CCL19, as well as CXCL13, suggesting an impact on T and B cell migration and/or lymphogenesis. However, the decrease in chemokines observed with LTα blockade was associated with only modest reduction in clinical activity (5)."
Not too overwhelming, I'd say.

But there has been a second study by W. Kennedy and colleagues [SAT0110]: "Efficacy and safety of pateclizumab (antilymphotoxin-alpha) in dmard-ir patients: results of a randomized, double-blind, placebo-controlled head-to-head phase 2 study with adalimumab". In their conclusion the authors state: "Pateclizumab treatment of DMARD-IR RA patients was associated with modest improvement in the signs and symptoms of RA, and was inferior to adalimumab after 12 weeks of treatment."

I don't think that pateclizumab will make it to the market as the demand for modest improvement isn't too big with better alternative options already in use. I'm a bit disappointed as two years ago I thought targeting lymphotoxin-αlpha could be an interesting approach. I guess we'll have to wait if pateclizumab is abandoned silently.