High Hopes and Aspirations or how ASP015K / Peficitinib brings back the Small Molecule Hype

ASP015K, now called peficitinib is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3, developed by Astellas Pharma for treatment of rheumatoid arthritis (RA) and other autoimmune diseases [1]. A year later, as the hype about JAK and small molecules were cooling down, I’ve written: “Could ASP015K keep up with its’ aspirations at the EULAR 2013 meeting?” And: “My positive impression dwindles considerably! I hope we’ll see results from a phase 2b study later this year.” [2] So we already had a Phase 2b study presented at the EULAR 2013 Meeting.

As tofacitinib and baricitinib are approved in the EU right now, hype and hopes in protein kinase inhibitors return. Last year I’ve speculated: “I guess that the pharmaceutical industry isn’t prudent enough not to overprice small molecules, so that our patient's needs are addressed.” [3] And I’ve proven right. [4]

Recently Gregory M. Weiss, M.D. has published an article [5]: “JAK Inhibitor Peficitinib Reduces RA Symptoms”. He refers to a phase 2b study. So, it seemed to me nothing new under the sun. I stumbled over the sentence: “The authors suggest that rheumatoid arthritis patients with elevated C-reactive protein levels may respond better to higher doses of peficitinib than those with elevated sedimentation rates.” Most of my patients, who have elevated sedimentation rates also have elevated C-reactive protein levels, and vice versa.

There is already a phase 3 study on Peficitinib under way [6]. I’ve checked the abstracts for the 2017 EULAR Meeting (still under embargo), but there isn’t any study mentioned, so that I expect news on this study could be published at the ACR 2017 Meeting later this year.

There will be an open extension phase 2b study on filgotinib being presented at the EULAR 2017 Meeting. No study on decernotinib expected at the EULAR 2017 Meeting.

The race for the high end price level small molecules is open again. Let’s hope that besides the hype there’ll be some benefit for our patients.

Links:

[1] http://rheumatologe.blogspot.de/2012/12/asp015k-at-acr-2012-in-washington.html

[2] http://rheumatologe.blogspot.de/2013/06/asp015k-at-eular-2013-meeting.html

[3] http://rheumatologe.blogspot.de/2016/08/protein-kinase-inhibitors-small.html

[4] http://rheumatologe.blogspot.de/2017/05/tofacitinib-xeljanz-kommt-gerade-an.html Text in German.

[5] http://www.rheumatologynetwork.com/rheumatoid-arthritis/jak-inhibitor-peficitinib-reduces-ra-symptoms?GUID=71CAAEF6-94A2-4616-B379-17C18CF13750&rememberme=1&ts=30052017

[6] http://adisinsight.springer.com/drugs/800028907

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WIN Olokizumab

I’ve just noticed that people have been interested in my article from 2013 “Olokizumab – any new developments?” I therefore adopted the WIN (=what is new?) from the ACR meeting sessions.

To tell the story in short, let me begin a little bit earlier than at “what is new?”. As nothing on olokizumab appeared at the EULAR meeting in Madrid in June 2013, I wondered: “Nothing! / Very strange as olokizumab targets interleukin-6 (IL-6). … Postponed or abandoned?” In July 2013 there had been an announcement by UCB: “UCB out-licenses RA drug olokizumab to Russia's R-Pharm”.

In 2014 I thought that olokizumab had been abandoned as nothing had been published at the EULAR 2014 Meeting in Paris.

MC Genovese and colleagues published: “Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study” in Annals of the Rheumatic Diseases (2014).

MC Genovese and colleagues (other group of researchers) published at the ACR 2015 Meeting in San Francisco: “Long-Term Safety and Efficacy of Olokizumab in Patients with Moderate-to-Severe Rheumatoid Arthritis Who Have Previously Failed Anti-TNF Treatment“. The researchers looked at data from Western and Asian patients. Conclusion: “OKZ [OLOKIZUMAB] was well-tolerated, with an expected safety profile for this class of agent. Reductions in disease activity were sustained to Wk48. These results support the development of OKZ for the treatment of moderate-to-severe RA in Western and Asian pts.”

These recent studies aren’t so interesting in the results, but still there is a story being told. UCB still hasn’t given up and keeps a low fire burning. I doubt that olokizumab will be approved as a drug against rheumatoid arthritis.

References:

Olokizumab – any new developments?

http://rheumatologe.blogspot.de/2013/09/olokizumab-any-new-developments.html

UCB out-licenses RA drug olokizumab to Russia's R-Pharm

http://www.pharmatimes.com/article/13-07-08/UCB_out-licenses_RA_drug_olokizumab_to_Russia_s_R-Pharm.aspx

Newer Biologics at the EULAR 2014 Meeting in Paris

http://rheumatologe.blogspot.de/2014/06/newer-biologics-at-eular-2014-meeting.html

Genovese MC, Fleischmann R, Furst D , Janssen N , Carter J, Dasgupta B , Bryson J , Duncan B, Zhu W, Pitzalis C, Durez P, Kretsos K. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014 Sep;73(9):1607-15. doi: 10.1136/annrheumdis-2013-204760. Epub 2014 Mar 18. http://www.ncbi.nlm.nih.gov/pubmed/24641941

Genovese MC, Fleischmann R, Tanaka Y, Furst DE, Yamanaka H, Joshi R, Zhu W, Shao J, Mashimo H, Takeuchi T. Long-Term Safety and Efficacy of Olokizumab in Patients with Moderate-to-Severe Rheumatoid Arthritis Who Have Previously Failed Anti-TNF Treatment [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/long-term-safety-and-efficacy-of-olokizumab-in-patients-with-moderate-to-severe-rheumatoid-arthritis-who-have-previously-failed-anti-tnf-treatment/. Accessed February 17, 2016.

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Tanezumab in Osteoarthritis at the ACR 2015 Meeting in San Francisco

There has been one publication on tanezumab in osteoarthritis at the ACR 2015 Annual Meeting in San Francisco. After 2013 we didn’t hear much about tanezumab, because the US FDA had imposed a partial clinical hold on studies due to unexpected adverse events. Pfizer announced earlier this year to resume phase 3 studies on chronic pain for tanezumab (see link below). “Tanezumab is a humanized monoclonal antibody that selectively targets nerve growth factor (NGF), a regulator of pain processing and sensitivity.”

P.G. Conaghan talked on: “What is new: osteoarthritis” at the 2013 EULAR Annual Meeting in Madrid. “New evidence supporting the analgesic efficacy of anti-nerve growth factor monoclonal antibodies has been provided with another RCT employing tanezumab; managing potential side effects of this class remains problematic.”

Leslie Tive and colleagues, who worked in the original studies, presented: “Pooled Efficacy and Safety from Phase 3 Controlled Studies of Tanezumab in Patients with Osteoarthritis”. Methods: “Four, phase 3 placebo (PBO)-controlled clinical trials of TNZ in patients with moderate-to-severe OA of the knee or hip completed before the clinical hold were pooled to evaluate efficacy and 9 phase 3 controlled OA studies were pooled to evaluate safety. […]”. Pooled data from older studies … “Patients received 1 to 3 injections of intravenous TNZ 2.5, 5, or 10 mg every 8 weeks, naproxen 500 mg twice daily (BID), celecoxib 100 mg BID, oxycodone controlled release 10-40 mg BID, or PBO.” In Results we read: “TNZ 10 mg but not 2.5 or 5 mg was associated with a higher rate of rapidly progressive OA than active comparator.” Conclusion: “TNZ provides significant improvement of pain, physical function, and PGA of OA. Non-joint-related safety was similar in patients treated with TNZ 2.5-10 mg versus active comparator but increased versus PBO-treated patients.”

I have my problems with the reappearance of tanezumab in osteoarthritis. A monoclonal autoantibody in osteoarthritis pain (not to treat structural deterioration)! The studies didn’t last long enough to evaluate long term safety. This evaluation doesn’t tell us, if tanezumab is better than naproxen, celecoxib, or oxycodone. It tells us that it’s better than placebo. Hooray! But let’s see if the phase 3 program comes up with stressable data.

References:

Pfizer And Lilly Preparing To Resume Phase 3 Chronic Pain Program For Tanezumab http://www.pfizer.com/news/press-release/press-release-detail/pfizer_and_lilly_preparing_to_resume_phase_3_chronic_pain_program_for_tanezumab

P.G. Conaghan: “WHAT IS NEW: OSTEOARTHRITIS”. Abstract No. SP0098. DOI: 10.1136/annrheumdis-2015-eular.6817 / http://ard.bmj.com/cgi/content/long/74/Suppl_2/25-c

Tive L, Radin D, Bello A, Nguyen H, Brown MT, West CR, Verburg KM. Pooled Efficacy and Safety from Phase 3 Controlled Studies of Tanezumab in Patients with Osteoarthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/pooled-efficacy-and-safety-from-phase-3-controlled-studies-of-tanezumab-in-patients-with-osteoarthritis/. Accessed December 7, 2015.

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A New Venture into the World of Gout

Any rheumatologist having crossed Gout Creek must feel motivated to write about gout. Has anyone else?

Well I've crossed Gout Creek (New Zealand, South Island) and there have been some interesting new studies, so I feel very motivated to put a few ideas together.

We all know that alcohol isn't doing good to gout patients, but beer and liquor are tought to be more harmful than for instance a glass of wine. A new study questions this dogma.

T. Neogi and colleagues published the following study: "Alcohol quantity and type on risk of recurrent gout attacks: An internet-based case-crossover study" (Link: http://www.amjmed.com/article/S0002-9343(14)00032-1/abstract). Results: The study included 724 participants with gout (mostly men). The risk of recurrent gout attack was 1.36 for > 1-2 and 1.51 for > 2-4 alcoholic beverages higher compared with no alcohol consumption in the 24 hours prior to the gout attack. Consuming wine, beer, or liquor, all had lead to an increased risk of gout attack. The author's concluded: "Episodic alcohol consumption, regardless of type of alcoholic beverage, was associated with an increased risk of recurrent gout attacks, including potentially with moderate amounts. Persons with gout should limit alcohol intake of all types to reduce the risk of recurrent gout attacks."

I don't think that the "dogma" has been fully refuted, but it seems to be a good idea to point out to gout patients that it's better to avoid alcohol in any form. "Really, no alcohol at all?" As most people have a all or nothing attitude, allowing a teeny weeny bit of wine might ease the way to keep gout patients out of harm.

There have been some interesting papers at the EULAR 2013 Meeting in Madrid, link: http://rheumatologe.blogspot.de/2013/07/gout-at-eular-2013-meeting-in-madrid.html.

I hadn't yet written on interesting studies on gout, which had been presented at the ACR 2013 Meeting in San Diego. I'll dicuss a couple of these studies here.

J.M.A. Wijnands and colleagues presented an abstract [No. 90]: "Insufficient Evidence For An Increase In Prevalence and Incidence Of Gout: A Systematic Review and Meta-Regression Analysis." Methods: "Pubmed, Embase and Web of Science were systematically searched for primary studies on the prevalence and incidence of gout in the general population." Conclusion: "There was insufficient evidence for an increase in prevalence or incidence of gout in recent years." That's reassuring to hear, but I see more patients with more severe gout in recent years, maybe the rate of referral has changed.

Seong-Kyu Kim and collegues looked at [No. 93]: "Higher Consumption Of Sugar-Sweetened Soft Drinks Increases The Risk Of Hyperuricemia In Korean Population: The Korean Multi-Rural Communities Cohort Study." The study was superbly powered with N=9400. Conclusion: "Higher consumption of sugar-sweetened soft drinks increased the risk of hyperuricemia in the Korean population, showing a differential linear trend for hyperuricemia according to gender."

M. De Vera and colleagues presented [No. 210]: "Medication Adherence In Patients With Gout: A Systematic Review." Conclusion: "This is the first systematic review of medication adherence, with particular focus on gout patients. Adherence rates may vary according to methods used to measure adherence. Overall, synthesis of current evidence suggest that medication non-adherence is substantial in gout. Findings highlight the importance of discussing adherence with gout medications during health care professional encounters with gout patients." Among the studies included in this review, allow me to quote: Zandman 2013. N=7,644, follow up after 6 years, proportion of days covered: more than 80% - 17% of patients were still adherent!

K. Logee and colleagues presented [No. 214]: "Use Of Dual-Energy Computed Tomography In Evaluation Of Axial Gout." Nice pictures! Conclusion: "Dual-energy CT can be used to visualize the presence of axial MSU deposition. This may lead to appropriate diagnosis and management of axial gout while avoiding invasive procedures and erroneous treatment." I think, we're still far away from the second half of the authors' conclusion.

P. Sunkureddi and colleagues presented the following study [No. 1177]: "Efficacy and Safety Of Canakinumab Pre-Filled Syringe Versus Triamcinolone Acetonide In Acute Gouty Arthritis Patients." Conclusion: "CAN-PFS (Canakinumab pre-filled syringe) was superior to TA (triamcinolone acetonide) in relieving pain and reducing risk of new attacks, and had a safety profile similar to CAN-LYO (Canakinumab lyophilized powder). The safety profile was also consistent with that observed in previous CAN-LYO studies. Efficacy and safety of the two CAN (Canakinumab) formulations were comparable." I know that this study won't have much impact on daily life, but I think it's an important study for the one patient we all might see in the next years, where everything else had failed.

K.G. Saag and colleagues looked at [No. 1178]: Effect Of Febuxostat On Serum Urate Levels In Gout Subjects With Hyperuricemia and Moderate-To-Severe Renal Impairment: A Randomized Controlled Trial." Conclusion: "In subjects with moderate-to-severe renal impairment, FEB (febuxostat) urate-lowering was efficacious, with no emergent serious safety issues at 12 m (months). The sUA (serum uric acid) was significantly reduced in subjects receiving either regimen of FEB compared to PLB (placebo)." I guess, febuxostat is now fully established, though the high price might still be a problem.

S. Baumgartner and colleagues looked at [No. 1189]: "Allopurinol Dose Titration and Efficacy: A Large-Scale, 6-Month, Multicenter, Prospective Study." Conclusion: " In this large, multinational, prospective observational study of gout, optimal allopurinol dose escalation occurred infrequently. Fewer than 50% of patients overall achieved target sUA level greater than 6.0 mg/dL and the majority of those with a baseline dose of or higher than 300 mg/day did not increase their dose. These data, consistent with published literature, likely reflect real-world circumstances in which a significant proportion of patients fail to reach sUA targets with allopurinol therapy as currently used." PDCA! We have good plans (plan), we put them into practice (do), we have to check more consequently (check), and act - increase the dosage. Hopefully, patients won't leave this quality improving cycle.

F. Perez-Ruiz and colleagues presented [No. 1191]: Low-Dose Anakinra Is Effective For The Prophylaxis Of Acute Episodes Of Inflammation In Severe Tophaceous Gout." Conclusion: "This pilot study is, to our knowledge, the first to prospectively explore in pre-established doses the efficacy of low-dose anakinra for the prophylaxis of AEIs in patients with severe comorbidities and difficult to treat tophaceous gout."

R.T. Keenan and colleagues presented [No. 1193]: "Target Tophus Size and Complete Response Rates In Patients Treated With Open-Label Pegloticase For Chronic Gout Refractory To Conventional Therapy." Conclusion: "Many small and medium subcutaneous tophi resolved within the first 6 months of pegloticase therapy. These data show that substantial incremental benefit in tophus response for unresolved small to medium tophi can be gained with 9–12 months of therapy in UA responders." I have seen patients, who would benefit from pegloticase, but there are problems with getting an appoval by insurance companies as it's an off-label use.

There were lots of interesting studies on gout at both the EULAR 2013 Meeting in Madrid and the ACR 2013 Meeting in San Diego. Let's hope that we can counsel patients even better now.

Picture of tophous gout

Rituximab a look at off-label use

I only just now chanced to look at a study from the German registry RABBIT on rituximab (RTX). A. Richter and colleagues looked at [FRI0212]: “Is there a downside in off-label use of rituximab? - 2-year data from the German biologics register RABBIT.” We look at 709 patients in all groups, but we don’t know anything on the distribution on groups like RTX + MTX, RTX + LEF , and RTX mono; the authors also calculated for RF pos. and RF neg. The authors concluded: “Off-label uses of RTX in combination with LEF or of RTX in monotherapy are not inferior to RTX+MTX therapy regarding safety, effectiveness and therapy adherence. RTX+LEF or RTX monotherapy are useful alternatives for patients being intolerant to MTX, with the particular feature that RTX monotherapy should be restricted to rheumatoid factor positive patients to ensure therapy adherence.“ The last conclusion is due to “rheumatoid factor negative patients had a two-fold increased hazard to drop-out if treated in RTX monotherapy (2.15, p≤0.01).”

Somehow I think this is good news as we have to work under conditions, where RTX + LEF is considered off-label and RTX won’t be reimbursed. Some rheumatologists here in Germany prescribe a very, very low dose MTX co medication not to risk being off-label. So any study proving that monotherapy is effective, is welcome. We would also like to reduce the prednisolone and maybe twice 500 mg RTX are as effective as twice 1000 mg. Lots of questions and I hope, we’ll see the answers soon.

28.08.2013

I’ve just looked at an article, which is of interest. M. Bredemeier and colleagues looked at: “Low- versus high-dose rituximab for rheumatoid arthritis: A systematic review and meta-analysis.” The authors concluded: “Low-dose RTX has similar effectiveness and met non-inferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for rheumatoid arthritis.”

The study looked at 2x500 mg against 2x1000 mg rituximab. It didn’t look at intervals. Spacing the interval might not look like a straight forward infringement of an off-label prohibition. But I’m already happy about this study as it points in the right direction, leading to cost reduction without loosing effectiveness. Link: http://onlinelibrary.wiley.com/doi/10.1002/acr.22116/abstract?systemMessage=Wiley+Online+Library+will+be+disrupted+on+31+August+from+10%3A00-12%3A00+BST+%2805%3A00-07%3A00+EDT%29+for+essential+maintenance

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.