Filgotinib at the ACR 2015 Meeting in San Francisco

There have been seven publications on Filgotinib at the ACR 2015 Annual Meeting in San Francisco. Filgotinib (already known as: GLPG0634) is a novel oral, potent and selective JAK1 inhibitor.

R Westhovens and colleagues presented results from a phase 2B dose ranging study over 12 weeks. Conclusion: "Over 12 weeks, filgotinib in combination with MTX demonstrated consistent efficacy on signs and symptoms of active RA with a rapid onset of action. [...]"

Arthur Kavanaugh et al. also looked at results from a phase 2B dose ranging study over 12 weeks. The reported on filgotinib as monotherapy. Conclusion: "Over 12 weeks, filgotinib as monotherapy demonstrated clear efficacy in treating the signs and symptoms of active RA with a rapid onset of action. Overall safety profile was favorable and consistent with previous studies conducted in RA with filgotinib."

Namour Florence and colleagues presented data in the influende of age and renal impairment from phase 1 studies. Conclusion: "Higher age and mild to moderate impairment of renal function has a limited impact on the PK [pharmacokinetics] of filgotinib. In severe renal impairment, the exposure to filgotinib’s active metabolite is elevated, consistent with its renal elimination pathway. This was not associated with safety signals in these Phase 1 studies."

There were of course more studies: René Galien and colleagues (filgotinib) decreases plasma markers of inflammation and joint damage), René Galien and another team (filgotinib changes lipid profile with a preferential increase in HDL), Namour Florence et al. (filgotinib shows similar pharmacokinetics and pharmacodynamics profiles in Japanese and Caucasian healthy volunteers), and René Galien and colleagues (further evidence for the JAK1 selectivity of filgotinib).

All in all, filgotinib has presented data up to 12 weeks. We have to wait for a phase 3 study ... and much longer for data on radiographic progression.

References:

Westhovens R, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective in Combination with Methotrexate in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-an-oral-jak1-selective-inhibitor-is-effective-in-combination-with-methotrexate-in-patients-with-active-rheumatoid-arthritis-results-from-a-phase-2b-dose-ranging-study/. Accessed November 18, 2015.

Kavanaugh A, Ponce L, Cseuz R, Reshetko O, Stanislavchuk MA, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor Is Effective As Monotherapy in Patients with Active Rheumatoid Arthritis: Results from a Phase 2B Dose Ranging Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-an-oral-jak1-selective-inhibitor-is-effective-as-monotherapy-in-patients-with-active-rheumatoid-arthritis-results-from-a-phase-2b-dose-ranging-study/. Accessed November 18, 2015.

Florence N, Fagard L, Van der Aa A, Goss S, Harrison P, Tasset C. Influence of Age and Renal Impairment on Pharmacokinetics of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/influence-of-age-and-renal-impairment-on-pharmacokinetics-of-filgotinib-glpg0634-a-selective-jak1-inhibitor/. Accessed November 18, 2015.

Galien R, Van der Aa A, Blanque R, Darquenne S, Harrison P, Tasset C. Selective JAK1 Inhibition with Filgotinib (GLPG0634) Decreases Plasma Markers of Inflammation and Joint Damage in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/selective-jak1-inhibition-with-filgotinib-glpg0634-decreases-plasma-markers-of-inflammation-and-joint-damage-in-patients-with-rheumatoid-arthritis/. Accessed November 18, 2015.

Galien R, Harrison P, Brys R, Van der Aa A, van 't Klooster G, Tasset C. 4-Week Treatment of Rheumatoid Arthritis Patients with the JAK1-Selective Inhibitor Filgotinib (GLPG0634) Changes Lipid Profile with a Preferential Increase in HDL [abstract]. Arthritis Rheumatol.2015; 67 (suppl 10). http://acrabstracts.org/abstract/4-week-treatment-of-rheumatoid-arthritis-patients-with-the-jak1-selective-inhibitor-filgotinib-glpg0634-changes-lipid-profile-with-a-preferential-increase-in-hdl/. Accessed November 18, 2015.

Florence N, Vayssière B, Galien R, Fagard L, Van der Aa A, Goss S, Harrison P, Tasset C. Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, Shows Similar Pharmacokinetics and Pharmacodynamics Profiles in Japanese and Caucasian Healthy Volunteers [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/filgotinib-glpg0634-a-selective-jak1-inhibitor-shows-similar-pharmacokinetics-and-pharmacodynamics-profiles-in-japanese-and-caucasian-healthy-volunteers/. Accessed November 18, 2015.

Galien R, Brys R, Van der Aa A, Harrison P, Tasset C. Absence of Effects of Filgotinib on Erythrocytes, CD8+ and NK Cells in Rheumatoid Arthritis Patients Brings Further Evidence for the JAK1 Selectivity of Filgotinib [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/absence-of-effects-of-filgotinib-on-erythrocytes-cd8-and-nk-cells-in-rheumatoid-arthritis-patients-brings-further-evidence-for-the-jak1-selectivity-of-filgotinib/. Accessed November 18, 2015.

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Baricitinib at the ACR 2015 Meeting in San Francisco

There have been seven publications on Baricitinib at the ACR 2015 Annual Meeting in San Francisco. Baricitinib is an oral inhibitor of Janus kinases selective for JAK 1 and 2.

The first study is a three arm study: baricitinib versus placebo or adalimumab. The study was published as a late breaking abstract. Peter C. Taylor and colleagues presented the results of a phase 3 study. In methods we read: "Pts with active RA (TJC≥6 & SJC≥6 & hsCRP≥6 mg/L) despite stable background MTX were randomized 3:3:2 to PBO, bari 4 mg once daily (QD), or adalimumab (ADA) 40 mg biweekly (Q2W), stratified by region and baseline joint erosion status. [...]" Conclusion: "In pts with active RA despite background MTX, once-daily oral bari was associated with significant clinical improvements compared to PBO and to ADA, with an acceptable safety and tolerability profile." There seems to be a slight advantage of baricitinib compared to adaliimumab.

Xin Zhang and colleagues worked on: "Evaluate the Dose Efficacy Response Relationship of Baricitinib in Patients with Rheumatoid Arthritis". The authors identified 4 mg QD identified as the preferred phase 3 dose, "splitting the dose into a BID regimen does not provide any advantage over QD dosing for any of the efficacy endpoints."

Roy Fleischmann and colleagues looked at: "Baricitinib, Methotrexate, or Baricitinib Plus Methotrexate in Patients with Early Rheumatoid Arthritis Who Had Received Limited or No Treatment with Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Phase 3 Trial Results". Study over 24 weeks. Conclusion: "In pts with early RA, all treatment groups experienced improvements in disease activity with bari 4 mg monotherapy producing significantly larger and more rapid improvements and higher rates of clinical remission compared to MTX monotherapy, with a satisfactory safety profile. MTX addition to bari 4 mg did not increase the benefit observed with bari monotherapy, while it appeared to increase the frequency of laboratory abnormalities." As methotrexate isn't tolerated by all patients, this could make baricitinib interesting.

Mark C. Genovese and colleagues presented: "Previous Biologic Disease-Modifying Antirheumatic Drug (bDMARD) Exposure and Efficacy and Safety Analysis from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitors". This post hoc analysis didn't reveal any "evidence of a qualitative interaction".

There were three more studies: Paul Emery and colleagues (Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients), Joel Kremer et al. (Response to Baricitinib at 4 Weeks Predicts Response at 12 and 24 Weeks), and Paul Emery and colleagues (Patient-Reported Outcomes from a Phase 3 Study of Baricitinib). Please see below for access to these studies.

Lots of interesting data! A new drug against rheumatoid arthritis has appeared on the horizon. But ... the evaluated and published data ends after 24 weeks. And there's no data yet on how successful baricitinb is concerning minimizing radiographic progression. Still some time needed before approval as a drug may be discussed. Anyway: good luck, baricitinib!

References:

Taylor PC, Keystone EC, van der Heijde D, Tanaka Y, Ishii T, Emoto K, Yang L, Arora V, Gaich CL, Rooney T, Schlichting DE, Macias W, de Bono S, Weinblatt ME. Baricitinib Versus Placebo or Adalimumab in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to Background Methotrexate Therapy: Results of a Phase 3 Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/baricitinib-versus-placebo-or-adalimumab-in-patients-with-active-rheumatoid-arthritis-ra-and-an-inadequate-response-to-background-methotrexate-therapy-results-of-a-phase-3-study/. Accessed November 20, 2015.

Zhang X, Chua L, Ernest CS II, Macias W, Rooney T, Tham LS. Evaluate the Dose Efficacy Response Relationship of Baricitinib in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/evaluate-the-dose-efficacy-response-relationship-of-baricitinib-in-patients-with-rheumatoid-arthritis/. Accessed November 20, 2015.

Fleischmann R, Takeuchi T, Schlichting DE, Macias WL, Rooney T, Gurbuz S, Stoykov I, Beattie SD, Kuo WL, Schiff M. Baricitinib, Methotrexate, or Baricitinib Plus Methotrexate in Patients with Early Rheumatoid Arthritis Who Had Received Limited or No Treatment with Disease-Modifying Anti-Rheumatic Drugs (DMARDs): Phase 3 Trial Results [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/baricitinib-methotrexate-or-baricitinib-plus-methotrexate-in-patients-with-early-rheumatoid-arthritis-who-had-received-limited-or-no-treatment-with-disease-modifying-anti-rheumatic-drugs-dmards-p/. Accessed November 20, 2015.

Genovese MC, Kremer JM, Kartman C, Schlichting DE, Xie L, Carmack T, Macias WL, Smolen JS. Previous Biologic Disease-Modifying Antirheumatic Drug (bDMARD) Exposure and Efficacy and Safety Analysis from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitors [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/previous-biologic-disease-modifying-antirheumatic-drug-bdmard-exposure-and-efficacy-and-safety-analysis-from-a-phase-3-study-of-baricitinib-in-patients-with-rheumatoid-arthritis-and-an-inadequate-re/. Accessed November 20, 2015.

Emery P, McInnes I, Genovese MC, Smolen JS, Kremer J, Dougados M, Schlichting DE, Rooney T, Issa M, de Bono S, Macias WL, Rogai V, Zuckerman SH, Taylor PC. Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients with Rheumatoid Arthritis in Two Phase 3 Studies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/characterization-of-changes-in-lymphocyte-subsets-in-baricitinib-treated-patients-with-rheumatoid-arthritis-in-two-phase-3-studies/. Accessed November 20, 2015.

Emery P, McInnes I, Genovese MC, Smolen JS, Kremer J, Dougados M, Schlichting DE, Rooney T, Issa M, de Bono S, Macias WL, Rogai V, Zuckerman SH, Taylor PC. Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients with Rheumatoid Arthritis in Two Phase 3 Studies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/characterization-of-changes-in-lymphocyte-subsets-in-baricitinib-treated-patients-with-rheumatoid-arthritis-in-two-phase-3-studies/. Accessed November 20, 2015.

Kremer J, Dougados M, Genovese MC, Emery P, Yang L, de Bono S, Holzkaemper T, Iikuni N, Schlichting DE, Smolen JS. Response to Baricitinib at 4 Weeks Predicts Response at 12 and 24 Weeks in Patients with Rheumatoid Arthritis: Results from Two Phase 3 Studies [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/response-to-baricitinib-at-4-weeks-predicts-response-at-12-and-24-weeks-in-patients-with-rheumatoid-arthritis-results-from-two-phase-3-studies/. Accessed November 20, 2015.

Emery P, Gaich CL, DeLozier AM, de Bono S, Liu J, Chang C, Dougados M. Patient-Reported Outcomes from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis with Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/patient-reported-outcomes-from-a-phase-3-study-of-baricitinib-in-patients-with-rheumatoid-arthritis-with-inadequate-response-to-conventional-synthetic-disease-modifying-antirheumatic-drugs/. Accessed November 20, 2015.

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Protein Kinase Inhibitors after the ACR 2015 Meeting in San Francisco – how much Hype is left?

I have already written about hype or hope in protein kinase inhibitors. Now, after the ACR 2015 Annual Meeting in San Francisco it’s time to ask: how much hype is left?

Here a chart, I’ve prepared only a year ago:

Xeljanz (tofacitinib) is on the market in the US for the treatment of rheumatoid arthritis, but still lacks approval in Europe.

Otezla (apremilast) has been approved in the US and later in Europe for the treatment of psoriatic arthritis.

One study on fostamatinib came up, but only on bovine cartilage cells – but still unexpected for me; see: links.

Baricitinib had been discussed in several studies, posters, talks at the meeting; I’ll write on the studies in detail, soon.

Addendum: somehow I've left out filgotinib. Filgotinib is still in the race. Please look for more details under links.

This list above is incomplete, I know, but it shows how many hopes we had. 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. This mass of different molecules with facets of different effects was fuelling the hype, which peaked, when Xeljanz got the FDA approval. But I assure you: the hype is gone. Xeljanz is struggling for EMEA approval. Fostamatinib like most others have been abandoned as potential drugs. Otezla is approved in Germany, but will hardly be used because of failure of obtain a positive GBA ruling. The GBA (Federal Joint Committee) “exerts a direct influence on the healthcare provisions”; for further details look at Wikipedia, you can use the link below. And I think that Baricitinib will reach approval, too.

I hope that the pharmaceutical industry is prudent enough not to overprice small molecules, so that our patient's needs are addressed.

Links:

http://rheumatologe.blogspot.de/2013/06/protein-kinase-inhibitors-hype-or-hope.html

http://rheumatologe.blogspot.de/2014/01/protein-kinase-inhibitors-where-do-we.html

http://rheumatologe.blogspot.de/2014/06/protein-kinase-inhibitors-at-eular-2014.html

http://rheumatologe.blogspot.de/2015/11/fostamatinib-at-acr-2015-meeting-in-san.html

https://en.wikipedia.org/wiki/Federal_Joint_Committee_(Germany)
http://rheumatologe.blogspot.de/2015/11/filgotinib-at-acr-2015-meeting-in-san.html

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Carpe Diem Haiku No. 862 Vistas

  

Snow fallen on peaks

Resting for a while, then melt

Monk is resting, too

Camels are ready

To move down from the mountains

Seasons guide nomads

Sharp ridges on top

Rounded base holds man and rock

Nature is yin-yang

http://chevrefeuillescarpediem.blogspot.de/2015/11/carpe-diem-862-vistas.html

Fostamatinib at the ACR 2015 Meeting in San Francisco

There has been one publication on Fostamatinib at the ACR 2015 Annual Meeting in San Francisco. After reading the study by M. Genovese and colleagues last year, I thought I’d never hear anything on fostamatinib again; follow the link below for the whole story. Let’s look at the study, I’ve found in the wake of this year’s ACR Meeting.

Cecilie F. Kjelgaard-Petersen and colleagues presented: “The Active Metabolite of Fostamatinib, R406, Only Decreases the Inflammation-Driven Extracellular Matrix Turnover of the Joint at High Concentrations Ex Vivo”. Background/Purpose: “Osteoarthritis (OA) and rheumatoid arthritis are degenerative diseases of the whole joint. […]” I wouldn’t classify RA as a degenerative disease, though mutilations might lead to further degeneration, also after successful therapy and in the absence of autoimmune inflammation. But let’s move on. “Fostamatinib has been tested in both phase II and phase III clinical trials with mixed results.” Well, I'd call this statement euphemistic, but this view is possible. Methods: ”Cartilage turnover was investigated using a bovine cartilage explant (BEX) model. […]” Conclusion: “These data show that R406 can inhibit pro-inflammatory ECM joint degradation at concentrations higher than 0.5 μM, but at 0.5 μM or lower R406 increased the inflammatory degradation of collagen type III and had no effect on aggrecan degradation. In contrast, the p38 inhibitor SB203580 had no effect on synovial ECM turnover or aggrecan degradation, underlining the importance of understanding the differences between inhibitors of pro-inflammatory mediators and their effect on the joint tissue.”

I think , we best sum it up this way: good study to know more about “differences between inhibitors of pro-inflammatory mediators and their effect on the joint tissue”, but I don’t see anything, that could lead to putting fostamatinib back on the agenda concerning rheumatoid arthritis.

References:

Kjelgaard-Petersen CF, Thudium CS, Siebuhr AS, Christiansen TG, Karsdal MA, Hägglund P, Bay-Jensen AC. The Active Metabolite of Fostamatinib, R406, Only Decreases the Inflammation-Driven Extracellular Matrix Turnover of the Joint at High Concentrations Ex Vivo [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/the-active-metabolite-of-fostamatinib-r406-only-decreases-the-inflammation-driven-extracellular-matrix-turnover-of-the-joint-at-high-concentrations-ex-vivo/. Accessed November 20, 2015.

Fostamatinib in Rheumatoid Arthritis

http://rheumatologe.blogspot.de/2014/10/fostamatinib-in-rheumatoid-arthritis.html

04.12.2015
Today I've read in the "Annals of the Rheumatic Diseases / The EULAR Journal" an article by P.C. Taylor and colleagues: "OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy". Conclusions: "Fostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24." "The modest clinical resulta in all of the phase III studies have let to a decision by the companies developing fostamatinib to not submit a regulatoty filing for its use in RA." "The relevance of these findings for other more selective SYK inhibitors remains to be seen.

Link:
http://ard.bmj.com/content/early/2014/07/29/annrheumdis-2014-205361.short?rss=1 

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ERAP1 at the ACR 2015 Meeting in San Francisco

There has been one publication on ERAP1 at the ACR 2015 Annual Meeting in San Francisco. ERAP1 (endoplasmic reticulum aminopeptidase 1) has a strong genetic association of with ankylosing spondylitis, which is restricted to HLA-B27 positive cases. I’ve become interested while being at the 2014 EULAR Meeting in Paris. And now we have a new tiny piece of evidence that there might be a drug in the far future.

Tri M. Tran and colleagues presented: “ERAP1 Deficiency Protects HLA-B27 Transgenic Rats from Arthritis”. Conclusion: “Complete absence of ERAP1 protected B27-TG rats from arthritis, but led to an increase in gut inflammation, suggesting different effects on pathogenic mechanisms involved in arthritis and colitis. B27-TG rats heterologous for ERAP1 exhibited higher incidence of arthritis concomitant with lower inflammation in the gut as compared to ERAP1-/- .This novel model provides an opportunity to better understand the mechanism(s) by which HLA-B27 contributes to SpA pathogenesis”.

Protection from arthritis, but increase in gut inflammation. What goes through my mind now? Far future, individually tailored therapy, basic science … Yes, and far too early to speculate on a new drug.

References:

Tran TM, Hong S, Gill T, Bennett J, Sikora K, Colbert RA. ERAP1 Deficiency Protects HLA-B27 Transgenic Rats from Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/erap1-deficiency-protects-hla-b27-transgenic-rats-from-arthritis/. Accessed November 20, 2015.

ERAP1 at the EULAR 2014 Meeting in Paris http://rheumatologe.blogspot.de/2014/07/erap1-at-eular-2014-meeting-in-paris.html

ABT-122 at the ACR 2015 Meeting in San Francisco

There has been one publication on ABT-122 at the ACR 2015 Annual Meeting in San Francisco. ABT-122 is an anti-TNF/IL-17 Dual Variable Domain immunoglobulin (DVD-Ig™). It had been "demonstrated that dual neutralization of TNF and IL-17 provides greater efficacy than blocking either cytokine alone in mouse collagen induced arthritis". But we already know, that for instance secukinumab (an anti-IL-17a MAB) did not achieve the primary endpoint (ACR20) in patients with rheumatoid arthritis. So, from the beginning I’m very sceptical. But let’s look at the study.

Roy Fleischmann and colleagues presented: “Safety, Tolerability, and Pharmacodynamics of ABT-122, a Dual TNF- and IL-17-Targeted Dual Variable Domain (DVD)-IgTM in Subjects with Rheumatoid Arthritis”. Background/Purpose: […] ABT-122 is […] is hypothesized to provide greater clinical responses in patients with RA.” Conclusion: “ABT-122 demonstrated a well tolerated safety profile in subjects with RA through 8 weeks of dosing up to 3 mg/kg, […] decreases in these chemokines [CXCL9, CXCL10, and CCL23] indicate that ABT-122 rapidly modulates potential pathophysiologic pathways in RA patients, with evidence for persistent effects after cessation of dosing. These results suggest that dual neutralization of TNF and IL-17 may provide an opportunity to control inflammation and its clinical manifestations in RA subjects and in other immune-mediated inflammatory diseases.” Thin ice!

I think the first step in convincing me would be testing ABT-122 against a TNF-inhibitor. As ABT-122 comes from AbbVie, testing against Humira shouldn’t be a problem. Until then, IL-17 in ABT-122 may be nothing more than a pinch of cinnamon in the coffee, which changes the flavour but not the caffeine content.

References:

Fleischmann R, Wagner F, Kivitz AJ, Mansikka HT, Khan N, Liu J, Gagnon J, Hong F, Ruzek M, Padley RJ. Safety, Tolerability, and Pharmacodynamics of ABT-122, a Dual TNF- and IL-17-Targeted Dual Variable Domain (DVD)-IgTM in Subjects with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/safety-tolerability-and-pharmacodynamics-of-abt-122-a-dual-tnf-and-il-17-targeted-dual-variable-domain-dvd-igtm-in-subjects-with-rheumatoid-arthritis/. Accessed November 20, 2015.