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Aksial SpA : Effekt av TNF-hemmer nr. 2 og andre biologiske legemidler

Aksial SpA : Effekt av TNF-hemmer nr. 2 og andre biologiske legemidler. Fredrikstad , 29. november 2013 Elisabeth Lie, MD, PhD Diakonhjemmet Hospital Dept. of Rheumatology. Outline. Background for switching TNFi Efficacy of treatment with a 2 nd TNFi in axial SpA including AS

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Aksial SpA : Effekt av TNF-hemmer nr. 2 og andre biologiske legemidler

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  1. AksialSpA: Effektav TNF-hemmer nr. 2 ogandrebiologiskelegemidler Fredrikstad, 29. november 2013 Elisabeth Lie, MD, PhD Diakonhjemmet Hospital Dept. of Rheumatology

  2. Outline Background for switching TNFi Efficacy of treatment with a 2ndTNFi in axial SpA including AS Does the reason for switching influence the efficacy of the 2ndTNFi? Efficacy of other biologics in AS/axial SpA Summary and conclusions

  3. Background

  4. TNFi – differences in structure Lee SJ et al, J AllergyClinImmunol 2010.

  5. Non-response in RCTs and LOS 1van der Heijde D et al, ArthritisRheum 2005. 2Davis JC et al, ArthritisRheum 2003. 3van der Heijde D et al, ArthritisRheum 2006. 4Inman RD et al, ArthritisRheum 2008. 5Landewé R et al, Ann Rheum Dis 2013. 6Fagerli KM et al, Rheumatology2012. 7Lord PAC et al, Rheumatology 2010. 8Glintborg B et al, Ann Rheum Dis 2013.

  6. Type of TNFi failures • Primarylackofefficacy • Partialresponse • Secondary loss ofefficacy • Adverseevents • Mild, moderate, severe • Infusion or injectionsitereactions • Infections

  7. Anti-drug antibodies in AS – IFX de Vries MK et al, Ann Rheum Dis 2007;66:1252-4.

  8. Anti-drug antibodies in AS – ADA de Vries MK et al, Ann Rheum Dis 2009;68:1787-8.

  9. ASAS/EULAR recommendations 2010 Update ofthe ASAS/EULAR recommendations for the management ofankylosingspondylitis ”Switching to a second TNF blockermight be beneficialespecially in patientswith loss ofresponse.” Braun J et al, Ann Rheum Dis 2011;70:896-904.

  10. Efficacy of a 2ndTNFiin AS/axial SpA

  11. RHAPSODY Rudwaleit M et al, J Rheumatol 2009;36:801-8. Rudwaleit M et al, Arthritis Res Ther 2010;12:R117. • Open-label, 12-week studyofadalimumab in AS • 1,250 patientsincluded – 326 patientswith prior useof IFX and/or ETN • 162 IFX only, 85 ETN only, 79 both IFX and ETN • Predictorsofresponse: Younger age, higher CRP, HLA-B27 positivity, TNFinaivety

  12. RHAPSODY IFX only: BASDAI 50 44%, ASAS40 48% ETN only: BASDAI 50 39%, ASAS40 33% IFX and ETN: BASDAI 50 32%, ASAS40 34% Rudwaleit M et al, J Rheumatol 2009;36:801-8. Rudwaleit M et al, Arthritis Res Ther 2010;12:R117.

  13. DANBIO • 432 patientswith AS treatedwith a 2ndTNFi • Of 1,436 patientswith AS startingTNFitreatment (=30%) • Reason for switching: LOE n=240, AE n=118, Other n=62, Not stated n=12 • Most common combinations 1st2ndTNFi: • IFXADA n=161 • IFXETN n=88 • ADAETN n=84 • ETNADA n=36 Glintborg B et al, Ann Rheum Dis 2013;72:1149-55.

  14. BASDAI response BASDAI 50%/20 mm response at 6 months: 54% for 1stTNFi 37% for 2ndTNFi Glintborg B et al, Ann Rheum Dis 2013;72:1149-55.

  15. Drug survival 47% remainingontherapyafter 2 years (vs. 58% for 1stTNFi) Glintborg B et al, Ann Rheum Dis 2013;72:1149-55.

  16. *BASDAI responsedefined as 50% or 2 units (20 mm) improvement

  17. Reason for switching and efficacy of the 2ndTNFi

  18. RHAPSODY Rudwaleit M et al, Arthritis Res Ther 2010;12:R117.

  19. SLR on 2ndTNFi in RA Systematicliteraturesearchof studies assessingefficacyofswitch to a 2ndTNFi 32 relevant studies selected – n=4,441 Only 1 randomisedstudyincluded Most patientsswitched from IFX to ETN (n=1,364), IFX to ADA (n=788), or ETN to ADA (n=210) Rémy A et al, ClinExpRheumatol 2011;29:96-103.

  20. 2ndTNFi in RA: Pooled results *Pooled data at 3-, 6- and 12-month follow-up. Values are percentages with 95% CI. Rémy A et al, ClinExpRheumatol 2011;29:96-103.

  21. 2ndTNFi in RA: Pooled results Rendas-Baum R et al, Arthritis Res Ther 2011;13:R25.

  22. RA: Reason for discontination 2ndTNFi Blom M et al, J Rheumatol 2009;36:2171-7.

  23. Meta-analysis of RCTs in RA Golimumab: GO-AFTER Abatacept: ATTAIN Rituximab: REFLEX Tocilizumab: RADIATE Schoels M et al, Ann Rheum Dis 2012;71:1303-8.

  24. Are there alternative treatments in axSpA?

  25. Anakinra N=9 Active AS (VAS pain/nightpain >30, CRP >10 mg/L) Failure ≥1 NSAID ”Anakinramay have a role in patientswith AS whocannottolerate anti-TNF treatment or for whom it has failed, butfurtherrandomisedcontrolled trials areneeded...” Tan AL et al, Ann Rheum Dis 2004;63:1041-5.

  26. Anakinra N=20 Active AS (BASDAI ≥4) NSAID-IR ”..anakinraseemed to be effective in a smallproportionofpatientswithactive AS.” Haibel H et al, Ann Rheum Dis 2005;64:296-8.

  27. Rituximab N=20 Active AS (BASDAI ≥4) TNFi-naïve n=10 TNFi-failures n=10 Song I-H et al, ArthritisRheum 2010;62:1290-7.

  28. Rituximab N=20 Active AS (BASDAI ≥4) TNFi-naïve n=10 TNFi-failures n=10 ”..rituximabtreatmentmightcurrently be considered in AS patientswith contraindications for TNF blockers...” Song I-H et al, ArthritisRheum 2010;62:1290-7.

  29. Rituximab 1-year follow-up ofptswith ASAS20 response at at least 2 consecutivevisits (n=9 – 6 TNFi-naïve, 3 TNFi-failures) ”A largercontrolledstudyevaluatingtheroleof B celldirectedtherapy in active AS seems to be justified.” Song I-H et al, Ann Rheum Dis 2013;72:305-6.

  30. Abatacept N=30 Active AS (BASDAI ≥4 + back pain≥4) TNFi-naïve n=15 TNFi-IR n=15 Song I-H et al, Ann Rheum Dis 2011;70:1108-10.

  31. Abatacept N=30 Active AS (BASDAI ≥4 + back pain≥4) TNFi-naïve n=15 TNFi-IR n=15 ”…a major response from treatmentwithabatacept in active AS could not be shown in this pilot study.” Song I-H et al, Ann Rheum Dis 2011;70:1108-10.

  32. Abatacept • N=7, 5 AS, 2 undiff. SpA • Failed at least 2 TNFi, all werewomen • Primaryendpoint: BASDAI response (50% or 2 cm improvement) at 24 weeks • No patientwith ≥50% decrease in BASDAI, only 1 patientwith ≥2 cm decrease in BASDAI • No improvement in pain or PGA • ”…abataceptdid not meaningfullyimprovediseaseactivity, function, or otherdiseaseparameters…” • ”…do not suggest a strongefficacyofabatacept in axial forms ofspondyloarthropathies.” Lekpa FK et al, Joint Bone Spine 2012;79:47-50.

  33. Tocilizumab AS (mod. NY), BASDAI ≥4, spinal pain≥40 (elevated CRP ≥3 mg/L) BUILDER-1 – TNFi-naïve BUILDER-2 – TNFi-IR ”TCZ is not an effectivetreatment for patientswith AS.” Sieper J et al, Ann Rheum Dis 2013 (epub June 13).

  34. Sarilumab Phase 2 study Active AS NSAID-IR or intolerant 5 sarilumabgroups vs. placebo 24.0% 38.0% p=0.143 ”The study failed to demonstrate the efficacy of sarilumab in patients with AS assessed by ASAS20 response.” Sieper J et al, Ann Rheum Dis 2012;71(Suppl 3):111.(OP0169 EULAR 2012)

  35. Secukinumab Anti-IL-17A; 28-week proof-of-conceptstudy Secukinumab 2 x 10 mg/kg i.v. vs. Placebo (4:1) AS (mod. NY), BASDAI ≥4, spinal pain ≥40 ”…rapidlyreducedclinical or biologicalsignsofactive AS…” Baeten D et al, Lancet 2013;382:1705-13.

  36. Ustekinumab Anti-IL-12/23 (p40 subunit) TOPAS: 28-wk prospective, open-label, proof-of-conceptstudy UST 90 mg s.c. BL, wk 4, wk 16 ”…ustekinumab treatment seems to be effective with a significant reduction of signs and symptoms of active AS.” Poddubnyy D et al, Arthritis Rheum 2013;65(suppl):766.(Abstract #1798, oral presentation)

  37. Otheremergingtherapies Tofacitinib(JAK-1/-3 inhibitor): In phase 2 Apremilast (PDE-4 inhibitor): In phase 3 Ixekizumab(anti-IL-17A): Starting phase 3 (SPIRIT A1)

  38. Summary and conclusions (1) Lack of response, loss of response and intolerance to 1stTNFi makes switching to a 2nd – and even 3rd, 4th – TNFi common practice Clinically meaningful responses with a 2ndTNFi– however reduced compared to 1stTNFi Success with 2ndTNFi better in cases of intolerance and loss of response ASAS/EULAR recommendations support switching to a 2ndTNFi, especially in cases with loss of response

  39. Summary and conclusions (2) Tocilizumab and sarilumab (anti-IL-6-R) clinical trial programs terminated No/questionableefficacyofanakinra and abatacept Rituximabeffective in TNFi-naïvepatients?? Promise for secukinumab (anti-IL-17) and ustekinumab (anti-IL-12/23)

  40. Takk for oppmerksomheten!

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