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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

AksialSpA: Effektav TNF-hemmer nr. 2 ogandrebiologiskelegemidler

Fredrikstad, 29. november 2013

Elisabeth Lie, MD, PhD

Diakonhjemmet Hospital

Dept. of Rheumatology

outline
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

tnfi differences in structure
TNFi – differences in structure

Lee SJ et al, J AllergyClinImmunol 2010.

non response in rcts and los
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.

type of tnfi failures
Type of TNFi failures
  • Primarylackofefficacy
  • Partialresponse
  • Secondary loss ofefficacy
  • Adverseevents
    • Mild, moderate, severe
    • Infusion or injectionsitereactions
    • Infections
anti drug antibodies in as ifx
Anti-drug antibodies in AS – IFX

de Vries MK et al, Ann Rheum Dis 2007;66:1252-4.

anti drug antibodies in as ada
Anti-drug antibodies in AS – ADA

de Vries MK et al, Ann Rheum Dis 2009;68:1787-8.

asas eular recommendations
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.

rhapsody
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
rhapsody1
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.

danbio
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.

basdai response
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.

drug survival
Drug survival

47% remainingontherapyafter 2 years (vs. 58% for 1stTNFi)

Glintborg B et al, Ann Rheum Dis 2013;72:1149-55.

rhapsody2
RHAPSODY

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

slr on 2 nd tnfi in ra
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.

2 nd tnfi in ra pooled results
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.

2 nd tnfi in ra pooled results1
2ndTNFi in RA: Pooled results

Rendas-Baum R et al, Arthritis Res Ther 2011;13:R25.

ra reason for discontination 2 nd tnfi
RA: Reason for discontination 2ndTNFi

Blom M et al, J Rheumatol 2009;36:2171-7.

meta analysis of rcts in ra
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.

anakinra
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.

anakinra1
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.

rituximab
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.

rituximab1
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.

rituximab2
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.

abatacept
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.

abatacept1
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.

abatacept2
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.

tocilizumab
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).

sarilumab
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)

secukinumab
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.

ustekinumab
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)

other emerging therapies
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)

summary and conclusions 1
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

summary and conclusions 2
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)