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SIAAIC - Firenze 10 Ottobre 2014 Artrite reumatoide: nuove strategie biologiche Prof. Fabrizio Cantini U.O.C. di Reumatologia Azienda USL 4 - Prato From the arrival of biologics to targeted strategic treatment in RA 2000s Many advances in

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Artrite reumatoide: nuove strategie biologiche

  • Prof. Fabrizio Cantini

U.O.C. di Reumatologia Azienda USL 4 - Prato

SIAAIC - Firenze 10 Ottobre 2014

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Many advances in RA treatment in past 15 years

  • Early initiation of DMARDs1
  • Composite measures of disease

activity2,3

  • Definition of disease activity states

including ACR-EULAR remission4

  • Biological agents5

2000s

T2T Recommendations

Today

  • 1. Lard LR, et al. Ann J Med 2001;111:446–51. 2. van der Heijde D, et al. J Rheumatol 1993;20:579–81. 3. Smolen JS, et al.

Rheumatology 2003;42;244–57.

  • 4. Felson DT, et al. Arthritis Rheum 2011;63:573–86. 5. Smolen JS, et al. Lancet 2007;370:1861–74.

Remission (or LDA) are achievable goals From the arrival of biologics to targeted strategic treatment in RA

  • F. Cantini
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SLIDE 3

Currently Available Biologics

Drug Dose/Admin. Target Use approval Off-label Infliximab (Remicade) 3-5 mg/Kg/iv TNFα RA,AS,PsA, UC,Crohn Dis. BD,Uveitis, Adalimumab (Humira) 40 mg/eow/sc TNFα RA,AS,PsA, Crohn Dis. BD,Uveitis Etanercept (Enbrel) 50 mg/we/sc TNFα RA,AS,PsA Golimumab (Simponi) 50 mg/mo/sc TNFα RA,AS,PsA Certolizumab (Cimzia) 400 mg/we 0,2,4 (loading) 200mg/eow/sc TNFα RA Anakinra (Kineret) 100 mg/day/sc IL1 RA AOSD Rituximab (Mabthera) 2X1000/mg/iv/ every 6 mo CD20 RA ANCA+ vasculitis Tocilizumab (Roactemra) 8 mg/Kg/mo IL6 RA GCA Abatacept (Orencia) 750 mg/mo/iv CD28 RA Sjogren S.

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DAS28 Remission (Primary Endpoint) and DAS Remission at Week 52

49.8*

*P<0.001

51.3* 27.8 27.8

ETANERCEPT IN EARLY RA COMET STUDY

10 20 30 40 50 60 DAS28 Remission DAS Remission

MTX ETN +MTX

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SLIDE 5

Overarching principles for RA treatment

–

Primary treatment goal: Long-term HRQoL

  • Symptom control, prevention of structural damage,

normalisation of function, social participation

–

Abrogation of inflammation is key

–

T2T: Measure disease activity, adjust therapy accordingly

–

Shared treatment decisions: Patients and rheumatologist

Smolen JS, et al. Ann Rheum Dis 2010;69:631–37

Recommendations for a T2T approach in RA

  • F. Cantini
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SLIDE 6

Raccomandazioni della task force T2T in ar

Il trattamento dell’AR deve basarsi su una decisione condivisa tra paziente e reumatologo

Smolen J, et al. Ann Rheum Dis 2010;69:964–75; Smolen J, et al. Ann Rheum Dis 2010;69:631–37.

Approccio Treat-to-target: principi

L’obiettivo primario del trattamento del paziente con AR è ottenere la migliore qualità di vita a lungo termine attraverso il controllo dei sintomi, la prevenzione del danno strutturale, la normalizzazione della funzione e della partecipazione sociale. L’eliminazione dell’infiammazione è il modo principale per raggiungere questi obiettivi. Il trattamento al target con misurazione dell’attività di malattia e aggiustamento della terapia

  • ttimizza i risultati nell’AR.
  • F. Cantini
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SLIDE 7

EULAR reccomendations and T2T

  • F. Cantini
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SLIDE 8

Algorithm based 2013 EULAR recommendations on RA management: Phase II

Failure for lack of efficacy and/or toxicity in Phase I

Prognostically unfavorable factors present Prognostically unfavorable factors absent

Add a biologic agent TNF inhibitor, ABA, or TCZ

Change to a second csDMARD strategy: LEF, SSA, MTX alone or in combinationb (ideally with addition of glucocorticoids as above)

No Achieve target within 6 monthsa Achieve target within 6 monthsa Failure Phase II: go to Phase III

No

Continue

Yes

Such as RF / ACPA, especially at high levels; very high disease activity, early joint damage

Phase II

aThe treatment target is remission according to ACR-EULAR definition or, if remission is unlikely to be achievable, at least low disease activity; bNot many data available for combinations without MTX ABA, abatacept; ACPA, anti-citrullinated protein antibody; RF, rheumatoid factor; TCZ, tocilizumab

  • F. Cantini
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SLIDE 9

clinical practice, but ACR-EULAR remission associated with superior outcomes

DAS28 (<2.6) SDAIa (≤3.3) CDAIa (≤2.8) RAPID3 (≤1) ACR/ EULAR BOOLb ACR/ EULARc ACR/ EULAR PRACd

3 mos 19.1 7.6 8.1 17.0 6.9 9.3 8.1 MHAQ non progr. 3-12 mos 65.7 63.9 64.9 65.2 64.2 63.6 65.6 6 mos 24.7 10.5 11.3 19.8 9.0 12.3 11.0 MHAQ non- progr. 6-12 mos 69.6 73.5 73.6 69.8 74.9 72.6 73.7 5788 patients receiving a synthetic or biologic DMARD

Patients (%) in remission at 3 and 6 months using various measures of remission

RAPID3, Routine Assessment of Patient Index Data, range 0 10. ‒ aACR/EULAR index-based remission definitions bBOOL, Boolean application tender joint count, swollen joint count, patient global assessment and CRP all must be ≤1. cACR/EULAR remission if either ACR/EULAR BOOL is satisfied or SDAI ≤3.3. dACR/EULAR PRAC, definition of ACR/EULAR BOOL for clinical practice without CRP. MHAQ, modified health assessment questionnaire

  • F. Cantini
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SLIDE 10
  • The earlier, the better

– Diagnosis, treatment

  • The earlier, the better

– Achieving remission??

  • F. Cantini
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Low probability of reaching low disease activity at 2 and 3 years if it is not attained at year 1

  • If DAS 28 remains 3.2–5.1 after 1 year of conventional DMARD therapy, the

likelihood of remission or a LDA state is low

Kiely P, et al. Rheumatology 2011;50:926–931

80 60 40 20 Patients with year 1 DAS28 (3.2–5.1) Year 2 Year 3 DAS28<2.6 DAS28<3.2 DAS28≥3.2

(n=418)

  • F. Cantini
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SLIDE 12

Rezaei H, et al. Ann Rheum Dis 2012;71:186–91

CDAI, clinical disease activity index; DAS28, 28-joint-based disease activity score; SDAI, simple disease activity index.

114 107 109 110 102 103 n =

High activity Moderate activity Low activity Remission

1 year MTX 18.1 mg/week 2 years MTX 16.5 mg/week 20 40 60 80 100

Patients (%)

DAS28 SDAI CDAI DAS28 SDAI CDAI

Disease activity

SWEFOT: DAS28 remission achieved in 60% and 72% of MTX patients at 1 and 2 years, respectively

  • F. Cantini

487 RA p. 2 years

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SLIDE 13 1 2 3 4 5 6 7 8 9 10
  • F. Cantini
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Initial combo with biologics not recommended in EULAR 2013 recommendations

  • A. 6 months of MTX for achieving LDA
  • B. T2T approach
  • C. Rescue with ADA+MTX to ensure optimal
  • utcomes (Data from OPTIMA study)
  • F. Cantini
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SLIDE 15

OPTIMA

  • F. Cantini
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ADA 40 mg eow + MTX * MTX ADA 40 mg eow + MTX

Yes

MTX *

PERIOD 1

26 weeks

* MTX titrated to 20 mg/wk by Wk 8

Open label ADA 40 mg eow + MTX

No

PERIOD 2

52 weeks

No

Open label ADA 40 mg eow + MTX

Yes

MTX

DAS28<3.2 wk 22 -26

ARM 1 ADA+MTX / MTX ARM 2 Sustained ADA+MTX ARM 3 ADA+MTX IR / ADA+MTX ARM 4 Sustained MTX ARM 5 MTX IR / ADA+MTX

26 78

DAS28<3.2 wk 22 -26

Study Design

  • F. Cantini

1032 RA p.

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SLIDE 17

*P<0.001 vs. PBO+MTX by chi-square test, NRI analysis for completers wk26

20 40 60 80 100

207/466 112/460 240/466 155/460 238/466 132/460

% of pts

ADA+MTX PBO+MTX

Kavanaugh A, et al. Ann Rheum Dis 2013;72:64-71

OPTIMA: targeting stable DAS28(CRP)<3.2 at wk26

  • F. Cantini
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SLIDE 18

20 40 60 80 100

% of patients

* P=0.023 ADA+MTX vs. PBO+MTX

*

DmTSS < 0.5 from bl to wk 78

Smolen J, et al. Lancet 2013

A greater proportion of pts receiving ADA+MTX achieved the primary endpoint vs. PBO+MTX

  • F. Cantini
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SLIDE 19

20 40 60 80 100 % of Patinets

*P=0.034; **P=0.002; ***P=0.019 ADA+MTX vs MTX+PBO

**

_ _

* ** *

Smolen J, et al. Lancet 2013

Although a high % of MTX+PBO achieved a LDA or clinical remission at week 78, a significantly greater % of ADA+MTX achieved LDA and clinical remission

  • F. Cantini
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SLIDE 20

The size of the “Opportunity Lost”due to delayed initiation of ADA

Mean mTSS Change from Baseline

Weeks

MTX IR ADA+MTX Period 1 Period 2 Pts identified retrospectively as MTX-IR

Smolen J, et al. Lancet 2013

  • F. Cantini

0,00 0,15 0,00 1,20 1,20 1,30 0,00 0,50 1,00 1,50 26 52 78 ADA+MTX (Period 1) (N=508) [arm 5 MTX IR / ADA+MTX] (n=347)

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PREMIER

  • F. Cantini
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PREMIER study

Percentage of Patients Achieving DAS28(CRP) <3.2 (A), DAS28(CRP) <2.6 (B), during the Course of 10 Years of Adalimumab ± MTX Treatment

A B

For 10-year completers, patients in the adalimumab + MTX DB group achieved DAS28 LDA (92.3%) and remission (75.6%) more readily than patients who initiated treatment with adalimumab (77.8% and 61.7%, respectively) or MTX (74.0% and 56.2%, respectively) monotherapy

Keystone E et al, J Rheumatol 2014.

  • F. Cantini
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SLIDE 23

Percentage of radiographic non- progressors over time

Over the course of the 10-year study, treatment initialization with adalimumab + MTX significantly limited radiographic progression (adalimumab + MTX vs adalimumab, p = 0.01; adalimumab + MTX vs MTX, p < 0.001), joint erosion, and JSN compared to initialization with either monotherapy

Keystone E et al, J Rheumatol 2014.

A B

  • F. Cantini
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SLIDE 24

Percentage of patients achieving CDC and CDR during the course

  • f 10 years of ADA ± MTX

treatment

For 10-year completers, CDC was reported in 17.8%, 8.6%, and 9.6% of adalimumab + MTX, adalimumab, and MTX patients, respectively. Increased proportion of combination therapy patients achieving CDC or CDR were all statistically significant compared to either monotherapy (p ≤ 0.01).

Keystone E et al, J Rheumatol 2014.

A B

  • F. Cantini
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SLIDE 25
  • A 56 settimane con adalimumab + MTX si è osservata una perdita del lavoro/imminente

perdita del lavoro significativamente inferiore rispetto a placebo + MTX (p=0,005)

  • Studio multicentrico, randomizzato, controllato, su pazienti con AR precoce (<2 anni), naïve al MTX, che

avevano riferito spontaneamente una riduzione della capacità lavorativa, sono stati randomizzati a ricevere adalimumab + MTX o placebo + MTX per 56 settimane.

  • Bejarano V et al, Arthrit Rheum 2008.

Adalimumab + MTX

18,7%

Placebo + MTX

39,7%

Pazienti che hanno perso il lavoro/ in procinto di perdere il lavoro nelle 56 settimane dello studio

p=0,005

  • F. Cantini
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SLIDE 26

Over 2 years, patients who received combination therapy missed approximately half as many days as patients who received methotrexate (17.4 versus 36.9 days for employed workers; 7.9 versus 18.6 days for homemakers).

Van Vollenhoven R et al, Arthritis Care Res 2010.

  • F. Cantini
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SLIDE 27

DE019

  • F. Cantini
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SLIDE 28

Radiographic changes at Wks 24 and 52

0,5 1 1,5 2

28

*p ≤0.05, **p≤0.01 vs placebo; ***p≤0.001 vs placebo 0,5 1 1,5 2 2,5 3 Mean change from baseline in mTSS Placebo + MTX ADA 20 mg weekly + MTX ADA 40 mg eow + MTX

Modified total Sharp score Joint erosions

Time (wks) Mean change from baseline in JE Time (wks)

Joint space narrowing

0,2 0,4 0,6 0,8 1 1,2 1,4 Mean change from baseline in JSN Time (wks)

Keystone EC et al. Arthritis Rheum 2004;50:1400–1411 Keystone EC, et al. J Rheumatol 2013 Jul 1 [Epub]

  • F. Cantini
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SLIDE 29

ACR responses over 10 yrs

29 100 80 60 40 20 Pts (%) 2 1 4 6 8 10 Time (Yrs) 3 5 7 9

207 200 151 132 149 122 122 93 104 77 95 64 81 56 After Yr 1 (vertical broken line), all ptss received open-label adalimumab 40 mg eow + MTX *** and * indicate p-values of <0.001 and <0.05, respectively n= n= Initial ADA + MTX Delayed ADA + MTX

ACR50 – initial ADA + MTX ACR50 – delayed ADA + MTX ACR70 – initial ADA + MTX ACR70 – delayed ADA + MTX ACR90 – initial ADA + MTX ACR90 – delayed ADA + MTX

* *** ***

Keystone EC, et al. J Rheumatol 2013 Jul 1 [Epub]

Blinded study Open-label extension

  • F. Cantini
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SLIDE 30

Proportion of pts achieving DAS28 LDA/remission and SDAI remission over 10 yrs

30 100 80 60 40 20 2 1 4 6 8 10 Time (yrs) 3 5 7 9 Pts (%)

After Yr 1 (vertical broken line), all ptss received open-label adalimumab 40 mg eow + MTX ** and * indicate p-values of <0.01 and <0.05, respectively 207 200 150 133 148 120 122 94 104 78 94 64 n= n= 81 57 Initial ADA + MTX Delayed ADA + MTX

DAS28 <3.2 – initial ADA + MTX DAS28 <3.2 – delayed ADA + MTX DAS28 <2.6 – initial ADA + MTX DAS28 <2.6 – delayed ADA + MTX SDAI ≤3.3 – initial ADA + MTX SDAI ≤ 3.3 – delayed ADA + MTX

NS * **

Keystone EC, et al. J Rheumatol 2013 Jul 1 [Epub]

Blinded study Open-label extension

  • F. Cantini
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SLIDE 31

Proportion of pts achieving normal functionality (HAQ-DI <0.5) over 10 yrs

207 200 152 132 149 122 122 96 104 78 95 65 n= n= 81 57 Initial ADA + MTX Delayed ADA + MTX

100 80 60 40 20 Blinded study Open-label extension HAQ-DI <0.5 – initial ADA + MTX HAQ-DI <0.5 – delayed ADA + MTX NS

After Yr 1 (vertical broken line), all ptss received open-label adalimumab 40 mg eow + MTX

Pts (%) Time (yrs) 2 1 4 6 8 10 3 5 7 9

Keystone EC, et al. J Rheumatol 2013 Jul 1 [Epub]

  • F. Cantini
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SLIDE 32

Mean change from baseline in mTSS, and cumulative probability plot of change from baseline in mTSS, over 10 yrs

32

Open-label extension 8 6 2 2 1 4 6 8 10 Mean change from baseline in mTSS Time (yrs) 4 50 25

  • 25
  • 50

2 1 4 6 8 10 Pts (%) Initial ADA + MTX (n=79) Delayed ADA + MTX (n=54) 6.2 0.7* Change from baseline in mTSS After Yr 1 (vertical broken line), all pts received open-label adalimumab 40 mg eow + MTX *=indicates p-value of 0.002 0.5 p=0.01 Initial ADA + MTX (n=79) Delayed ADA + MTX (n=54)

Change from baseline in mTSS Cumulative probability plot of change from baseline in mTSS

Keystone EC, et al. J Rheumatol 2013 Jul 1 [Epub]

Blinded study −2

  • F. Cantini
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SLIDE 33

Comprehensive disease control at 10 yrs

Pts (%) 40 30 20 10 DAS28(CRP) <3.2 HAQ-DI <0.5 mTSS ≤0.5 DAS28(CRP) <2.6 HAQ-DI <0.5 mTSS ≤0.5 11.3 30.3* 11.3 27.6** Delayed ADA + MTX (n=53) Initial ADA + MTX (n=76)

*p=0.01; **p=0.03

∆mTSS, change in modified total Sharp score Keystone EC, et al. J Rheumatol 2013 Jul 1 [Epub]

  • F. Cantini
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SLIDE 34

CONCERTO

  • F. Cantini
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SLIDE 35

CONCERTO is portrayed in the EULAR 2013 recommendations

UPDATE 2013 “… Task Force felt that all bDMARDs should be used preferentially in combination with MTX or other csDMARDs. … a dose

  • f 10 mg MTX or more a week

appears to be effective and appropriate for use with ADA and IFX and, until proven otherwise, also with all other TNFis.”

35

Smolen JS, et al. Ann Rheum Dis 2014;73:492–509

  • F. Cantini
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SLIDE 36

CONCERTO study design

Supplementation with folic acid (5 mg/week) For suspected MTX intolerance and toxicity:

  • Blinded MTX dose reduction – reduce by 5 mg for MTX 10 mg and 20 mg groups, no change in MTX 2.5 mg and

5 mg groups

  • Temporary MTX discontinuation at any time during trial, including during escalation period
  • Re-introduction/re-escalation of MTX if issue resolved within 4 weeks

8 20 mg MTX (blinded) + open-label ADA 40 mg eow (n=98) 4 2 Week 16 26 12 X-ray Screening 20

15 mg 17.5 mg

X-ray

12.5 mg

2.5 mg MTX (blinded) + open-label ADA 40 mg eow (n=98) 5 mg MTX (blinded) + open-label ADA 40 mg eow (n=100) 10 mg MTX (blinded) + open-label ADA 40 mg eow (n=99) Early RA MTX naive

Burmester G, et al. Ann Rheum Dis 2014; 18 Feb (EPub)

  • F. Cantini
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SLIDE 37

Primary endpoint: DAS28(CRP) <3.2 at 26 weeks (NRI)

100 80 60 40 20 37 Proportion of pts (%)

40 mg ADA + 2.5 mg MTX 40 mg ADA + 5 mg MTX 40 mg ADA + 10 mg MTX 40 mg ADA + 20 mg MTX

42.9 44.0 56.6 60.2 p < . 5

Burmester G, et al. Ann Rheum Dis 2014; 18 Feb (EPub)

Statistically significant increasing trend in the proportion of pts achieving DAS28(CRP) LDA with increasing dose of MTX (from 2.5 mg to 20 mg) in combination with ADA

  • F. Cantini
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SLIDE 38

Clinical and functional efficacy over 26 weeks (NRI)

38 Internal medical material only | External distribution must pass local MedReg review

*, ** and *** denote statistically significant differences between the MTX dose groups at the 0.05, 0.01 and 0.001 levels, respectively 20 40 60 100 26 20 16 12 8 4 2 Proportion of pts (%) Time (weeks)

DAS28(CRP) <3.2 * ** **

20 40 60 100 26 20 16 12 8 4 2 Time (weeks)

DAS28(CRP) <2.6 ** **

20 40 60 100 26 20 16 12 8 4 2 Proportion of pts (%) Time (weeks) 70 100 80 90 60 26 20 16 12 8 4 2 Time (weeks)

** * *** ACR70 HAQ-DI change from baseline ≤ –0.22 * *

ADA + 2.5 mg MTX ADA + 5 mg MTX ADA + 10 mg MTX ADA + 20 mg MTX

  • Following 26 wks of treatment, there were statistically significant increasing trends in the proportion of

pts achieving DAS28 <3.2 (p<0.01), DAS28 <2.6 (p<0.01) and ACR70 (p<0.01) with increasing doses of MTX

Burmester G, et al. Ann Rheum Dis 2014; 18 Feb (EPub)

  • F. Cantini
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SLIDE 39

Clinical efficacy over 26 weeks: CDAI and SDAI (NRI)

Internal medical material

  • nly | External

distribution must pass local MedReg review

ADA + 2.5 mg MTX ADA + 5 mg MTX ADA + 10 mg MTX ADA + 20 mg MTX

  • Statistically significant increasing trends with increasing MTX dose were observed for CDAI LDA

(p=0.026) and remission (p=0.022) and for SDAI LDA (p<0.05) and remission (p≤0.01)

  • The 10 mg and 20 mg MTX groups displayed nearly identical rates of LDA and remission at Wk 26

20 40 70 100 26 20 16 12 8 4 2 Proportion of pts (%) Time (weeks) 10 30 50 60 20 40 70 100 26 20 16 12 8 4 2 Proportion of pts (%) Time (weeks) 10 30 50 60 20 40 70 100 26 20 16 12 8 4 2 Time (weeks) 10 30 50 60 20 40 70 100 26 20 16 12 8 4 2 Time (weeks) 10 30 50 60

* CDAI LDA * ** ** *** CDAI remission * * * ** ** ** *** SDAI LDA SDAI remission

Burmester G, et al. Ann Rheum Dis 2014; 18 Feb (EPub) *, ** and *** denote statistically significant differences between the MTX dose groups at the 0.05, 0.01 and 0.001 levels, respectively

  • F. Cantini
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SLIDE 40

Radiographic outcomes: Radiographic non-progression (NRI)

20 40 60 80 100 Proportion of pts (%) 40

aChange from baseline in mTSS at 26 wks ≤0.5

Burmester G, et al. Ann Rheum Dis 2014; 18 Feb (EPub)

  • F. Cantini
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SLIDE 41

  

KEY IMPLICATIONS :

1.

After DMARD failure, no preference given among biologic agents (including BioSimilars).

2.

When initiating a biologic, MTX in combination with biologic is preferred.

3.

If a first bDMARD has failed, patient should be treated with a second bDMARD (another aTNF or MOA)

  • F. Cantini