Pros and Cons of Combination MTX+ Biologics vs Monotherapy...

Pros and Cons of Combination

MTX+ Biologics vs Monotherapy

with Biologics: the place of

immunogenicity

Daniel E Furst MD

University of California in Los Angeles

University of Washington

University of Florence

Arthritis Associates of Southern California

Seattle Rheumatology Associates

© your company name. All rights reserved. Title of your presentation

Disclosures

• Abbvie

• Actelion

• Amgen

• BMS

• Corbus

• Cytori

• NIH

• Novartis

• Pfizer

• Roche/Genentech

• UCB

Why does it matter whether we

use MTX with biologics or use

biologics as monotherapy?

© your company name. All rights reserved. Title of your presentation

Treatment Adherence Issues in RAPrevalence

• Adherence Estimated 50-80% in RA patient population1,10

• Discrepancies in reported rates due to different approaches to measuring adherence2, 4

Patients at- risk for low treatment adherence

1Van den Bemt et al., Expert Rev. Clin. Immunol. 2012; 8(4):337–351; 2 Salt et al., Orthop Nurs. 2010 ; 29(4): 260–275; 3Benner et

al., Am J Health Syst Pharm. 2009;66(16):1471–7; 4Shi et al., Expert Rev Pharmacoecon Outcomes Res. 2007 Apr;7(2):187-202; 5Barlow et al., Am J Pharm Benefi ts. 2012;4(Special Issue):SP49-SP56) ; 6Klippel JH, Am J of Pharm Benefits, 2012; 7Zolnierek et

al., Med Care. 2009 August ; 47(8): 826–834.; 8Elliott et al., Dis Manage Health Outcomes 2008; 16 (1): 13-29; 9Martin et al., J

Rheumatol. 2008;35(4):618–24; 10de Achaval et al., J Musculoskel Med, 2010; 27(10):399-94.

Presence of

Complex Disease

Socioeconomi

c Factors

Patient-Related

Factors

Health Education

Gaps

Multiple

comorbidities1,3,4

Low SES7 Low self

efficacy1,2,10

Low health literacy1

Frequent or

complex

medication dosing

regimens1

Low

educational

attainment7

Depression10 Poor patient-

provider

communication2,8,9

Lack of insurance coverage for

treatment and/or high cost of

medications5,6, 10

Lack of social

support and other

life stressors2,8,10

Am J Managed Care, 2003;9:5136-5144

Direct Medical Costs for RA in

2001Physician/

Health Professional

Visits (7%)Testing† (7.8%)

Outpatient

Surgery (1.2%)

Hospitalization

(16.5%)

Nonbiologic

DMARDs

(6.8%)Biologic

DMARDs

(34.7%)

Other

Medications*

(24.8%)

Michaud K et al. Arthritis Rheum. 2003;48:2750-2762.

*NSAIDs, GI medication, non-RA medications; †radiographs, MRI, CT scans, endoscopies, laboratory

tests, mammograms, bone density tests, and other examinations

Why does it matter if MTX is added?

• Why not to add MTX:

• Added toxicity

• Added complexity

• Decreases adherence

• Why add MTX:

• Added efficacy(?)

• Decrease cost of

biologics(?)

Pros and Cons of Combination

MTX+ Biologics vs Monotherapy

with Biologics: the place of

immunogenicity

Daniel E Furst MD

University of California in Los Angeles

University of Washington

University of Florence

Arthritis Associates of Southern California

Seattle Rheumatology Associates

Outline

• The clinical effect(s) or non-effects of MTX on Biologics

• Possible explanations for these effects.

MTX Effects( or non-effects) on

Biologics

• TNFi

• Abatacept

• Rituximab

• Tocilizumab

TEMPO Trial—only examining 2 arms-Etan vs Etan+MTX

Etanercept (n=223)MTX + Etanercept

(n=231)

DA

S S

core

Analysis using LOCF.

Data on file, Wyeth.

0

1

2

3

4

5

6

0 4 8 12 16 20 24 32 40 48 52Weeks

**

2

*P<0.01 combination vs MTX or

etanercept.

Low disease activity DAS<=2.4

63%

46%

28%

54%

42%

26%

73%

62%

46%

0

20

40

60

80

100

ACR20 ACR50 ACR70

% o

f p

ati

en

ts

MTX Adalimumab MTX + adalimumab

PREMIER Trial:

ACR Responses at Week 52

*

*P=0.043 for MTX vs adalimumab, others NS.†P<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone.

Breedveld et al. ACR, 2004. Presentation L5.

†

†

†

Change in Total Sharp Score

* p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone

** p<0.001 for adalimumab vs MTX alone

PREMIER Study

0

1.9

0

5.5

0

10.4

1.30.8

3

2.1

5.7

3.5

0

2

4

6

8

10

12

0 26 52 78 104

Adalimumab + MTX

Adalimumab

MTX

**

**

**

*

**

Clinical Remission by DAS28<2.6(low disease activity)

*p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone

43

2321

49

25 25

0

10

20

30

40

50

60

Adalimumab + MTX Adalimumab MTX

Week 52

Week 104

% P

ati

en

ts

*

*

PREMIER Study

With TNFi, MTX improves

response in most ways,

including radiographically

remission data are less impressive

( ? Measurement effect)

MTX Effects( or non-effects) on

Biologics

• TNFi

• Abatacept

• Rituximab

• Tocilizumab

Early

RA if <3.2withdraw

ALL

study meds

DA

S2

8 (

CR

P)

Placebo + MTX

Abatacept + placebo

Abatacept + MTX

DA

S2

8 (

CR

P)

Co-primary endpoints:

0 12 2418

Randomization*

*Randomization stratified by corticosteroid use at baseline

Months

TREATMENT

RE-EXPOSURE period:

If flare or worsening symptoms

during Months 15–24

then 6 months’ open-label

abatacept + MTX

Co-primary:

DAS-defined remission

(DAS28 [CRP] <2.6)

at Month 12

Co-primary:

DAS-defined remission

at Month 12

AND

Month 18

if ≥3.2

then D/C

15

MRI was performed at Months 0, 6, 12, 18, and 24

Thanx to Vivien Bykerk Emery P. et al. ARD. 2014

Proportion of Patients with DAS28-CRP Remission over Time (>3

Months’ ≤6 Months’ Disease Duration)

0 29 57 85 113 141 169 197 225 253 281 309 337 365 394 422 450 534

Error bars represent 95% CI

14.7%

14.3%

13.8%

Visit DayPro

port

ion o

f P

atients

(%

)

Withdrawal period

Proportion of Patients with Boolean Remission over Time

(>6 Months’ Disease Duration)

0 29 57 85 113 141 169 197 225 253 281 309 337 365 394 422 450 534

Error bars represent 95% CI

8.2%4.4%2.6%

Visit DayPro

port

ion o

f P

atients

(%

)

Withdrawal period

With abatacept, MTX response is

probably still real

measurement effect is also

pronounced

WA16291: Design and Treatment

Groups MTX (>10mg/wk)

Rituximab, (1g x 2)

Rituximab, (1g x 2)

Cytoxan (750mg x 2)

Rituximab (1g x 2)

Baseline 24 weeks

MTX (>10mg/wk)

17 day corticosteroid

regimen in all arms

R

R = randomisation

N=40/arm

MTX

inadequate

responders

Phase 2a-Baseline Disease Characteristics

Rituximab

(n=40)

Rituximab

+ MTX

(n=40)

Previous DMARDs

(mean)2.5 2.5

Disease duration

(yrs)9 12

SJC (mean) 21 23

TJC (mean) 34 32

RF (median IU/mL) 159 149

CRP (mean mg/dL) 26 29

ESR (mean mm/h) 47 53

DAS28 6.8 6.8

Emery P et al. Arthritis Rheum. 2003;48:S439.Szczepanski L et al. Arthritis Rheum. 2003;48:S121..

Phase IIa

ACR Responses 24 Wk

15

33§

65*

23

43||

73‡

0

10

20

30

40

50

60

70

80

ACR20 ACR50 ACR70

Rituximab

RTX+MTX

¶

P values using Fisher’s Exact test, comparing MTX with each rituximab group

Emery P et al. Arthritis Rheum. 2003;48:S439.Szczepanski L et al. Arthritis Rheum. 2003;48:S121.

*P=0.025, †P=0.001, ‡P=0.003, §P=0.059, ||P=0.005, ¶P=0.048

(n=40)

(n=40)

With Rituximab, the pattern

holds

BUT here the response is less

impressive

41

31

61 63

29

6

28

41

16

26

16

0

10

20

30

40

50

60

70

80

MTX TCZ2mg/kg

TCZ4mg/kg

TCZ8mg/kg

ACR20 ACR50 ACR70

DBRCT CHARISMA: ACR response rates at Week 16 of TCZ monotherapy and in combination with MTX-only examine 2 of the 8 arms (small number of pts/gp))

ACR20, ACR50 and ACR70 response rates at week 16 in the groups of patients receiving methotrexate (MTX) plus placebo, those receiving tocilizumab (TCZ) monotherapy, and those receiving combination therapy with TCZ plus MTX

Maini RN, et al. Arthritis Rheum 2006;54:2817‒2829

Pa

tien

ts (

%)

Monotherapy Combination

41

64 63

74

2932

37

53

16 14 12

37

0

10

20

30

40

50

60

70

80

MTX TCZ 2mg/kg +

MTX

TCZ 4mg/kg +

MTX

TCZ 8mg/kg +

MTX

ACR20 ACR50 ACR70

**

**

***

****** **

Pa

tien

ts (

%)

**p<0.05

***p=0.001 vs MTX

Conclusion: response in short term in small number of pts

The FUNCTION trial:DAS28 remission and CDAI remission at 24 weeks

44.8

24.5

38.7

20.5

0

10

20

30

40

50

DAS28-ESR <2.6 (primary endpoint) CDAI remission

Pa

tie

nts

(%

)

TCZ 8 mg/kg + MTX (n=290)

TCZ 8 mg/kg (n=292)

Burmester G, et al. Oral presentation #OP0041. Thursday 13 June Hall 4

Conclusion: longer study and no differences

TCZ Mono.(N=115) vs TCZ+MTX(N=118) in MTX-IR: 24 wk,

randomized, OL Trial- longer study, larger numbers

Takeuchi T, Kaneky Y et al ARD 2013, 72(Suppl 3): 62(OPO040)

But no differences in CDAI,SDAI Remission

Also no differences in ACR70,HAQ-DI,EQ-5D

P=0.04

Conclusion: Altho DAS28 Remission favors TCZ/MTX, But 7 other measures not different—BUT OL

With Tocilizumab, the pattern

is broken

MTX adds only a little if at all

Why would this be?

One reason could be

immunogenicity.

To examine this we can look at:

SLR and meta-analysis of anti-drug

antibodies against TNFi in RA and

other rheumatic diseases

Thomas SS…Furst DE,

Biodrugs.2015.27:241-258


Biodrugs.2015.27:241-258

ADAB Positivity by Medication


Biodrugs.2015.27:241-258

% Anti-Drug Anti-bodies by TNFi

0.3

0.23

0.060.04

0.02

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

IFX ADAB CZP GOL ETAN

% ADAB+


Biodrugs.2015.27:241-258

Anti-Drug Antibody positivity by

Disease

Disease RR 95%CI #Articles ELISA RIA Other

RA 0.14 0.09-0.19 34 17 10 7

Inflamm.Bowel

Disease

0.25 0.16-0.34 19 13 4 2

SpA 0.07 0.02-0.13 9 4 5 0


Biodrugs.2015.27:241-258

Effect of Immunosuppression on Anti-

Drug Antibody positivity by Disease

Disease RR 95%CI #Articles ELISA RIA Other

RA 0.78 0.68-0.90 16 11 4 1

Inflamm.Bowel

Disease

0.63 0.55-0.73 14 12 2 0

SpA 0.32 0.16-0.55 6 2 3 1


Biodrugs.2015.27:241-258

Effect of ADAB+ on Response


Biodrugs.2015.27:241-258

Effect of Anti-Drug Antibody positivity on

Response by Disease

Disease RR 95%CI #Articles

RA 0.50 0.36-0.69 10

Inflamm.Bowel

Disease

0.52 0.25-1.06 5

SpA 0.45 0.25-0.80 4

Effect of ADAB+ on Response by

Medication

Drug RR 95%CI # Articles

Infliximab 0.46 0.30-0.69 8

Adalimumab 0.35 0.20-0.58

Golimumab 0.71 0.41-1.25 2

Certolizumab 1.14 -- 1

Etanercept 0.75 0.24-2.33 3


Biodrugs.2015.27:241-258

Random effect analysis on ADAB% by medication

Variable Name estimate p value

age 0.00 0.35

gender 0.00 0.65

Disease Duration 0.02 0.002

Assay 0.14 0.003

MTX% 0.00 0.06

Other IS% 0.00 0.60

Prednisone% 0.00 0.58

Baseline_RA -0.06 0.26

Baseline_IBD 0.00 0.65

Mixed effect model on ADAB% with individual variable as fixed

effect

By Univariate analysis, ADAB% is significantly affected by Disease

duration (p=0.002) and assay (0.003). For instance, every unit increase of

disease duration (week or month?) will increase ADAB+ by 2 percent; RIA

methods would measure 14% more ADAB+ than ELISA methods on

average.

The effect of MTX% to ADAB% is marginally significant (p=0.06), but the

effect is very small (nearly zero).Thomas SS…Furst DE,

Biodrugs.2015.27:241-258

Immunogenicity of Rituximab in RA: an

overviewMok CC. Drug Res Devel Ther 2014. 8:87-100

high

N=8 trials

N=3361

No relationship to:

RTX dose (500 vs

1000 mg)

Efficacy

Safety

May be found at only

1 visit

Conclusion: may develop immunogenicity as much as TNFi

No comment regarding method to detect ADA nor MTX etc

Immunogenicity of Abatacept in RAKremer JM, et al. Ann Int Med, 2006. 144: 865-76; Genovese MC et al. NEJM, 2005.

353:1114-23

ADAB %

Note: No comment with respect to efficacy or

safety but numbers very small (N=9)

Kremer: N=657 RA

Genovese: N=258 RA

Conclusion: very low immunogenicity;

no details regarding bkgrnd med( eg MTX)

Immunogenicity of Tocilizumab in RA:

in pts with AEs Stubenauch K, et al. ClinTher 2010:32:1577-1609

• 5 core trials

• N=2816 samples

• 10 of 11 tests positive by ELISA but only one + on repeat testing using more specific tests (surface plasmin resonance)

Conclusion: very low

immunogenicity.

No idea of background meds

IFX Biosimilar Immunogenicity vs IFX

reference compound: effect on safetySmolen JS, Choe J-Y et al. ARD EULAR 2016. abd FRI0162

• DB RCT of IFX vsSB2(biosimilar)

• At wk 54, 94 IFX started SB2, 101 IFX continued IFX; 201 SB2 continued SB2

• TEAE: IFX/SB2: 36.2%; IFX/IFX: 35.6%; SB2/SB2: 40.3%

• Efficacy remained: “sustained and comparable”

Conclusion: biosimilar IFX and

SB2 were equally effective,

safe and immunogenic

New anti-drug anti-bodies

14.6 14.914.1

0

4

8

12

16

IFX/SB2 IFX/IFX SB2/SB2

%

Factors that might affect

inconsistencies

• Immunogenicity

• Assays used to measure immunogenicity

• Outcome measures

• Patient Demographics

• Disease activity

• Previous Drug Usage and concomitant drug usage

• Placebo effects

• Pharmacokinetics( careful here)

Remission Rates Using Different Definitions

Across 21 NA and European CountriesSokka T et al. A&R 2007

5 10 15 20 25 30

Remission Rates(%)

ACR Remission

DAS28

CDAI

CLIN28

8.8

20.2

14.8

13.2

Factors that mite affect

inconsistencies

• Immunogenicity






• Placebo effects


Predictors of sustained DMARD-free

remission with routine DMARD use

Leiden Early Arthritis Clinic (EAC) n=454British Early Rheumatoid Arthritis Study (ERAS) n=895

Sustained DMARD-free remission achieved 15 % of patients in Leiden EAC & 9.4% in ERAS

Thanx to Vivien BykerkVan der Woude et al. Arth Rheum 2009


inconsistencies

• Immunogenicity






• Placebo effects


OPTIMA: Predictors of sustained

Biologic-Free DiseaseEmery et al EULAR 2011

Weeks 52-78

% P

atients

Better functional Status (lower HAQ) at

Baseline Predicts Biologic-Free Disease

Control, Weeks 52-78

DAS28<2.6

+HAQ<0.5

+ΔmTSS<0.

5OR 95% CI

P

value

Baseline

HAQ0.42 0.21, 0.83 0.01

SDAI≤3.3

+HAQ<0.5

+ΔmTSS<0.

5

Baseline

HAQ0.37 0.17, 0.18 0.009

In some patients,

treatment with anti-TNFs Halts radiographic progression

even in the absence of clinical

response (uncoupling)

ETN

-4

-2

0

2

4

6

8

CRP>15CRP

normal

CRP=5–15

MTX + ETN

-4

-2

0

2

4

6

8

CRP>15CRP

normal

CRP=5–15

-4

-2

0

2

4

6

8MTX

Radio

gra

phic

pro

gre

ssio

n

CRP>15CRP

normal

CRP=5–15

Landewe R, et al. ACR, San Diego 2005, #867

The same pattern of response was noted with ta- DAS

Etanercept + MTX

Disease Activity and Radiographic Progression

ETN + MTX uncouples the

relationship that exists between

disease activity and radiographic

progression in RA patients


inconsistencies

• Immunogenicity






• Placebo effects


Remission frequencies(DAS28

Remission for at least 3 months) in % of

pts.Einarsson et al. THU0252, EULAR 2011

242 (28%)

0 DMARDs

481 (55%)

1 DMARD

117 (13%)

2 DMARDs

32 (4%)

3 DMARDs

Concomitant Therapy at Study

Entry

Patients with Concomitant DMARD

Information

n=872

Genovese M, et al. N Engl J Med 2005;353:1114.


inconsistencies

• Immunogenicity






• Placebo effects


The Magnitude of the Placebo

Effect in RA over 24 wks: a meta-

analysisAzais J, Barnetche T et al. EULAR 2015. Abs SAT

0153

• 22 RCTs-

• 6 IFX;5 ETA;4 ADA; 3 CZP; 4 GOL

• 13 RCTs used ACR 20; 14 RCTs used ACR50 0

5

10

15

20

25

30

35

ACR 20 ACR 50 IV SQ

24.7

10.7

31.9

23.3

Percent

P<0.001


inconsistencies

• Immunogenicity






• Placebo effects

• Pharmacokinetics

0

20

40

60

80

100

< 0.1 0.1 - 1 > 1 - 10 > 10

Serum Infliximab Concentration (mcg/mL)

AC

R20

Res

po

nse

Ra

te (

%)

3 mg/kg q 8 wks 3 mg/kg q 4 wks

10 mg/kg q 8 wks 4 mg/kg q 4 wks

Trough Serum Levels of Infliximab

and Clinical Improvement

ATTRACT

Lack of response to Adalimumab correlates with

anti-ADA Ab and lower trough levels(higher

clearance)Wang SL, Hauensteain S et al A&R, 2012, 64(Suppl): s819(abs1931 )

• 100 ADA- treated pts

• Antibody and ADA

concentrations used

validated techniques

• Among 100 normals,

cutoff: 0.55 U/ml(

mean+3SD)

Conclusion: anti-drug antibodies affect pharmacokinetics


inconsistencies

• Immunogenicity






• Placebo effects


Outline

• The clinical effect(s) of MTX on Biologics

• Possible explanations for these effects.

Pros and Cons of Combination MTX+ Biologics vs Monotherapy...

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