Dr. Sanjiv N Amin, MD.3rd Floor Bombay Mutual Terrace, 534 Mamasaheb Varerkar Bridge, Mumbai 400007

Indian Perspective :Use of Biologic therapy in Rheumatoid Arthritis in resource limited setting -Challenges and Solutions

RA - Challenges – India Perspective…

The RA patients in India needing Biologics

Treat to Target, in Clinical Practice, Real Life –•unrealistic attaining DAS (ESR) <2.6, use Physician Global, Hb rise, NSAID count…

Latent Tuberculosis Infection•TST, Interferon γ release assays, Empiric ATT

Switch or swap TNFi

Paradigm shift of treatment of RA in India

Over 1.5 million patients estimated to suffer from RA in India…

^ Population- 1.26 billion in India

^ 20% -have the ability to pay for quality private healthcare

^ Prevalence : 0.5-0.7% of population in most countries

Over 1.5 million affording

population estimated to

suffer from RA

Methotrexate (MTX) monotherapy

Combination therapy – MTX plus DMARDs

Combination therapy – Biologic plus

MTX/DMARDs

Multiple treatment protocols are followed – biologics are prescribed only if monotherapy with MTX or a combination of MTX and DMARDs fail

West India rheumatology practice in 2007

Characteristic West IndiaN = 757

BeStN = 508

Mean age (years) 46.82 ± 12.48

54

Women 630 (83.2%) 70 %

Body mass index men women

23.99 ± 5.9423.88 ± 5.04

Mean disease duration < 24 months > 24 months

268489

AllNone

Anti CCP results available 402

X-ray hands & anti CCP results available 152

Family history +ve for RA 86 (11.36%)

Mean DAS 6.25 4.5

• MTX 15 mg 618

MTX + LEF 97

LEF 20 mg OD 07

SLZ 1 Gm BD 9

SLZ + HCQ 6

MTX + SLZ + HCQ 6

MTX + SLZ 14

West India Rheumatology Practice in 2007

Reduction inDAS > 1.2

Low diseaseDAS < 3.2

RemissionDAS < 2.6

MTX at visit 1

MTX+SLZ at visit 2

MTX+SLZ+HCQ

at visit 2

MTX+LEF at visit 2

No of Patients

618 618+18 618+07 618+102

Mean (SD) DAS at V1

6.251.37

Mean (SD) DAS at V3

4.52 1.38

4.38 1.46

4.38 1.40

4.5 1.38

No (%) of patients with DAS<2.6 at V3

53 (7.51%)

46 (7.23%)

46 (7.36%)

48 (6.66%)

V2 V3 V2 V3 V2 V30

102030405060708090

100

45.461.4

6.316.1

2.4 6.1

54.638.6

93.783.9

97.6 93.9

Improved Not Improved

Perc

enta

ge o

f pati

ents

Overall Disease Outcome: MTX at Visit 1 →Combination at Visit 2

West India rheumatology practice in 2007: Summary of observations

• Methotrexate 15 mg/week SC or IM : well tolerated and improvement of DAS > 1.2 in half the patients

• Around 20% patients attain low disease activity• Less than 10% attain remission or DAS <2.6.

“Methotrexate 25 mg/week may improve outcomes as indicated by the recent BeSt study”

• Early intervention with MTX and other DMARDsBetter outcome:

• Combinations of MTX + SLZ ± HCQS or MTX + LEF

Better outcome or similar outcome than MTX alone

7

 Overview of Patients on Tocilizumab: 2009

• First patient infused : Feb

2009

• Total no of patients on

Tocilizumab in 6 months: 25

• No. of Patients analyzed : 25 RA

Total No of patients 25

No of patients judged responders 20 (80%)

No of patients judged non responders 5 (20%)

No of Cases 25

Age (years) Mean Range

45.4317 – 73 Yrs.

Sex (%) Male Female

05 (20%)20 (80%)

Disease Duration Mean Range

9.90.5 – 26 Yrs.

X ray Hands (%)Erosion (Present)Joint Space Narrow

24/25 (96%)23/25 (92%)

Biologic naïve patientsExposed to biologics

187 (TNF NR)

Out of the 7 patients who were exposed to TNFi5 responded well to therapy with Tocilizumab.

Tocilizumab 2010: Sustained improvement in DAS 28

Duration in Months Mean DAS 28 Mean + SD

Responders Non Responders

Mean Change (M0 – M3) -2.19 ± 0.75 (36.1%) -0.54 ± 0.30(7.8%)

Mean Change (M0 – M6) -2.84 ± 1.14 (45.4%) -0.13 ± 0.0 (2%)

Baseline 3 months0

2

4

6

8

10

12

14

6.06

3.87

6.97

6.43

Non respondersResponders

Baseline 6months02468

101214

6.25

3.41

6.39

6.26

9

Tocilizumab 2010: Clinically Important Reduction in CRP

Duration in Months Mean CRP (Mean + SD)

Responders Non Responders

Mean Change (M0 – M3) -27.68 ± 22.14 (70.8%) -9.29 ± 22.65 (20.7%)

Mean Change (M0 – M6) -33.99 ± 25.38 (82.2%) 18.3 ± 0.0 (61.4%)

Baseline 6 months0

10

20

30

40

50

60

70

80

41.33

7.34

29.8

18.3

Baseline 3 months0

10

20

30

40

50

60

70

80

90

39.12

11.44

44.79

35.5Non respondersResponders

10

Tocilizumab 2010: Improvement in Anemia Status

Duration in Months Mean Hb Mean + SD

Mean Change (M0 – M3) 1.36 + 1.28(13.8%)

Mean Change (M0 – M6) 1.57 + 1.52(15.8%)

Baseline 3 months 6 months9

9.5

10

10.5

11

11.5

12

9.86

11.22

11.5

Haemoglobin

In the Real World, West India: Tocilizumab 2010...

Initial experience of Tocilizumab is encouraging • “biologic naïve” • “heavily pre-treated”

RA patients• few non responders

Significant improvement within 1 month of TCZ →continued to improve with time• ↓ Mean SJC/TJC, &

DAS• ↓ CRP , ↑

Hemoglobin

No adverse effects were observed during the 12.6 patient years

Tocilizumab is a new safe &

effective treatment option for RA patients.

Overview of Patients in West India, on Etanercept 25 mg Biosimilar: 2013-2014

Parameters RANumber of patients

19

Gender M=4, F=15Mean age (yrs) 42.8+14.06

Mean disease duration (in years)

9.95

Past history of TB 3BMI 24.0+4.8

Past history of Biologics

1- INF4- TCZ

Patients on Etanercept Biosimilar

83

Number of patients analyzed-

58

Ankylosing Spondylitis

39

Rheumatoid Arthritis 19

Etanercept Biosimilar dose received

25 mg sc. once a week

ACR 20 & 50 responders at Visit 2 (20 weeks)- Etanercept 25 mg Biosimilar 2013-14

ACR 20 responders ACR 50 responders0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0 42.1

5.3

ACR Response

%ag

e of

resp

onde

rs

DAS 28 score- Etanercept 25 mg Biosimilar 2013-14

Baseline Visit 2- 20 weeks0

2

4

6

8

10

12

14

16

18

20

12

4

7

11

0

1

Low- DAS 28<2.6Moderate- DAS 28 3.2-5.4High- DAS 28>5.4

DAS Score

6.06 + 1.04    4.79 + 1.42 Mean DAS 28 scores

Reduction in Inflammatory Markers - Etanercept 25 mg Biosimilar 2013-14

Baseline Visit 248

50

52

54

56

58

60

6261.32

52.8

ESR

ESR

Baseline Visit 205

101520253035404550

45.42

14.18

CRP

CRP

TB prophylaxis - Etanercept 25 mg Biosimilar, 2013-14

• All patients were started on TB prophylaxis

• Drugs given were Rifampicin 450 mg + Isoniazid 300 mg

• Duration of treatment was 6 months

Summary: Etanercept 25 mg Biosimilar 2013-14

Etanercept biosimilar

TNFα bio similar is effective in ‘change’ of disease activity in RA in the Indian patients

Safety profile

High with just one injection site reaction in 83 patients

ProphylaxisRifampicin + Isoniazid could be effective in a TB endemic

population

HIV and TB1. “In resource-constrained settings with high TB incidence and transmission,

adults and adolescents living with HIV, who have an unknown or positive tuberculin skin test (TST) status and among whom active TB disease has been safely ruled out, should receive at least 36 months of IPT. IPT should be given to such individuals regardless of whether or not they are receiving ART. IPT should also be given irrespective of the degree of immunosuppression, history of previous TB treatment, and pregnancy.”

2. Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

3. The optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown. The 6EH and 36H regimens were similarly effective in preventing TB, when compared to historical incidence rates. However, there was a trend to lower TB incidence with 36H. There was no increase in isoniazid resistance compared to the expected rate in HIV-infected patients.

1. WHO Global TB Program 2015 update;2. Lancet 2016; 387: 1198–2093. www.plosone.org Dec 2012, Vol 7, Issue 12

Parameters RA (N=64)Gender Male=11, Female= 53Mean age in yrs. ± SD 45± 15.45Mean disease duration in months ±SD

84 ±74.95

Past history of Tuberculosis

2

BMI in kg/m2 ± SD 22.82±5.6Past history of Biologics Total=26

02- REM04- ETA09- TCZ05- ETA-TCZ01- ETA-REM03- ETA-REM-TCZ01- ETA-EXEM01- ETA-EXEM-TCZ

West India rheumatology practice in 2016 -Infliximab Biosimilar

Past history of RA patients(N=64)

No. (percentage)

DM 5 (7.8%)

Hypertension 14 (21.8%)

CAD 2 (3.1%)

Hypothyroid 6 (9.3%)

TB 2 (3.1%)

Microscopic polyangiitis

1 (1.5%)

Peptic ulcer 1 (1.5%)

West India rheumatology practice in 2016, Infliximab Biosimilar

Extra articular manifestation

RA(N=64)

Iron deficiency anemia

1

Psoriasis 4

Sacroilitis 1

Sjogren 4

Uveitis 1

AAD 1

Subcutaneous nodule

2

DMARDs prior (N=64) No. (Percentage)Corticosteroids 10 (15.6%)MTX 6 (9.37%)MTX+LEF 10 (15.6%)MTX+SLZ± HCQS 47 (73.4%)No 1 (1.5%)

Physicians assessment of patients (N=64)

Responder 25 (39.06%)

Non-responder and ADRs

39 (60.93%)

Outcomes with of Infliximab Biosimilar, Real Life -2016 Western Rheumatology Practice

Adverse Reaction (N=64)

None 58 (90.6%)Abdominal pain 1

Anaphylaxis 1Giddiness 1

RHUPUS flare 1Urticaria 2

Switched to other biologics (N=17)

ETAbs 25 2 (11.7%)

RTX 7 (41.1%)

TCZ 8 (47%)

Baselin

e

3 - 4 m

t F UP

6-12 mt F

-up0

2

4

6

8

10

12

5.11

3.60 3.47

5.79

5.09

DAS 28Non responder

Responder

Baseline 3 - 4 mt F UP 6-12 mt F-up0

10

20

30

40

50

60

70

80

90

39.13

16.7013.70

42.80

36.67

SDAI

Efficacy with Infliximab Biosimilar in Real Life-2016 Western Rheumatology Practice

Baselin

e

3 - 4 m

t F UP

6-12 mt F

-up05

1015202530

11.08

3.64 3.40

15.03

12.39

Tender Joint

Baseline 3 - 4 mt F UP 6-12 mt F-up0123456789

10

3.96

0.92 1.20

5.56

4.14

Swollen Joint

Baseline 3 - 4 mt F UP 6-12 mt F-up0

20406080

100120140

56.54 58.81 55.00

59.67 60.46

Body weight

Physical parameters with Infliximab Biosimilar-2016 Western Rheumatology Practice

Non responder

Responder

Baseline 3 - 4 mt F UP 6-12 mt F-up0

20406080

100120140

59.36

32.7647.29

61.36

58.36

ESR

Baseline 3 - 4 mt F UP 6-12 mt F-up0

10203040506070

33.05

12.327.63

32.39

28.16

CRP

Baseline 3 - 4 mt F UP 6-12 mt F-up0

5

10

15

20

25

9.75 11.13 11.62

10.0910.42

Hemoglobin

Laboratory Parameters with Infliximab Biosimilar -2016 Western Rheumatology Practice

Non responder

Responder

COHORT RESPONDER NON-RESPONDER

1 biologic failure (N=15)

5-TCZ4-ETAbs2-INF

4-TCZ

>1 biologic failure (N=11)

1 10

Previous biologic failure (N=26)

12 (46.15%) 14 (53.84%)

Biologic Naïve(N=35)

13 (37.14%) 22 (62.85%)

Overall (N=64*)

25 (40.98%) 35 (59.01%)

Physicians assessment with Infliximab Biosimilar in different cohorts

*3 patients – ADRs -- Omitted

Series10%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

45.4

16

15.44

23.16

MTx Combination DMARDsBiologics Unmet need

Treatment responders, West India, 2007 to 2016, with available csDMARD & bDMARDs

20

32

40

8

No improvement

LDAS: Mean DAS lowering > 1.2

DAS: 2.6 and 3.2

DAS< 2.6

Does physician’s assessment correlate with DAS 28 score?

Infliximab Biosimilar RA cohort(N=64)

R NRRemission: DAS< 2.6 5 3

DAS 2.6 and 3.2 8 0

Mean DAS lowering of 1.2 or more 10 12

No improvement 2 24*

Total 25 39

Correlation of DAS with Physicians Outcome- Infliximab Biosimilar

*3 patients – ADRs

If TNFi Fails, Should I Switch to Another TNFi or a Biologic With A Different MOA?

QUESTION:

Comparison of Drug Discontinuation due to Inefficacy and Adverse Events Between

Anti TNF Agents & Non-Anti-TNF biologic Agents in

Anti-TNF Inadequate Responder RA Patients

Martin-du-Pan S, et al. ARD 2012;71(6):997-999

Comparison of Drug Discontinuation to Inefficacy & Adverse Events Between Anti-TNF Agents & Non-Anti-TNF Biologic Agents in Anti-TNF Inadequate Responder RA Patients (SCQM - Swiss Registry)

Results:• Based on 1485 treatment courses: 853 alternate anti-TNF; 632 non-anti-TNF

Martin-du-Pan S, et al. ARD 2012;71(6):997-999.

Time to Discontinuation of Biologic Agents

In real life, in EU….

• In TNFi-IRs, biologic agents with a different mode of action appear to have lower drug discontinuation rates than alternative anti-TNF agents – regardless of reason for discontinuation

• Caveats:– Non RCTs for comparison data – More data needed with multiple previous TNF-IRs

DIFFERENT COHORTS INFLIXIMABbs OUTCOME FATE OF INFLIXIMABbs NON-REPONDERS

Responder Non-responder Shift to Responder Non-responder

Biologic naïve pts 1322

(3 ADRs)

3-RTX5-TCZ2- ETAbs12-DMARDs

2-RTX 4-TCZ1-ETAbs

1 (Death)1-TCZ1-ETAbs

Prior TCZ Rx before Infimab

513

4-RTX2-TCZ7-DMARDs

1-RTX1-TCZ

3-RTX1-TCZ

Prior INF Rx before Infimab

3

Prior ETAbs 25Rx before Infliximabbs

4

Prior ADAbsRx before Infliximabbs

1 1- TCZ 1-TCZ

Total 25 36* 17-shift to biologics

9 8

Fate of non-responders with Infliximab Biosimilar in different cohorts, West India, 2016, real life…

• Around 60% patients have meaningful response to DMARDs, of which 25% have low disease activity or remission

• Adding a TNF inhibitor adds another 15% have meaningful response, of which 50% have low disease activity or remission

• Empirical primary TB treatment for 4 months can be an option for patients prescribed TNFi

• If one Biologic fails, swap to another MOA Biologic may be better than a switch. If two Biologics fail, chance of the third being effective is small

• Change from innovator Infliximab to biosimilar Infliximab was tolerated and remained effective in three patients

Rheumatoid Arthritis- West India, Real Life...

At The End of The Day….

The Trend is to Optimize The Use of Current Biologics

But……

We Still Have A Long Way to Go For A Paradigm Shift In Improving RA!

Baricitinib, oral reversible inhibitor of JAK 1 & 2, interferes inflammation mediated by IL-6, IL-12, IL-23 and Interferon α

RA BEACON, Taylor PC, Keystone EC, van der Heijde D et al. Arthritis Rheumatology 2015;67 (Supplement 10)

Placebo Baricitinib Adalimumab

ACR 20 40% 70% 61%

ACR 50 17% 45% 31%

ACR 70 5% 19% 13%

The ADACTA study (not a usual care study without radiographicdata) showed a clear superiority of Tocilizumabmonotherapy against Adalimumab

Gabay C, Emery P, van Vollenhoven R et al.Lancet 2013;381:1541-50

Smart pricing of oral JAK 1 & 2 inhibitors, compared with bDMARDs, will change rheumatoid arthritis treatment algorithms!

And, Take Home Thoughts….

Make in India !

FIRE IN THE BLOOD

2013 documentary by Dylan Mohan Gray

THANK YOU!!!!!