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Abstract Number: L9

Tofacitinib Monotherapy Versus Methotrexate in Methotrexate-Naïve Patients with Rheumatoid Arthritis: Radiographic, Clinical and Functional Comparison

Roy Fleischmann1, E. B. Lee2, S Hall3, B. E. Wilkinson4, John D. Bradley5, D. Gruben4, T. Koncz6, S. Krishnaswami7, G. Wallenstein6, S. H. Zwillich4 and R.F. van Vollenhoven8, 1Metroplex Clinical Research Center, Dallas, TX, 2Seoul National University, Seoul, South Korea, 3Cabrini Health and Monash University, Melbourne, Australia, 4Pfizer Inc, Groton, CT, 5Pfizer Inc., Groton, CT, 6Pfizer Inc, New York, NY, 7Clinical Pharmacology, Pfizer Inc, Groton, CT, 8The Karolinska Institute, Stockholm, Sweden

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: methotrexate (MTX), randomized trials, rheumatoid arthritis (RA) and tofacitinib

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Session Information

Session Title: ACR Late-Breaking Abstract Poster Session

Session Type: Late-Breaking Abstracts

Background/Purpose: Tofacitinib is a novel, oral Janus kinase inhibitor for the treatment of RA. This Phase 3, 24-mo study (ORAL Start; NCT01039688) compared efficacy, including inhibition of structural damage, and safety of tofacitinib monotherapy vs methotrexate (MTX) in MTX-naïve patients (pts) with active RA. Primary efficacy endpoints (Mo 6) for tofacitinib vs MTX of mean changes from baseline (BL) in van der Heijde modified Total Sharp Score (mTSS) and ACR70 response have been presented.1 Results here are from final analyses (24‑mo).

Methods: Pts were randomized 2:2:1 to tofacitinib 5 mg twice daily (BID), 10 mg BID, or MTX 10 mg/wk with 5 mg/wk increments every 4 wks to 20 mg/wk (mean MTX dose at end of titration [Mo 3], 18.5 mg/wk). Safety and tolerability were also evaluated.

Results: 956 pts received tofacitinib 5 mg BID (N=373), 10 mg BID (N=397), or MTX (N=186). Demographic and BL RA disease characteristics, including radiographic scores, were similar across groups.1 Mean changes from BL in mTSS and ACR20/50/70 response rates were statistically superior for both doses of tofacitinib vs MTX at all time points when measured (ACR20/50/70, first post-BL visit at Mo 1; mTSS, first post-BL visit at Mo 6) through Mo 24 (Table). Erosion and joint space narrowing scores, and HAQ-DI and DAS28‑4[ESR] scores, were also significantly different for tofacitinib vs MTX at all time points measured through Mo 24 (Table).

Incidences of adverse events (AEs), serious AEs, serious infections, and discontinuations due to AEs were similar across groups (Table). Most AEs were mild or moderate; most frequent AE in all groups was infection. Herpes zoster occurred in 3.5%, 4.5%, and 1.1% of tofacitinib 5 mg BID, 10 mg BID, and MTX pts, respectively. Six confirmed malignancies were reported: tofacitinib 5 mg BID (non-Hodgkin’s lymphoma and chronic lymphocytic leukemia); 10 mg BID (prostate cancer, Burkitt’s B-cell lymphoma, colon cancer); and MTX (gastric cancer). An adrenal adenoma with cellular atypia, which the local pathologist was uncertain whether malignant or benign, was also reported in a patient receiving tofacitinib 5 mg BID. Four deaths occurred: tofacitinib 5 mg BID (non-Hodgkin’s lymphoma [post-study], cardiac failure [post-study], sudden cardiac death) and 10 mg BID (colon cancer). At Mo 24, changes in laboratory parameters (neutrophils, lymphocytes, serum creatinine, LDL, and HDL) relative to BL were numerically higher for tofacitinib compared to MTX; liver enzyme elevations were more frequent with MTX (Table).

Conclusion: Tofacitinib monotherapy in MTX-naïve pts demonstrated significant, durable, and clinically meaningful improvements in RA signs and symptoms and physical functioning, and inhibition of progression of structural damage, vs MTX over 24 mo. Safety was similar to that reported in other tofacitinib Phase 3 trials.

 

  1. Lee EB, et al. Arthritis Rheum. 2012;64:S1049, Abst 2486.

Table. Efficacy and safety at Month 24

 

Tofacitinib
  5 mg BID

(N=373)

Tofacitinib
  10 mg BID
  (N=397)

Methotrexate

  (N=186)

Efficacy

 

 

 

Clinical

 

 

 

ACR20 response rate (%)a

64.2***

64.2***

42.4

ACR50 response rate (%)a

49.3***

49.2***

28.3

ACR70 response rate (%)a

34.4***

37.6***

15.2

LS mean   change from BL in DAS28‑4(ESR)b

-2.99***

-3.16***

-2.40

Rate of DAS28-4(ESR)   <2.6 (%)a

20.8**

22.3***

9.94

Rate of DAS28-4(ESR) ≤3.2   (%)a

34.8***

36.0***

15.8

Functional

 

 

 

LS mean change from BL in   HAQ-DIb

-0.90**

-1.01***

-0.70

Radiographic

 

 

 

LS mean change from BL in mTSSc

0.55**

0.28***

2.08

LS mean change from BL in erosion   scorec

0.16***

0.16***

0.98

LS mean change from BL in JSN   scorec

0.39*

0.12**

1.10

No radiographic progression   (mTSS change from BL ≤0.5) (%)c

79.9**

83.7***

64.9

Safety

 

 

 

Discontinuations (%):d

28.7

28.0

43.0

   Discontinuations due to lack of efficacy   (%)d

5.4

2.8

14.0

   Discontinuations due to AEs (%)d

10.2

9.8

12.9

Rate of AEs (%)d

79.6

84.1

79.0

Rate of infections and   infestations (%)d

42.1

50.4

34.9

Rate of gastrointestinal   disorders (%)d

27.6

32.5

40.9

Rate of serious AEs (%)d

10.7

10.8

11.8

Rate of serious infection   events (%)d

3.0

2.0

2.7

Rate of AST >3 × ULN   (%)d,e

1.6

1.5

3.3

Rate of ALT >3 × ULN   (%)d,e

3.0

3.0

7.1

Rate of serum creatinine   ≥33% increase from BL (%)d,e

9.9

9.5

2.7

LDL-c,   mg/dL, mean % change from BLc

18.6***

21.6***

3.91

HDL-c,   mg/dL, mean % change from BLc

16.8**

17.4***

6.98

LS mean   change from BL:

 

 

 

   Absolute neutrophil count, 103/mm3c

-1.26

-1.61**

-1.03

   Absolute lymphocyte count, 103/mm3c

-0.35***

-0.44***

-0.22

   Hemoglobin, g/dLd

0.57

0.24

0.30

 

 

 

 

***p<0.0001; **p<0.001;   *p≤0.05 vs methotrexate.

aFull analysis set, non-responder   imputation. bFull analysis set, longitudinal model, no imputation.   cFull analysis set, linear extrapolation. dNo   statistical testing versus methotrexate was performed. eConfirmed   by two consecutive tests.

ACR, American College of   Rheumatology; AE, adverse event; AST, aspartate transaminase; BID, twice   daily; BL, baseline; DAS, Disease Activity Score; ESR, erythrocyte   sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index;   HDL-c, high-density lipoprotein-cholesterol; JSN, joint space narrowing; LDL-c,   low-density lipoprotein-cholesterol; LS, least squares; mTSS, modified   Total Sharp Score; ULN, upper limit of normal.

 

:


Disclosure:

R. Fleischmann,

Pfizer Inc,

2,

Pfizer Inc,

5;

E. B. Lee,

Pfizer Inc,

5;

S. Hall,

Pfizer Inc,

2,

Pfizer Inc,

5;

B. E. Wilkinson,

Pfizer Inc,

1,

Pfizer Inc,

3;

J. D. Bradley,

Pfizer Inc,

3;

D. Gruben,

Pfizer Inc,

1,

Pfizer Inc,

3;

T. Koncz,

Pfizer Inc,

1,

Pfizer Inc,

3;

S. Krishnaswami,

Pfizer Inc.,

1,

Pfizer Inc.,

3;

G. Wallenstein,

Pfizer Inc,

1,

Pfizer Inc,

3;

S. H. Zwillich,

Pfizer Inc,

1,

Pfizer Inc,

3;

R. F. van Vollenhoven,

Pfizer Inc,

2,

Pfizer Inc,

5.

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