Session Information
Session Type: ACR Late-breaking Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose:
This was the first investigation of the
effects of tofacitinib (TOFA) in adult patients (pts) with active ankylosing
spondylitis (AS). TOFA is an oral Janus kinase inhibitor under investigation
for the treatment of AS.
Methods: This was a 16-week
(wk), Phase 2, multicenter, randomized, double-blind, placebo (PBO)-controlled,
dose-ranging study (NCT01786668) to investigate efficacy, safety, and
dose-response of TOFA in pts with AS. Pts fulfilling the modified New York
criteria (central read) were randomized 1:1:1:1 to PBO or TOFA 2, 5, or 10 mg
twice daily (BID) for 12 wks plus 4 wks follow-up. The primary efficacy
endpoint was ASAS20 response rate at Wk 12 using a 3-parameter Bayesian Emax
model by assuming a monotonic response. Secondary endpoints included ASAS40
response rate, AS disease activity score using C-reactive protein (ASDAS), Bath
AS disease activity index 50% (BASDAI50) response rate, Bath AS functional
index, Bath AS metrology index (linear method), Spondyloarthritis Research Consortium
of Canada (SPARCC) score of sacroiliac (SI) joints and spine. Safety endpoints
included adverse event (AE), and laboratory outcomes.
Results: 208 pts were
randomized and 207 treated; 196 pts completed the study. 51 pts in the PBO
group and 52 in each TOFA group were included in analyses. Baseline
demographics and disease characteristics were balanced in general between
groups and typical of AS populations (87.4% HLA-B27 positive; 81.2% white;
69.1% male; mean age 42 years; mean disease duration 6.3 years; mean BASDAI 6.7).
The Table summarizes efficacy results. The ASAS20 Emax
model showed TOFA 10 mg BID had a high response rate and its confidence
bounds met a pre-specified efficacy decision rule. Observed ASAS20 response
rates were significantly greater with TOFA 5 mg BID vs PBO, compared with
2 or 10 mg BID. All TOFA groups had ASAS40, ASDAS, and BASDAI50 improvements of
similar magnitude vs PBO. TOFA 2 mg BID did not differ vs PBO in remaining
clinical efficacy measures or SPARCC scores. TOFA 5 and 10 mg BID had greater
clinical efficacy vs PBO, with minimal differences between doses, and
significantly improved SPARCC SI joint and spine scores vs PBO.
The
Table summarizes safety results. No TOFA-related safety issues unique to the AS
population or new safety concerns were identified. Two treatment-related herpes
zoster cases were reported (1 each with TOFA 2 and 10 mg BID). No cases of
tuberculosis, malignancy, gastrointestinal perforation, or death were reported.
Dose-dependent changes in laboratory outcomes commonly reported in other TOFA
studies were observed and returned to approximately baseline values by Wk 16.
Conclusion:
TOFA 5 and 10 mg BID demonstrated greater clinical and imaging efficacy vs PBO in
reducing the signs and symptoms of AS in adults with active AS. Safety was
similar to that reported for TOFA studies in other indication
|
Table. Summary of efficacy and safety endpoints |
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|
|
Placebo (n=51) |
TOFA 2 mg BID (n=52) |
TOFA 5 mg BID (n=52) |
TOFA 10 mg BID (n=52) |
|
Primary endpoint ASAS20 Emax model estimatesa |
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|
ASAS20 response rate, % |
40.1 |
56.0 |
63.0 |
67.4 |
|
ASAS20 response rate vs placebo, % 50% credible interval 60% credible interval 95% credible interval |
N/A |
15.8 (11.1, 19.9) (10.2, 21.2) (5.0, 30.3) |
22.9 (17.8, 28.0) (16.5, 29.3) (8.4, 37.7) |
27.3 (21.8, 33.0) (20.3, 34.4) (10.7, 43.4) |
|
Secondary efficacy endpoints at Wk 12 |
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|
ASAS20 response rate (%), observeda |
41.2 |
51.9 |
80.8*** |
55.8 |
|
ASAS40 response rate (%), observeda |
19.6 |
42.3* |
46.2** |
38.5* |
|
CBL in ASDAS, LS mean (SE) |
-0.7 (0.1) |
-1.2 (0.1)** |
-1.4 (0.1)*** |
-1.4 (0.1)*** |
|
BASDAI50 response rate (%), observeda |
23.5 |
46.2* |
42.3* |
42.3* |
|
CBL in BASFI, LS mean (SE) |
-1.4 (0.3) |
-1.9 (0.3) |
-2.4 (0.3)* |
-2.2 (0.3)* |
|
CBL in BASMI, LS mean (SE) |
-0.2 (0.1) |
-0.3 (0.1) |
-0.4 (0.1) |
-0.6 (0.1)* |
|
CBL in SPARCC MRI of the SI joints, LS mean (SE) |
-0.8 (0.8) |
-1.7 (0.8) |
-3.2 (0.8)* |
-3.6 (0.8)* |
|
CBL in SPARCC MRI of the spine, LS mean (SE) |
-0.1 (1.1) |
-3.1 (1.1) |
-5.5 (1.1)*** |
-6.6 (1.1)*** |
|
Safety endpoints |
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|
TEAEs, n (%) |
22 (43.1) |
23 (44.2) |
28 (53.8) |
27 (51.9) |
|
Treatment related |
14 (27.5) |
14 (26.9) |
12 (23.1) |
14 (26.9) |
|
Serious AEs, n (%) |
2 (3.9) |
0 |
1 (1.9) |
1 (1.9) |
|
Treatment related |
1 (2.0)b |
0 |
0 |
0 |
|
Discontinuations due to AEs, n (%) |
3 (5.9) |
0 |
1 (1.9) |
1 (1.9) |
|
Treatment related |
2 (3.9)c |
0 |
1 (1.9)c |
1 (1.9)c |
|
AST >3x ULN, n (%) |
1 (2.0) |
0 |
3 (5.8) |
0 |
|
ALT >3x ULN, n (%) |
1 (2.0) |
0 |
2 (3.8) |
1 (2.0) |
|
Wk 12 CBL in serum creatinine, g/dL, mean (SD) |
0.0 (0.1) |
0.0 (0.1) |
0.0 (0.1) |
0.1 (0.1) |
|
Wk 12% CBL in LDL-C, mean (SD) |
-1.2 (15.8) |
7.2 (13.5) |
9.6 (21.0) |
23.5 (28.3) |
|
Wk 12% CBL in HDL-C, mean (SD) |
1.0 (17.4) |
10.0 (15.1) |
11.0 (18.6) |
18.5 (17.0) |
|
Wk 12 CBL in ANC, cells 103/mm3, mean (SD) |
-0.3 (1.2) |
-0.3 (1.6) |
-0.3 (1.4) |
-0.9 (1.6) |
|
Wk 12 CBL in ALC, cells 103/mm3, mean (SD) |
0.0 (0.4) |
0.1 (0.4) |
-0.1 (0.4) |
0.0 (0.4) |
|
Wk 12 CBL in Hb, g/dL, mean (SD) |
-0.2 (0.6) |
0.1 (0.6) |
0.3 (0.7) |
0.1 (0.9) |
|
*p<0.05, **p<0.01, ***p<0.001 aNRI/LOCF bvertigo cspinal pain (placebo), hypertransaminasemia (placebo), peripheral swelling (TOFA 5 mg BID), herpes zoster (TOFA 10 mg BID) d50, 51, 52, and 50 patients receiving PBO, and TOFA 2, 5, and 10 mg BID, respectively were included in this analysis. AE, adverse event; ALC, absolute lymphocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; ASAS, assessments in ankylosing spondylitis improvement; ASDAS, ankylosing spondylitis disease activity score using C-reactive protein; AST, aspartate aminotransferase; BASDAI, Bath ankylosing spondylitis disease activity index; BASFI, Bath ankylosing spondylitis functional index; BASMI, Bath ankylosing spondylitis metrology index (linear method); BID, twice daily; CBL, change from baseline; Hb, hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; LS, least squares; N/A, not applicable; NRI, non-responder imputation; SD, standard deviation; SE, standard error; SPARCC, spondyloarthritis research consortium of Canada; TEAE, treatment-emergent AE; TOFA, tofacitinib; ULN, upper limit of normal; Wk, week. |
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To cite this abstract in AMA style:
van der Heijde D, Deodhar AA, Wei JC, Drescher E, Fleishaker D, Hendrikx T, Li D, Menon S, Kanik KS. Tofacitinib in Patients with Ankylosing Spondylitis: A Phase 2, 16-Week, Randomized, Placebo-Controlled, Dose-Ranging Study [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/tofacitinib-in-patients-with-ankylosing-spondylitis-a-phase-2-16-week-randomized-placebo-controlled-dose-ranging-study/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/tofacitinib-in-patients-with-ankylosing-spondylitis-a-phase-2-16-week-randomized-placebo-controlled-dose-ranging-study/