Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Tumor Necrosis Factor alpha (TNFα) inhibitors.
ATC code: L04AB04
Mechanism of action
Adalimumab binds specifically to TNF and neutralizes the biological function of TNF by blocking its interaction with the p55 and p75 cell surface TNF receptors.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 0.1-0.2 nM).
Pharmacodynamic effects
After treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was observed, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration. Patients treated with adalimumab usually experienced improvement in hematological signs of chronic inflammation.
A rapid decrease in CRP levels was also observed in patients with Crohn's disease, ulcerative colitis and hidradenitis suppurativa after treatment with adalimumab. In patients with Crohn’s disease, a reduction of the number of cells expressing inflammatory markers in the colon including a significant reduction of expression of TNFα was seen. Endoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab-treated patients.



Clinical efficacy and safety
Rheumatoid arthritis
Adalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The efficacy and safety of adalimumab were assessed in five randomized, double-blind and well-controlled studies. Some patients were treated for up to 120 months duration. Injection site pain of adalimumab was assessed in two randomized, active control, single-blind, two-period crossover studies.
RA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old, had failed therapy with at least one disease-modifying, anti-rheumatic drug and had insufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) every week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, 40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks.
RA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses of 20 or 40 mg of adalimumab were given by subcutaneous injection every other week with placebo on alternative weeks or every week for 26 weeks; placebo was given every week for the same duration. No other disease-modifying anti-rheumatic drugs were allowed.


RA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or have been intolerant to 10 mg of methotrexate every week. There were three groups in this study. The first received placebo injections every week for 52 weeks. The second received 20 mg of adalimumab every week for 52 weeks. The third group received 40 mg of adalimumab every other week with placebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of adalimumab/MTX was administered every other week up to 10 years.
RA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old. Patients were permitted to be either disease-modifying, anti-rheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. These therapies include methotrexate, leflunomide, hydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomized to 40 mg of adalimumab or placebo every other week for 24 weeks.
RA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early rheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy of adalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 40 mg every other week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104 weeks, 497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was administered every other week up to 10 years.
RA studies VI and VII each evaluated 60 patients with moderately to severely active rheumatoid arthritis who were ≥ 18 years old. Enrolled patients were either current users of Humira 40 mg/0.8 ml and rated their average injection site pain as at least 3 cm (on a 0-10 cm VAS) or were biologic-naïve subjects who were starting Humira 40 mg/0.8 ml. Patients were randomized to receive a single dose of Humira 40 mg/0.8 ml or Humira 40 mg/0.4 ml, followed by a single injection of the opposite treatment at their next dose.
The primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was the percent of patients who achieved an ACR 20 response at week 24 or 26. The primary endpoint in RA study V was the percent of patients who achieved an ACR 50 response at week 52. RA studies III and V had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by X-ray results). RA study III also had a primary endpoint of changes in quality of life. The primary endpoint in RA studies VI and VII was injection site pain immediately after injection as measured by a 0-10 cm VAS.
ACR response
The percent of adalimumab-treated patients achieving ACR 20, 50 and 70 responses was consistent across RA studies I, II and III. The results for the 40 mg every other week dose are summarized in table 2.
Table 2. ACR responses in placebo-controlled trials (percent of patients) Response             RA study Ia**                   RA study IIa**             RA study IIIa** 
Placebo/    Adalimuma        Placebo       Adalimumabb      Placebo/     Adalimuma MTXc        bb/ MTXc                                        MTXc         bb/ MTXc n = 110          n = 113 n = 207 n = 60        n = 63                                       n = 200

ACR 20

6 months       13.3%         65.1%         19.1%            46.0%          29.5%          63.3% 
12 months        NA            NA             NA               NA           24.0%          58.9% ACR 50

6 months        6.7%         52.4%          8.2%            22.1%           9.5%          39.1% 12 months        NA            NA             NA               NA            9.5%          41.5% 
ACR 70

6 months        3.3%         23.8%          1.8%            12.4%           2.5%          20.8% 
12 months        NA            NA             NA               NA            4.5%          23.2% a
RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeks b
40 mg adalimumab administered every other week c
MTX = methotrexate
** p < 0.01, adalimumab versus placebo
In RA studies I-IV, all individual components of the ACR response criteria (number of tender and swollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) scores and CRP (mg/dL) values) improved at 24 or 26 weeks compared to placebo. In RA study III, these improvements were maintained throughout 52 weeks.
In the open-label extension for RA study III, most patients who were ACR responders maintained response when followed for up to 10 years. Of 207 patients who were randomized to adalimumab 40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 5 years.
Among those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; and 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab 40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 patients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses.
In RA study IV, the ACR 20 response of patients treated with adalimumab plus standard of care was statistically significantly better than patients treated with placebo plus standard of care (p < 0.001).

In RA studies I-IV, adalimumab-treated patients achieved statistically significant ACR 20 and 50 responses compared to placebo as early as one to two weeks after initiation of treatment.
In RA study V with early rheumatoid arthritis patients who were methotrexate-naïve, combination therapy with adalimumab and methotrexate led to faster and significantly greater ACR responses than methotrexate monotherapy and adalimumab monotherapy at week 52 and responses were sustained at week 104 (see table 3).
Table 3. ACR responses in RA study V (percent of patients)

Response           MTX         Adalimumab       Adalimumab        p-valuea    p-valueb     p-valuec n = 274          /MTX n = 257 n = 268

ACR 20

Week 52       62.6%           54.4%              72.8%         0.013       < 0.001       0.043 
Week 104      56.0%           49.3%              69.4%         0.002       < 0.001       0.140 
ACR 50

Week 52       45.9%           41.2%              61.6%        < 0.001      < 0.001       0.317 
Week 104      42.8%           36.9%              59.0%        < 0.001      < 0.001       0.162 ACR 70

Week 52       27.2%           25.9%              45.5%        < 0.001      < 0.001       0.656 Week 104      28.4%           28.1%              46.6%        < 0.001      < 0.001       0.864 a p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test b p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test c p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapy using the Mann-Whitney U test
In the open-label extension for RA study V, ACR response rates were maintained when followed for up to 10 years. Of 542 patients who were randomized to adalimumab 40 mg every other week, 170 patients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients (90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients (60.0%) had ACR 70 responses.
At week 52, 42.9% of patients who received adalimumab/methotrexate combination therapy achieved clinical remission (DAS28 (CRP) < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy and 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexate combination therapy was clinically and statistically superior to methotrexate (p < 0.001) and adalimumab monotherapy (p < 0.001) in achieving a low disease state in patients with recently diagnosed moderate to severe rheumatoid arthritis. The response for the two monotherapy arms was similar (p = 0.447). Of 342 subjects originally randomized to adalimumab monotherapy or adalimumab/methotrexate combination therapy who entered the open-label extension study, 171 subjects completed 10 years of adalimumab treatment. Among those, 109 subjects (63.7%) were reported to be in remission at 10 years.


Radiographic response
In RA study III, where adalimumab-treated patients had a mean duration of rheumatoid arthritis of approximately 11 years, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing score. Adalimumab/methotrexate patients demonstrated significantly less radiographic progression than patients receiving methotrexate alone at 6 and 12 months (see table 4).
In the open-label extension of RA study III, the reduction in rate of progression of structural damage is maintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated with 40 mg adalimumab every other week were evaluated radiographically. Among those, 48 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less. At 10 years, 79 of 207 patients originally treated with 40 mg adalimumab every other week were evaluated radiographically. Among those, 40 patients showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less.
Table 4. Radiographic mean changes over 12 months in RA study III

Placebo/              Adalimumab                  Placebo/MTX-                p-value MTXa                   /MTX                    adalimumab /MTX
(95% CIb)
40 mg every other week
Total Sharp Score               2.7                   0.1                   2.6 (1.4, 3.8)              < 0.001c 
Erosion score                   1.6                   0.0                   1.6 (0.9, 2.2)              < 0.001 
JSNd score                      1.0                   0.1                   0.9 (0.3, 1.4)               0.002 a methotrexate b
95% CIs for the differences in change scores between methotrexate and adalimumab c
Based on rank analysis d
Joint Space Narrowing
In RA study V, structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (see table 5).
Table 5. Radiographic mean changes at week 52 in RA study V

MTX               Adalimumab       Adalimumab/           p-valuea        p-valueb     p-valuec n = 274           MTX n = 257
(95% CI)              (95% CI)              n = 268
(95% CI)

Total sharp     5.7 (4.2-7.3)         3.0 (1.7-4.3)     1.3 (0.5-2.1)        < 0.001         0.0020       < 0.001 score
Erosion         3.7 (2.7-4.7)         1.7 (1.0-2.4)     0.8 (0.4-1.2)        < 0.001         0.0082       < 0.001 score
JSN score       2.0 (1.2-2.8)         1.3 (0.5-2.1)         0.5 (0-1.0)      < 0.001         0.0037        0.151 


a p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test b p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexate combination therapy using the Mann-Whitney U test c p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapy using the Mann-Whitney U test
Following 52 weeks and 104 weeks of treatment, the percentage of patients without progression (change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with adalimumab/methotrexate combination therapy (63.8% and 61.2% respectively) compared to methotrexate monotherapy (37.4% and 33.5% respectively, p < 0.001) and adalimumab monotherapy (50.7%, p < 0.002 and 44.5%, p < 0.001 respectively).
In the open-label extension of RA study V, the mean change from baseline at year 10 in the modified Total Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomized to methotrexate monotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy, respectively. The corresponding proportions of patients with no radiographic progression were 31.3%, 23.7% and 36.7% respectively.
Quality of life and physical function
Health-related quality of life and physical function were assessed using the disability index of the Health Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, which was a pre-specified primary endpoint at week 52 in RA study III. All doses/schedules of adalimumab in all four studies showed statistically significantly greater improvement in the disability index of the HAQ from baseline to month 6 compared to placebo and in RA study III the same was seen at week 52. Results from the Short Form Health Survey (SF-36) for all doses/schedules of adalimumab in all four studies support these findings, with statistically significant physical component summary (PCS) scores, as well as statistically significant pain and vitality domain scores for the 40 mg every other week dose. A statistically significant decrease in fatigue as measured by functional assessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was assessed (RA studies I, III, IV).
In RA study III, most subjects who achieved improvement in physical function and continued treatment maintained improvement through week 520 (120 months) of open-label treatment.
Improvement in quality of life was measured up to week 156 (36 months) and improvement was maintained through that time.
In RA study V, the improvement in the HAQ disability index and the physical component of the SF-36 showed greater improvement (p < 0.001) for adalimumab/methotrexate combination therapy versus methotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through week 104. Among the 250 subjects who completed the open-label extension study, improvements in physical function were maintained through 10 years of treatment.
Injection site pain
For the pooled crossover RA studies VI and VII, a statistically significant difference for injection site pain immediately after dosing was observed between Humira 40 mg/0.8 ml and Humira 40 mg/0.4ml (mean VAS of 3.7 cm versus 1.2 cm, scale of 0-10 cm, P< 0.001). This represented an 84% median reduction in injection site pain.



Axial spondyloarthritis
Ankylosing spondylitis (AS)
Adalimumab 40 mg every other week was assessed in 393 patients in two randomized, 24 week double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in all groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1%) patients were treated concomitantly with disease-modifying anti-rheumatic drugs, and 37 (9.4%) patients with glucocorticoids. The blinded period was followed by an open-label period during which patients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 weeks. Subjects (n = 215, 54.7%) who failed to achieve ASAS 20 at weeks 12, or 16 or 20 received early escape open-label adalimumab 40 mg every other week subcutaneously and were subsequently treated as non-responders in the double-blind statistical analyzes.
In the larger AS study I with 315 patients, results showed statistically significant improvement of the signs and symptoms of ankylosing spondylitis in patients treated with adalimumab compared to placebo. Significant response was first observed at week 2 and maintained through 24 weeks (table 6).
Table 6. Efficacy responses in placebo-controlled AS study – study I reduction of signs and symptoms

Response                                   Placebo                         Adalimumab N = 107                           N = 208
ASASa 20

Week 2                            16%                              42%*** 
Week 12                           21%                              58%*** 
Week 24                           19%                              51%*** ASAS 50

Week 2                             3%                              16%*** Week 12                           10%                              38%*** 
Week 24                           11%                              35%*** 
ASAS 70

Week 2                             0%                               7%** 
Week 12                            5%                              23%*** 
Week 24                            8%                              24%*** 
BASDAIb 50

Week 2                             4%                              20%*** 
Week 12                           16%                              45%*** 
Week 24                           15%                              42%*** ***, ** Statistically significant at p < 0.001, < 0.01 for all comparisons between adalimumab and placebo at weeks 2, 12 and 24 a
Assessments in Ankylosing Spondylitis b
Bath Ankylosing Spondylitis Disease Activity Index
Adalimumab-treated patients had significantly greater improvement at week 12 which was maintained through week 24 in both the SF-36 and Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL).
Similar trends (not all statistically significant) were seen in the smaller randomized, double-blind, placebo controlled AS study II of 82 adult patients with active ankylosing spondylitis.
Axial spondyloarthritis without radiographic evidence of AS
The safety and efficacy of adalimumab were assessed in two randomized, double-blind placebo-controlled studies in patients with non-radiographic axial spondyloarthritis (nr-axSpA). Study nr-axSpA I evaluated patients with active nr-axSpA. Study nr-axSpA II was a treatment withdrawal study in active nr-axSpA patients who achieved remission during open-label treatment with adalimumab.
Study nr-axSpA I
In Study nr-axSpA I, adalimumab 40 mg every other week was assessed in 185 patients in a randomized, 12 week double-blind, placebo-controlled study in patients with active nr-axSpA (mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.4 for patients treated with adalimumab and 6.5 for those on placebo) who have had an inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs.
Thirty-three (18%) patients were treated concomitantly with disease-modifying anti-rheumatic drugs, and 146 (79%) patients with NSAIDs at baseline. The double-blind period was followed by an open-label period during which patients receive adalimumab 40 mg every other week subcutaneously for up to an additional 144 weeks. Week 12 results showed statistically significant improvement of the signs and symptoms of active nr-axSpA in patients treated with adalimumab compared to placebo (table 7.
Table 7. Efficacy response in placebo-controlled Study nr-axSpA I
Double-Blind Response at week                   Placebo                      Adalimumab 12                                              N = 94                          N = 91 ASASa 40                                          15%                          36%*** 
ASAS 20                                          31%                            52%** 
ASAS 5/6                                          6%                            31%*** 
ASAS Partial Remission                            5%                             16%* 
BASDAIb 50                                       15%                            35%** 
ASDASc,d,e                                       -0.3                           -1.0*** 
ASDAS Inactive Disease                            4%                            24%***  hs-CRPd,f,g                                      -0.3                           -4.7*** 
SPARCCh MRI Sacroiliac Jointsd,i                 -0.6                            -3.2** 
SPARCC MRI Spined,j                              -0.2                            -1.8** a
Assessment of SpondyloArthritis international Society b
Bath Ankylosing Spondylitis Disease Activity Index c
Ankylosing Spondylitis Disease Activity Score d
Mean change from baseline

e n = 91 placebo and n = 87 adalimumab f
High sensitivity C-Reactive Protein (mg/L) g n = 73 placebo and n = 70 adalimumab h
Spondyloarthritis Research Consortium of Canada i n = 84 placebo and adalimumab j n = 82 placebo and n = 85 adalimumab
***, **, * Statistically significant at p < 0.001, < 0.01, and < 0.05, respectively, for all comparisons between adalimumab and placebo
In the open-label extension, improvement in the signs and symptoms was maintained with adalimumab therapy through week 156.
Inhibition of inflammation
Significant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac Joints and the Spine was maintained in adalimumab-treated patients through week 156 and week 104, respectively.
Quality of life and physical function
Health-related quality of life and physical function were assessed using the HAQ-S and the SF-36 questionnaires. Adalimumab showed statistically significantly greater improvement in the HAQ-S total score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to placebo. Improvement in health-related quality of life and physical function was maintained during the open-label extension through week 156.
Study nr-axSpA II
673 patients with active nr-axSpA (mean baseline disease activity [BASDAI] was 7.0) who had an inadequate response to ≥ 2 NSAIDs, or an intolerance to or a contraindication for NSAIDs enrolled into the open-label period of Study nr-axSpA II during which they received adalimumab 40 mg eow for 28 weeks. These patients also had objective evidence of inflammation in the sacroiliac joints or spine on MRI or elevated hs-CRP. Patients who achieved sustained remission for at least 12 weeks (N = 305) (ASDAS < 1.3 at weeks 16, 20, 24, and 28) during the open-label period were then randomized to receive either continued treatment with adalimumab 40 mg eow (N = 152) or placebo (N = 153) for an additional 40 weeks in a double-blind, placebo-controlled period (total study duration 68 weeks). Subjects who flared during the double-blind period were allowed adalimumab 40 mg eow rescue therapy for at least 12 weeks.
The primary efficacy endpoint was the proportion of patients with no flare by week 68 of the study.
Flare was defined as ASDAS ≥ 2.1 at two consecutive visits four weeks apart. A greater proportion of patients on adalimumab had no disease flare during the double-blind period, when compared with those on placebo (70.4% vs. 47.1%, p < 0.001) (figure 1).



Figure 1: Kaplan-Meier curves summarizing time to flare in study nr-axSpA II 


Note: P = Placebo (Number at Risk (flared)); A = Adalimumab (Number at Risk (flared)).
Among the 68 patients who flared in the group allocated to treatment withdrawal, 65 completed 12 weeks of rescue therapy with adalimumab, out of which 37 (56.9%) had regained remission (ASDAS < 1.3) after 12 weeks of restarting the open-label treatment.
By Week 68, patients receiving continuous adalimumab treatment showed statistically significant greater improvement of the signs and symptoms of active nr-axSpA as compared to patients allocated to treatment withdrawal during the double-blind period of the study (table 8).
Table 8. Efficacy response in placebo-controlled period for study nr-axSpA II 
Double-Blind                                                            Placebo        Adalimumab Response at Week 68                                                      N=153             N=152 
ASASa,b 20                                                               47.1%           70.4%*** 
ASASa,b 40                                                               45.8%           65.8%*** 
ASASa Partial Remission                                                  26.8%            42.1%** ASDASc Inactive Disease                                                  33.3%           57.2%*** 
Partial Flared                                                           64.1%           40.8%*** a
Assessment of SpondyloArthritis international Society b
Baseline is defined as open-label baseline when patients have active disease c
Ankylosing Spondylitis Disease Activity Score d
Partial flare is defined as ASDAS ≥ 1.3 but < 2.1 at 2 consecutive visits ***, ** Statistically significant at p < 0.001 and < 0.01, respectively, for all comparisons between adalimumab and placebo


Psoriatic arthritis
Adalimumab, 40 mg every other week, was studied in patients with moderately to severely active psoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week duration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory drug therapy and of these, approximately 50% were taking methotrexate. PsA study II with 12-week duration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab was administered every other week (eow).
There is insufficient evidence of the efficacy of adalimumab in patients with ankylosing spondylitis- like psoriatic arthropathy due to the small number of patients studied.
Table 9. ACR response in placebo-controlled psoriatic arthritis studies (percent of patients) 
PsA study I                              PsA study II

Response                        Placebo         Adalimumab            Placebo         Adalimumab N = 162           N = 151             N = 49            N = 51
ACR 20

Week 12                          14%               58%***               16%                  39%* 
Week 24                          15%               57%***               N/A                  N/A 
ACR 50

Week 12                           4%               36%***                2%              25%*** Week 24                           6%               39%***               N/A                  N/A 
ACR 70
Week 12                           1%               20%***                0%                  14%* 
Week 24                           1%               23%***               N/A                  N/A 
*** p < 0.001 for all comparisons between adalimumab and placebo
* p < 0.05 for all comparisons between adalimumab and placebo
N/A not applicable
ACR responses in PsA study I were similar with and without concomitant methotrexate therapy. ACR responses were maintained in the open-label extension study for up to 136 weeks.
Radiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists, and feet were obtained at baseline and week 24 during the double-blind period when patients were on adalimumab or placebo and at week 48 when all patients were on open-label adalimumab. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS used for rheumatoid arthritis), was used.
Adalimumab treatment reduced the rate of progression of peripheral joint damage compared with placebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebo group (at week 24) compared with 0.0 ± 1.9 (p < 0.001) in the adalimumab group (at week 48).
In subjects treated with adalimumab with no radiographic progression from baseline to week 48 (n = 102), 84% continued to show no radiographic progression through 144 weeks of treatment.



Adalimumab-treated patients demonstrated statistically significant improvement in physical function as assessed by HAQ and Short Form Health Survey (SF-36) compared to placebo at week 24.
Improved physical function continued during the open-label extension up to week 136.
Psoriasis
The safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis (≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were candidates for systemic therapy or phototherapy in randomized, double-blind studies. 73% of patients enrolled in psoriasis studies I and II had received prior systemic therapy or phototherapy. The safety and efficacy of adalimumab were also studied in adult patients with moderate to severe chronic plaque psoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy in a randomized double-blind study (psoriasis study III).
Psoriasis study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at least a PASI 75 response (PASI score improvement of at least 75% relative to baseline), entered period B and received open-label 40 mg adalimumab every other week. Patients who maintained ≥ PASI 75 response at week 33 and were originally randomized to active therapy in period A, were re-randomized in period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. Across all treatment groups, the mean baseline PASI score was 18.9 and the baseline Physician’s Global Assessment (PGA) score ranged from “moderate” (53% of subjects included) to “severe” (41%) to “very severe” (6%).
Psoriasis study II (CHAMPION) compared the efficacy and safety of adalimumab versus methotrexate and placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter dose increases up to week 12, with a maximum dose of 25 mg or an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data available comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving MTX who achieved a ≥ PASI 50 response at week 8 and/or 12 did not receive further dose increases.
Across all treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” (< 1%) to “moderate” (48%) to “severe” (46%) to “very severe” (6%).
Patients participating in all phase 2 and phase 3 psoriasis studies were eligible to enroll into an open-label extension trial, where adalimumab was given for at least an additional 108 weeks.
In psoriasis studies I and II, a primary endpoint was the proportion of patients who achieved a PASI 75 response from baseline at week 16 (see tables 10 and 12).



Table 10. Ps study I (REVEAL) - efficacy results at 16 weeks

Placebo                    Adalimumab 40 mg eow
N = 398                          N = 814 n (%)                         n (%)
≥ PASI 75a                                                  26 (6.5)                    578 (70.9)b 
PASI 100                                                    3 (0.8)                     163 (20.0)b 
PGA: Clear/minimal                                          17 (4.3)                    506 (62.2)b a
Percent of patients achieving PASI 75 response was calculated as center-adjusted rate b p < 0.001, adalimumab versus placebo
Table 11. Ps study II (CHAMPION) efficacy results at 16 weeks

Placebo                      MTX         Adalimumab 40 mg eow
N = 53                     N = 110             N = 108 n (%)                       n (%)               n (%)
≥ PASI 75                                  10 (18.9)                   39 (35.5)         86 (79.6)a, b 
PASI 100                                    1 (1.9)                     8 (7.3)          18 (16.7)c, d 
PGA: Clear/minimal                         6 (11.3)                    33 (30.0)         79 (73.1)a, b a p < 0.001 adalimumab versus placebo b p < 0.001 adalimumab versus methotrexate c p < 0.01 adalimumab versus placebo d p < 0.05 adalimumab versus methotrexate
In psoriasis study I, 28% of patients who were PASI 75 responders and were re-randomized to placebo at week 33 compared to 5% continuing on adalimumab, p < 0.001, experienced “loss of adequate response” (PASI score after week 33 and on or before week 52 that resulted in a < PASI 50 response relative to baseline with a minimum of a 6-point increase in PASI score relative to week 33). Of the patients who lost adequate response after re-randomization to placebo who then enrolled into the open-label extension trial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and 24 weeks of retreatment, respectively.
A total of 233 PASI 75 responders at week 16 and week 33 received continuous adalimumab therapy for 52 weeks in psoriasis study I, and continued adalimumab in the open-label extension trial. PASI 75 and PGA of clear or minimal response rates in these patients were 74.7% and 59.0%, respectively, after an additional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all patients who dropped out of the study for adverse events or lack of efficacy, or who dose-escalated, were considered non-responders, PASI 75 and PGA of clear or minimal response rates in these patients were 69.6% and 55.7%, respectively, after an additional 108 weeks of open-label therapy (total of 160 weeks).
A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. During the withdrawal period, symptoms of psoriasis returned over time with a median time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of these patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) of patients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16 weeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1%[123/178] and 88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period, respectively). A similar safety profile was observed during retreatment as before withdrawal.


Significant improvements at week 16 from baseline compared to placebo (studies I and II) and MTX (study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In study I, improvements in the physical and mental component summary scores of the SF-36 were also significant compared to placebo.
In an open-label extension study, for patients who dose escalated from 40 mg every other week to 40 mg weekly due to a PASI response below 50%, 26.4% (92/349) and 37.8% (132/349) of patients achieved PASI 75 response at week 12 and 24, respectively.
Psoriasis study III (REACH) compared the efficacy and safety of adalimumab versus placebo in 72 patients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 16 weeks. At week 16, a statistically significantly greater proportion of patients who received adalimumab achieved PGA of “clear” or “almost clear” for the hands and/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [p = 0.014]).
Psoriasis study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patients with moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed by open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included the Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see table 12).
Adalimumab demonstrated a treatment benefit in nail psoriasis patients with different extents of skin involvement (BSA ≥ 10% (60% of patients) and BSA < 10% and ≥ 5% (40% of patients)).
Table 12. Ps study IV efficacy results at 16, 26 and 52 weeks

Endpoint                               Week 16                      Week 26                 Week 52 Placebo-controlled           Placebo-controlled           Open-label

Placebo      Adalimumab      Placebo      Adalimumab        Adalimumab N = 108      40 mg eow       N = 108
40 mg eow         40 mg eow
N = 109
N = 109            N = 80

≥ mNAPSI 75 (%)                 2.9           26.0a          3.4              46.6a           65.0 PGA-F clear/minimal and         2.9           29.7a          6.9              48.9a           61.3 ≥ 2-grade improvement
(%)

Percent change in total         -7.8         -44.2 a        -11.5          -56.2a             -72.2 fingernail NAPSI (%) a p < 0.001, adalimumab versus placebo


Adalimumab-treated patients showed statistically significant improvements at week 26 compared with placebo in the DLQI.



Hidradenitis suppurativa
The safety and efficacy of adalimumab were assessed in randomized, double-blind, placebo-controlled studies and an open-label extension study in adult patients with moderate to severe hidradenitis suppurativa (HS) who were intolerant, had a contraindication or an inadequate response to at least a 3-month trial of systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or III disease with at least 3 abscesses or inflammatory nodules.
Study HS-I (PIONEER I) evaluated 307 patients with 2 treatment periods. In Period A, patients received placebo or adalimumab at an initial dose of 160 mg at week 0, 80 mg at week 2, and 40 mg every week starting at week 4 to week 11. Concomitant antibiotic use was not allowed during the study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomized in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomized to placebo in Period A were assigned to receive adalimumab 40 mg every week in Period B.
Study HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In Period A, patients received placebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and 40 mg every week starting at week 4 to week 11. 19.3% of patients had continued baseline oral antibiotic therapy during the study. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-randomized in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab 40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomized to placebo in Period A were assigned to receive placebo in Period B.
Patients participating in Studies HS-I and HS-II were eligible to enroll into an open-label extension study in which adalimumab 40 mg was administered every week. Mean exposure in all adalimumab population was 762 days. Throughout all 3 studies patients used topical antiseptic wash daily.
Clinical response
Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was assessed using Hidradenitis Suppurativa clinical response (HiSCR; at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric Rating Scale in patients who entered the study with an initial baseline score of 3 or greater on a 11 point scale.
At week 12, a significantly higher proportion of patients treated with adalimumab versus placebo achieved HiSCR. At week 12, a significantly higher proportion of patients in study HS-II experienced a clinically relevant decrease in HS-related skin pain (see table 13). Patients treated with adalimumab had significantly reduced risk of disease flare during the initial 12 weeks of treatment.
Table 13. Efficacy results at 12 weeks, HS studies I and II

HS study I                            HS study II

Placebo       Adalimumab 40 mg         Placebo      Adalimumab 40 mg weekly                                 weekly
Hidradenitis                N = 154            N = 153             N = 163             N = 163 Suppurativa Clinical
40 (26.0%)        64 (41.8%)*         45 (27.6%)         96 (58.9%)*** Response (HiSCR)a

≥ 30% Reduction in          N = 109            N = 122             N = 111             N = 105 Skin Painb
27 (24.8%)         34 (27.9%)         23 (20.7%)         48 (45.7%)*** 

*P < 0.05, ***P < 0.001, adalimumab versus placebo a
Among all randomized patients b
Among patients with baseline HS-related skin pain assessment ≥ 3, based on Numeric Rating Scale 0 – 10; 0 = no skin pain, 10 = skin pain as bad as you can imagine

Treatment with adalimumab 40 mg every week significantly reduced the risk of worsening of abscesses and draining fistulas. Approximately twice the proportion of patients in the placebo group in the first 12 weeks of Studies HS-I and HS-II, compared with those in the adalimumab group experienced worsening of abscesses (23.0% versus 11.4%, respectively) and draining fistulas (30.0% versus 13.9%, respectively).
Greater improvements at week 12 from baseline compared to placebo were demonstrated in skin-specific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI; Studies HS-I and HS-II), patient global satisfaction with medication treatment as measured by the Treatment Satisfaction Questionnaire-medication (TSQM; Studies HS-I and HS-II), and physical health as measured by the physical component summary score of the SF-36 (study HS-I).
In patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR rate at week 36 was higher in patients who continued weekly adalimumab than in patients in whom dosing frequency was reduced to every other week, or in whom treatment was withdrawn (see table 14).
Table 14. Proportion of patientsa achieving HiSCRb at weeks 24 and 36 after treatment reassignment from weekly adalimumab at week 12

Placebo (treatment         Adalimumab 40 mg        Adalimumab 40 mg withdrawal)              every other week            weekly
N = 73                     N = 70                   N = 70

Week 24                           24 (32.9%)                 36 (51.4%)               40 (57.1%) 
Week 36                           22 (30.1%)                 28 (40.0%)               39 (55.7%) a
Patients with at least a partial response to adalimumab 40 mg weekly after 12 weeks of treatment b
Patients meeting protocol-specified criteria for loss of response or no improvement were required to discontinue from the studies and were counted as non-responders

Among patients who were at least partial responders at week 12, and who received continuous weekly adalimumab therapy, the HiSCR rate at week 48 was 68.3% and at week 96 was 65.1%. Longer term treatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings.
Among patients whose adalimumab treatment was withdrawn at week 12 in Studies HS-I and HS-II, the HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similar to that observed before withdrawal (56.0%).
Crohn’s disease
The safety and efficacy of adalimumab were assessed in over 1,500 patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to receive at least one of these medications.



Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD study I (CLASSIC I) and CD study II (GAIN). In CD study I, 299 TNF-antagonist naïve patients were randomized to one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0 and 80 mg at week 2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week 2. In CD study II, 325 patients who had lost response or were intolerant to infliximab were randomized to receive either 160 mg adalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. The primary non-responders were excluded from the studies and therefore these patients were not further evaluated.
Maintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854 patients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients were randomized to 40 mg every other week, 40 mg every week, or placebo with a total study duration of 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and analyzed separately from those not in clinical response at week 4. Corticosteroid taper was permitted after week 8.
CD study I and CD study II induction of remission and response rates are presented in table 15.
Table 15. Induction of clinical remission and response (percent of patients) 
CD study I: infliximab-naïve patients            CD study II: infliximab experienced patients

Placebo      Adalimumab        Adalimumab        Placebo     Adalimumab 80/40 mg          160/80 mg        N = 166      160/80 mg
N = 74
N = 76
N = 75                                          N = 159
Week 4

Clinical remission         12%             24%              36%*            7%            21%* 
Clinical response          24%             37%             49%**            25%           38%** (CR-100)

All p-values are pairwise comparisons of proportions for adalimumab versus placebo * p < 0.001
** p < 0.01
Similar remission rates were observed for the 160/80 mg and 80/40 mg induction regimens by week 8 and adverse events were more frequently noted in the 160/80 mg group.
In CD study III, at week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. Of those in clinical response at week 4, 48% had been previously exposed to other TNF-antagonists. Maintenance of remission and response rates are presented in table 16. Clinical remission results remained relatively constant irrespective of previous TNF-antagonist exposure.
Disease-related hospitalizations and surgeries were statistically significantly reduced with adalimumab compared with placebo at week 56.



Table 16. Maintenance of clinical remission and response (percent of patients) 
Placebo         40 mg adalimumab             40 mg every other week      adalimumab every week

Week 26                               N = 170              N = 172                 N = 157 
Clinical remission                     17%                  40%*                     47%* 
Clinical response (CR-100)             27%                  52%*                     52%* 
Patients in steroid-free             3% (2/66)          19% (11/58)**           15% (11/74)** remission for > = 90 daysa

Week 56                               N = 170              N = 172                 N = 157 
Clinical remission                     12%                  36%*                     41%* 
Clinical response (CR-100)             17%                  41%*                     48%* 
Patients in steroid-free             5% (3/66)          29% (17/58)*            20% (15/74)** remission for > = 90 daysa

* p < 0.001 for adalimumab versus placebo pairwise comparisons of proportions ** p < 0.02 for adalimumab versus placebo pairwise comparisons of proportions a
Of those receiving corticosteroids at baseline
Among patients who were not in response at week 4, 43% of adalimumab maintenance patients responded by week 12 compared to 30% of placebo maintenance patients. These results suggest that some patients who have not responded by week 4 benefit from continued maintenance therapy through week 12. Therapy continued beyond 12 weeks did not result in significantly more responses (see section 4.2).
117/276 patients from CD study I and 272/777 patients from CD studies II and III were followed through at least 3 years of open-label adalimumab therapy. 88 and 189 patients, respectively, continued to be in clinical remission. Clinical response (CR-100) was maintained in 102 and 233 patients, respectively.
Quality of life
In CD study I and CD study II, statistically significant improvement in the disease-specific inflammatory bowel disease questionnaire (IBDQ) total score was achieved at week 4 in patients randomized to adalimumab 80/40 mg and 160/80 mg compared to placebo and was seen at weeks 26 and 56 in CD study III as well among the adalimumab treatment groups compared to the placebo group.
Ulcerative colitis
The safety and efficacy of multiple doses of adalimumab were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3) in randomized, double-blind, placebo-controlled studies.
In study UC-I, 390 TNF-antagonist naïve patients were randomized to receive either placebo at weeks 0 and 2, 160 mg adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab at week 0 followed by 40 mg at week 2. After week 2, patients in both adalimumab arms received 40 mg every other week. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at week 8.

In study UC-II, 248 patients received 160 mg of adalimumab at week 0, 80 mg at week 2 and 40 mg every other week thereafter, and 246 patients received placebo. Clinical results were assessed for induction of remission at week 8 and for maintenance of remission at week 52.
Patients induced with 160/80 mg adalimumab achieved clinical remission versus placebo at week 8 in statistically significantly greater percentages in study UC-I (18% versus 9% respectively, p = 0.031) and study UC-II (17% versus 9% respectively, p = 0.019). In study UC-II, among those treated with adalimumab who were in remission at week 8, 21/41 (51%) were in remission at week 52.
Results from the overall UC-II study population are shown in table 17.
Table 17. Response, remission and mucosal healing in study UC-II (percent of patients) Placebo            Adalimumab 40 mg eow
Week 52                                               N = 246                  N = 248 
Clinical response                                       18%                     30%* Clinical remission                                      9%                      17%* 
Mucosal healing                                         15%                     25%* 
Steroid-free remission for ≥ 90 daysa                   6%                      13%* (N = 140)               (N = 150)

Week 8 and 52

Sustained response                                      12%                     24%** 
Sustained remission                                     4%                       8%* Sustained mucosal healing                               11%                     19%* 
Clinical remission is Mayo score ≤ 2 with no subscore > 1;
Clinical response is decrease from baseline in Mayo score ≥ 3 points and ≥ 30% plus a decrease in the rectal bleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1;
* p < 0.05 for adalimumab versus placebo pairwise comparison of proportions ** p < 0.001 for adalimumab versus placebo pairwise comparison of proportions a
Of those receiving corticosteroids at baseline
Of those patients who had a response at week 8, 47% were in response, 29% were in remission, 41% had mucosal healing, and 20% were in steroid-free remission for ≥ 90 days at week 52.
Approximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab.
The efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve patients. Among patients who had failed prior anti-TNF treatment, week 52 remission was achieved by 3% on placebo and 10% on adalimumab.
Patients from studies UC-I and UC-II had the option to roll over into an open-label long-term extension study (UC III). Following 3 years of adalimumab therapy, 75% (301/402) continued to be in clinical remission per partial Mayo score.



Hospitalization rates
During 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalizations and UC-related hospitalizations were observed for the adalimumab-treated arm compared to the placebo arm. The number of all cause hospitalizations in the adalimumab treatment group was 0.18 per patient year versus 0.26 per patient year in the placebo group and the corresponding figures for UC-related hospitalizations were 0.12 per patient year versus 0.22 per patient year.
Quality of life
In study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel Disease Questionnaire (IBDQ) score.
Intestinal Behcet's disease
Phase 3 Clinical study in Japan
In an open-label and uncontrolled study in 20 patients*with intestinal Behcet's disease who have had an inadequate response to conventional therapy (steroid or immunomodulator), marked improvement rate at week 24 (the proportion of the subjects whose global assessment of gastrointestinal symptoms and endoscopic improvement are both ≤ 1) was 45.0% (9/20).
Common adverse events (at week 52) were nasopharyngitis 9 cases (45.0%), diarrhea, Behcet’s syndrome (exacerbation of original disease), contused wound and cough 3 cases (15.0%) each.
*
The patients who were diagnosed to have the complete type, incomplete type or suspected according to the diagnostic criteria for Behcet’s disease by the research division of the Ministry of Health, Labor and Welfare and were observed to have a typical ulcer of 1 cm or larger in longer diameter in the ileocecal region.
Uveitis
The safety and efficacy of adalimumab were assessed in adult patients with non-infectious intermediate, posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two randomized, double-masked, placebo-controlled studies (UV I and II). Patients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted.
Study UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral prednisone at a dose of 10 to 60 mg/day). All patients received a 2 week standardized dose of prednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete corticosteroid discontinuation by week 15.
Study UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment (oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent a mandatory taper schedule, with complete corticosteroid discontinuation by week 19.
The primary efficacy endpoint in both studies was ‘time to treatment failure’. Treatment failure was defined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory retinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected visual acuity (BCVA).
Patients who completed Studies UV I and UV II were eligible to enroll in an uncontrolled long-term extension study with an originally planned duration of 78 weeks. Patients were allowed to continue on study medication beyond week 78 until they had access to adalimumab.



Clinical response
Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with adalimumab versus patients receiving placebo (see table 18). Both studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo (see figure 2).
Table 18. Time to treatment failure in studies UV I and UV II

Analysis             N               Failure            Median     HRa       95% CI      p-value b time to
Treatment                            N (%)                                   for HRa failure
(months)


Time to treatment failure at or after week 6 in study UV I
Primary analysis (ITT)

Placebo              107               84 (78.5)        3.0        --        --         -- 
Adalimumab           110               60 (54.5)        5.6        0.50      0.36,      < 0.001 0.70
Time to treatment failure at or after week 2 in study UV II
Primary analysis (ITT)


Placebo              111             61 (55.0)          8.3        --        --         -- Adalimumab           115             45 (39.1)          NEc        0.57      0.39,      0.004 0.84

Note: Treatment failure at or after week 6 (study UV I), or at or after week 2 (study UV II), was counted as event. Drop outs due to reasons other than treatment failure were censored at the time of dropping out a
HR of adalimumab versus placebo from proportional hazards regression with treatment as factor b
2-sided p-value from log rank test c
NE = not estimable. Fewer than half of at-risk subjects had an event



Figure 2: Kaplan-Meier curves summarizing time to treatment failure on or after week 6 (study UV I) or week 2 (study UV II)



Note: P# = Placebo (number of events/number at risk); A# = Adalimumab (number of events/number at risk).
In study UV I statistically significant differences in favor of adalimumab versus placebo were observed for each component of treatment failure. In study UV II, statistically significant differences were observed for visual acuity only, but the other components were numerically in favor of adalimumab.
Of the 424 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 60 subjects were regarded ineligible (e.g. due to deviations or due to complications secondary to diabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 364 remaining patients, 269 evaluable patients (74%) reached 78 weeks of open-label adalimumab treatment. Based on the observed data approach, 216 (80.3%) were in quiescence (no active inflammatory lesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, and 178 (66.2 %) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.6% of the eyes at week 78. Data beyond week 78 were generally consistent with these results but the number of enrolled subjects declined after this time.
Overall, among the patients who discontinued the study, 18% discontinued due to adverse events, and 8% due to insufficient response to adalimumab treatment.

Quality of life
Patient reported outcomes regarding vision-related functioning were measured in both clinical studies, using the NEI VFQ-25. Adalimumab was numerically favored for the majority of subscores with statistically significant mean differences for general vision, ocular pain, near vision, mental health, and total score in study UV I, and for general vision and mental health in study UV II. Vision related effects were not numerically in favor of adalimumab for color vision in study UV I and for color vision, peripheral vision and near vision in study UV II.
Immunogenicity
Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. There is no apparent correlation between the presence of anti-adalimumab antibodies and the occurrence of adverse events.
Patients in rheumatoid arthritis Studies I, II and III were tested at multiple time points for anti- adalimumab antibodies during the 6 to 12 month period. In the pivotal trials, anti-adalimumab antibodies were identified in 5.5 % (58/1053) of patients treated with adalimumab, compared to 0.5% (2/370) on placebo. In patients not given concomitant methotrexate, the incidence was 12.4%, compared to 0.6% when adalimumab was used as add-on to methotrexate.
In patients with psoriatic arthritis, anti-adalimumab antibodies were identified in 38/376 subjects (10%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 13.5 % (24/178 subjects), compared to 7 % (14 of 198 subjects) when adalimumab was used as add-on to methotrexate.
In patients with ankylosing spondylitis anti-adalimumab antibodies were identified in 17/204 subjects (8.3%) treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 16/185 (8.6%), compared to 1/19 (5.3%) when adalimumab was used as add-on to methotrexate.
In patients with non-radiographic axial spondyloarthritis, anti-adalimumab antibodies were identified in 8/152 subjects (5.3%) who were treated continuously with adalimumab.
In patients with Crohn’s disease, anti-adalimumab antibodies were identified in 7/269 subjects (2.6 %) and in 19/487 subjects (3.9%) with ulcerative colitis.
In adult patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 subjects (8.4%) treated with adalimumab monotherapy.
In adult plaque psoriasis patients on long-term adalimumab monotherapy who participated in a withdrawal and retreatment study, the rate of antibodies to adalimumab after retreatment (11 of 482 subjects, 2.3%) was similar to the rate observed prior to withdrawal (11 of 590 subjects, 1.9%).
In patients with moderate to severe hidradenitis suppurativa, anti-adalimumab antibodies were identified in 10/99 subjects (10.1%) treated with adalimumab.
In adult patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab.
In Japanese patients with intestinal Behcet’s disease, anti-adalimumab antibodies were identified in 5% (1/20) of patients treated with adalimumab.
Because immunogenicity analyzes are product-specific, comparison of antibody rates with those from other products is not appropriate.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption and distribution
After subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab was slow, with peak serum concentrations being reached about 5 days after administration. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from 11 to 15 mL/hour, the distribution volume (Vss) ranged from 5 to 6 liters and the mean terminal phase half-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several rheumatoid arthritis patients ranged from 31-96% of those in serum.
Following subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid arthritis (RA) patients the mean steady-state trough concentrations were approximately 5 µg/mL (without concomitant methotrexate) and 8 to 9 µg/mL (with concomitant methotrexate), respectively.
The serum adalimumab trough levels at steady-state increased roughly proportionally with dose following 20, 40 and 80 mg subcutaneous dosing every other week and every week.
Following subcutaneous administration of 40 mg of adalimumab every other week in adult non-radiographic axial spondyloarthritis patients, the mean (±SD) trough steady-state concentration at Week 68 was 8.0 ± 4.6 µg/mL.
In adult patients with psoriasis, the mean steady-state trough concentration was 5 µg/mL during adalimumab 40 mg every other week monotherapy treatment.
In adult patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 80 mg on week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 µg/mL at week 2 and week 4. The mean steady-state trough concentration at week 12 through week 36 were approximately 8 to 10 µg/mL during adalimumab 40 mg every week treatment.
In patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 5.5 µg/mL during the induction period. A loading dose of 160 mg adalimumab on week 0 followed by 80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 µg/mL during the induction period. Mean steady-state trough levels of approximately 7 µg/mL were observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab every other week.
For patients who stayed on their randomized therapy, the mean (±SD) adalimumab trough concentrations at week 52 were 9.5 ± 5.6 µg/mL for the standard dose group and 3.5 ± 2.2 µg/mL for the low dose group. The mean trough concentrations were maintained in patients who continued to receive adalimumab treatment every other week for 52 weeks. For patients who dose escalated from every other week to weekly regimen, the mean (±SD) serum concentrations of adalimumab at week 52 were 15.3 ± 11.4 µg/mL (40/20 mg, weekly) and 6.7 ± 3.5 µg/mL (20/10 mg, weekly).
In patients with ulcerative colitis, a loading dose of 160 mg adalimumab on week 0 followed by 80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 µg/mL during the induction period. Mean steady-state trough levels of approximately 8 µg/mL were observed in ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab every other week.
In adult patients with uveitis, a loading dose of 80 mg adalimumab on week 0 followed by 40 mg adalimumab every other week starting at week 1, resulted in mean steady-state concentrations of approximately 8 to 10 µg/mL.
Population pharmacokinetic and pharmacokinetic/pharmacodynamic modelling and simulation predicted comparable adalimumab exposure and efficacy in patients treated with 80 mg every other week when compared with 40 mg every week (including adult patients with RA, HS, UC, CD or Ps, patients with adolescent HS, and pediatric patients ≥ 40 kg with CD).
In subjects with Behcet's disease, the mean steady-state trough adalimumab serum concentration was approximately 9 μg/mL during the treatment of 40 mg given every other week starting 4 week after an initial 160 mg dose on week 0 followed by 80 mg on week 2 as subcutaneous injections (Japanese Subjects).
Elimination
Population pharmacokinetic analyzes with data from over 1,300 RA patients revealed a trend toward higher apparent clearance of adalimumab with increasing body weight. After adjustment for weight differences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum levels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be lower in patients with measurable AAA.
Hepatic or renal impairment
Adalimumab has not been studied in patients with hepatic or renal impairment.