Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) 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 IC 50 of 0.1-0.2 nM).

Pharmacodynamic effects

After treatment with Humira, 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 remodelling responsible for cartilage destruction were also decreased after Humira administration. Patients treated with Humira usually experienced improvement in haematological signs of chronic inflammation.

A rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis and hidradenitis suppurativa after treatment with Humira.
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

Humira was evaluated in over 3000 patients in all rheumatoid arthritis clinical trials. The efficacy and safety of Humira were assessed in five randomised, double-blind and well-controlled studies. Some patients were treated for up to 120 months duration.

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 Humira 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 Humira 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 Humira every week for 52 weeks. The third group received 40 mg of Humira 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 Humira/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 randomised to 40 mg of Humira 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 Humira 40 mg every other week/methotrexate combination therapy, Humira 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.
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.

ACR response

The percent of Humira-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 summarised in Table 4.
Table 4
ACR Responses in Placebo-Controlled Trials
(Percent of Patients)

Response               RA Study Ia**                 RA Study IIa**                 RA Study IIIa** 
Placebo/     Humirab/ MTXc      Placebo        Humirab        Placebo/    Humirab/ MTXc MTXc            n=63            n=110          n=113          MTXc          n=207 n=60                                                         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 Humira administered every other week c
MTX = methotrexate
**p<0.01, Humira 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 Humira 40 mg every other week, 114 patients continued on Humira 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 Humira 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 Humira 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, Humira-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 Humira and methotrexate led to faster and significantly greater ACR responses than methotrexate monotherapy and Humira monotherapy at Week 52 and responses were sustained at Week 104 (see Table 5).


Table 5
ACR Responses in RA Study V
(percent of patients)
MTX            Humira     Humira/MTX
Response                                                             p-valuea      p-valueb      p-valuec n=257          n=274        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 Humira/methotrexate combination therapy using the Mann-Whitney U test.
b. p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate combination therapy using the Mann-Whitney U test c. p-value is from the pairwise comparison of Humira 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 randomised 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 Humira/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 Humira monotherapy. Humira/methotrexate combination therapy was clinically and statistically superior to methotrexate (p<0.001) and Humira 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 Humira 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. Humira/methotrexate patients demonstrated significantly less radiographic progression than patients receiving methotrexate alone at 6 and 12 months (see Table 6).

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 Humira 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 Humira 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 6
Radiographic Mean Changes Over 12 Months in RA Study III

Placebo/          Humira /MTX         Placebo/MTX-            p-value MTXa               40 mg every         Humira /MTX other week       (95% Confidence
Intervalb)
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% confidence intervals for the differences in change scores between methotrexate and Humira.
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 7).

Table 7
Radiographic Mean Changes at Week 52 in RA Study V

MTX               Humira       Humira/MTX n=257              n=274           n=268
(95%               (95%            (95%        p-valuea   p-valueb   p-valuec confidence         confidence      confidence interval)          interval)       interval)
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 score       3.7 (2.7-4.7)    1.7 (1.0-2.4)  0.8 (0.4-1.2)  <0.001     0.0082 <0.001 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 Humira/methotrexate combination therapy using the Mann-Whitney U test.
. b p-value is from the pairwise comparison of Humira monotherapy and Humira/methotrexate combination therapy using the Mann-Whitney U test
. c p-value is from the pairwise comparison of Humira 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 Humira/methotrexate combination therapy (63.8% and 61.2% respectively) compared to methotrexate monotherapy (37.4% and 33.5% respectively, p<0.001) and Humira 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 Humira 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 Humira 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 Humira/methotrexate combination therapy versus methotrexate monotherapy and Humira 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.

Juvenile idiopathic arthritis (JIA)

Polyarticular juvenile idiopathic arthritis (pJIA)
The safety and efficacy of Humira was assessed in two studies (pJIA I and II) in children with active polyarticular or polyarticular course juvenile idiopathic arthritis, who had a variety of JIA onset types (most frequently rheumatoid-factor negative or positive polyarthritis and extended oligoarthritis).
 pJIA I

The safety and efficacy of Humira were assessed in a multicentre, randomised, double-blind, parallel − group study in 171 children (4-17 years old) with polyarticular JIA. In the open-label lead in phase (OL LI) patients were stratified into two groups, MTX (methotrexate)-treated or non- MTX- treated. Patients who were in the non-MTX stratum were either naïve to or had been withdrawn from MTX at least two weeks prior to study drug administration. Patients remained on stable doses of NSAIDs and or prednisone (≤ 0.2 mg /kg/day or 10 mg/day maximum). In the OL LI phase all patients received 24 mg/m2 up to a maximum of 40 mg Humira every other week for 16 weeks. The distribution of patients by age and minimum, median and maximum dose received during the OL LI phase is presented in Table 8.

Table 8
Distribution of patients by age and adalimumab dose received during the OL LI phase 

Age Group                   Number of patients at Baseline     Minimum, median and n (%)                              maximum dose
4 to 7 years                31 (18.1)                          10, 20 and 25 mg
8 to 12 years               71 (41.5)                          20, 25 and 40 mg 13 to 17 years              69 (40.4)                          25, 40 and 40 mg 
Patients demonstrating a Pediatric ACR 30 response at week 16 were eligible to be randomised into the double blind (DB) phase and received either Humira 24 mg/m2 up to a maximum of 40 mg, or placebo every other week for an additional 32 weeks or until disease flare. Disease flare criteria were defined as a worsening of ≥ 30% from baseline in ≥ 3 of 6 Pediatric ACR core criteria, ≥ 2 active 

joints, and improvement of > 30% in no more than 1 of the 6 criteria. After 32 weeks or at disease flare, patients were eligible to enrol into the open label extension phase.
Table 9
Ped ACR 30 Responses in the JIA study

Stratum                                       MTX                             Without MTX Phase
OL-LI 16 weeks
Ped ACR 30                          94.1% (80/85)                       74.4% (64/86) response (n/N)
Efficacy Outcomes
Double Blind 32 weeks         Humira / MTX     Placebo / MTX        Humira             Placebo (N = 38)         (N = 37)             (N= 30)            (N = 28)

Disease flares at    36.8% (14/38)      64.9% (24/37)b     43.3% (13/30)      71.4% the end of 32                                                                 (20/28)c weeksa (n/N)
Median time to       >32 weeks          20 weeks           >32 weeks          14 weeks disease flare a
Ped ACR 30/50/70 responses week 48 significantly greater than those of placebo treated patients b p = 0.015 c p = 0.031

Amongst those who responded at week 16 (n=144), the Pediatric ACR 30/50/70/90 responses were maintained for up to six years in the OLE phase in patients who received Humira throughout the study. Over all 19 subjects, of which 11 of the baseline age group 4 to 12 and 8 of the baseline age group 13 to 17 years were treated 6 years or longer.

Overall responses were generally better and, fewer patients developed antibodies when treated with the combination of Humira and MTX compared to Humira alone. Taking these results into consideration, Humira is recommended for use in combination with MTX and for use as monotherapy in patients for whom MTX use is not appropriate (see section 4.2).
 pJIA II

The safety and efficacy of Humira was assessed in an open-label, multicenter study in 32 children (2 - <4 years old or aged 4 and above weighing < 15 kg) with moderately to severely active polyarticular JIA. The patients received 24 mg/m2 body surface area (BSA) of Humira up to a maximum of 20 mg every other week as a single dose via SC injection for at least 24 weeks. During the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

At Week 12 and Week 24, PedACR30 response was 93.5% and 90.0%, respectively, using the observed data approach. The proportions of subjects with PedACR50/70/90 at Week 12 and Week 24 were 90.3%/61.3%/38.7% and 83.3%/73.3%/36.7%, respectively. Amongst those who responded (Pediatric ACR 30) at Week 24 (n=27 out of 30 patients), the Pediatric ACR 30 responses were maintained for up to 60 weeks in the OLE phase in patients who received Humira throughout this time period. Overall, 20 subjects were treated for 60 weeks or longer.

Enthesitis-related arthritis

The safety and efficacy of Humira were assessed in a multicenter, randomised, double-blind study in 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were randomised to receive either 24 mg/m2 body surface area (BSA) of Humira up to a maximum of 40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-label (OL) period during which patients received 24 mg/m2 BSA of Humira up to a maximum of 40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was the percent change from Baseline to Week 12 in the number of active joints with arthritis (swelling not due to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with mean percent decrease of -62.6% (median percent change -88.9%) in patients in the Humira group compared to -11.6% (median percent change -50.0%) in patients in the placebo group. Improvement in number of active joints with arthritis was maintained during the OL period through Week 156 for the 26 of 31 (84%) patients in the Humira group who remained in the study. Although not statistically significant, the majority of patients demonstrated clinical improvement in secondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count (SJC), Pediatric ACR 50 response, and Pediatric ACR 70 response.

Axial Spondyloarthritis

Ankylosing spondylitis (AS)
Humira 40 mg every other week was assessed in 393 patients in two randomised, 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 Humira 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 analyses.

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 Humira compared to placebo.
Significant response was first observed at Week 2 and maintained through 24 weeks (Table 10).

Table 10
Efficacy Responses in Placebo-Controlled AS Study – Study I
Reduction of Signs and Symptoms

Response                              Placebo                  Humira 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 Humira and placebo at Weeks 2, 12 and 24 a
Assessments in Ankylosing Spondylitis b
Bath Ankylosing Spondylitis Disease Activity Index

Humira treated patients had significantly greater improvement at Week 12 which was maintained through Week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL).
Similar trends (not all statistically significant) were seen in the smaller randomised, 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 Humira 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 Humira.

Study nr-axSpA I

In Study nr-axSpA I, Humira 40mg 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 Humira 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%) of 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 Humira 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 Humira compared to placebo (Table 11).

Table 11
Efficacy Response in Placebo-Controlled Study - nr-axSpA

Double-Blind                                       Placebo      Humira Response at Week 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-CRP d,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 Humira f high sensitivity C-Reactive Protein (mg/L) g n=73 placebo and n=70 Humira h
Spondyloarthritis Research Consortium of Canada i n=84 placebo and Humira j n=82 placebo and n=85 Humira
***, **, * Statistically significant at p < 0.001, < 0.01, and
< 0.05, respectively, for all comparisons between Humira and placebo.
In the open-label extension, improvement in the signs and symptoms was maintained with Humira 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 Humira-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. Humira 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 Humira 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 Humira 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 Humira 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 Humira 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
PROBABILITY OF NO FLARE


TIME (WEEKS)
Treatment            Placebo            Humira     ∆ Censored

Note: P = Placebo (Number at Risk (flared)); A = HUMIRA (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 Humira, 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 Humira 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 15).

Table 12
Efficacy Response in Placebo-Controlled Period for Study nr-axSpA II

Double-Blind                                                            Placebo              Humira 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 Humira and placebo.

Psoriatic arthritis

Humira, 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 Humira was administered every other week.

There is insufficient evidence of the efficacy of Humira in patients with ankylosing spondylitis-like psoriatic arthropathy due to the small number of patients studied.

Table 13
ACR Response in Placebo-Controlled Psoriatic Arthritis Studies
(Percent of Patients)



PsA Study I                 PsA Study II
Placebo      Humira         Placebo       Humira
Response
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 Humira and placebo
*    p<0.05 for all comparisons between Humira 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 Humira or placebo and at Week 48 when all patients were on open-label Humira. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS used for rheumatoid arthritis), was used.

Humira 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 Humira group (at week 48).

In subjects treated with Humira with no radiographic progression from baseline to Week 48 (n=102), 84% continued to show no radiographic progression through 144 weeks of treatment.

Humira 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 Humira 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 randomised, 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 Humira 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 Humira 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 Humira every other week. Patients who maintained ≥PASI 75 response at Week 33 and were originally randomised to active therapy in Period A, were re-randomised in period C to receive 40 mg Humira 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 Humira 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 Humira followed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are no data available comparing Humira 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 enrol into an open- label extension trial, where Humira 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 14 and 15).

Table 14
Ps Study I (REVEAL) - Efficacy Results at 16 Weeks
Placebo         Humira 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 PASI75 response was calculated as center- adjusted rate b p<0.001, Humira vs. placebo

Table 15
Ps Study II (CHAMPION) Efficacy Results at 16 Weeks
Placebo          MTX      Humira 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:               6 (11.3)       33 (30.0)      79 (73.1) a, b
Clear/minimal a p<0.001 Humira vs. placebo b p<0.001 Humira vs. methotrexate c p<0.01 Humira vs. placebo d p<0.05 Humira vs. methotrexate

In Psoriasis Study I, 28% of patients who were PASI 75 responders and were re-randomised to placebo at Week 33 compared to 5% continuing on Humira, p<0.001, experienced “loss of adequate response” (PASI score after Week 33 and on or before Week 52 that resulted in a  20% BSA involvement or > 10% BSA involvement with very thick lesions or PASI ≥ 20 or ≥ 10 with clinically relevant facial, genital, or hand/ foot involvement) who were inadequately controlled with topical therapy and heliotherapy or phototherapy.


Patients received Humira 0.8mg/kg eow (up to 40 mg), 0.4 mg/kg eow (up to 20 mg), or methotrexate 0.1 – 0.4 mg/kg weekly (up to 25 mg). At week 16, more patients randomised to Humira 0.8 mg/kg had positive efficacy responses (e.g., PASI 75) than those randomised to 0.4mg/kg eow or MTX.


Table 16: Paediatric Plaque Psoriasis Efficacy Results at 17 Weeks
MTXa               Humira 0.8mg/kg eow
N=37               N=38
PASI 75b                           12 (32.4%)         22 (57.9%)
PGA: Clear/minimalc                15 (40.5%)         23 (60.5%) a
MTX = methotrexate b
P=0.027, Humira 0.8 mg/kg versus MTX c
P=0.083, Humira 0.8 mg/kg versus MTX


Patients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to 36 weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades).
Patients were then re-treated with adalimumab 0.8 mg/kg eow for an additional 16 weeks and response rates observed during retreatment were similar to the previous double-blind period: PASI 75 response of 78.9% (15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects).

In the open label period of the study, PASI 75 and PGA clear or minimal responses were maintained for up to an additional 52 weeks with no new safety findings.


Hidradenitis suppurativa
The safety and efficacy of Humira were assessed in randomised, 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 Humira 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 Humira in Period A were re-randomised in Period B to 1 of 3 treatment groups (Humira 40 mg every week, Humira 40 mg every other week, or placebo from Week 12 to Week 35). Patients who had been randomised to placebo in Period A were assigned to receive Humira 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 Humira 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 Humira in Period A were re-randomised in Period B to 1 of 3 treatment groups (Humira 40 mg every week, Humira 40 mg every other week, or placebo from Week 12 to Week 35). Patients who had been randomised 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 enrol into an open-label extension study in which Humira 40mg 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 Humira 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 18). Patients treated with Humira had significantly reduced risk of disease flare during the initial 12 weeks of treatment.

Table 18: Efficacy Results at 12 Weeks, HS Studies I and II

HS Study I                      HS Study II
Placebo       Humira 40 mg       Placebo     Humira 40 mg
Weekly                        Weekly
Hidradenitis Suppurativa                N = 154            N = 153        N=163          N=163 Clinical Response (HiSCR)a             40 (26.0%)      64 (41.8%) *     45 (27.6%)   96 (58.9%) *** 
≥30% Reduction in Skin                  N = 109         N = 122           N=111            N=105 Painb                                  27 (24.8%)      34 (27.9%)       23 (20.7%)     48 (45.7%) *** 
* P < 0.05, ***P < 0.001, Humira versus placebo a
.    Among all randomised 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 Humira 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 Humira group experienced worsening of abscesses (23.0% vs 11.4%, respectively) and draining fistulas (30.0% vs 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 Humira 40 mg weekly at Week 12, the HiSCR rate at Week 36 was higher in patients who continued weekly Humira than in patients in whom dosing frequency was reduced to every other week, or in whom treatment was withdrawn (see Table 19).

Table 19: Proportion of Patientsa Achieving HiSCRb at Weeks 24 and 36 After Treatment Reassignment from Weekly Humira at Week 12
Placebo
(treatment            Humira 40 mg         Humira 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 Humira 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 nonresponders.

Among patients who were at least partial responders at Week 12, and who received continuous weekly Humira therapy, the HiSCR rate at Week 48 was 68.3% and at Week 96 was 65.1%. Longer term treatment with Humira 40 mg weekly for 96 weeks identified no new safety findings.

Among patients whose Humira treatment was withdrawn at Week 12 in Studies HS-I and HS-II, the HiSCR rate 12 weeks after re-introduction of Humira 40 mg weekly returned to levels similar to that observed before withdrawal (56.0 %).

Adolescent hidradenitis suppurativa

There are no clinical trials with Humira in adolescent patients with HS. Efficacy of adalimumab for the treatment of adolescent patients with HS is predicted based on the demonstrated efficacy and exposure-response relationship in adult HS patients and the likelihood that the disease course, pathophysiology, and drug effects are substantially similar to that of adults at the same exposure levels. Safety of the recommended adalimumab dose in the adolescent HS population is based on cross-indication safety profile of adalimumab in both adults and paediatric patients at similar or more frequent doses (see section 5.2).

Crohn’s disease

The safety and efficacy of Humira were assessed in over 1500 patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in randomised, 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 naive patients were randomised to one of four treatment groups; placebo at Weeks 0 and 2, 160 mg Humira 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 randomised to receive either 160 mg Humira 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 randomised 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 analysed 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 20.

Table 20
Induction of Clinical Remission and Response
(Percent of Patients)
CD Study I: Infliximab Naive        CD Study II : Infliximab Experienced Patients                            Patients
Placebo    Humira       Humira          Placebo         Humira 160/80 mg N=74     80/40 mg     160/80 mg         N=166               N=159
N=75        N=76
Week 4
Clinical remission             12%       24%          36%*               7%                  21%* 


Clinical response (CR-      24%         37%         49%**            25%                    38%** 100)
All p-values are pairwise comparisons of proportions for Humira 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 21.
Clinical remission results remained relatively constant irrespective of previous TNF antagonist exposure.
Disease-related hospitalisations and surgeries were statistically significantly reduced with adalimumab compared with placebo at Week 56.
Table 21
Maintenance of Clinical Remission and Response
(Percent of Patients)
Placebo            40 mg Humira         40 mg Humira every other week         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 remission         3% (2/66)     19% (11/58)**            15% (11/74)** 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 remission         5% (3/66)     29% (17/58)*             20% (15/74)** for >=90 daysa
* p<0.001 for Humira versus placebo pairwise comparisons of proportions ** p<0.02 for Humira 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 Humira 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 randomised to Humira 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.

Paediatric Crohn’s disease
Humira was assessed in a multicenter, randomized, double-blind clinical trial designed to evaluate the efficacy and safety of induction and maintenance treatment with doses dependent on body weight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, with moderate to severe Crohn´s disease (CD) defined as Paediatric Crohn's Disease Activity Index (PCDAI) score > 30. Subjects had to have failed conventional therapy (including a corticosteroid and/or an immunomodulator) for CD. Subjects may also have previously lost response or been intolerant to infliximab.

All subjects received open-label induction therapy at a dose based on their Baseline body weight: 160 mg at Week 0 and 80 mg at Week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, for subjects < 40 kg.

At Week 4, subjects were randomized 1:1 based on their body weight at the time to either the Low Dose or Standard Dose maintenance regimens as shown in Table 22.


Table 22
Maintenance regimen
Patient Weight            Low dose                Standard dose
< 40 kg              10 mg eow                  20 mg eow
≥ 40 kg              20 mg eow                  40 mg eow
Efficacy Results

The primary endpoint of the study was clinical remission at Week 26, defined as PCDAI score ≤10.
Clinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points from Baseline) rates are presented in Table 23. Rates of discontinuation of corticosteroids or immunomodulators are presented in Table 24.


Table 23
Paediatric CD Study
PCDAI Clinical Remission and Response
Standard Dose        Low Dose
40/20 mg eow      20/10 mg eow           P value*
N = 93            N = 95
Week 26
Clinical
38.7%             28.4%                0.075 remission
Clinical response        59.1%             48.4%                0.073 Week 52
Clinical
33.3%             23.2%                0.100 remission
Clinical response        41.9%             28.4%                0.038 * p value for Standard Dose versus Low Dose comparison.


Table 24
Paediatric CD Study
Discontinuation of Corticosteroids or Immunomodulators and Fistula Remission Standard Dose              Low Dose                    1
40/20 mg eow            20/10 mg eow           P value
Discontinued
N= 33                   N=38 corticosteroids
Week 26                 84.8%                   65.8%               0.066 Week 52                        69.7%                   60.5%                      0.420 Discontinuation of
2           N=60                    N=57
Immunomodulators
Week 52                          30.0%                   29.8%                      0.983 3
Fistula remission                    N=15                    N=21
Week 26                       46.7%                   38.1%                      0.608 Week 52                       40.0%                   23.8%                      0.303 1 p value for Standard Dose versus Low Dose comparison.
2
Immunosuppressant therapy could only be discontinued at or after Week 26 at the investigator's discretion if the subject met the clinical response criterion 3 defined as a closure of all fistulas that were draining at Baseline for at least 2 consecutive post- Baseline visits.

Statistically significant increases (improvement) from Baseline to Week 26 and 52 in Body Mass Index and height velocity were observed for both treatment groups.

Statistically and clinically significant improvements from Baseline were also observed in both treatment groups for quality of life parameters (including IMPACT III).

One hundred patients (n=100) from the Paediatric CD Study continued in an open-label long-term extension study. After 5 years of adalimumab therapy, 74.0% (37/50) of the 50 patients remaining in the study continued to be in clinical remission, and 92.0% (46/50) of patients continued to be in clinical response per PCDAI.

Ulcerative Colitis

The safety and efficacy of multiple doses of Humira 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 randomised, double-blind, placebo-controlled studies.
In study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at Weeks 0 and 2, 160 mg Humira at Week 0 followed by 80 mg at Week 2, or 80 mg Humira at Week 0 followed by 40 mg at Week 2. After Week 2, patients in both adalimumab arms received 40 mg eow.
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 Humira at Week 0, 80 mg at Week 2 and 40 mg eow 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 Humira achieved clinical remission versus placebo at Week 8 in statistically significantly greater percentages in study UC-I (18% vs. 9% respectively, p=0.031) and study UC-II (17% vs. 9% respectively, p=0.019). In study UC-II, among those treated with Humira 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 25.
Table 25
Response, Remission and Mucosal Healing in Study UC-II
(Percent of Patients)
Placebo         Humira 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 days a                   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 Humira vs. placebo pairwise comparison of proportions
**p<0.001 for Humira vs. 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.

Hospitalisation rates
During 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-related hospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. The number of all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year vs.
0.26 per patient year in the placebo group and the corresponding figures for UC-related hospitalisations were 0.12 per patient year vs. 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

Clinical study in Japan
In an open-label and uncontrolled study in patients with intestinal Behcet's disease who have had an inadequate response to conventional therapy (steroid or immunosuppressant), 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)1.
1
Note) 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 Humira were assessed in adult patients with non-infectious intermediate, posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two randomised, double- masked, placebo-controlled studies (UV I and II). Patients received placebo or Humira 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 standardised 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).

Clinical Response

Results from both studies demonstrated statistically significant reduction of the risk of treatment failure in patients treated with Humira versus patients receiving placebo (See Table 26). Both studies demonstrated an early and sustained effect of Humira on the treatment failure rate versus placebo (see Figure 2).

Table 26
Time to Treatment Failure in Studies UV I and UV II

Analysis                 N        Failure      Median Time to        HRa CI 95%            P Value b a
Treatment                   N (%)        Failure (months)              for HR 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, 0.70 < 0.001 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, 0.84 0.004 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 vs 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)



TREATMENT FAILURE RATE (%)



TIME (MONTHS)
Study UV I    Treatment            Placebo             adalimumab
TREATMENT FAILURE RATE (%)


TIME (MONTHS)
Study UV II   Treatment            Placebo             adalimumab
Note: P# = Placebo (Number of Events/Number at Risk); A# = HUMIRA (Number of Events/Number at Risk).

In Study UV I statistically significant differences in favour 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 favour of adalimumab.

Of the 417 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 46 subjects were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, due to cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 371 remaining patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment.
Based on the observed data approach, 222 (80.4%) 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 184 (66.7 %) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 letters deterioration) in 88.4% of the eyes at week 78. Among the patients who discontinued the study prior to week 78, 11% discontinued due to adverse events, and 5% 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. Humira was numerically favoured 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 favour of Humira for colour vision in Study UVI and for colour vision, peripheral vision and near vision in Study UV II.

Paediatric Uveitis

The safety and efficacy of Humira was assessed in a randomized, double-masked, controlled study of 90 paediatric patients from 2 to < 18 years of age with active JIA-associated noninfectious anterior uveitis who were refractory to at least 12 weeks of methotrexate treatment. Patients received either placebo or 20 mg adalimumab (if < 30 kg) or 40 mg adalimumab (if ≥ 30 kg) every other week in combination with their baseline dose of methotrexate.

The primary endpoint was ‘time to treatment failure’. The criteria determining treatment failure were worsening or sustained non-improvement in ocular inflammation, partial improvement with development of sustained ocular co-morbidities or worsening of ocular co-morbidities, non-permitted use of concomitant medications, and suspension of treatment for an extended period of time.

Clinical Response

Adalimumab significantly delayed the time to treatment failure, as compared to placebo (See Figure 3, P < 0.0001 from log rank test).The median time to treatment failure was 24.1 weeks for subjects treated with placebo, whereas the median time to treatment failure was not estimable for subjects treated with adalimumab because less than one-half of these subjects experienced treatment failure.
Adalimumab significantly decreased the risk of treatment failure by 75% relative to placebo, as shown by the hazard ratio (HR = 0.25 [95% CI: 0.12, 0.49]).



Figure 3: Kaplan-Meier Curves Summarizing Time to Treatment Failure in the Paediatric Uveitis Study

PROBABILITY OF FAILING TREATMENT



TIME (WEEKS)
Treatment                                      Placebo                Adalimumab Note: P = Placebo (Number at Risk); H = HUMIRA (Number at Risk).

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 polyarticular juvenile idiopathic arthritis who were 4 to 17 years, anti adalimumab antibodies were identified in 15.8% (27/171) of patients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 25.6% (22/86), compared to 5.9% (5/85) when adalimumab was used as add-on to methotrexate. In patients with polyarticular Juvenile idiopathic arthritis who were 2 to < 4 years old or aged 4 and above weighing < 15 kg, anti-adalimumab antibodies were identified in 7% (1/15) of patients, and the one patient was receiving concomitant methotrexate.

In patients with enthesitis-related arthritis, anti-adalimumab antibodies were identified in 10.9% (5/46) of patients treated with adalimumab. In patients not given concomitant methotrexate, the incidence was 13.6% (3/22), compared to 8.3% (2/24) 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 paediatric psoriasis, anti-adalimumab antibodies were identified in 5/38 subjects (13%) treated with 0.8mg/kg adalimumab monotherapy.

In patients with moderate to severe hidradenitis suppurativa, anti-adalimumab antibodies were identified in 10/99 subjects (10.1%) treated with adalimumab.

In patients with moderately to severely active paediatric Crohn’s disease, the rate of anti-adalimumab antibody development in patients receiving adalimumab was 3.3%.

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 analyses 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 (V ss ) ranged from 5 to 6 litres 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 the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with polyarticular juvenile idiopathic arthritis (JIA) who were 4 to 17 years, the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.6 ± 5.6 µg/mL (102%CV) for adalimumab without concomitant methotrexate and 10.9 ± 5.2 µg/mL (47.7% CV) with concomitant methotrexate.

In patients with polyarticular JIA who were 2 to <4 years old or aged 4 and above weighing <15 kg dosed with adalimumab 24 mg/m2, the mean trough steady-state serum adalimumab concentrations was 6.0 ± 6.1 µg/ml (101% CV) for adalimumab without concomitant methotrexate and 7.9 ± 5.6 µg/ml (71.2% CV) with concomitant methotrexate.

Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state (values measured at Week 24) serum adalimumab concentrations were 8.8 ± 6.6 μg/mL for adalimumab without concomitant methotrexate and 11.8 ± 4.3 μg/mL with concomitant methotrexate.

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.

Following the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other week to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab trough concentration was approximately 7.4 ± 5.8 µg/mL (79% CV).

In adult patients with hidradenitis suppurativa, a dose of 160 mg Humira 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.

Adalimumab exposure in adolescent HS patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related arthritis). The recommended adolescent HS dosing schedule is 40 mg every other week. Since exposure to adalimumab can be affected by body size, adolescents with higher body weight and inadequate response may benefit from receiving the recommended adult dose of 40 mg every week.

In patients with Crohn’s disease, the loading dose of 80 mg Humira on Week 0 followed by 40 mg Humira on Week 2 achieves serum adalimumab trough concentrations of approximately 5.5 µg/ml during the induction period. A loading dose of 160 mg Humira on Week 0 followed by 80 mg Humira 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 Humira every other week.

In paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was 160/80 mg or 80/40 mg at Weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg.
At Week 4, patients were randomized 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose (20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum adalimumab trough concentrations achieved at Week 4 were 15.7±6.6 μg/mL for patients ≥ 40 kg (160/80 mg) and 10.6 ±6.1 μg/mL for patients < 40 kg (80/40 mg).

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 eow for 52 weeks. For patients who dose escalated from eow 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 Humira on Week 0 followed by 80 mg Humira 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 Humira 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.

Adalimumab exposure in paediatric uveitis patients was predicted using population pharmacokinetic modelling and simulation based on cross-indication pharmacokinetics in other paediatric patients (paediatric psoriasis, juvenile idiopathic arthritis, paediatric Crohn’s disease, and enthesitis-related arthritis). No clinical exposure data are available on the use of a loading dose in children < 6 years.
The predicted exposures indicate that in the absence of methotrexate, a loading dose may lead to an initial increase in systemic exposure.

Exposure-response relationship in paediatric population

On the basis of clinical trial data in patients with JIA (pJIA and ERA), an exposure-response relationship was established between plasma concentrations and PedACR 50 response. The apparent adalimumab plasma concentration that produces half the maximum probability of PedACR 50 response (EC50) was 3 μg/ml (95% CI: 1-6 μg/ml).

Exposure-response relationships between adalimumab concentration and efficacy in paediatric patients with severe chronic plaque psoriasis were established for PASI 75 and PGA clear or minimal, respectively. PASI 75 and PGA clear or minimal increased with increasing adalimumab concentrations, both with a similar apparent EC50 of approximately 4.5 μg/mL (95% CI 0.4-47.6 and 1.9-10.5, respectively).

In Japanese 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.

Elimination

Population pharmacokinetic analyses 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
Humira has not been studied in patients with hepatic or renal impairment