Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Idacio is a biosimilar medicinal product, that has been demonstrated to be similar in quality, safety and efficacy to the reference medicinal product Humira. More detailed information is available on the website of the Ministry of Health http://www.health.gov.il/hozer/dr_127.pdf.

Pharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNF-α) inhibitors.
ATC code: L04AB04

Mechanism of action

Adalimumab binds specifically to TNF and neutralises 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 remodelling responsible for cartilage destruction were also decreased after adalimumab administration.
Patients treated with adalimumab 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 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 randomised, 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 randomised, 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 randomised 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 adalimumab 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 adalimumab 40 mg/0.8 ml. Patients were randomised to receive a single dose of adalimumab 40 mg/0.8 ml or adalimumab 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 summarised in Table 7.

Table 7
ACR Responses in Placebo-
Controlled Trials (Percent of
Patients)

Response             RA Study Ia**                 RA Study IIa**                RA Study IIIa** 
Placebo/   Adalimumab b/        Placebo       Adalim         Placebo/    Adalimumab MTXc            MTXc            n=110         umab b         MTXc           b / MTXc n=60           n=63                        n=113            n=200          n=207 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 randomised 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 8).


Table 8
ACR Responses in
RA Study V
(percent of patients)

MTX              Adalim       Adalimumab/
Response                                                          p-valuea     p-valueb       p-valuec n=257             umab           MTX 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 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 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 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   randomised      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 9).

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 9
Radiographic Mean Changes Over 12 Months in RA Study III

Placebo/           Adalimumab           Placebo/MTX-             p-value MTXa               /MTX 40 mg            adalimumab every other          /MTX (95% week               Confidence
Total Sharp Score       2.7                   0.1              2.6        b <0.001c
(1.4, 3.8)
Interval  )
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 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 10).

Table 10
Radiographic Mean Changes at Week 52 in RA Study V

MTX              Adalimumab        Adalimumab/M n=257             n=274 (95%            TX n=268
(95%               confidence           (95%          p-valuea    p-valueb     p-valuec confidence             interval)       confidence interval)                              interval)


Total          5.7 (4.2-7.3)        3.0 (1.7-4.3)      1.3 (0.5-2.1)    <0.001      0.0020       <0.001 Sharp
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 Idacio_solution-for-i
. c p-value is from the pairwise comparison of adalimumab     monotherapy and methotrexate Monotherapy using the Mann-Whitney U test njection_50mg-ml_SPC_5-2021_clean.docx 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 randomised 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 adalimumab 40 mg/0.8 ml and adalimumab 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 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 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 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 adalimumab compared to placebo. Significant response was first observed at Week 2 and maintained through 24 weeks (Table 11).


Table 11
Efficacy Responses in Placebo-Controlled AS Study –
Study I Reduction of Signs and Symptoms

Response                               Placebo                  Adalim N=107                     umab
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 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 adalimumab were assessed in two randomised, 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 40mg every other week was assessed in 185 patients in a randomised, 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 12).

Table 12
Efficacy Response in Placebo-Controlled Study - nr-axSpA I

Double-Blind                                      Placebo        Adalimumab 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 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 randomised 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
PROBABILITY OF NO FLARE



TIME (WEEKS)
Treatment            Placebo    Adalimumab      ∆ Censored

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 13).

Table 13
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%*** a
ASAS 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.

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 14
ACR Response in Placebo-Controlled Psoriatic Arthritis
Studies (Percent of Patients)

PsA Study I                              PsA Study II


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



ACR 20
Week 12                14%                 58%***           16%                      39%* 15%                 57%***           N/A                      N/A
Week 24


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 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 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 randomised 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 randomised to active therapy in Period A, were re-randomised 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 enrol 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 17 and 18).
Table 15
Ps Study I (REVEAL) - Efficacy Results at 16 Weeks
Placebo           Adalimumab 40 mg
N=398               eow 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, adalimumab vs. placebo

Table 16
Ps Study II (CHAMPION) Efficacy Results at 16 Weeks
Placebo         MTX          Adalimumab 40
N=53           N=110         mg eow 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 adalimumab vs. placebo b p<0.001 adalimumab vs. methotrexate c p<0.01 adalimumab vs. placebo d p<0.05 adalimumab 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 adalimumab, p<0.001, experienced “loss of adequate response” (PASI score after Week 33 and on or before Week 52 that resulted in a =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 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 randomised 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 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 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 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 adalimumab 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 adalimumab 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 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 22.
Table 22
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 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 adalimumab vs. placebo pairwise comparison of proportions
**p<0.001 for adalimumab 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
Phase III Clinical study in Japan
In an open-label and uncontrolled study in 20 patients note) 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.

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 adalimumab 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 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 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).

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 23).
Both studies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus placebo (see Figure 2).
Table 23
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                    --      --          -- c
Adalimumab         115      45 (39.1)    NE                     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# = ADALIMUMAB (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 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 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 adalimumab for colour vision in Study UVI and for colour 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 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 (Vss) 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 g/ml (without concomitant methotrexate) and 8 to 9 g/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 g/ml.

In adult patients with psoriasis, the mean steady-state trough concentration was 5 g/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 g/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 randomised 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 adalimumab on Week 0 followed by 80 mg adalimumab on Week 2 achieves serum adalimumab trough concentrations of approximately 12 g/ml during the induction period. Mean steady-state trough levels of approximately 8 g/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 g/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).

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 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

Adalimumab has not been studied in patients with hepatic or renal impairment