Humira
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Humira - Scientific Information

Manufacture: AbbVie
Country: Canada
Condition: Ankylosing Spondylitis, Crohn's Disease, Maintenance, Crohn's Disease, Acute, Crohn's Disease, Hidradenitis Suppurativa, Plaque Psoriasis, Psoriatic Arthritis, Psoriasis, Rheumatoid Arthritis, Spondyloarthritis, Ulcerative Colitis
Class: Antirheumatics, TNF alfa inhibitors
Form: Liquid solution, Subcutaneous (SC)
Ingredients: adalimumab, citric acid monohydrate, dibasic sodium phosphate dihydrate, mannitol, monobasic sodium phosphate dihydrate, polysorbate 80, sodium citrate, sodium chloride

Pharmaceutical information

Drug Substance

Proper name: adalimumab
Chemical name: Not applicable. Adalimumab is not a chemical. It is an immunoglobulin (recombinant human IgG1 monoclonal antibody).
Molecular formula and molecular mass: Total apparent molecular weight of 148 kilodaltons (kDa), as determined by Q-TOF and SDS-PAGE analysis.

Structural formula:

Physicochemical properties: Adalimumab is an IgG antibody composed of two kappa light chains each with a molecular weight of approximately 23 kDa and two IgG1 heavy chains each with a molecular weight of approximately 51 kDa for a total apparent molecular weight of 148 kDa, as determined by Q-TOF and SDS-PAGE analysis.

HUMIRA is supplied as a sterile, preservative-free solution for subcutaneous administration. The solution of adalimumab is clear and colorless, with a pH of 5.2.
Product characteristics: HUMIRA (adalimumab) is a recombinant human immunoglobulin (IgG1) monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1:κ constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kDa.

Clinical trials

Adult

Rheumatoid Arthritis

Study Demographics and Trial Design

The efficacy and safety of HUMIRA (adalimumab) were assessed in five randomized, double- blind studies in patients ≥ 18 years of age with active rheumatoid arthritis diagnosed according to the American College of Rheumatology (ACR) criteria. Patients had at least six swollen and nine tender joints. HUMIRA was administered subcutaneously in combination with methotrexate (12.5 to 25 mg, Studies DE009, DE019 and DE013), or as monotherapy (Studies DE011 and DE013), or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study DE031). Table 1 summarizes the controlled clinical trials that were done in patients with active rheumatoid arthritis.

Table 1. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Rheumatoid Arthritis
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
DE009
(RA I)
Multicenter,
double-blind,
randomized,
placebo-controlled
HUMIRA 20 mg, 40 mg, or
80 mg; eow
Placebo
Subcutaneous
24 weeks
200


60
54.8±11.9


55.2±10.9
75.5


83.3
DE011
(RA II)
Multicenter,
double-blind,
randomized,
placebo-controlled
HUMIRA 20 mg or 40 mg;
ew or eow
Placebo
Subcutaneous
26 weeks
434


110
53.0±12.3


53.5±13.2
77.4


77.3
DE019
(RA III)
Multicenter,
double-blind,
randomized,
placebo-controlled
HUMIRA 20 mg ew or
40 mg eow
Placebo
Subcutaneous
52 weeks
419

200
56.2±12.1

55.6±12.0
75.9

73.0
Open-label
extension
HUMIRA 40 mg eow
up to 10 years
457 55.7±12.02 74.7
DE031
(RA IV)
Multicenter,
double-blind,
randomized,
placebo-controlled
HUMIRA 40 mg eow
Placebo
Subcutaneous
24 weeks
315
315
55.2±12.7
55.7±12.4
80.0
79.7
DE009,
DE011,
DE019,
DE031
Combined
Multicenter,
double-blind,
randomized,
placebo-controlled
HUMIRA
Placebo
1368
685
54.7±12.3
55.3±12.3
77.3
77.7
DE013
(RA V)
Phase 3,
multicenter,
double-blind,
active comparator-
controlled,
parallel-group
HUMIRA 40 mg eow
HUMIRA 40 mgeow +
MTX ew
MTX ew
Subcutaneousand oral
104 weeks
274
268


257
52.1±13.5
51.9±14.0


52.0±13.1
77.4
72.0


73.9
Definition(s): ew = every week; eow = every other week; MTX = methotrexate

Mean ages across the four studies ranged from 53.0 years (HUMIRA group, Study DE011) to 56.2 years (HUMIRA group, Study DE019). The mean age in Study DE013 was 51.9 years (HUMIRA + methotrexate group) to 52.0 years (methotrexate group). Mean weight ranged from 68.5 kg (HUMIRA group, Study DE011) to 80.3 kg (placebo group, Study DE019). The mean weight in Study DE013 was 74.4 kg (HUMIRA group) to 76.8 kg (HUMIRA + methotrexate group). As expected, based on the demographics of the disease, patients were predominantly female, with the percentage of female patients ranging from 73.0% (placebo group, Study DE019) to 83.3% (placebo group, Study DE009). Similarly, the percentage of females in Study DE013 ranged from 72.0% (HUMIRA + methotrexate group) to 77.4% (HUMIRA group). Patients were predominantly Caucasian, with the percentage of Caucasian patients ranging from 75.0% (placebo group, Study DE009) to 99.1% (placebo group, Study DE011). The percentage of Caucasian patients in Study DE013 ranged from 93.3% (HUMIRA + methotrexate group) to 94.2 % (methotrexate group). The high percentage of Caucasian patients in Study DE011 was consistent with the populations of the geographic regions in which this study was conducted (i.e., Europe, Canada, and Australia). Overall, the demographic characteristics of the study patients were fairly representative of rheumatoid arthritis in the general population. There were no notable differences between the studies in any of the demographic characteristics analyzed.

Description of Clinical Studies

HUMIRA was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. Some patients were treated for up to 10 years. The efficacy and safety of HUMIRA were assessed in five randomized, double-blind, well-controlled studies.

Study DE009 evaluated 271 patients with moderately to severely active rheumatoid arthritis who had failed therapy with at least one but no more than four DMARDs, and had inadequate response to methotrexate.

Study DE011 evaluated 544 patients with moderately to severely active rheumatoid arthritis who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of HUMIRA were given by subcutaneous injection as monotherapy every other week or weekly for 26 weeks.

Study DE019 evaluated 619 patients with moderately to severely active rheumatoid arthritis who had an inadequate response to methotrexate. Patients received placebo, 40 mg of HUMIRA every other week with placebo injections on alternate weeks, or 20 mg of HUMIRA weekly for up to Week 52. Study DE019 had an additional primary endpoint at Week 52 of inhibition of disease progression (as detected by X-ray results). Upon completion of the first 52 weeks, 457 patients enrolled in an open-label extension phase in which 40 mg of HUMIRA was administered every other week for up to ten years. 202 patients completed 10 years of the study; the efficacy demonstrated at 5 years (reduction in signs and symptoms of RA, improvement in physical function, inhibition of structural joint damage, and rates of clinical response including remission) was maintained through 10 years with continued HUMIRA in these patients. For efficacy results in these patients, see (CLINICAL TRIALS, Adult, Rheumatoid Arthritis, Study Results, Clinical Response, Studies DE009, DE011 and DE019; Radiographic Response; and Quality of Life and Physical Function Response). For a description of safety in these patients, see (ADVERSE REACTIONS, Adverse Drug Reaction Overview).

Study DE031 assessed safety in 636 patients with moderately to severely active rheumatoid arthritis who were either DMARD- naïve or were permitted to remain on their pre-existing rheumatologic therapy provided that therapy was stable for a minimum of 28 days. Patients were randomized to 40 mg of HUMIRA or placebo every other week for 24 weeks.

Study DE013 evaluated 799 patients with moderate to severely active early rheumatoid arthritis (disease duration less than three years) who were ≥ 18 years old and methotrexate naïve. This study compared the efficacy of HUMIRA + methotrexate combination therapy and methotrexate monotherapy in reducing the signs and symptoms and rate of progression of joint damage in rheumatoid arthritis. Patients were randomized to receive HUMIRA 40 mg every other week + methotrexate combination therapy, HUMIRA 40 mg every other week monotherapy, or methotrexate given weekly, for 104 weeks.

Study Results

Clinical Response
Studies DE009, DE011 and DE019

The percent of HUMIRA-treated patients achieving ACR 20/50/70 responses was consistent across all three trials. The results of the three trials are summarized in Table 2.

Table 2. ACR Responses in Placebo-Controlled Trials (Percent of Patients)
Response Study DE009* Study DE011* Study DE019*
Placebo
+ MTX
N = 60
HUMIRA
40 mg eow
+ MTX
N = 63
Placebo
N = 110
HUMIRA
40 mg eow
N = 113
HUMIRA
40 mg ew
N = 103
Placebo
+ MTX
N = 200
HUMIRA
40 mg eow
+ MTX
N = 207
ACR 20 6 months 13.3% 65.1%** 19.1% 46.0%** 53.4%** 29.5% 63.3%**
12 months NA NA NA NA NA 24.0% 58.9%**
ACR 50 6 months 6.7% 52.4%** 8.2% 22.1%** 35.0%** 9.5% 39.1%**
12 months NA NA NA NA NA 9.5% 41.5%**
ACR 70 6 months 3.3% 23.8%** 1.8% 12.4%** 18.4%** 2.5% 20.8%**
12 months NA NA NA NA NA 4.5% 23.2%**
* Study DE009 at Week 24, Study DE011 at Week 26, and Study DE019 at Weeks 24 and 52
** p < 0.01 for HUMIRA versus placebo
Definition(s): MTX = methotrexate; ACR = American College of Rheumatology

The results of the components of the ACR response criteria for Studies DE011 and DE019 are shown in Table 3. ACR response rates and improvement in all components of ACR response were maintained to Week 104. Over the two years in Study DE019, 24% of HUMIRA patients receiving 40 mg every other week achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period. ACR responses were maintained in similar proportions of patients for up to five years with continuous HUMIRA treatment in the open-label portion of Study DE019.

Table 3. Components of ACR Response in Studies DE011 and DE019
Parameter
(median)
Study DE011 Study DE019
Placebo
N = 110
HUMIRA
40 mg eow
N = 103
Placebo + MTX
N = 200
HUMIRA 40 mg eow + MTX
N = 207
Baseline Week 26 Baseline Week 26 Baseline Week 24 Week 52B Baseline Week 24 Week 52
Number of tender joints
(Scale 0 to 68)
35 26 31 16** 26 15 15 24 8.0* 6.0*
Number of swollen joints
(Scale 0 to 66)
19 16 18 10** 17 11 11 18 5.0* 4.0*
Physician global assessment
disease activity
7 6.1 6.6 3.7** 6.3 3.5 3.8 6.5 2.0* 1.6*
Patient global assessments disease
activity
7.5 6.3 7.5 4.5** 5.4 3.9 4.3 5.2 2.0* 1.8*
Pain
7.3 6.1 7.3 4.1** 6 3.8 4.6 5.8 2.1* 1.9*
Disability index (HAQ)
2 1.9 1.9 1.5** 1.5 1.25 1.25 1.5 0.75* 0.75*
CRP (mg/dL) 3.9 4.3 4.6 1.8** 1 0.9 0.9 1 0.40* 0.40*
 Visual analogue scale; 0 = best; 10 = worst
Disability index of the Health Assessment Questionnaire (HAQ); 0 = best; 3 = worst, measures the patient’s ability to perform the following: dress/groom, arise, eat, walk,
reach, grip, maintain hygiene, and maintain daily activity
*p < 0.001 for HUMIRA versus placebo, based on mean change from baseline
Definition(s):MTX = methotrexate; CRP = C-reactive protein

The time course of ACR 20 response for Study DE019 is shown in Figure 1. In Study DE019, 85% of patients with ACR 20 responses at Week 24 maintained the response at Week 52. The time course of ACR 20 response for Studies DE009 and DE011 were similar.


Figure 1. Study DE019 ACR 20 Responses Over 52 Weeks

In the open-label extension for Study DE019, durable and sustained ACR 20, 50 and 70 responses have been observed through 5 and 10 years. Of 207 patients, 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.

Study DE031

In Study DE031, 53% of patients treated with HUMIRA 40 mg every other week plus standard of care had an ACR 20 response at Week 24 compared to 35% on placebo plus standard of care (p < 0.001). No unique adverse reactions related to the combination of HUMIRA and other DMARDs were observed.

In all four studies, HUMIRA-treated patients achieved ACR 20/50/70 responses faster and more often than placebo-treated patients. In Study DE009, there was a statistically significant difference in ACR 20 responses at Week 1 (first study visit) between patients treated with HUMIRA (26.0%) and placebo (5.0%). Statistically significant differences in ACR 20 responses were also seen in Studies DE011, DE019 and DE031 at Week 2 (first study visit) between patients treated with HUMIRA (36.4, 29.1 and 33.7%, respectively) and placebo (7.3, 13.0 and 8.6%, respectively). A similar pattern of the time to first ACR 50 and 70 responses was noted in all four studies.

Study DE013

In Study DE013, for early rheumatoid arthritis patients who were methotrexate naïve, the combination therapy with HUMIRA + methotrexate led to faster and significantly greater ACR responses than methotrexate monotherapy at Week 52, and responses were sustained at Week 104. The clinical responses for Study DE013 are presented in Table 4.

At Week 52, all individual components of the ACR response criteria improved with HUMIRA + methotrexate therapy, and improvements were maintained to Week 104.

Over the two-year study, 48.5% of patients who received HUMIRA + methotrexate combination therapy achieved a major clinical response (ACR 70 for six continuous months) compared to 27.2% of patients who received methotrexate monotherapy (p < 0.001).

Table 4. Clinical Responses in Study DE013 (All Randomized Subjects)

Response
MTXa
N = 257
(%)
HUMIRAb
N = 274
(%)
HUMIRA + MTX
N = 268
(%)
ACR 20 Week 52 62.6 54.4 72.8
Week 104 56.0 49.3 69.4
ACR 50 Week 52 45.9 41.2 61.6
Week 104 42.8 36.9 59.0
ACR 70 Week 52 27.2 25.9 45.5
Week 104 28.4 28.1 46.6
Major Clinical Responsec
27.2 24.5 48.5
a. p < 0.05 for HUMIRA + MTX versus MTX for ACR 20
p < 0.001 for HUMIRA + MTX versus MTX for ACR 50 and 70 and Major Clinical Response
b. p < 0.001 for HUMIRA + MTX versus HUMIRA
c. Major Clinical Response is achieving ACR 70 response for a continuous six-month period
Definition(s): MTX = methotrexate; ACR = American College of Rheumatology

At Week 52 and Week 104 of treatment in Study DE013, HUMIRA + methotrexate combination therapy was superior to methotrexate monotherapy in achieving a low disease state in patients with recently diagnosed moderate to severe rheumatoid arthritis, as demonstrated by the number of patients who achieved clinical remission [disease activity score (DAS28) < 2.6] at Week 52 and change from baseline in DAS28 at Week 52 and Week 104.

DAS28 responses for Study DE013 are presented in Table 5.

Table 5. Change in DAS28 from Baseline at Weeks 52 and 104 in Study DE013 (All Randomized Subjects)
DAS28 MTX
N = 257
HUMIRA
N = 274
HUMIRA + MTX
N = 268
Week 52 n
Baseline (mean)
Change at Week 52 (mean±SD)
% of subjects in remission
(DAS28 < 2.6) at Week 52
184
6.3
-2.8±1.4a

20.6%a
185
6.4
-2.8±1.5b

23.4%b
206
6.3
-3.6±1.3

42.9%
Week 104 n
Baseline (mean)
Change at Week 104 (mean±SD)
% of subjects in remission
(DAS28 < 2.6) at Week 104
161
6.3
-3.1±1.4a

24.9%
158
6.3
-3.2±1.4b

25.2%
191
6.3
-3.8±1.3

49.3%
a. p < 0.001 for HUMIRA + MTX versus MTX
b. p < 0.001 for HUMIRA + MTX versus HUMIRA
Definition(s): MTX = methotrexate; DAS = disease activity score; SD = standard deviation
Radiographic Response

In Study DE019, 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 total Sharp score (TSS) and its components, the erosion score and joint space narrowing (JSN) score at Month 12 compared to baseline. At baseline, the median TSS was approximately 55 in the placebo and 40 mg every other week groups. The 12-month results are shown in Table 6. HUMIRA + methotrexate-treated patients demonstrated less radiographic progression than patients receiving methotrexate alone at Week 52.

Table 6. Radiographic Mean Changes Over 12 Months in Study DE019 with Background Methotrexate
LOCF Placebo + MTX
N = 200
HUMIRAa+ MTX
N = 207
HUMIRAa+ MTX
and Placebo + MTX
(95% CI**)
p-value
Change in Modified
Total Sharp Score
(Mean)
2.7 0.1 -2.6 (1.4, 3.8) < 0.001*
Change in Erosions
(Mean)
1.6 0 -1.6 (0.9, 2.2) < 0.001
Change in JSN Score
(Mean)
1 0.1 -0.9 (0.3, 1.4) 0.002
a. 40 mg administered every other week
* Based on analysis of ranked ANCOVA
** 95% confidence intervals for the differences in change scores between MTX and HUMIRA
Definition(s): MTX = methotrexate; LOCF =last observation carried forward; JSN = joint space narrowing;
CI = confidence interval

Data from the open-label extension of Study DE019 indicate that 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, 59.3% (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, 50.6% (40 patients) showed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or less.

In Study DE013, HUMIRA-treated patients had a mean duration of rheumatoid arthritis of less than nine months and had not previously received methotrexate. Structural joint damage was assessed radiographically and expressed as change in modified total Sharp score (TSS). The Week 52 results are shown in Table 7. A statistically significant difference for change in modified total Sharp score, erosion score and JSN were observed at Week 52 and maintained at Week 104.

Table 7. Radiographic Mean Change (95% Confidence Interval) in Study DE013
Response MTXa
N = 257
HUMIRAa,b
N = 274
HUMIRA+MTX
N = 268
Week 52 Total Sharp Score 5.7 (4.2, 7.3) 3.0 (1.7, 4.3) 1.3 (0.5, 2.1)
Erosion Score 3.7 (2.7, 4.8) 1.7 (1.0, 2.4) 0.8 (0.4, 1.2)
JSN Score 2.0 (1.2, 2.8) 1.3 (0.5, 2.1) 0.5 (0.0, 1.0)
Week 104 Total Sharp Score 10.4 (7.7, 13.2) 5.5 (3.6, 7.4) 1.9 (0.9, 2.9)
Erosion Score 6.4 (4.6, 8.2) 3.0 (2.0, 4.0) 1.0 (0.4, 1.6)
JSN Score 4.1 (2.7, 5.4) 2.6 (1.5, 3.7) 0.9 (0.3, 1.5)
a. p < 0.001 for HUMIRA + MTX versus MTX at Week 52 and Week 104 and for HUMIRA + MTX versus HUMIRA at
Week 104
b. p < 0.01 for HUMIRA + MTX versus HUMIRA at Week 52
Definition(s):MTX = methotrexate; JSN = joint space narrowing

The percentage of patients without progression (change from baseline in modified total Sharp score ≤ 0.5) was significantly higher with HUMIRA + methotrexate combination therapy compared to methotrexate monotherapy at Week 52 (63.8 and 37.4% respectively, p < 0.001) and Week 104 (61.2 and 33.5% respectively, p < 0.001).

Quality of Life and Physical Function Response

In Studies DE009, DE011, DE019 and DE031, HUMIRA showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ) from baseline to the end of study, and significantly greater improvement than placebo in the health outcomes as assessed by the Short Form Health Survey (SF-36). Improvement was seen in both the Physical Component Summary (PCS) and the Mental Component Summary (MCS).

In Study DE019, the mean (CI) improvement in HAQ from baseline at Week 52 was -0.60 (-0.65, -0.55) for the HUMIRA patients and -0.25 (-0.33, -0.17) for placebo + methotrexate (p < 0.001) patients. Eighty-two percent (82%) of HUMIRA-treated patients who achieved a 0.5 or greater improvement in HAQ at Week 52 in the double-blind portion of the study maintained that improvement through Week 104 of open-label treatment, and a similar proportion of patients maintained this response through Week 260 (five years) and Week 520 (10 years). After five years, the proportion of subjects who were HAQ responders at the 0.22, 0.50, 0.75 and 1.0 levels were 76.5, 60.0, 47.5 and 30.8% respectively. A total of 149 patients who received HUMIRA for 10 years were assessed for HAQ. After 10 years, the proportions of patients who were HAQ responders at the 0.22, 0.50, 0.75 and 1.0 levels were 73.8 (n = 110), 57.0 (n = 85), 44.3 (n = 66) and 26.2% (n = 39) respectively. Improvement in SF-36 was measured and maintained up to Week 156 (3 years).

In Study DE013, the active comparator-controlled study in early rheumatoid arthritis, the improvement in the HAQ disability index, and the physical component of the SF-36, showed greater improvement (p < 0.001) for the HUMIRA + methotrexate combination therapy versus the methotrexate monotherapy at Week 52, which was maintained through Week 104.

At Week 52 and Week 104 of treatment, 69.4% (186/268) and 63.8% (171/268) of subjects, respectively, treated with HUMIRA + methotrexate combination therapy had a decrease (i.e., improvement) in the disability index of the HAQ of ≥ 0.3 units. In comparison, 61.5% (158/257; p = 0.562) and 53.3% (137/257; p = 0.0146) of subjects treated with methotrexate monotherapy, and 55.1% (151/274; p < 0.001) and 48.2% (132/274; p < 0.001) of subjects treated with HUMIRA monotherapy had a decrease in the disability index of the HAQ of ≥ 0.3 units at Weeks 52 and 104, respectively.

Psoriatic Arthritis

The efficacy of HUMIRA was assessed in two randomized, double-blind, placebo-controlled studies in 413 patients. The primary study treated 313 adult patients with moderately to severely active psoriatic arthritis who had an inadequate response to nonsteroidal anti-inflammatory drug (NSAID) therapy. Of the 313 treated in this study, 158 (50.5%) were described as taking methotrexate at the time of randomization. Doses of HUMIRA 40 mg every other week were administered for 24 weeks. Table 8 summarizes the controlled clinical trials that were done in patients with active psoriatic arthritis.

Table 8. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Psoriatic Arthritis
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
M02-518
(PsA I)
Multicenter,
double-blind,
randomized,
placebo-controlled,
stratified by MTX
use and extent of
psoriasis (≥ 3% or
< 3% BSA)
HUMIRA 40 mg eow
Placebo
Subcutaneous
24 weeks
151
162
48.6±12.5
49.2±11.1
43.7
45.1
M02-570
(PsA II)
Multicenter,
double-blind,
randomized,
placebo-controlled,
stratified by
DMARD use
(yes, no)
HUMIRA 40 mg eow
Placebo
Subcutaneous
24 weeks
51
49
50.4±11.0
47.7±11.3
43.1
49.0
M02-518
and
M02-570
Multicenter,
double-blind,
randomized,
placebo-controlled,
stratified with
MTX (M02-518),
and DMARDs
(M02-570)
HUMIRA 40 mg eow
Placebo
Subcutaneous
24 weeks
202
211
49.1±12.2
48.9±11.2
43.6
46.0
Definition(s): eow = every other week; MTX = methotrexate; BSA = body surface area; DMARDs = disease-modifying
anti-rheumatic drugs

Mean ages across the two studies ranged from 47.7 years (placebo group, Study M02-570) to 50.4 years (HUMIRA group, Study M02-570). Mean weight ranged from 85.5 kg (placebo group, Study M02-518) and 91.5 kg (HUMIRA group, Study M02-570). The percentage of females ranged from 43.1 % (HUMIRA group, Study M02-570) and 45.1% (placebo group, Study M02-518). Patients were predominantly Caucasian, with the percentage of Caucasian patients ranging from 93.8% (placebo group, Study M02-518) to 98.0% (HUMIRA group, Study M02-570). There were no notable differences between the studies in any of the demographic characteristics analyzed. Upon completion of both studies, 383 patients enrolled in an open-label extension study (Table 9) in which HUMIRA 40 mg is administered every other week.

Table 9. Summary of Open-Label Clinical Trials Evaluating Long-Term Safety and Efficacy in Patients with Psoriatic Arthritis
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
(Years)
Gender
(% Female)
M02-537
(PsA III)
Multicenter,
open-label,
multi-national
continuation of
studies M02-518
and M02-570.
HUMIRA 40 mg eow
Subcutaneous
120 weeks or when
commercially available,
whichever is later
395 49.0±11.7
(20.0 to 88.0)
44.6
Definition(s): eow = every other week
Description of Clinical Studies

Study M02-518 evaluated the effectiveness and safety of HUMIRA either alone or in combination with concomitant methotrexate in subjects with moderately to severely active PsA who have had an inadequate response or intolerance to NSAID therapy.

Study M02-570 evaluated the effectiveness and safety of HUMIRA either alone or in combination with any concomitant DMARD (except cyclosporine or tacrolimus) in subjects with moderately to severely active psoriatic arthritis who have had an inadequate response to DMARD therapy.

Study M02-537 evaluates the long-term safety and efficacy of HUMIRA 40 mg every other week in the treatment of psoriatic arthritis in subjects who completed the controlled Studies M02-518 and M02-570.

Study Results

Clinical Response
Studies M02-518, M02-570 and M02-537

HUMIRA was superior to placebo in all measures of disease activity (p < 0.001) as shown in Table 10 and Table 11. Among patients with psoriatic arthritis who received HUMIRA, the clinical responses were apparent at the time of the first visit (Week 2), significant at Week 12, and maintained at Week 24 in the double-blind period of the study. Table 13 presents data from the ongoing open-label study regarding improvement in arthritic manifestations of psoriatic arthritis.

Patients with a psoriasis involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. In these patients, the skin lesions of psoriasis were improved with HUMIRA, relative to placebo, as measured by the PASI. Results were similar with and without concomitant methotrexate therapy. The small number of patients with moderate to severe psoriasis requires additional data to adequately assess the PASI response.

Table 10. ACR and PASI Response in Placebo-Controlled Psoriatic Arthritis Study (Study M02-518) (Percent of Patients)
Response Placebo
N = 162
HUMIRA
N = 151
ACR 20 Week 12 14% 58%
Week 24 15% 57%
ACR 50 Week 12 4% 36%
Week 24 6% 39%
ACR 70 Week 12 1% 20%
Week 24 1% 23%
Response Placebo
N = 69
HUMIRA
N = 69
PASI 50 Week 12 15% 72%
Week 24 12% 75%
PASI 75 Week 12 4% 49%
Week 24 1% 59%
p < 0.001 for all comparisons between HUMIRA and placebo
Definition(s): ACR = American College of Rheumatology; PASI = Psoriasis Area and Severity Index

Table 11. Components of Disease Activity in Psoriatic Arthritis (Study M02-518)
Parameter
mean (median)
Placebo
N = 162
HUMIRA
N = 151
Baseline Week 24 Baseline Week 24
Number of tender joints (Scale 0 to 78) 25.8(23.0) 22.3 (17.0) 23.3 (19.0) 11.8 (5.0)
Number of swollen joints (Scale 0 to 76) 14.6(11.0) 12.1 (8.0) 13.4 (10.0) 7.6 (3.0)
Physician global assessmenta 53.2(53.0) 46.0 (48.0) 53.5 (54.0) 21.4 (16.0)
Patient global assessmenta
47.2(49.0) 47.6 (49.0) 47.5 (48.0) 24.2 (18.5)
Paina
47.6(47.5) 47.9(49.0) 50.6 (53.0) 25.4 (19.0)
Disability index (HAQ)b
1.0(1.0) 0.9 (0.8) 1.0 (0.9) 0.6 (0.4)
CRP (mg/dL)c
1.4 (0.8) 1.4 (0.7) 1.4 (0.8) 0.5 (0.2)
As observed analysis presented, N at Week 24 may be less than 162 for placebo or 151 for HUMIRA
p < 0.001 for HUMIRA versus placebo comparisons based on mean change from baseline
a. Visual analogue scale; 0 = best, 100 = worst
b. Disability index of the Health Assessment Questionnaire (HAQ); 0 = best, 3 = worst; measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity
c. C-reactive protein (CRP) normal range: 0 to 0.287 mg/dL
Radiographic Response

Radiographic changes in the hands wrists, and feet were assessed in the psoriatic arthritis study 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 by readers blinded to treatment group to assess the radiographs.

Week 24

The mean change in modified total Sharp score was evaluated and demonstrated that HUMIRA-treated patients had significantly less progression in their X-rays, compared to placebo-treated patients. As shown in Table 12, the mean change from baseline in both the erosion and the joint space narrowing scores in the HUMIRA treatment group was significantly superior to placebo. As with other TNF agents, the median change in Sharp scores for both patient groups were zero.

Table 12. Radiographic Mean Changes at Week 24 in Placebo-Controlled Psoriatic Arthritis Study (Study M02-518)
Response Placebo
N = 152
HUMIRA
N = 144
p-value
Total Sharp score 1 -0.2 < 0.001
Erosion score 0.6 0 < 0.001
JSN score 0.4 -0.2 < 0.001
Analysis of patients with X-ray films at both baseline and Week 24
Definition(s):JSN = joint space narrowing
Week 48

HUMIRA-treated patients demonstrated greater inhibition of radiographic progression at Week 48 compared to placebo-treated patients at Week 24 (see Table 13).

Table 13. Change in Modified Total Sharp Score in Psoriatic Arthritis (Study M02-537)
Response Placebo
N = 141
HUMIRA
N = 133
Week 24 Week 24 Week 48
Modified Total
Sharp Score
Baseline mean 22.1 23.4 23.4
Mean change ± SD 0.9 ± 3.06 -0.1 ± 1.69** 0.1 ± 2.74**
Change (range) -3.5 to 22.0 -6.8 to 12.5 -5.9 to 24.2
Erosion Score Baseline mean 11.8 12.4 12.4
Mean change ± SD 0.5 ± 1.91 0.0 ± 0.91** 0.1 ± 1.79*
Change (range) -2.2 to 14.5 -2.2 to 7.5 -4.4 to 16.5
JSN score Baseline mean 10.4 11.0 11.0
Mean change ± SD 0.4 ± 1.60 -0.1 ± 1.06** 0.0 ± 1.33**
Change (range) -3.5 to 10.2 -5.7 to 5.0 -4.0 to 7.7
* p < 0.05 for the difference between HUMIRA, Week 48 and placebo, Week 24 (primary analysis)
** p < 0.001 for the difference between HUMIRA, Week 48 and placebo, Week 24 (primary analysis)
X-rays with less than 50% assessments were imputed
Definition(s): JSN = joint space narrowing;SD = standard deviation
Physical Function Response

Disability and physical function were assessed in psoriatic arthritis study using Health Assessment Questionnaire Disability Index (HAQ-DI). The HUMIRA-treated patients had significantly greater improvement in the disability index of the HAQ from baseline to Week 24, compared to placebo and were maintained up to Week 84 (see Table 14 and Table 15).

Table 14. Disability Index of the HAQ (Full Analysis Set) (Study M02-518)
Disability Index of the HAQ Placebo
N = 162
HUMIRA 40 mg eow
N = 151
p-valuea
N Mea±D N Mean±SD
Week 12 Baseline 154 1.0 142 1.0 < 0.001*
Change Observed 154 -0.1±0.45 142 -0.4±0.45
Week 24 Baseline 145 1.0 141 1.0 < 0.001*
Change Observed 145 -0.1±0.42 141 -0.4±0.49
* Statistically significant at the p = 0.001 level
a. p-value for differences between treatment groups from an ANOVA model with treatment group and baseline
methotrexate use/extent of psoriasis (≥ 3% BSA, < 3% BSA) as factors
Definition(s):HAQ = Health Assessment Questionnaire; BSA = body surface area; eow = every other week;
SD = standard deviation

Table 15. Mean Change From Baseline in Disability Index of HAQ by Visit (Observed) (Study M02-518 Subjects Randomized to HUMIRA)
Visit N Baselinea
Mean
Visit Mean Change from Baseline
Mean Standard
Deviation
Range (Min to Max)
Week 24 137 1.0 0.6 -0.4 0.48 -1.8 to 1.1
Week 26 137 1.0 0.5 -0.4 0.50 -2.1 to 0.9
Week 30 137 1.0 0.6 -0.4 0.49 -1.9 to 1.0
Week 36 137 1.0 0.6 -0.4 0.50 -1.9 to 1.1
Week 42 135 1.0 0.6 -0.4 0.50 -1.9 to 1.0
Week 48 134 1.0 0.6 -0.4 0.54 -2.3 to 0.9
Week 60 132 1.0 0.5 -0.4 0.49 -1.9 to 0.6
Week 72 129 1.0 0.6 -0.4 0.49 -1.9 to 0.6
Week 84 79 0.9 0.5 -0.4 0.49 -1.9 to 0.8
Note:The disability index of the Health Assessment Questionnaire (HAQ) has a range from 0 to 3 with a higher score indicating a greater extent of functional limitations
a. Last assessment prior to the first HUMIRA injection

A subset of the subjects is still being followed in the ongoing study.

Results from the Short Form Health Survey (SF-36) support these findings, with statistically significant Physical Component Summary (PCS) scores, as well as statistically significant pain and vitality domain scores at Week 24, which were maintained to Week 72.

Ankylosing Spondylitis

Study Demographics and Trial Design

The safety and efficacy of HUMIRA 40 mg every other week were assessed in 393 adult patients in two randomized, 24-week double-blind, placebo-controlled studies in patients with active ankylosing spondylitis who have had an inadequate response to or intolerance to one or more NSAIDs, and who may have additionally failed DMARD therapy. The larger study enrolled 315 adult patients with active ankylosing spondylitis [defined as fulfilling at least two of the following three criteria: (1) a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 cm, (2) a visual analogue score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour]. The primary efficacy endpoint was percentage of ASAS 20 responders at Week 12 measured by the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Additional pre-determined endpoints included: response as defined by ASAS 5/6 criteria,

ASAS 40/50/70 and partial remission, Bath Ankylosing Spondylitis Metrology Index (BASMI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). 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 80 weeks.

Study Results

Clinical Response

Results showed statistically significant reduction in signs and symptoms of ankylosing spondylitis in patients treated with HUMIRA compared to placebo in Study M03-607. Significant improvement in measures of disease activity was first observed at Week 2 and maintained through Week 24 as shown in Figure 2 and Table 16.

Patients with total spinal ankylosis were included in the larger study (n = 11). Responses of these patients were similar to those without total ankylosis.


Figure 2. ASAS 20 Response by Visit, Study M03-607

At Week 12, the ASAS 20/50/70 responses were achieved by 58, 38, and 23%, respectively, of patients receiving HUMIRA, compared to 21, 10, and 5% respectively, of patients receiving placebo (p < 0.001). At Week 24, the ASAS 20/50/70 responses were achieved by 51, 35 and 24%, respectively, of patients receiving HUMIRA, compared to 19, 11, and 8%, respectively, of patients receiving placebo (p < 0.001). These results were sustained in patients receiving open-label HUMIRA through Week 52.

In a sub-group analysis by region an HUMIRA versus placebo treatment group difference was observed between the United States (US) and European (EU) subjects (21.7 and 50.9% respectively). This difference in the treatment effect is driven by the different placebo ASAS 20 response rates (33.3% for US versus 10.2% for EU). However, the HUMIRA ASAS 20 response rates were 55 and 61.1% in the US and EU respectively.

A low level of disease activity [defined as a value < 20 (on a scale of 0 to 100 mm) in each of the four ASAS response parameters] was achieved at Week 24 in 22% of HUMIRA-treated patients versus 6% in placebo-treated patients (p < 0.001).

Other secondary and additional measures of efficacy such as response as defined by ASAS 5/6 criteria, ASAS 40, metrology (BASMI), enthesitis (MASES), and disease activity (BASDAI) were statistically significant at Weeks 12 and 24.

Table 16. Components of Ankylosing Spondylitis Disease Activity in Study M03-607
Parameters Placebo
N = 107
HUMIRA
N = 208
Baseline
Mean
Week 24
Mean
Baseline
Mean
Week 24
Mean
ASAS 20 Response Criteria*
  Patient's Global Assessment of Disease
Activitya
  Total Back Pain
  Inflammationb
  BASFI

65

67
6.7
56

60

58
5.6
51

63

65
6.7
52

38

37
3.6
34
BASDAI* Score 6.3 5.5 6.3 3.7
CRP* 2.2 2 1.8 0.6
a. Percent of subjects with at least a 20% and 10-unit improvement measured on a visual analogue scale (VAS) with
0 = "none" and 100 = "severe"
b. Mean of questions 5 and 6 of BASDAI
* Statistically significant as p < 0.001 for all comparisons between HUMIRA and placebo at Week 24
Definition(s): BASFI = Bath Ankylosing Spondylitis Functional Index; BASDAI = Bath Ankylosing Spondylitis
Disease Activity Index; CRP = C-reactive protein (mg/dL)

Similar results (not all statistically significant) were seen in the second randomized trial, a multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis (Study M03-606).

Patients treated with HUMIRA achieved statistically significant greater improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.15 versus -0.95, p < 0.001) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (6.93 versus 1.55, p < 0.001) compared to placebo-treated patients at Week 12, which were maintained through Week 24.

Crohn’s Disease

Study Demographics and Trial Design

The safety and efficacy of multiple doses of HUMIRA were assessed in over 1,500 adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] ≥ 220 and ≤ 450) in randomized, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to receive at least one of these medications.

Table 17 summarizes the controlled clinical trials and Table 18 summarizes the open-label clinical trials that were done in patients with moderately to severely active Crohn’s disease.

Table 17. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Crohn’s Disease
Study# Trial Design Dosage, Route of
Administration and Duration     
Study
Subjects
(n)
Mean Age
(Range)       
Gender
(% Female)
M02-403
(CD I)
Randomized,
double-blind,
placebo-controlled,
multicenter, dose
ranging study in
anti-TNF naïve
patients
HUMIRA 160 mg at Week 0
and 80 mg at Week 2; or
HUMIRA 80 mg at Week 0
and 40 mg at Week 2; or
HUMIRA 40 mgat Week 0
and 20 mg at Week 2
Placebo
Subcutaneous
4 weeks
225






74
39 ± 12
(18 to 74)







37 ± 13
(19 to 74)
55.6








50.0
M04-691
(CD II)
Randomized,
double-blind,
placebo-controlled,
multicenter study
in patients who had
lost response to or
were intolerant to
infliximab
HUMIRA 160 mg at Week 0
and 80 mg at Week 2
Placebo
Subcutaneous
4 weeks
159


166
39.4 ± 11.9
(19 to 75)


37.4 ± 11.9
(18 to 75)
68.6


60.8
M02-404
(CD III)
Randomized,
double-blind,
multicenter,
placebo-controlled
Initial Open-Label:
HUMIRA
80 mg at Week 0
and 40 mg at Week 2
Post-Randomization (Week 4)
HUMIRA 40 mg eow

HUMIRA 40 mg ew

Placebo

Not randomized

Subcutaneous
56 weeks






260

257

261

76






36.8 ± 11.5
(17 to 73)
37.8 ± 12.1
(18 to 75)
36.9 ± 11.4
(18 to 75)
36.1 ± 13.6
(19 to 75)






62.7

61.1

62.1

60.5
M05-769
(CD VI)
Randomized,
double-blind, placebo-controlled, multicenter, efficacy and safety study.
Patients received OL induction
therapy of HUMIRA
160/80 mg at Weeks 0/2, and were stratified by responder status to HUMIRA 40 mg eow or placebo for up to 52 weeks. At Week 52, patients
were switched to OL
HUMIRA 40 mg eow for up
to an additional 36 weeks.)
HUMIRA B eow

Placebo















64

65















37
(18 to 74)
37
(18 to 67)















62.5

63.1
Definition(s):ew = every week; eow = every other week; TNF = tumor necrosis factor; OL =open-label

Table 18. Summary of Open-Label Clinical Trials Supporting Safety and Efficacy in Patients with Crohn’s Disease
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
M02-433
(CD IV)
Open-label
extension of
placebo-controlled
Study M02-403
Patients received OL
HUMIRA 40 mg at baseline
(Week 0) and week 2. At
Week 4, patients were assigned
to one of three blinded
treatment groups
(HUMIRA
eow, ew, or
placebo) or OL
HUMIRA
eow treatment,
based on clinical remission
status at baseline. After 1 year
(Week 56), patients entered
long-term extension phase up
to more than 5 years (including
preceding M02-403 study);
those receiving blinded
treatment were switched to OL
HUMIRA
eow, and those in
the OL group continued their
OL treatment.
All




























276




























39
(18 - 74)




























54.7
M04-690
(CD V)
Open-label
extension of
placebo-controlled
Studies M04-691
or M02-404
Patients entering from a
blinded cohort were assigned
to OL HUMIRA
40 mg eow;
patients entering the study
from an OL cohort continued
their previous dosing regimen
of eow or ew.
Study M02-404 cohort
Study M04-691 cohort










467
310










All
38
(17to75)










All
62.4
Definition(s): ew = every week; eow = every other week; OL =open-label
Description of Clinical Studies

Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies, Studies M02-403 and M04-691.

In Study M02-403, 299 TNF-blocker naïve patients were randomized to one of four treatment groups; the placebo group received placebo at Weeks 0 and 2, the 160/80 group received 160 mg HUMIRA at Week 0 and 80 mg at Week 2, the 80/40 group received 80 mg at Week 0 and 40 mg at Week 2, and the 40/20 group received 40 mg at Week 0 and 20 mg at Week 2.

In Study M04-691, 325 patients who had lost response or were intolerant to infliximab were randomized to receive either 160 mg HUMIRA at Week 0 and 80 mg at Week 2 or placebo at Weeks 0 and 2.

Maintenance of clinical remission was evaluated in Study M02-404.

In Study M02-404, 854 patients received open-label 80 mg HUMIRA at Week 0 and HUMIRA 40 mg at Week 2. At Week 4, patients were stratified by their responder status and previous anti-tumor necrosis factor (TNF) use (no, yes) and randomized to one of three blinded treatment groups: HUMIRA 40 mg every other week, HUMIRA 40 mg every week or placebo with a total study duration of 56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at Week 4 were stratified and analyzed separately from those not in clinical response at Week 4. Corticosteroid tapering was permitted after Week 8.

Study M05-769 assessed mucosal healing in 135 patients; patients received open-label induction therapy of HUMIRA 160/80 mg at weeks 0/2, and were stratified by responder status to HUMIRA 40 mg every other week (eow) or placebo for up to 52 weeks. At Week 52, patients were switched to open-label HUMIRA 40 mg eow for up to an additional 36 weeks.

Study Results

Clinical Responses
Studies M02-403 and M04-691

A statistically significantly greater percentage of the patients treated with HUMIRA 160/80 mg achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF-blocker naïve (Study M02-403) or had lost response or are intolerant to infliximab (Study M04-691) (Table 19 and Table 20, respectively).

The percentage of subjects who achieved clinical remission with HUMIRA 160/80 mg induction therapy was greater for those receiving corticosteroids versus those who did not.

Table 19. Induction of Clinical Remission and Response in Infliximab Naïve Patients (Study M02-403) (Percent of Patients)
Response Placebo
N = 74
HUMIRA 160/80 mg
N = 76
Week 4 Clinical remission 12% 36%*
Differencea (95% CI) 23.4 (10.3, 36.4)
Clinical response (CR-100) 24% 49%**
Differencea (95% CI) 24.4 (9.5, 39.3)
Clinical response (CR-70) 34% 58%**
Differencea (95% CI) 24.1 (8.6, 39.6)
All p-values are pairwise comparisons of proportions for HUMIRA versus placebo
* p < 0.001
** p < 0.01
a. Difference refers to the difference between the proportion (%) of HUMIRA-treated subjects achieving clinical
remission and clinical response compared with the placebo-treated subjects; 95% CI based on normal approximation of
the binomial
Definition(s): CI = confidence interval; Clinical remission = Crohn's Disease Activity Index (CDAI) score < 150;
Clinical response 100 (CR-100) and a clinical response 70 (CR-70) = decreases from baseline in CDAI
scores of at least 100 points and at least 70 points, respectively

Table 20. Induction of Clinical Remission and Response in Infliximab Experienced Patients (Study M04-691) (Percent of Patients)
Response Placebo
N = 166
HUMIRA 160/80 mg
N = 159
Week 4 Clinical remission 7% 21%*
Differencea (95% CI) 14.2 (6.7, 21.6)
Clinical response (CR-100) 25% 38%**
Differencea (95% CI) 13.7 (3.7, 23.7)
Clinical response (CR-70) 34% 52%**
Differencea (95% CI) 17.8 (7.3, 28.4)
p-values are pairwise comparisons of proportions for HUMIRA versus placebo
* p < 0.001
** p < 0.01
a. Difference refers to the difference between the proportion (%) of HUMIRA-treated subjects achieving clinical
remission and clinical response compared with the placebo-treated subjects; 95% CI based on normal approximation of
the binomial
Definition(s): CI = confidence interval; Clinical remission = Crohn's Disease Activity Index (CDAI) score < 150;
Clinical response 100 (CR-100) and a clinical response 70 (CR-70) = decreases from baseline in CDAI
scores of at least 100 points and at least 70 points, respectively

Clinical Remission at Week 4 by baseline predictors in infliximab experienced patients is presented in Table 21.

Table 21. Clinical Remission at Week 4 by Baseline Predictors in Infliximab Experienced Patients (Study M04-691)
Baseline Predictors Placebo
N = 166
HUMIRA 160/80 mg
N = 159
Corticosteroid User 3/73 (4.1) 18/55 (32.7)
Corticosteroid Nonuser 9/93 (9.7) 16/104 (15.4)
Aminosalicylate User 6/60 (10.0) 6/45 (13.3)
Aminosalicylate Nonuser 6/106 (5.7) 28/114 (24.6)
CDAI Score ≤ 300 8/81 (9.9) 24/75 (32.0)
> 300 4/85 (4.7) 10/84 (11.9)
Definition(s): CDAI = Crohn's disease activity index
Study M02-404

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 anti-TNF therapy. At Weeks 26 and 56, statistically significantly greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the HUMIRA maintenance groups compared to patients in the placebo maintenance group (Table 22).

Table 22. Maintenance of Clinical Remission and Response (Percent of Patients) (Study M02-404)
Response Placebo
N = 170
HUMIRA 40 mg eow
N = 172
HUMIRA 40 mg ew
N = 157
Week 26 Clinical remission 17% 40%* 47%*
Differencea (95% CI) 22.5 (13.2, 31.7) 29.4 (19.8, 39.1)
Clinical response (CR-100) 27% 52%* 52%*
Differencea (95% CI) 25.3 (15.3, 35.3) 25.8 (15.5, 36.0)
Clinical response (CR-70) 28% 54%* 56%*
Differencea (95% CI) 25.8 (15.8, 35.9) 27.8 (17.5, 38.1)
Week 56 Clinical remission 12% 36%* 41%*
Differencea (95% CI) 24.3 (15.6, 32.9) 29.6 (20.5, 38.7)
Clinical response (CR-100) 17% 41%* 48%*
Differencea (95% CI) 24.8 (15.6, 34.0) 31.3 (21.7, 40.9)
Clinical response (CR-70) 18% 43%* 49%*
Differencea (95% CI) 25.4 (16.9, 34.7) 31.4 (21.7, 41.1)
* p < 0.001 for HUMIRA versus placebo pairwise comparisons of proportions
a. Difference refers to the difference between the proportion (%) of HUMIRA-treated subjects achieving clinical remission
and clinical response compared with the placebo-treated subjects; 95% CI based on normal approximation of the binomial
Definition(s): eow = every other week; ew = every week; CI = confidence interval; Clinical remission = Crohn's Disease
Activity Index (CDAI) score < 150; Clinical response 100 (CR-100) and clinical response 70 (CR-70) =
decreases from baseline in CDAI scores of at least 100 points and at least 70 points, respectively

More patients receiving HUMIRA maintenance therapy were able to achieve remission and discontinue corticosteroids for at least 90 days than those receiving placebo at Week 26 (19% HUMIRA every other week and 15% HUMIRA every week versus 3% placebo, p < 0.02) and at Week 56 (29% HUMIRA every other week and 20% HUMIRA every week versus 5% placebo, p < 0.01).

In Study M02-404, 117 patients had at least one draining fistula at Baseline and Screening. Of those, 23 out of 70 in the HUMIRA group (both regimens) and 6 out of 47 in the placebo group had no draining fistula at the last two evaluations.

Of those in response at Week 4 who attained remission during the study, patients in the HUMIRA maintenance groups maintained remission for a significantly longer time than patients in the placebo maintenance group (Figure 3).


Figure 3. Days in Clinical Remission for Patients Who Had Achieved Clinical Remission (Induction Period) by Week 4 in Study M02-404

Some patients who experience decrease in their response may benefit from an increase in dose to HUMIRA 40 mg every week. Supportive evidence for a restoration of clinical response as a result of dose escalation was derived from the modified-intent-to treat (mITT) Analysis Set of Study M02-404 in subjects who initially responded but lost response to HUMIRA 40 mg every other week dosing. In those subjects who responded at Week 4, were in remission at Week 12 but lost remission after Week 12, and were dose escalated to HUMIRA 40 mg every week (n = 14), clinical remission was restored in 71% (10/14) of these subjects, with median time to restored clinical remission of 9 weeks.

Some patients who have not responded by Week 4 (induction period) may benefit from continued maintenance therapy through Week 12. Available data suggest that the clinical response is usually achieved at Week 4 of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Symptoms, overall well-being and functioning were assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). Treatment with HUMIRA resulted in statistically significant improvements in IBDQ total score which measures bowel symptoms, systemic symptoms, emotional well-being and social functioning, compared with placebo (p < 0.001) at Week 4 in Studies M02-403 and M04-691 and Weeks 26 and 56 in Study M02-404.

Study M05-769

An endoscopy study (n=135) assessed rates of mucosal healing in patients with moderate to severe Crohn’s Disease given either HUMIRA or placebo. After 8 weeks of randomised treatment (Week 12 of study), although the results were not statistically significant (p = 0.056), there was a trend towards higher levels of mucosal healing in subjects given HUMIRA compared with subjects given placebo (mucosal healing in 27.4% (17/62) HUMIRA vs 13.1% (8/61) given placebo. In this study, the placebo group received open-label HUMIRA induction therapy.

Ulcerative Colitis

Study Demographics and Trial Design

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 on a scale of 0 to 12 points, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppresants such as corticosteroids, azathioprine, or 6-MP in two randomised, double-blind, placebo-controlled studies (M06-826 and M06-827) and an open-label extension study. Both studies M06-826 and M06-827 enrolled TNF-blocker naïve patients, but M06-827 also allowed entry of patients who lost response or were intolerant to TNF-blockers. Forty percent (40%) of patients enrolled in Study M06-827 had previously used another TNF-blocker.

Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted. In Studies M06-826 and M06-827, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients continued to receive at least one of these medications.

Table 23 summarizes the controlled clinical trials and Table 24 summarizes the open-label clinical trial that were done in patients with ulcerative colitis (UC).

Table 23. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Ulcerative Colitis
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
M06-826
(UC I)
(ULTRA I)
Randomized,
double-blind
(Weeks 0 to 8),
placebo-controlled,
multicenter
induction study
followed by an
open-label
extension (Weeks 8
to 52) in anti-TNF
naïve subjects
HUMIRA 160 mg at Week 0,
80 mg at Week 2, and 40 mg
eow starting at Week 4
223* 38 ± 13
(18 to 75)
38.1
HUMIRA 80 mg at Week 0
and 40 mg eow starting at
Week 2
130 42 ± 14
(18 to 75)
40.0
Placebo 222* 40 ± 13
(18 to 74)
37.4
Subcutaneous
52 weeks
M06-827
(UC II)
(ULTRA II)
Randomized,
double-blind,
placebo-controlled,
multicenter
induction and
maintenance study
HUMIRA 160 mg at Week 0,
80 mg at Week 2, and 40 mg
eow starting at Week 4
248 40 ± 12
(18 to 72)
42.7
Placebo 246 41 ± 13
(18 to 79)
38.2
Subcutaneous
52 weeks
Definition(s): ew = every week; eow = every other week
* 130 subjects were randomized for the primary efficacy analysis

Table 24. Summary of Open-Label Clinical Trials Supporting Safety and Efficacy in Patients with Ulcerative Colitis
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
M10-223
(UC III)
Open-label
extension of
controlledStudies
M06-826 and
M06-827
Patients entering the study
from a blinded cohort were
assigned to adalimumab 40 mg
eow; those entering the study
from an open-label cohort
continued their previous dosing
regimen of adalimumab 40 mg
eow or ew.
Subcutaneous
up to 292 weeks
498 42 ± 13
(19 to 76)
36.9
Definition(s): ew = every week; eow = every other week
Description of Clinical Studies

Induction of clinical remission (defined as Mayo score ≤ 2 with no individual subscore > 1) at Week 8 was evaluated in Study M06-826. In Study M06-826, 390 TNF- blocker naïve patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Week 0, 2, 4 and 6. The 160/80 group received 160 mg HUMIRA at Week 0 and 80 mg at Week 2, and the 80/40 group received 80 mg HUMIRA at Week 0 and 40 mg at Week 2. After Week 2, patients in both HUMIRA treatment groups received 40 mg every other week (eow). Clinical remission was assessed at Week 8.

Induction of clinical remission at Week 8, clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were studied in Study M06-827. In Study M06-827, 518 patients were randomized to receive either HUMIRA 160 mg at Week 0, 80 mg at Week 2, and 40 mg eow starting at Week 4 through Week 50, or placebo starting at Week 0 and eow through Week 50. Corticosteroid taper was permitted starting at Week 8.

Study Results

Clinical Responses

In both Studies M06-826 and M06-827, a greater proportion of subjects induced with 160/80 mg HUMIRA achieved clinical remission versus placebo at Week 8 (Table 25). In Study M06-826, there was no statistically significant difference in clinical remission observed between the HUMIRA 80/40 mg group and the placebo group at Week 8 and no statistically significant difference in clinical response or mucosal healing observed between the HUMIRA 160/80 mg group and the placebo group at Week 8. Response at Week 8 was achieved by 54.6% (71/130) in the HUMIRA 160/80 mg group and 44.6% (58/130) in the placebo group with a treatment difference and 95% confidence interval (CI) of 10.0% (-2.1, 22.1). Mucosal healing at Week 8 was achieved by 46.9% (61/130) in the HUMIRA group and 41.5% (54/130) in the placebo group with a treatment difference and 95% CI of 5.4% (-6.7, 17.4).

In Study M06-827 clinical remission at Week 52 was a co-primary endpoint, achieved by 17.3% (43/248) of the HUMIRA group and 8.5%(21/246) of the placebo group. Sustained clinical remission (at both Weeks 8 and 52) was achieved by 8.5% (21/248) of the HUMIRA group and 4.1% (10/246) of the placebo group. Among those treated with HUMIRA who were in remission at Week 8, 51% (21/41) were in remission at Week 52. In the HUMIRA group 46.8% (116/248) patients moved to open label escape therapy for lack of response and 54.9% (135/246) patients in the placebo group. During the double-blind period, 5.6% (14/248) in the HUMIRA group and 7.7% (19/246) in the placebo group withdrew without final evaluation due to non- colitis related reasons (not lack of efficacy or colitis related adverse event). In the HUMIRA group 79 (31.9%) patients completed the Week 8 and 52 visits and 56 (22.8%) patients in the placebo group.

Response at Week 8 and at Week 52 were achieved in 50.4% (125/248) and 30.2% (75/248) of the HUMIRA group and 34.6% (85/246) and 18.3% (45/246) in the placebo group respectively with a treatment difference and 95% CI of 15.9% (7.0, 24.2) and 11.9% (4.3, 19.2). Sustained response (at both Weeks 8 and 52) was achieved by 23.8% (59/248) of the HUMIRA group and 12.2% (30/246) of the placebo group with a treatment difference and 95% CI of 11.6% (4.7, 18.1).

Mucosal healing (endoscopic improvement of the mucosa) at Week 8 and at Week 52 were achieved in 41.1% (102/248) and 25.0% (62/248) in the HUMIRA group and 31.7% (78/246) and 15.4% (38/246) of the placebo group with a treatment difference and 95% CI of 9.4% (0.8, 17.6) and 9.6% (2.3, 16.4). Sustained mucosal healing (at both Weeks 8 and 52) was achieved by 18.5% (46/248) of the HUMIRA group and 10.6% (26/246) of the placebo group with a treatment difference and 95% CI of 8.0% (1.6, 14.0).

In the HUMIRA group, 13.3% (20/150) of the patients who were on corticosteroids at baseline were able to discontinue corticosteroids before Week 52 and achieved remission at Week 52 compared to 5.7% (8/140) in the placebo group.

Table 25. Study M06-826 and M06-827: Summary of Results of Primary and Ranked Co-Primary and Ranked Secondary Endpoints
Analysisa Placebo Adalimumab
160/80/40
Treatment
Difference
(95% CI)
Study M06-826 N = 130 N = 130
Primary Endpoint
Clinical remission at Week 8 9.2% 18.5%* 9.2 (0.9, 17.6)
Study M06-827 N = 246 N = 248
Ranked Co-Primary Endpoints
1.Remission at Week 8
2.Remission at Week 52
9.3%
8.5%
16.5%*
17.3%*
7.2 (1.2, 12.9)
8.8 (2.8, 14.5)
Note: According to the NRI method, all missing remission values were considered to be non-remission.Subjectswho
switched to OL adalimumab were considered to be non-remitters at and after the time of the switch.
Clinical remission per Mayo score:Mayo score ≥ 2 with no individual subscore > 1
Mayo score consists of four subscores (stool frequency [SFS], rectal bleeding [RBS], findings of endoscopy, and physician's
global assessment). Mayo scores range from 0-12.
* p <0.05 for HUMIRA vs. placebo pairwise comparison of proportions

In the subgroup of patients in Study M06-827 with prior TNF-blocker use, the treatment difference for induction of clinical remission was lower than that seen in the whole study population, and the treatment differences for sustained clinical remission and clinical remission at Week 52 appeared to be similar to those seen in the whole study population.

Hidradenitis Suppurativa

Study Demographics and Trial Design

The safety and efficacy of HUMIRA were assessed in two randomized, double-blind, placebo- controlled studies in adult patients with moderate to severe hidradenitis suppurativa (HS) who were intolerant, had a contraindication or an inadequate response to systemic antibiotic therapy. In both studies, patients had Hurley Stage II or III disease with at least 3 abscesses or inflammatory nodules. Table 26 summarizes the clinical trials in patients with moderate to severe hidradenitis suppurativa.

Table 26. Summary of Clinical Trials Evaluating Safety and Efficacy in Patients with Hidradenitis Suppurativa
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
M11-313
(PIONEER I)
Randomized,
double-blind,
placebo-
controlled,
2-period
Period A - 12 weeks
HUMIRA 160 mg at Week 0,
80 mg at Week 2, then 40 mg
every week from Week 4 to
Week 11;
Placebo

Period B - 24 weeks
HUMIRA 40 mg every week;
HUMIRA 40 mg every other
week;
Placebo

Subcutaneous
36 weeks
307 37.0
(18 to 67)
63.8
M11-810
(PIONEER II)
Randomized,
double-blind,
placebo-
controlled,
2-period
Period A - 12 weeks
HUMIRA 160 mg at Week 0,
80 mg at Week 2, then 40 mg
every week from Week 4 to
Week 11;
Placebo

Period B - 24 weeks
HUMIRA 40 mg every week;
HUMIRA 40 mg every other
week;
Placebo

Subcutaneous
36 weeks
326 35.5
(18 to 69)
67.8
Description of Clinical Studies

Both studies consisted of an initial 12-week double-blind treatment period (Period A), and a subsequent 24-week double-blind treatment period (Period B). 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. After 12 weeks of therapy, patients who had received HUMIRA in Period A were re-randomized 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). In Period B, patients who had been randomized to placebo in Period A were assigned to receive HUMIRA 40 mg every week (M11-313) or placebo (M11-810) in a blinded fashion. In both studies, the randomization in Period A was to be stratified by baseline Hurley Stage (II versus III). A subject's Hurley Stage was determined by the worst Hurley Stage across all affected anatomic regions. Baseline concomitant antibiotic use (yes versus no) was an additional randomisation factor in Study M11 810.

Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12 as the primary endpoint. Reduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was assessed using HiSCR which was defined as achieving at least a 50% reduction from baseline in AN [total abscess and inflammatory nodule] count plus 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.

The majority of patients were female, obese (≥ 90 kg, BMI ≥ 30), current smokers, and had HS disease duration of over 9 years; the patients had a mean modified Sartorius Score of 131.6, AN count of 12.8, and draining fistula count of 3.8.

Patients participating in Studies M11-313 and M11-810 were eligible to enroll into an open-label extension study (Study M12-555) in which HUMIRA 40 mg was administered every week. Study M12-555 aimed to determine the long-term safety, tolerability and efficacy of adalimumab in subjects with moderate to severe HS for at least 60 weeks.

Throughout all 3 studies, patients used topical antiseptic wash daily.

Study Results

Clinical Responses
Studies M11-313 and M11-810

In Period A of Studies M11-313 and M11-810, 40 mg of adalimumab treatment every week resulted in statistically significant greater proportion of patients achieving HiSCR at Week 12 in subjects with moderate to severe HS compared with placebo. Results are shown in Table 27.

Table 27. Clinical Response at 12 Weeks, M11-313 and M11-810
Endpoint M11-313 (PIONEER I) M11-810 (PIONEER II)
Placebo HUMIRA
40 mg weekly
Placebo HUMIRA
40 mg weekly
Hidradenitis Suppurativa
Clinical Response(HiSCR)
N = 154
40 (26.0%)
N = 153
64 (41.8%)
N = 163
45 (27.6%)
N = 163
96 (58.9%)
Difference (95% CI)a 15.9 % (5.3%, 26.5%) 31.5% (20.7, 42.2%)
P-valueb 0.003 < 0.001
a. 95% CI for stratum-adjusted difference was calculated according to the extended Mantel-Haenszel statistic for the
comparison of two treatment groups, adjusting for baseline Hurley Stage (II/III) in M11-313 and adjusting for baseline
Hurley Stage (II/III) and baseline antibiotic use (Yes/No) in M11-810.
b. P-value was calculated from the Cochran-Mantel-Haenszel test adjusting for baseline Hurley Stage (II/III) in M11-313, and
adjusting for baseline Hurley Stage (II/III) and baseline antibiotic use (Yes/No) in M11-810.

At Week 12, a significantly higher proportion of patients treated with HUMIRA in Study M11-810 experienced at least a 30% decrease in HS-related skin pain versus placebo (45.7% vs 20.7%, P < 0.001), whereas the difference was not significant in Study M11-313 (27.9% vs 24.8%, P = 0.628). During the initial 12 weeks of treatment, 13.7% of patients treated with HUMIRA experienced flare compared to 35.7% in the placebo group in Study M11-313. The corresponding observed percentage was 11.0% and 35.0% for the HUMIRA and placebo group, respectively, in Study M11-810.

Among patients who were randomized to HUMIRA in Period A, achieved HiSCR at Week 12, and re-randomized to HUMIRA every week (N = 52), HUMIRA every other week (N = 52) and placebo (N = 53), 24 (46.2%), 22 (42.3%), and 32 (60.4%) discontinued prior to Week 36, respectively; 17 (32.7%), 20 (38.5%), and 27 (50.9%) discontinued primarily due to experiencing protocol specified loss of response.

In patients with at least a partial response (≥ 25% improvement in AN count) to HUMIRA 40 mg weekly at Week 12, the proportion of patients achieving HiSCR at Week 24 was 57.1% in HUMIRA 40 mg weekly, 51.4% in HUMIRA 40 mg every other week and 32.9% in the placebo group. The corresponding proportion at Week 36 was 55.7% in HUMIRA 40 mg weekly, 40.0% in HUMIRA 40 mg every other week and 30.1% in the placebo group.

Psoriasis

Study Demographics and Trial Design

The safety and efficacy of HUMIRA were assessed in over 1,600 patients 18 years of age or older with moderate to severe chronic plaque psoriasis who were candidates for systemic therapy or phototherapy in randomized, double-blind, well-controlled studies.

Table 28 summarizes the controlled clinical trials that were done in patients with moderate to severe plaque psoriasis.

Table 28. Summary of Controlled Clinical Trials Supporting Safety and Efficacy in Patients with Psoriasis
Study# Trial Design Dosage, Route of
Administration and
Duration          
Study
Subjects
(n)
Mean Age
(Range)
Gender
(% Female)
M03-656
(Ps I)
Period A: Double-blind,
placebo-controlled
treatment period in patients
with moderate to severe
chronic plaque psoriasis
(PASI ≥ 12, BSA ≥ 10%);
patients were randomly
assigned (2:1) to receive
HUMIRA or placebo

Period B: Open-label
treatment period; all patients
who achieved a ≥ PASI 75
response at Week 16
received HUMIRA

Period C: Double-blind,
placebo-controlled
treatment period; patients
who maintained a
≥ PASI 75 response at
Week 33 and were
originally randomized to
active therapy in Period A
were rerandomized (1:1) to
receive HUMIRA or
placebo
Initial Dose
HUMIRA 80 mg
Period A - 16 weeks
HUMIRA 40 mg eow
Placebo

Period B - 17 weeks
HUMIRA 40 mg eow

Period C - 19 weeks
HUMIRA 40 mg eow
Placebo

Subcutaneous
52 weeks




814
398



606





250

240




44.1±13.2
45.4±13.4



43.9±13.2





44.3±13.0

43.4±13.2




32.9
35.4



30.7





29.6

25.4
M04-716
(Ps II)
Randomized, double-blind,
double-dummy, multicenter,
placebo- and
active-controlled study in
patients with moderate to
severe plaque psoriasis
(PASI ≥ 10, BSA ≥ 10%)
who were candidates for
systemic therapy or
phototherapy and had
inadequate response to
topical therapy
HUMIRA 80 mg
followed by 40 mg eow

Placebo

MTX capsules
(7.5 to 25.0 mg)

Subcutaneous and oral
16 weeks
108





53


110
42.9±12.6





40.7±11.4


41.6±12.0
35.2





34.0


33.6
M02-528
(Ps III)
Randomized, double-blind,
placebo-controlled,
multicenter, dose-ranging
study in patients with
moderate to severe plaque
psoriasis (BSA ≥ 5%) and
inadequate response to
topical therapy
HUMIRA 80 mg
followed by 40 mg eow
HUMIRA 80 mg
followed by 40 mg ew
Placebo
Subcutaneous
12 weeks
45


50


52
45.8±11.6


43.8±13.3


43.3±13.1
28.9


34.0


34.6

Definition(s): ew = every week; eow = every other week; MTX = methotrexate; PASI = Psoriasis Area and Severity
Index; BSA = body surface area

Across all treatment groups of Study M03-656, the mean baseline Psoriasis Area and Severity Index (PASI) score was 18.9 and the baseline physician’s global assessment (PGA) score ranged from “moderate” (52.6%) to “severe” (41.3%) to “very severe” (6.1%).

Across all treatment groups of Study M04-716, the mean baseline PASI score was 19.7 and the baseline PGA score ranged from “mild” (0.4%) to “moderate” (47.8%) to “severe” (45.6%) to “very severe” (6.3%).

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. 1,468 patients received at least one dose of HUMIRA during the open-label trial. 1,018/1,468 (69%) patients received adalimumab for a minimum of 108 weeks. Patients from Study M03-656 who enrolled into the open-label trial may have received up to 160 weeks of continuous HUMIRA exposure in the first portion of the extension. 183/233 (79%) eligible patients from Study M03-656 completed 160 weeks from the first dose of adalimumab in M03-656 to the end of the first portion of the extension trial.

Study Results

Clinical Response

In Studies M03-656, M04-716 and M02-528, the primary endpoint was the proportion of patients who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 for Studies M03-656 and M04-716 and Week 12 for Study M02-528. Other evaluated outcomes in Studies M03-656, M04-716 and M02-528 included the PGA and other PASI measures.

Study M03-656 had an additional primary endpoint of loss of adequate response after Week 33 and on or before Week 52. Loss of adequate response is defined as a PASI score after Week 33 and on or before Week 52 that resulted in a < PASI 50 response relative to baseline with a minimum of a 6-point increase in PASI score relative to Week 33.

In Study M03-656, response to HUMIRA was rapid, with significantly greater improvements compared to placebo in mean percentage PASI, PASI 75/90 response rates, and PGA clear or minimal scores by Week 4, the first study visit (all p <0.001 vs. placebo).

In Studies M03-656 and M04-716, more patients randomized to HUMIRA than to placebo achieved at least a 75% reduction from baseline of PASI score at Week 16 (see Table 29 and Table 30). Other relevant clinical parameters, including PASI 90, PASI 100 (corresponding to a complete clearance of psoriasis skin signs) and PGA of “clear or minimal,” were also improved over placebo.

In Study M04-716, superior results were achieved for PASI 75, PASI 90, PASI 100 and PGA of “clear or minimal” in patients randomized to the HUMIRA treatment group versus those randomized to receive methotrexate.

Table 29. Psoriasis Study M03-656 Efficacy Results at Week 16 (Percent of Patients)
Response Placebo
N = 398
HUMIRA 40 mg eow
N = 814
≥ PASI 75 6.5% 70.9%a
≥ PASI 90 1.8% 45.0%a
PASI 100 0.8% 20.0%a
PGA: Clear/minimal 4.3% 62.2%a
a. p < 0.001 for HUMRIA versus placebo
Definition(s): eow = every other week; PASI = Psoriasis Area Severityindex; PGA = physician's global assessment

Table 30. Psoriasis Study M04-716 Efficacy Results at Week 16 (Percent of Patients)
Response Placebo
N = 53
MTX
N = 110
HUMIRA 40 mg eow
N = 108
≥ PASI 75 18.9% 35.5% 79.6%a,b
≥ PASI 90 11.3% 13.6% 51.9%a,b
PASI 100 1.9% 7.3% 16.7%a,b
PGA: Clear/minimal 11.3% 30.0% 73.1%a,b
a. p < 0.001 for HUMRIA versus placebo
b. p < 0.001 for HUMIRA versus methotrexate
Definition(s): eow = every other week; PASI = Psoriasis Area Severityindex; PGA = physician's global assessment

PASI 75, PASI 90 and PASI 100 Responses from Week 0 to Week 24 for Study M03-656 are presented in Figure 4.


Figure 4. Psoriasis Study M03-656 Response Rate from Week 0 to Week 24

Results from Study M02-528 supported the efficacy demonstrated in Studies M03-656 and M04-716.

In Study M03-656, patients who were PASI 75 responders and were re-randomized to continue HUMIRA therapy at Week 33 were less likely to experience a loss of adequate response on or before Week 52 than the PASI 75 responders who were re-randomized to placebo at Week 33 (4.9% versus 28.4%, p < 0.001).

A total of 233 PASI 75 responders at Week 16 and Week 33 received continuous HUMIRA therapy for 52 weeks in Psoriasis Study M03-656, and continued HUMIRA in the open-label extension trial. The proportion of patients with full skin clearance (PASI 100) was generally maintained through Week 108 [31.8% at OLE entry (n=74/233); 30.1% at Week 108 (n=69/229 (total of 160 weeks)].

A total of 94 patients were randomized to HUMIRA therapy in Psoriasis Study M04-716, and continued HUMIRA in the open label extension trial. The proportion of patients with PASI 75 after an additional 108 weeks of open-label therapy was 58.1% (n=54/93) (total of 124 weeks).

A total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-label extension study. Median time to relapse (decline to PGA “moderate” or worse) was approximately 5 months [95% C.I. (127, 146 days)]. None of these patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) of patients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16 weeks of retreatment, 69.1% (123/178) for patients who relapsed and 88.8% (95/107) for patients who did not relapse during the withdrawal period.

In the open-label extension study, 349/1,256 (27.8%) patients dose escalated from 40 mg every other week to 40 mg weekly due to a PASI response below 50% and were evaluated 12 weeks after dose escalation, and 93/349 (26.6%) patients achieved PASI 75 response.

There were no clinical trials conducted to evaluate the efficacy and safety of HUMIRA in psoriatic arthritis subjects with both active arthritis and moderate to severe psoriasis.

Quality of Life

Patient Reported Outcomes (PRO) were evaluated by several measures. Quality of Life was assessed using the disease-specific Dermatology Life Quality Index (DLQI) in Study M03-656 and Study M04-716.

In Study M03-656, patients receiving HUMIRA demonstrated clinically meaningful improvement in the DLQI total score, disease severity, pain, and pruritus compared to the placebo group at both Weeks 4 and 16. The DLQI result was maintained at Week 52.

In Study M04-716, patients receiving HUMIRA demonstrated clinically meaningful improvement in the DLQI total score, disease severity, and pruritus compared to the placebo and methotrexate groups at Week 16, and clinically meaningful improvement in pain compared to the placebo group at Week 16.

The Short Form Health Survey (SF-36) was used to assess general health-related quality of life in Study M03-656. The HUMIRA-treated patients had significantly greater improvement in the SF-36 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores.

Pediatric

Polyarticular Juvenile Idiopathic Arthritis

Study Demographics and Trial Design

The safety and efficacy of HUMIRA was assessed in two studies (Studies DE038 and M10-444) 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).

Table 31. Summary of Clinical Trial Evaluating Safety and Efficacy in Patients with Polyarticular Juvenile Idiopathic Arthritis
Study# Trial Design Dosage, Route of
Administration and Duration
Study
Subjects
(n)
Mean Age
(Range)
(Years)
Gender
(% Female)
DE038
(JIA I)
Multicenter,
double-blind,
randomized,
placebo-controlled,
open-label
extension
OL LI Phase
24 mg adalimumab/m2 BSA
(up to a maximum of 40 mg total
body dose) subcutaneous eow
171 11.3±3.53
(4 to 17)
78.9%
DB Phase
24 mg adalimumab/m2 BSA (up
to a maximum of 40 mg total
body dose) subcutaneous eow
or
Placebo subcutaneous eow
133 11.6±3.61
(4 to 17)
77.4%
OLE BSA Phase
24 mg adalimumab/m2 BSA
(up to a maximum of 40 mg total
body dose) subcutaneous eow
128 12.0±3.59
(4 to 18)
76.6%
OLE FD Phase
20 mg adalimumab
subcutaneous eow, < 30 kg body
weight
or
40 mg adalimumab
subcutaneous eow, ≥ 30 kg body
weight
106 13.7±3.82
(6 to 20)
73.6%
M10-444
(JIA II)
Multicenter, open-
label
24 mg adalimumab/m2 BSA (up
to a maximum of 20 mg total
body dose) subcutaneous eow
32 3.04±0.723
(2.0 to 4.6)
87.5%
Definition(s): BSA = body surface area; DB = double blind; eow = every other week; OL BSA = open-label body surface
area; OL FD = open-label fixed dose; OL LI = open-label lead in; SC = subcutaneous.
Study DE038

The safety and efficacy of HUMIRA were assessed in a multicentre, randomized, double-blind, parallel-group study in 171 children (4 to 17 years old) with moderate or severe polyarticular juvenile idiopathic arthritis (JIA). In the open-label lead in phase (OL LI) patients were stratified into two groups, methotrexate (MTX)-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 32.

Table 32. Distribution of Patients by Age and HUMIRA dose received during the OL LI phase
Age Group Number of patients at Baseline n (%) Minimum, median and
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 randomized 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 enroll into the open label extension phase.

The primary efficacy variable was the proportion of patients in the non-MTX stratum who experienced disease flare in the double-blind phase. Key secondary endpoints were analysis and comparison of disease flare at Week 48 including the proportion of patients with disease flare in those treated with MTX, time to onset (from double blind Baseline) of flare for patients in the non-MTX stratum, and time to onset (from double blind Baseline) of flare for patients treated with MTX. Subjects were clinically assessed at baseline, and for clinical response to adalimumab at Weeks 2, 4 and then every 4 weeks up to Week 48 or at early termination and throughout the OLE phases.

Study M10-444

The safety and efficacy of HUMIRA was assessed in an open-label, multicenter study in 32 children (2 to <4 years old or aged 4 and above weighing <15 kg) with moderately to severely active polyarticular JIA. The primary objective of the study was the evaluation of safety.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 up to a maximum of 120 weeks duration. During the study, most subjects used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs.

Study Results

Table 33. Major Efficacy Results in the JIA Study (DE038)
Stratum Methotrexate Without Methotrexate
Phase
OL-LI 16 weeks
Ped ACR 30 response*
(n/N)
94.1% (80/85)
N=85*
74.4% (64/86)
N=86*
Double Blind HUMIRA
(n = 38)
Placebo
(n = 37)
HUMIRA
(n = 30)
Placebo
(n = 28)
Disease flares at the end of
32 weeks (n/N)
36.8% (14/38) 64.9% (24/37) 43.3% (13/30) 71.4% (20/28)a
Median time to disease
flare
>32 weeks 20 weeks >32 weeks 14 weeks
a. p = 0.031
* N and PedACR30 response rates are from the Open-Label Lead-In phase prior to the randomization to the Double-
Blind phase.

Twelve patients were treated for 6 years or longer.

The percentage of patients achieving PedACR30 responses were higher (94% vs. 74%) and, fewer patients developed antibodies (5.9% vs. 25.6%) when treated with the combination of HUMIRA and MTX compared to HUMIRA monotherapy. Therefore, HUMIRA is recommended for use in combination with MTX, and for use as monotherapy only in patients for whom MTX use is not appropriate.

Pediatric Crohn’s Disease

Study Demographics and Trial Design

The safety and efficacy of HUMIRA were assessed in a multicenter, randomized, double-blind clinical study (M06-806) in 192 pediatric patients, 6 to 17 years of age (mean age 13.6 years), with moderately to severely active Crohn’s disease defined as Pediatric Crohn’s Disease Activity Index (PCDAI) score > 30 who have had an inadequate response to conventional therapy or had lost response to infliximab (approximately 44%). Of the 192 pediatric patients, 188 were randomized during the double-blind period (median baseline PCDAI value of 40, range 25.0 to 62.5).

Patients received open-label induction therapy at a dose based on their Baseline body weight. At Week 4, 188 patients were randomized 1:1 based on their body weight to the DB Maintenance period. The majority of patients were male (55.9%), Caucasian (88.3%), ≥ 13 years of age (64.9%) and weighed ≥ 40 kg (64.4%). The greatest proportion of patients had Crohn’s disease of the colon (81.9%) and or ileum (77.1%). There were no statistically significant differences observed between the dose regimen groups in Baseline characteristics. 102 patients were 13 to 17 years of age weighing ≥ 40 kg (median PCDAI value of 40.0, range 25.0 to 62.5).

Study Results

Study M06-806
Clinical Response

Clinical remission (defined as PCDAI score ≤ 10) and clinical response (defined as reduction in PCDAI score of at least 15 points from Baseline) rates for the indicated pediatric patient population with Crohn’s disease are presented in Table 34.

Table 34. Rates of Clinical Remission and Response During the Double-Blind Maintenance Phase
Response High-Dose
40 mg eow
N = 52
Low-Dose
20 mg eow
N = 50
Week 26

Clinical remission
Clinical response

40.4%
63.5%
36.0%
54.0%

Of the 52 patients who received High-Dose, the rates of clinical remission and clinical response at Week 52 were 32.7 and 42.3%, respectively. Of the 50 patients who received Low-Dose, the rates of clinical remission and clinical response at Week 52 were 30.0 and 32.0%, respectively.

The rate of clinical remission was higher among all HUMIRA patients who had no prior exposure to infliximab compared to those with prior exposure to infliximab (53.8% versus 22.0% and 38.5% versus 24.0% at Weeks 26 and 52, respectively).

At Week 26, a higher proportion of patients achieved PCDAI clinical remission if they were naïve to infliximab therapy [High-Dose 63.0% (17/27) and Low-Dose 44.0% (11/25)], compared to patients who had previously failed infliximab therapy [High-Dose 16.0% (4/25) and Low- Dose 28.0% (7/25)]. At Week 52, a higher proportion of patients achieved PCDAI clinical remission if they were naïve to infliximab therapy [High-Dose 44.4% (12/27) and Low-Dose 32.0% (8/25)], compared to patients who had previously failed infliximab therapy [High-Dose 20.0% (5/25) and Low-Dose 28.0% (7/25)].

The median baseline PCDAI value for patients naïve to infliximab was 37.5 (range 25.0 to 50.0) and 37.5 (range 30.0 to 55.0) for High-Dose and Low-Dose, respectively. The median baseline PCDAI value for patients who had previously failed infliximab therapy was 40.0 (range 32.5 to 62.5) and 40.0 (range 32.5 to 60.0) for High-Dose and Low-Dose, respectively.

Of the patients who had fistulas at Baseline, 55.6% (5/9) and 53.8% (7/13) in the High-Dose and Low-Dose groups, respectively, achieved fistula healing (defined as closure of all fistulas that were draining at Baseline for at least 2 consecutive post Baseline visits) at Week 26, and 55.6% (5/9) and 23.1% (3/13), respectively, achieved fistula healing at Week 52.

The rates of early discontinuation during the double-blind period were 17.3% (9/52) in the High-Dose group and 22.0% (11/50) in the Low-Dose group.

Comparative Bioavailability Studies

A Phase 1, single-dose, open-label, randomized study conducted to evaluate the bioavailability, safety and tolerability of a single-dose subcutaneous administration of HUMIRA in the abdomen and thigh via an autoinjector compared to that of administration from a prefilled syringe, demonstrated comparable bioavailability of the autoinjector and the prefilled syringe (Table 35).

Table 35. Comparative Bioavailability of HUMIRA After a Single Subcutaneous Dose Administered via an Autoinjector Versus Administration via a Prefilled Syringe
From Measured Data Uncorrected for Potency
Geometric Mean&
Arithmetic Mean (CV %)
Parameter Test*
(Regimen A)
Reference
(Regimen B)
Point Estimate 90% Confidence
Interval
AUC0-360
(mcg•h/mL)
1186
1260 (28)
1225
1276 (29)
0.968 0.904 – 1.036
AUC0-1344
(mcg•h/mL)
2249
2454 (33)
2390
2544 (37)
0.941 0.865 – 1.025
Cmax
(mcg/mL)
4.52
4.815 (32)
4.63
4.815 (30)
0.978 0.915 – 1.044
Tmax§
(h)
--
142.3 (54)
--
151.4 (58)
* Regimen A: HUMIRA 40 mg administered subcutaeously via an auotinjector
Regimen B: HUMIRA 40 mg administered subcutaeously via a prefilled syringe
§ Expressed as the arithmetic mean (CV%) only
& Antilogarithm of the least squares means for logarithm from analysis of covariance

Detailed pharmacology

General

HUMIRA (adalimumab) was evaluated in a series of safety pharmacology studies conducted in standard animal models. Adalimumab was shown to have no biologically relevant activity on behavioral / central nervous system, cardiovascular / respiratory, gastrointestinal, genitourinary, hemolytic / coagulation or local anesthetic parameters. A slight prolongation of hexobarbital- induced sleep time noted at high doses in male mice is thought to be of no toxicological relevance.

Pharmacodynamics

By use of multiple in vivo and in vitro preclinical systems, the preclinical pharmacology program demonstrated that adalimumab has a high and specific affinity to human TNF, demonstrates potency for TNF neutralization, and is highly effective in preventing polyarthritis in a transgenic human-TNF mouse model.

In a series of in vitro studies employing sensitive BIAcore technology and competitive receptor binding experiments, the affinity of adalimumab for human TNF was demonstrated to be high. Adalimumab was also shown to bind to pro-TNF. Further, adalimumab neutralized the biological effects of TNF in cell cytotoxicity and cell activation assays. Adalimumab has specific affinity to human TNF, but does not bind to other tested TNF family members or cytokines.

Adalimumab drug substance batch AFP810 is a typical batch produced by an extended-batch cell culture process (C2-extended, also referred to as CHO-2b in some reports). Previous adalimumab was derived from an early D8E clone and was produced by a repeated-batch fermentation process (C1-repeated, also referred to as CHO-1 in some reports). AFP704 is a typical batch from this earlier manufacturing process. A study was conducted to compare drug substance batch AFP704 and drug substance batch AFP810 in in vitro and in vivo assays. The sensorgrams for the two batches of adalimumab are presented in Figure 5.


Figure 5. Binding Sensorgrams of Adalimumab Batches AFP704 and AFP810

Parameters of apparent kinetic rate constants of binding between adalimumab and TNF are listed in Table 36.

Table 36. Apparent Kinetic Rate Constants for Binding of TNF to Adalimumab Batches
AFP704
(C1-repeated)
AFP810
(C2-extended)
Average*
kd, off-rate 3.31 x 10-5s-1 4.58 x 10-5s-1 3.95 x 10-5s-1
ka, on-rate 5.82 x 105M-1s-1 5.37 x 105M-1s-1 5.60 x 105M-1s-1
Kd -- -- 7.05 x 10-11M
* Kd was determined based on the average off and on-rate constant values

Both the apparent kinetic rate constants and the derived dissociation constants (Kd) of the two batches of adalimumab were very similar. An average dissociation constant of 7.05 x 10-11M indicates that adalimumab has a high affinity for TNF. Furthermore, the average dissociation rate constant (Kd) of 3.95 x 10-5s-1 corresponds to approximately five hours of adalimumab:TNF complex half-life, which may be beneficial for safe removal of the TNF:adalimumab complex from circulation.

The specificity of adalimumab for TNF from different species was investigated in an L929 bioassay. The order of magnitude of adalimumab neutralization potency for human, chimpanzee, rhesus, cynomolgus, marmoset, baboon, and canine TNF was similar (see Table 37).

Table 37. TNF Species Specificity of Adalimumab
TNF Source Adalimumab IC50
M
Murine Recombinant > 2.0 x 10-7
Rat Recombinant >> 1.0 x 10-6
Rabbit LPS-stimulated PBMC 1.5 x 10-6
Porcine Recombinant 1.0 x 10-7
Canine LPS-stimulated WB 2.2 x 10-10
Marmoset LPS-stimulated PBMC 4.0 x 10-10
Baboon Recombinant 6.0 x 10-11
Chimpanzee LPS-stimulated PBMC 5.5 x 10-11
Cynomolgus LPS-stimulated PBMC 8.0 x 10-11
Rhesus LPS-stimulated PBMC 4.0 x 10-11
Human Recombinant 1.3 x 10-10

Neutralization potency for porcine and rabbit TNF was weaker than in human TNF. Adalimumab neutralized murine TNF very weakly, and did not neutralize rat TNF at all. The results demonstrate that monkeys are the most relevant species to human while rodents are not relevant species for assessing the mechanism-based toxicity of adalimumab.

Adalimumab as a human IgG1 antibody exhibits the expected effector functions including Fc receptor binding and complement activation; however, this was found to be of no toxicological relevance.

In contrast to certain murine monoclonal antibodies, adalimumab does not cause the release of cytokines or shedding of cell surface molecules from human peripheral blood cells ex vivo.

In vivo testing was limited to human TNF-induced pathologies in animals. Treatment with adalimumab protected mice against TNF lethality in a dose dependent manner. The neutralization potency of adalimumab in vivo was further demonstrated by the prevention of TNF-induced pyrexia in rabbits. Adalimumab inhibited the TNF-induced rise in body temperature in a dose dependent manner. Further, adalimumab administered either alone or in preformed immune complexes with TNF is not pyrogenic in rabbits (Figure 6).


Figure 6. Inhibition of TNF-Induced Pyrexia with Adalimumab in Rabbits
Time 0 refers to the initiation of temperature recordings after the rabbits had settled down in the holding stalls

The prevention of polyarthritis in Tg197 mice carrying the human TNF transgene is an accepted model of rheumatoid arthritis in humans. Joint distortion, swelling, joint deformation, ankylosis and impaired movement were present in untreated, PBS-treated and human IgG1-treated control mice, but were completely absent in mice treated with adalimumab. Similarly, microscopic examinations of mice treated with adalimumab showed no evidence of the synovial thickening, cartilage destruction or bone erosion present in control mice. At lower doses a dose-response relationship of adalimumab to arthritis scores and histology scores was evident. These findings strongly suggest that adalimumab may be an effective therapy for the treatment of rheumatoid arthritis in humans (Figure 7).


Figure 7. Mean Arthritic Scores of Study Groups During the Study Period
For each group, average ± standard error of arthritic score is indicated. Arthritic scores were recorded as follows; 0 = no arthritis, (normal appearance and flexion); 1 = mild arthritis (joint distortion); 2 = moderate arthritis (swelling, joint deformation) and 3 = severe arthritis (ankylosis detected on flexion and severely impaired movement)

In vivo Use of Methotrexate

Methotrexate is widely used in the treatment of patients with rheumatoid arthritis. Adalimumab, either alone or in combination with methotrexate, was effective in preventing the progression of polyarthritis in human TNF transgenic Tg197 mice. In contrast to clinical results, methotrexate was not effective in this model alone and appeared to offer no additional benefit to the adalimumab treatment regimen (Figure 8).


Figure 8. Mean Arthritic Scores of Study Groups During the Study Period
For each group, average ± standard error of arthritic score is indicated

Pharmacokinetics

All pharmacokinetic evaluations relied on bioanalytical data obtained from two enzyme-linked immunosorbent assay (ELISA) methods that detected only free drug. The fact that both assays required binding to immobilized TNF ensured that only active drug was detected and the requirement to displace the detector-adalimumab or bind a second TNF molecule excluded interference from non-binding antibody fragments. On the other hand, interference from adalimumab:anti-adalimumab antibody complexes was expected, especially when these anti- antibodies are against the idiotype and presumed to be neutralizing.

Free anti-adalimumab antibodies could be directly detected by a sensitive double-antigen ELISA, where these antibodies bridge immobilized capture- and labeled detector-adalimumab. As in the adalimumab ELISA, this assay cannot detect adalimumab:anti-adalimumab antibody complexes either. For the analysis of murine anti-human antibodies (MAHAs) this limitation was overcome by using a sandwich assay, which employed anti-mouse antibodies and detected both free and partly complexed MAHAs. This assay format could not be used for primate anti-human antibody (PAHA) analyses because the anti-monkey IgG detection antibody would have cross-reacted with adalimumab.

The pharmacokinetics of adalimumab were investigated after intravenous and subcutaneous administration, because the pivotal toxicity studies used intravenous administration whereas subcutaneous administration is the intended route in patients. In monkeys, adalimumab was almost completely absorbed after subcutaneous injection. The high bioavailability proved the drug to be suitable for subcutaneous administration (Figure 9).

Figure 9. Profiles of Serum Levels After Subcutaneous Administration (mean + SD) of 1, 3 and 10 mg/kg and Intravenous Administration (mean - SD) of 3 mg/kg Body Weight to Male Monkeys

After injection/absorption of adalimumab, serum level-time curves declined in at least two distinct phases. The rather low peripheral apparent volume of distribution suggests that adalimumab may remain in extracellular space.

In both animal species (mice and monkeys), the pharmacokinetics of adalimumab were linear as long as anti-adalimumab antibodies were absent. Area under the curve (AUC) values and maximum serum concentrations increased with dose. Clearance values were dose-independent and pharmacokinetic parameters showed no gender dependency in the relevant monkey test species. Exposure of the animals to adalimumab during the toxicity studies could be demonstrated.

Elimination of adalimumab was slow. Terminal half-lives were 4 to 11 days in mice and 13.5 ± 4.6 days in monkeys in repeat dose studies. The terminal half-life observed in monkeys is similar to the half-life of endogenous IgG in humans.

Administration of adalimumab from several production drug substance batches, produced in different cell lines and with different manufacturing processes had no significant influence on the pharmacokinetic parameters in monkeys. Also, administration of adalimumab in formulations that differed both in concentration of adalimumab and the presence or absence of 0.1% polysorbate 80 had no significant influence on the pharmacokinetic parameters in monkeys.

Toxicology

Acute Toxicity – Single-Dose Studies

Three single-dose toxicity studies (two in mouse and one in rat) were conducted to obtain the qualitative and quantitative information about the acute toxicity profile of adalimumab after single intravenous administration.

In a mouse study, a single dosage of adalimumab (898 mg/kg) or vehicle control (phosphate buffered saline, PBS) was administered via a tail vein (5/sex/group). The animals were examined for clinical signs for 14 days after treatment. Necropsy was performed 14 days after treatment.

At the highest technically feasible dosage of 898 mg/kg adalimumab based on a 10 mL/kg injection volume and the highest available drug concentration, no deaths occurred. No clinical sign was observed that could be attributed to adalimumab. Body weight gains of the drug-treated mice were comparable to those of the control mice. Pathomorphology did not reveal any toxicologically relevant change. The minimal lethal dosage of adalimumab in mice is greater than 898 mg/kg.

A second single-dose study was done in mice and included an investigation of the formation of MAHAs. Four groups of mice (5/sex/group) were included in this study. The animals were treated intravenously with either a single dosage of vehicle (PBS), or 1.6 mg/kg, 16 mg/kg, or 786 mg/kg of adalimumab (drug substance batch AFP603). Clinical signs, especially the hair coat, were assessed. Blood samples were collected before treatment and at Weeks 3, 5, 7, 9, 11, and 13 after drug administration to determine the adalimumab concentration in serum with an ELISA and to detect MAHA formation with two different ELISA techniques. All animals were sacrificed and subjected to gross examination upon termination of the study. Spleen and skin were evaluated histopathologically.

The general deportment of the mice and the body weight gains were not affected by treatment with adalimumab. One male at 1.6 mg/kg died on Day 13 during blood sampling under halothane anesthesia. The death of this animal was considered to be associated with the halothane anesthesia and not associated with the adalimumab treatment. Local hair loss in the nasolabial area associated with loss of tactile hairs was observed in all females at 1.6 mg/kg and four out of five females in the control group from Week 5 onwards. The results indicate that the hair loss is not associated with adalimumab treatment since the same effect also was observed in the control mice.

The serum concentration curve of adalimumab was plotted for one mouse from each group. In the control and 1.6 mg/kg groups, the adalimumab serum concentration was always less than 0.6 mcg/mL, whereas at 16 mg/kg group, 70 mcg/mL was found at Week 3. No adalimumab was detected from Week 5 onwards at this dose. At 786 mg/kg group, a concentration as high as 484 mcg/mL was found at Week 3 and a measurable concentration of adalimumab was found up to nine weeks post injection.

The time course of MAHA development also was measured in one mouse from each group. MAHAs were not detected in the control mouse or any pre-treatment sample. Using a double sandwich (double antigen) MAHA assay (called MAHA-1 assay in the report) sensitive to inhibition by adalimumab in the blood, MAHAs were detected as early as Week 5 for the mouse treated at 1.6 mg/kg and not detected until Week 11 for the mouse treated at 16 mg/kg, whereas MAHAs were not detected at any time point for the mouse treated at 786 mg/kg, which was attributed to the assay interference by the high concentrations of circulating adalimumab. Using a direct capture (sandwich) MAHA assay (called MAHA-2 assay in the report) that is less sensitive to adalimumab interference, MAHAs were detected from Week 5 onwards in mice at 1.6 mg/kg and 16 mg/kg and at Weeks 9 and 13 in the 786 mg/kg mouse. Once the kinetics and titers were determined from the sample mouse of each group, MAHAs in all mice treated with adalimumab were analyzed at a dilution of 1:1000 at Week 5 for the 1.6 mg/kg and 16 mg/kg mice, and at Week 13 for the 786 mg/kg mice by the direct capture MAHA assay. MAHAs were detected in all samples, indicating that all the adalimumab-treated mice were MAHA positive after a single intravenous injection.

In the rat single-dose study, a single dosage of adalimumab (898 mg/kg, drug substance batch AF601-Ex pool) or vehicle control (PBS) was administered via a tail vein (5/sex/group). The animals were examined for clinical signs for 14 days after drug administration. Necropsy was performed 14 days after treatment.

At the highest technically feasible dosage of 898 mg/kg adalimumab based on a 10 mL/kg injection volume and the highest available drug concentration, no deaths occurred. Drug-related clinical signs were not observed. Body weight gains of the drug-treated rats were comparable to those of the control rats. Necropsy showed slightly to moderately enlarged spleens in three males at 898 mg/kg, and slightly enlarged spleens in three males in the control group. Histopathology of the enlarged spleens revealed moderate to marked extramedullary hematopoiesis. These changes were not attributed to the drug treatment because they were observed in the control group as well as in the treatment group.

In summary, adalimumab is well tolerated at the highest technically feasible dose and the minimal lethal dose after a single intravenous injection is greater than 898 mg/kg in mice and rats. Adalimumab is immunogenic in mice after a single intravenous dose.

Long-Term Toxicity – Multiple-Dose Studies

Mouse (Four-Week Study)

In a four-week mouse study, the mice were randomly distributed into three study groups. The highest dose in this study provided 16 times the maximum dosage of 10 mg/kg used in early clinical studies.

The mice were intravenously administered either vehicle control (PBS) or adalimumab (drug substance batch AFP603) once per week on days 1, 8, 15, 22, and 29. The main study group was terminated on Day 30 and the recovery study group was allowed to recover for four weeks without further treatment after the last dose. The mice were observed for drug-related clinical signs at least once daily. Body weight and food consumption was recorded once weekly. Blood samples (0.3 mL) in the main and recovery study groups were collected from the retro-orbital venous plexus under light ether anesthesia on Days 30 and 57 (recovery group only) from mice chosen for hematology, clinical biochemistry and immunogenicity analyses.

There was no clinical sign of toxicity or behavioral changes related to drug treatment. Body weight and body weight gain of drug-treated animals remained in the same range as controls over the treatment and recovery periods.

The results of the toxicokinetic evaluation, using adalimumab level values from pooled serum, revealed that weekly iv administrations of 32, 70.9 and 157.2 mg/kg of adalimumab to mice for four weeks resulted in an increase of serum Cmax and AUC values (Cmax: 1193, 1528,4231 mcg/mL in males, 794, 2069, 5028 mcg/mL in females; AUC: 66782, 104612, 190342 mcg•h/mL in males, 81598, 120693, 240366 mcg•h/mL in females). A slightly lower terminal half-life was observed for male mice than for female mice (97 to 112 hours versus 134 to 259 hours). The AUC values increased in a slightly less than proportional manner and were somewhat higher in female mice. There was, however a high degree of variability in the data.

Significant formation of MAHAs was detected in male and female mice in all drug-treated groups starting on the 8th day after the first administration. The level of MAHAs increased with subsequent doses. Significant differences were observed between 32.0 mg/kg and 70.9 mg/kg dosages (p < 0.01) and the 32.0 mg/kg and 157.2 mg/kg dosages (p < 0.01), but not between the 70.9 mg/kg and 157.2 mg/kg dosages (p > 0.05). This indicates that the MAHAs are detected at all dose levels. Whether the differences between dose levels are due to assay interference or true differences in immunogenicity can not be determined.

Monkey (Four-Week Study)

A four-week study was performed to investigate the potential toxicity of adalimumab in cynomolgus monkeys. A total of 32 monkeys (16 males and 16 females) were distributed randomly into four dosage groups, and were administered either the vehicle control (PBS), or adalimumab at 32, 70.9, or 157.2 mg/kg (drug substance batch AFP603) via intravenous injection (vena saphena magna of the right or left hind leg). The injections were given once per week on days 1, 8, 15, 22, and 29 for a total of five doses.

The toxicokinetic results showed a dose-proportional increase of serum maximum concentration (Cmax) of adalimumab and serum AUC. The central volume of distribution (Vc = dose / C(0)) was 39.7 ± 7.9 mL/kg (mean ± standard deviation). The AUCs corresponding to single-dose amounts of 32, 70.9, and 157.2 mg/kg, were 201317 ± 88835, 359667 ± 127283 and 808900 ± 200581 mcg•h/mL, respectively. The terminal half-life was 13.5 ± 4.6 days and the clearance was 0.20 ± 0.07 mL/h/kg. No sex dependency of pharmacokinetic parameters and no influence of dose on total clearance were noted.

Immunohistochemistry data showed a minimal decrease of CD21+ B-cells in the spleen follicles of the male monkeys treated with 70.9 and 157.2 mg/kg.) A reduced cytoplasmic immunostaining of IgG and IgM was also observed in the germinal centers of the follicles in most treated monkeys at all doses. No such change was observed in the follicles in the lymph nodes. All these changes were very subtle and generally reversible. Therefore, these changes were considered to be the result of pharmacologically functional effects of adalimumab rather than toxicological effects. No deposits of immune-complexes were found in kidney, lung, liver, skin, spleen, thymus, lymph nodes, skeletal muscle, and heart.

Monkey (39-Week Study)

A 39-week study in cynomolgus monkeys was done to evaluate the potential toxicity and reversibility of any toxic effect of adalimumab. A total of 32 animals (16 males and 16 females) were randomly distributed into four groups, and were administered either vehicle control (PBS buffer) or adalimumab at 32, 82.9, or 214.8 mg/kg. The test article or control agent was administered by intravenous injection into a vena saphena magna, once per week for 39 weeks (total of 40 injections).

There were no significant differences in clinical signs of toxicity or behavior and food consumption over the treatment and recovery periods in the drug-treated groups as compared to the control animals. Body weights of the animals treated with 32 and 82.9 mg/kg were not affected as compared with the control animals. In the 214.8 mg/kg group, a slight, transient decrease in the body weight was observed in test Week 4, and completely recovered from test Week 6 onwards. The body weights of the female animals in this group were decreased slightly from test Week 2 onwards. The decreases were not statistically significant at p ≤ 0.01 as compared with the control animals and were within the normal fluctuation of body weight.

The examination of immune complexes showed a reduced antigen expression of IgG and IgM in the follicular dendritic cells of the spleen in all drug-treated monkeys. Concomitantly, the follicular dendritic cells were reduced in number and the normally dense network was altered. In parallel, the IgG or IgM positive plasma cell count increased slightly in the spleen independently of the different compartments. These changes were considered to be the pharmacologically functional effects of adalimumab rather than toxicological effects.

Toxicokinetic results reported in Report No. MPF/EBB 9741 showed an increase of steady-state serum concentrations and AUC values. At dosages of 32, 82.9, and 214.8 mg/kg of adalimumab, the corresponding Cmax (mean ± standard deviation) at five minutes after the last administration were 2731 ± 467, 6527 ± 2450, 13563 ± 1740 mcg/mL and the corresponding serum AUCs were 304774 ± 74634, 617368 ± 233959, and 1299965 ± 228114 mcg•h/mL, respectively. The corresponding clearances were 0.11 ± 0.04, 0.16 ± 0.07, and 0.17 ± 0.03 mL/h/kg, respectively. The terminal half-life, evaluated from data obtained during the recovery phase of two male and two female monkeys, was 16.2 ± 3.4 days. No sex dependency of pharmacokinetic parameters and no influence of dose on the clearance were noted.

The distribution of adalimumab in the vascular compartment was broad in the lungs, liver, and skin at 214.8 mg/kg. Cartilage staining in the bronchi with anti-adalimumab antibodies was observed in several treated monkeys at 32 mg/kg onwards. In the synovial membrane, adalimumab was detected in the vascular compartment mainly at 214.8 mg/kg, and additionally in one male monkey at 82.9 mg/kg.

Most of the immunohistochemical changes observed in kidneys, spleen, and lungs were found to be reversible. However, the cellular diminution in the thymus in males was partially reversed, and did not reach the cellularity of the control animals after a 20-week recovery period. No adalimumab could be detected after the 20-week recovery period in the vessels of the organs and tissues examined.

Mutagenicity and Carcinogenicity

No carcinogenicity study was performed for adalimumab.

In vitro Genotoxicity

The mutagenic potential of adalimumab was tested in the Ames test and in the Escherichia coli reverse mutation assay. These tests are based on the ability of the test article to induce reverse mutations in selected loci of bacteria. Salmonella typhimurium strains TA 98, TA 100, TA 1535, and TA 1537, as well as Escherichia coli strain WP2 uvrA were used. Adalimumab (drug substance batch AF601-Ex pool) was tested at concentrations of 0, 20, 100, 500, 2500 and 5000 mcg/plate. Three plates were used per dose. Positive controls and a vehicle control (PBS buffer) were included in each experiment. Both the standard plate test (Ames test) and preincubation test with and without the addition of an exogenous metabolic activation system (S-9 fraction prepared from the livers of Aroclor 1254 treated rats) were performed. The results were considered positive if the revertant rate of a treatment group was at least twice that of the spontaneous revertant rate (vehicle control), a dose-response relationship occurred, and the experiments were reproducible.

No bacteriotoxic effect, such as reduced His- or Trp- background growth and decreased number of His+ or Trp+ revertants, were observed in adalimumab-treated plates when compared to the vehicle control. There was no increase in the number of mutant colonies under any experimental conditions in any strain of bacteria for the test article, whereas the positive controls showed the expected response when compared to the vehicle control. Therefore, the test substance is not mutagenic either in the Ames test or in the E. coli reverse mutation assays.

In vivo Genotoxicity

The potential clastogenic and spindle poison effects of adalimumab were tested in an in vivo micronucleus assay in NMRI mice after a single intravenous dose. The mice were randomly allocated into eight groups: two vehicle control groups (five mice/sex/group), four treatment groups (five mice/sex/group), and two positive control groups (five mice/group). The mice were intravenously treated once either with the vehicle control (PBS buffer); 224.5, 449.0, or 898 mg/kg (two groups) of adalimumab (drug substance batch AF601-Ex pool); or positive controls of 20 mg cyclophosphamide (two male and three female) or 0.15 mg/kg vincristine (three male and two female). All animals were sacrificed 24 hours after treatment except for one vehicle control group and one 898 mg/kg group, which were sacrificed 48 hours after dosing.

Bone marrow slides were prepared and stained with eosin and methylene solution, followed by Giemsa stain. The slides were examined microscopically for the following parameters: number of polychromatic erythrocytes (PCE), number of PCE containing micronuclei (MN), number of normochromatic erythrocytes (NCE), number of NCE containing MN, number of small micronuclei, and number of large micronuclei. The ratio of PCE to NCE was calculated. The results were considered positive if the following criteria were met: a dose-related and significant increase in the number of micronucleated PCE at the 24-hour and/or 48-hour intervals, and the proportion of cells containing micronuclei exceeded both the values of the concurrent negative control range and the negative historical control range.

The number of PCE and NCE containing MN in the adalimumab-treated groups was not significantly different from the concurrent, negative controls at any of the sacrificed intervals. However, the percentage of small MN in PCE in the cyclophosphamide-treated group and the percentage of large MN in PCE in the vincristine-treated group increased significantly as compared with the vehicle control. The ratio of PCE to NCE in all dose groups was always in the same range as that of the control values, suggesting normal erythropoiesis.

The results indicate that adalimumab does not have clastogenic activity or spindle poison effects. Also, no inhibition of erythropoiesis induced by the treatment with adalimumab was observed in NMRI mice.

Reproduction and Teratology

In pregnant monkeys adalimumab was distributed into the serum of the fetus and into the amnion fluid showing a distribution pattern that would be expected of a human IgG in a pregnant woman. No drug-related toxicity was observed. Distribution of adalimumab into the milk was not determined.