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Mechanism Of Action
Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In Ps, treatment with HUMIRA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which HUMIRA exerts its clinical effects is unknown.
Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M).
After treatment with HUMIRA, a decrease in levels of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP levels was also observed in patients with Crohn's disease, ulcerative colitis and hidradenitis suppurativa. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after HUMIRA administration.
The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of HUMIRA to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.
The single dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/hr. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.
In RA patients receiving 40 mg HUMIRA every other week, adalimumab mean steady-state trough concentrations of approximately 5 μg/mL and 8 to 9 μg/mL, were observed without and with methotrexate (MTX), respectively. MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA. Mean serum adalimumab trough levels at steady state increased approximately proportionally with dose following 20, 40, and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.
Adalimumab mean steady-state trough concentrations were slightly higher in psoriatic arthritis patients treated with 40 mg HUMIRA every other week (6 to 10 μg/mL and 8.5 to 12 μg/mL, without and with MTX, respectively) compared to the concentrations in RA patients treated with the same dose.
The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
In patients with CD, the loading dose of 160 mg HUMIRA on Week 0 followed by 80 mg HUMIRA on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 μg/mL were observed at Week 24 and Week 56 in CD patients after receiving a maintenance dose of 40 mg HUMIRA every other week.
In patients with UC, the loading dose of 160 mg HUMIRA on Week 0 followed by 80 mg HUMIRA on Week 2 achieves mean serum adalimumab trough levels of approximately 12 μg/mL at Week 2 and Week 4. Mean steady-state trough level of approximately 8 μg/mL was observed at Week 52 in UC patients after receiving a dose of 40 mg HUMIRA every other week, and approximately 15 μg/mL at Week 52 in UC patients who increased to a dose of 40 mg HUMIRA every week.
In patients with Ps, the mean steady-state trough concentration was approximately 5 to 6 μg/mL during HUMIRA 40 mg every other week monotherapy treatment.
In subjects with HS, a dose of 160 mg HUMIRA on Week 0 followed by 80 mg on Week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/mL at Week 2 and Week 4. The mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 μg/mL during HUMIRA 40 mg every week treatment.
Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies, and lower clearance with increasing age in patients aged 40 to > 75 years.
Minor increases in apparent clearance were also predicted in RA patients receiving doses lower than the recommended dose and in RA patients with high rheumatoid factor or CRP concentrations. These increases are not likely to be clinically important.
No gender-related pharmacokinetic differences were observed after correction for a patient's body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
No pharmacokinetic data are available in patients with hepatic or renal impairment.
In Study JIA-I for patients with polyarticular JIA who were 4 to 17 years of age, the mean steady-state trough serum adalimumab concentrations for patients weighing < 30 kg receiving 20 mg HUMIRA subcutaneously every other week as monotherapy or with concomitant MTX were 6.8 μg/mL and 10.9 μg/mL, respectively. The mean steady-state trough serum adalimumab concentrations for patients weighing ≥ 30 kg receiving 40 mg HUMIRA subcutaneously every other week as monotherapy or with concomitant MTX were 6.6 μg/mL and 8.1 μg/mL, respectively. In Study JIA-II for patients with polyarticular JIA who were 2 to < 4 years of age or 4 years of age and older weighing < 15 kg, the mean steady-state trough serum adalimumab concentrations for patients receiving HUMIRA subcutaneously every other week as monotherapy or with concomitant MTX were 6.0 μg/mL and 7.9 μg/mL, respectively.
In pediatric subjects with CD weighing ≥ 40 kg, the mean ±SD serum adalimumab concentrations were 15.7±6.5 mcg/mL at Week 4 following subcutaneous doses of 160 mg at Week 0 and 80 mg at Week 2 and the mean ±SD steady-state trough serum adalimumab concentrations were 10.5±6.0 mcg/mL at Week 52 following subcutaneous doses of 40 mg every other week. In pediatric subjects with CD weighing < 40 kg, the mean ±SD serum adalimumab concentrations were 10.6±6.1 mcg/mL at Week 4 following subcutaneous doses of 80 mg at Week 0 and 40 mg at Week 2 and the mean ±SD steady-state trough serum adalimumab concentrations were 6.9±3.6 mcg/mL at Week 52 following subcutaneous doses of 20 mg every other week.
The efficacy and safety of HUMIRA were assessed in five randomized, double-blind studies in patients ≥ 18 years of age with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 6 swollen and 9 tender joints. HUMIRA was administered subcutaneously in combination with methotrexate (MTX) (12.5 to 25 mg, Studies RA-I, RA-III and RA-V) or as monotherapy (Studies RA-II and RA-V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study RA-IV).
Study RA-I evaluated 271 patients who had failed therapy with at least one but no more than four DMARDs and had inadequate response to MTX. Doses of 20, 40 or 80 mg of HUMIRA or placebo were given every other week for 24 weeks.
Study RA-II evaluated 544 patients who had failed therapy with at least one DMARD. Doses of placebo, 20 or 40 mg of HUMIRA were given as monotherapy every other week or weekly for 26 weeks.
Study RA-III evaluated 619 patients who had an inadequate response to MTX. 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 52 weeks. Study RA-III had an additional primary endpoint at 52 weeks 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 5 years.
Study RA-IV assessed safety in 636 patients who were either DMARD-naive 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 RA-V evaluated 799 patients with moderately to severely active RA of less than 3 years duration who were ≥ 18 years old and MTX na´ve. Patients were randomized to receive either MTX (optimized to 20 mg/week by week 8), HUMIRA 40 mg every other week or HUMIRA/MTX combination therapy for 104 weeks. Patients were evaluated for signs and symptoms, and for radiographic progression of joint damage. The median disease duration among patients enrolled in the study was 5 months. The median MTX dose achieved was 20 mg.
The percent of HUMIRA treated patients achieving ACR 20, 50 and 70 responses in Studies RA-II and III are shown in Table 2.
Table 2: ACR Responses in Studies RA-II and RA-III
(Percent of Patients)
|Response||Study RA-II Monotherapy (26 weeks)||Study RA-III Methotrexate Combination (24 and 52 weeks)|
|HUMIRA 40 mg every other week
|HUMIRA 40 mg weekly
|HUMIRA/MTX 40 mg every other week
|* p < 0.01, HUMIRA vs. placebo|
The results of Study RA-I were similar to Study RA-III; patients receiving HUMIRA 40 mg every other week in Study RA-I also achieved ACR 20, 50 and 70 response rates of 65%, 52% and 24%, respectively, compared to placebo responses of 13%, 7% and 3% respectively, at 6 months (p < 0.01).
The results of the components of the ACR response criteria for Studies RA-II and RA-III are shown in Table 3. ACR response rates and improvement in all components of ACR response were maintained to week 104. Over the 2 years in Study RA-III, 20% of HUMIRA patients receiving 40 mg every other week (EOW) 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 5 years with continuous HUMIRA treatment in the open-label portion of Study RA-III.
Table 3: Components of ACR Response in Studies RA-II
|Parameter (median)||Study RA-II||Study RA-III|
|Baseline||Wk 26||Baseline||Wk 26||Baseline||Wk 24||Baseline||Wk 24|
|Number of tender joints (0-68)||35||26||31||16*||26||15||24||8*|
|Number of swollen joints (0-66)||19||16||18||10*||17||11||18||5*|
|Physician global assessmentb||7.0||6.1||6.6||3.7*||6.3||3.5||6.5||2.0*|
|Patient global assessmentb||7.5||6.3||7.5||4.5*||5.4||3.9||5.2||2.0*|
|Disability index (HAQ)c||2.0||1.9||1.9||1.5*||1.5||1.3||1.5||0.8*|
|a 40 mg HUMIRA administered every other week
b Visual analogue scale; 0 = best, 10 = worst
c Disability Index of the Health Assessment Questionnaire; 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, HUMIRA vs. placebo, based on mean change from baseline
The time course of ACR 20 response for Study RA-III is shown in Figure 1.
In Study RA-III, 85% of patients with ACR 20 responses at week 24 maintained the response at 52 weeks. The time course of ACR 20 response for Study RA-I and Study RA-II were similar.
Figure 1: Study RA-III ACR 20 Responses over 52 Weeks
In Study RA-IV, 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 (adalimumab) and other DMARDs were observed.
In Study RA-V with MTX na´ve patients with recent onset RA, the combination treatment with HUMIRA plus MTX led to greater percentages of patients achieving ACR responses than either
MTX monotherapy or HUMIRA monotherapy at Week 52 and responses were sustained at Week 104 (see Table 4).
Table 4: ACR Response in Study RA-V (Percent of
|Major Clinical Response a||28%||25%||49%|
|a Major clinical response is defined as
achieving an ACR70 response for a continuous six month period
b p < 0.05, HUMIRA/MTX vs. MTX for ACR 20 p < 0.001, HUMIRA/MTX vs. MTX for ACR 50 and 70, and Major Clinical Response
c p < 0.001, HUMIRA/MTX vs. HUMIRA
At Week 52, all individual components of the ACR response criteria for Study RA-V improved in the HUMIRA/MTX group and improvements were maintained to Week 104.
In Study RA-III, 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 results are shown in Table 5. HUMIRA/MTX treated patients demonstrated less radiographic progression than patients receiving MTX alone at 52 weeks.
Table 5: Radiographic Mean Changes Over 12 Months in
|Placebo/MTX||HUMIRA/MTX 40 mg every other week||Placebo/MTX-HUMIRA/MTX (95% Confidence Interval*)||P-value**|
|Total Sharp score||2.7||0.1||2.6 (1.4, 3.8)||< 0.001|
|Erosion score||1.6||0.0||1.6 (0.9, 2.2)||< 0.001|
|JSN score||1.0||0.1||0.9 (0.3, 1.4)||0.002|
|*95% confidence intervals for the differences in change
scores between MTX and HUMIRA.
**Based on rank analysis
In the open-label extension of Study RA-III, 77% of the original patients treated with any dose of HUMIRA were evaluated radiographically at 2 years. Patients maintained inhibition of structural damage, as measured by the TSS. Fifty-four percent had no progression of structural damage as defined by a change in the TSS of zero or less. Fifty-five percent (55%) of patients originally treated with 40 mg HUMIRA every other week have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage with 50% showing no progression of structural damage defined by a change in the TSS of zero or less.
In Study RA-V, structural joint damage was assessed as in Study RA-III. Greater inhibition of radiographic progression, as assessed by changes in TSS, erosion score and JSN was observed in the HUMIRA/MTX combination group as compared to either the MTX or HUMIRA monotherapy group at Week 52 as well as at Week 104 (see Table 6).
Table 6: Radiographic Mean Change* in Study RA-V
|52 Weeks||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)|
|104 Weeks||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)|
|* mean (95% confidence interval)
a p < 0.001, HUMIRA/MTX vs. MTX at 52 and 104 weeks and for HUMIRA/MTX vs. HUMIRA at 104 weeks
b p < 0.01, for HUMIRA/MTX vs. HUMIRA at 52 weeks
Physical Function Response
In studies RA-I through IV, HUMIRA showed significantly greater improvement than placebo in the disability index of Health Assessment Questionnaire (HAQ-DI) 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 RA-III, the mean (95% CI) improvement in HAQ-DI from baseline at week 52 was 0.60 (0.55, 0.65) for the HUMIRA patients and 0.25 (0.17, 0.33) for placebo/MTX (p < 0.001) patients. Sixty-three percent of HUMIRA-treated patients achieved a 0.5 or greater improvement in HAQ-DI at week 52 in the double-blind portion of the study. Eighty-two percent of these patients maintained that improvement through week 104 and a similar proportion of patients maintained this response through week 260 (5 years) of open-label treatment. Mean improvement in the SF-36 was maintained through the end of measurement at week 156 (3 years).
In Study RA-V, the HAQ-DI and the physical component of the SF-36 showed greater improvement (p < 0.001) for the HUMIRA/MTX combination therapy group versus either the MTX monotherapy or the HUMIRA monotherapy group at Week 52, which was maintained through Week 104.
Juvenile Idiopathic Arthritis
The safety and efficacy of HUMIRA was assessed in two studies (Studies JIA-I and JIA-II) in patients with active polyarticular juvenile idiopathic arthritis (JIA).
The safety and efficacy of HUMIRA were assessed in a multicenter, randomized, withdrawal, double-blind, parallel-group study in 171 patients who were 4 to 17 years of age with polyarticular JIA. In the study, the patients were stratified into two groups: MTX-treated or non-MTX-treated. All patients had to show signs of active moderate or severe disease despite previous treatment with NSAIDs, analgesics, corticosteroids, or DMARDS. Patients who received prior treatment with any biologic DMARDS were excluded from the study.
The study included four phases: an open-label lead in phase (OL-LI; 16 weeks), a double-blind randomized withdrawal phase (DB; 32 weeks), an open-label extension phase (OLE-BSA; up to 136 weeks), and an open-label fixed dose phase (OLE-FD; 16 weeks). In the first three phases of the study, HUMIRA was administered based on body surface area at a dose of 24 mg/m² up to a maximum total body dose of 40 mg subcutaneously (SC) every other week. In the OLE-FD phase, the patients were treated with 20 mg of HUMIRA SC every other week if their weight was less than 30 kg and with 40 mg of HUMIRA SC every other week if their weight was 30 kg or greater. Patients remained on stable doses of NSAIDs and or prednisone ( ≤ 0.2 mg/kg/day or 10 mg/day maximum).
Patients demonstrating a Pediatric ACR 30 response at the end of OL-LI phase were randomized into the double blind (DB) phase of the study and received either HUMIRA or placebo every other week for 32 weeks or until disease flare. Disease flare was 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 the time of disease flare during the DB phase, patients were treated in the open-label extension phase based on the BSA regimen (OLE-BSA), before converting to a fixed dose regimen based on body weight (OLE-FD phase).
Study JIA-I Clinical Response
At the end of the 16-week OL-LI phase, 94% of the patients in the MTX stratum and 74% of the patients in the non-MTX stratum were Pediatric ACR 30 responders. In the DB phase significantly fewer patients who received HUMIRA experienced disease flare compared to placebo, both without MTX (43% vs. 71%) and with MTX (37% vs. 65%). More patients treated with HUMIRA continued to show pediatric ACR 30/50/70 responses at Week 48 compared to patients treated with placebo. Pediatric ACR responses were maintained for up to two years in the OLE phase in patients who received HUMIRA throughout the study.
HUMIRA was assessed in an open-label, multicenter study in 32 patients who were 2 to < 4 years of age or 4 years of age and older weighing < 15 kg with moderately to severely active polyarticular JIA. Most patients (97%) received at least 24 weeks of HUMIRA treatment dosed 24 mg/m² up to a maximum of 20 mg every other week as a single SC injection up to a maximum of 120 weeks duration. During the study, most patients used concomitant MTX, with fewer reporting use of corticosteroids or NSAIDs. The primary objective of the study was evaluation of safety [see ADVERSE REACTIONS].
The safety and efficacy of HUMIRA was assessed in two randomized, double-blind, placebo controlled studies in 413 patients with psoriatic arthritis (PsA). Upon completion of both studies, 383 patients enrolled in an open-label extension study, in which 40 mg HUMIRA was administered every other week.
Study PsA-I enrolled 313 adult patients with moderately to severely active PsA ( > 3 swollen and > 3 tender joints) who had an inadequate response to NSAID therapy in one of the following forms: (1) distal interphalangeal (DIP) involvement (N=23); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of plaque psoriasis) (N=210); (3) arthritis mutilans (N=1); (4) asymmetric PsA (N=77); or (5) AS-like (N=2). Patients on MTX therapy (158 of 313 patients) at enrollment (stable dose of ≤ 30 mg/week for > 1 month) could continue MTX at the same dose. Doses of HUMIRA 40 mg or placebo every other week were administered during the 24-week double-blind period of the study.
Compared to placebo, treatment with HUMIRA resulted in improvements in the measures of disease activity (see Tables 7 and 8). Among patients with PsA who received HUMIRA, the clinical responses were apparent in some patients at the time of the first visit (two weeks) and were maintained up to 88 weeks in the ongoing open-label study. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses. At 24 weeks, the proportions of patients achieving a 75% or 90% improvement in the PASI were 59% and 42% respectively, in the HUMIRA group (N=69), compared to 1% and 0% respectively, in the placebo group (N=69) (p < 0.001). PASI responses were apparent in some patients at the time of the first visit (two weeks). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline.
Table 7: ACR Response in Study PsA-I (Percent of
|* p < 0.001 for all comparisons between HUMIRA and placebo|
Table 8: Components of Disease Activity in Study PsA-I
|Baseline||24 weeks||Baseline||24 weeks|
|Number of tender jointsa||23.0||17.0||20.0||5.0|
|Number of swollen jointsb||11.0||9.0||11.0||3.0|
|Physician global assessmentc||53.0||49.0||55.0||16.0|
|Patient global assessmentc||49.5||49.0||48.0||20.0|
|Disability index (HAQ) d||1.0||0.9||1.0||0.4|
|* p < 0.001 for HUMIRA vs. placebo comparisons based on
a Scale 0-78
b Scale 0-76
c Visual analog scale; 0=best, 100=worst
d Disability Index of the Health Assessment Questionnaire; 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.
e Normal range: 0-0.287 mg/dL
Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by ≥ 3 tender joints and ≥ 3 swollen joints at enrollment.
Radiographic changes were assessed in the PsA studies. Radiographs of hands, wrists, and feet were obtained at baseline and Week 24 during the double-blind period when patients were on HUMIRA or placebo and at Week 48 when all patients were on open-label HUMIRA. A modified Total Sharp Score (mTSS), which included distal interphalangeal joints (i.e., not identical to the TSS used for rheumatoid arthritis), was used by readers blinded to treatment group to assess the radiographs.
HUMIRA-treated patients demonstrated greater inhibition of radiographic progression compared to placebo-treated patients and this effect was maintained at 48 weeks (see Table 9).
Table 9: Change in Modified Total Sharp Score in
|Week 24||Week 24||Week 48|
|Mean Change ± SD||0.9 ± 3.1||-0.1 ± 1.7||-0.2 ± 4.9*|
|* < 0.001 for the difference between HUMIRA, Week 48 and Placebo, Week 24 (primary analysis)|
Physical Function Response
In Study PsA-I, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 40 mg of HUMIRA every other week showed greater improvement from baseline in the HAQ-DI score (mean decreases of 47% and 49% at Weeks 12 and 24 respectively) in comparison to placebo (mean decreases of 1% and 3% at Weeks 12 and 24 respectively). At Weeks 12 and 24, patients treated with HUMIRA showed greater improvement from baseline in the SF-36 Physical Component Summary score compared to patients treated with placebo, and no worsening in the SF-36 Mental Component Summary score. Improvement in physical function based on the HAQ-DI was maintained for up to 84 weeks through the open-label portion of the study.
The safety and efficacy of HUMIRA 40 mg every other week was assessed in 315 adult patients in a randomized, 24 week double-blind, placebo-controlled study in patients with active ankylosing spondylitis (AS) who had an inadequate response to glucocorticoids, NSAIDs, analgesics, methotrexate or sulfasalazine. Active AS was defined as patients who fulfilled at least two of the following three criteria: (1) a Bath AS disease activity index (BASDAI) score ≥ 4 cm, (2) a visual analog score (VAS) for total back pain ≥ 40 mm, and (3) morning stiffness ≥ 1 hour. The blinded period was followed by an open-label period during which patients received HUMIRA 40 mg every other week subcutaneously for up to an additional 28 weeks.
Improvement in measures of disease activity was first observed at Week 2 and maintained through 24 weeks as shown in Figure 2 and Table 10.
Responses of patients with total spinal ankylosis (n=11) were similar to those without total ankylosis.
Figure 2: ASAS 20 Response By Visit, Study AS-I
At 12 weeks, 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). Similar responses were seen at Week 24 and were sustained in patients receiving open-label HUMIRA for up to 52 weeks.
A greater proportion of patients treated with HUMIRA (22%) achieved a low level of disease activity at 24 weeks (defined as a value < 20 [on a scale of 0 to 100 mm] in each of the four ASAS response parameters) compared to patients treated with placebo (6%).
Table 10: Components of Ankylosing Spondylitis Disease
|Baseline mean||Week 24 mean||Baseline mean||Week 24 mean|
|ASAS 20 Response Criteria*|
|Patient’s Global Assessment of Disease Activitya*||65||60||63||38|
|Total back pain*||67||58||65||37|
|Tragus to wall (cm)||15.9||15.8||15.8||15.4|
|Lumbar flexion (cm)||4.1||4.0||4.2||4.4|
|Cervical rotation (degrees)||42.2||42.1||48.4||51.6|
|Lumbar side flexion (cm)||8.9||9.0||9.7||11.7|
|Intermalleolar distance (cm)||92.9||94.0||93.5||100.8|
|a Percent of subjects with at least a 20% and
10-unit improvement measured on a Visual Analog Scale (VAS) with 0 = “none” and
100 = “severe”
b mean of questions 5 and 6 of BASDAI (defined in 'd')
c Bath Ankylosing Spondylitis Functional Index
d Bath Ankylosing Spondylitis Disease Activity Index
e Bath Ankylosing Spondylitis Metrology Index
f C-Reactive Protein (mg/dL)
* statistically significant for comparisons between HUMIRA and placebo at Week 24
A second randomized, multicenter, double-blind, placebo-controlled study of 82 patients with ankylosing spondylitis showed similar results.
Patients treated with HUMIRA achieved improvement from baseline in the Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) score (-3.6 vs. -1.1) and in the Short Form Health Survey (SF-36) Physical Component Summary (PCS) score (7.4 vs. 1.9) compared to placebo-treated patients at Week 24.
Adult Crohn's Disease
The safety and efficacy of multiple doses of HUMIRA were assessed in adult patients with moderately to severely active Crohn's disease, CD, (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 79% of patients continued to receive at least one of these medications.
Induction of clinical remission (defined as CDAI < 150) was evaluated in two studies. In Study CD-I, 299 TNF-blocker na´ve 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. Clinical results were assessed at Week 4.
In the second induction study, Study CD-II, 325 patients who had lost response to, or were intolerant to, previous infliximab therapy were randomized to receive either 160 mg HUMIRA at Week 0 and 80 mg at Week 2, or placebo at Weeks 0 and 2. Clinical results were assessed at Week 4.
Maintenance of clinical remission was evaluated in Study CD-III. In this study, 854 patients with active disease received open-label HUMIRA, 80 mg at week 0 and 40 mg at Week 2. Patients were then randomized at Week 4 to 40 mg HUMIRA every other week, 40 mg HUMIRA every week, or placebo. The total study duration was 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.
Induction of Clinical Remission
A greater percentage of the patients treated with 160/80 mg HUMIRA achieved induction of clinical remission versus placebo at Week 4 regardless of whether the patients were TNF blocker na´ve (CD-I), or had lost response to or were intolerant to infliximab (CD-II) (see Table 11).
Table 11: Induction of Clinical Remission in Studies
CD-I and CD-II (Percent of Patients)
|HUMIRA 160/80 mg
|HUMIRA 160/80 mg
|Clinical remission is CDAI score < 150; clinical
response is decrease in CDAI of at least 70 points.
* p < 0.001 for HUMIRA vs. placebo pairwise comparison of proportions
** p < 0.01 for HUMIRA vs. placebo pairwise comparison of proportions
Maintenance of Clinical Remission
In Study CD-III at Week 4, 58% (499/854) of patients were in clinical response and were assessed in the primary analysis. At Weeks 26 and 56, greater proportions of patients who were in clinical response at Week 4 achieved clinical remission in the HUMIRA 40 mg every other week maintenance group compared to patients in the placebo maintenance group (see Table 12). The group that received HUMIRA therapy every week did not demonstrate significantly higher remission rates compared to the group that received HUMIRA every other week.
Table 12: Maintenance of Clinical Remission in CD-III
(Percent of Patients)
|40 mg HUMIRA every other week
|Clinical remission is CDAI score < 150; clinical
response is decrease in CDAI of at least 70 points.
*p < 0.001 for HUMIRA vs. placebo pairwise comparisons of proportions
Of those in response at Week 4 who attained remission during the study, patients in the HUMIRA every other week group maintained remission for a longer time than patients in the placebo maintenance group. Among patients who were not in response by Week 12, therapy continued beyond 12 weeks did not result in significantly more responses.
Pediatric Crohn's Disease
A randomized, double-blind, 52-week clinical study of 2 dose levels of HUMIRA (Study PCD-I) was conducted in 192 pediatric patients (6 to 17 years of age) with moderately to severely active Crohn's disease (defined as Pediatric Crohn's Disease Activity Index (PCDAI) score > 30).2 Enrolled patients had over the previous two year period an inadequate response to corticosteroids or an immunomodulator (i.e., azathioprine, 6-mercaptopurine, or methotrexate). Patients who had previously received a TNF blocker were allowed to enroll if they had previously had loss of response or intolerance to that TNF blocker.
Patients received open-label induction therapy at a dose based on their body weight ( ≥ 40 kg and < 40 kg). Patients weighing ≥ 40 kg received 160 mg (at Week 0) and 80 mg (at Week 2). Patients weighing < 40 kg received 80 mg (at Week 0) and 40 mg (at Week 2). At Week 4, patients within each body weight category ( ≥ 40 kg and < 40 kg) were randomized 1:1 to one of two maintenance dose regimens (high dose and low dose). The high dose was 40 mg every other week for patients weighing ≥ 40 kg and 20 mg every other week for patients weighing < 40 kg. The low dose was 20 mg every other week for patients weighing ≥ 40 kg and 10 mg every other week for patients weighing < 40 kg.
Concomitant stable dosages of corticosteroids (prednisone dosage ≤ 40 mg/day or equivalent) and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted throughout the study.
At Week 12, patients who experienced a disease flare (increase in PCDAI of ≥ 15 from Week 4 and absolute PCDAI > 30) or who were non-responders (did not achieve a decrease in the PCDAI of ≥ 15 from baseline for 2 consecutive visits at least 2 weeks apart) were allowed to dose-escalate (i.e., switch from blinded every other week dosing to blinded every week dosing); patients who dose-escalated were considered treatment failures.
At baseline, 38% of patients were receiving corticosteroids, and 62% of patients were receiving an immunomodulator. Forty-four percent (44%) of patients had previously lost response or were intolerant to a TNF blocker. The median baseline PCDAI score was 40.
Of the 192 patients total, 188 patients completed the 4 week induction period, 152 patients completed 26 weeks of treatment, and 124 patients completed 52 weeks of treatment. Fifty-one percent (51%) (48/95) of patients in the low maintenance dose group dose-escalated, and 38% (35/93) of patients in the high maintenance dose group dose-escalated.
At Week 4, 28% (52/188) of patients were in clinical remission (defined as PCDAI ≤ 10).
The proportions of patients in clinical remission (defined as PCDAI ≤ 10) and clinical response (defined as reduction in PCDAI of at least 15 points from baseline) were assessed at Weeks 26 and 52.
At both Weeks 26 and 52, the proportion of patients in clinical remission and clinical response was numerically higher in the high dose group compared to the low dose group (Table 13). The recommended maintenance regimen is 20 mg every other week for patients weighing < 40 kg and 40 mg every other week for patients weighing ≥ 40 kg. Every week dosing is not the recommended maintenance dosing regimen [see DOSAGE AND ADMINISTRATION].
Table 13: Clinical Remission and Clinical Response in
|Low Maintenance Dose†(20 or 10 mg every other week)
N = 95
|High Maintenance Dose# (40 or 20 mg every other week)
N = 93
|†The low maintenance dose was 20 mg every other week for
patients weighing ≥ 40 kg and 10 mg every other week for patients
weighing < 40 kg.
#The high maintenance dose was 40 mg every other week for patients weighing ≥ 40 kg and 20 mg every other week for patients weighing < 40 kg.
‡Clinical remission defined as PCDAI ≤ 10.
§Clinical response defined as reduction in PCDAI of at least 15 points from baseline.
The safety and efficacy of HUMIRA were assessed in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 on a 12 point scale, with an endoscopy subscore of 2 to 3 on a scale of 0 to 3) despite concurrent or prior treatment with immunosuppressants such as corticosteroids, azathioprine, or 6-MP in two randomized, double-blind, placebo-controlled clinical studies (Studies UC-I and UC-II). Both studies enrolled TNF-blocker na´ve patients, but Study UC-II also allowed entry of patients who lost response to or were intolerant to TNF-blockers. Forty percent (40%) of patients enrolled in Study UC-II had previously used another TNF-blocker.
Concomitant stable doses of aminosalicylates and immunosuppressants were permitted. In Studies UC-I and II, patients were receiving aminosalicylates (69%), corticosteroids (59%) and/or azathioprine or 6-MP (37%) at baseline. In both studies, 92% of patients received at least one of these medications.
Induction of clinical remission (defined as Mayo score ≤ 2 with no individual subscores > 1) at Week 8 was evaluated in both studies. Clinical remission at Week 52 and sustained clinical remission (defined as clinical remission at both Weeks 8 and 52) were evaluated in Study UC-II.
In Study UC-I, 390 TNF-blocker na´ve patients were randomized to one of three treatment groups for the primary efficacy analysis. The placebo group received placebo at Weeks 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).
In Study UC-II, 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.
In both Studies UC-I and UC-II, a greater percentage of the patients treated with 160/80 mg of HUMIRA compared to patients treated with placebo achieved induction of clinical remission. In Study UC-II, a greater percentage of the patients treated with 160/80 mg of HUMIRA compared to patients treated with placebo achieved sustained clinical remission (clinical remission at both Weeks 8 and 52) (Table 14).
Table 14: Induction of Clinical Remission in Studies
UC-I and UC-II and Sustained Clinical Remission in Study UC-II (Percent of
|Study UC-I||Study UC-II|
|HUMIRA 160/80 mg
|Treatment Difference (95% CI)||Placebo
|HUMIRA 160/80 mg
|Treatment Difference (95% CI)|
|Induction of Clinical Remission (Clinical Remission at Week 8)||9.2%||18.5%||9.3%*
|Sustained Clinical Remission (Clinical Remission at both Weeks 8 and 52)||N/A||N/A||N/A||4.1%||8.5%||4.4%*
|Clinical remission is defined as Mayo score ≤ 2
with no individual subscores > 1.
* p < 0.05 for HUMIRA vs. placebo pairwise comparison of proportions
In Study UC-I, there was no statistically significant difference in clinical remission observed between the HUMIRA 80/40 mg group and the placebo group at Week 8.
In Study UC-II, 17.3% (43/248) in the HUMIRA group were in clinical remission at Week 52 compared to 8.5% (21/246) in the placebo group (treatment difference: 8.8%; 95% confidence interval (CI): [2.8%, 14.5%]; p < 0.05).
In the subgroup of patients in Study UC-II with prior TNF-blocker use, the treatment difference for induction of clinical remission appeared to be 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. The subgroup of patients with prior TNF-blocker use achieved induction of clinical remission at 9% (9/98) in the HUMIRA group versus 7% (7/101) in the placebo group, and sustained clinical remission at 5% (5/98) in the HUMIRA group versus 1% (1/101) in the placebo group. In the subgroup of patients with prior TNF-blocker use, 10% (10/98) were in clinical remission at Week 52 in the HUMIRA group versus 3% (3/101) in the placebo group.
The safety and efficacy of HUMIRA were assessed in randomized, double-blind, placebo-controlled studies in 1696 adult subjects with moderate to severe chronic plaque psoriasis (Ps) who were candidates for systemic therapy or phototherapy.
Study Ps-I evaluated 1212 subjects with chronic Ps with ≥ 10% body surface area (BSA) involvement, Physician's Global Assessment (PGA) of at least moderate disease severity, and Psoriasis Area and Severity Index (PASI) ≥ 12 within three treatment periods. In period A, subjects received placebo or HUMIRA at an initial dose of 80 mg at Week 0 followed by a dose of 40 mg every other week starting at Week 1. After 16 weeks of therapy, subjects who achieved at least a PASI 75 response at Week 16, defined as a PASI score improvement of at least 75% relative to baseline, entered period B and received open-label 40 mg HUMIRA every other week. After 17 weeks of open label therapy, subjects who maintained at least a PASI 75 response at Week 33 and were originally randomized to active therapy in period A were re-randomized in period C to receive 40 mg HUMIRA every other week or placebo for an additional 19 weeks. Across all treatment groups the mean baseline PASI score was 19 and the baseline Physician's Global Assessment score ranged from “moderate” (53%) to “severe” (41%) to “very severe” (6%).
Study Ps-II evaluated 99 subjects randomized to HUMIRA and 48 subjects randomized to placebo with chronic plaque psoriasis with ≥ 10% BSA involvement and PASI ≥ 12. Subjects received placebo, or an initial dose of 80 mg HUMIRA at Week 0 followed by 40 mg every other week starting at Week 1 for 16 weeks. Across all treatment groups the mean baseline PASI score was 21 and the baseline PGA score ranged from “moderate” (41%) to “severe” (51%) to “very severe” (8%).
Studies Ps-I and II evaluated the proportion of subjects who achieved “clear” or “minimal” disease on the 6-point PGA scale and the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline at Week 16 (see Table 15 and 16).
Additionally, Study Ps-I evaluated the proportion of subjects who maintained a PGA of “clear” or “minimal” disease or a PASI 75 response after Week 33 and on or before Week 52.
Table 15: Efficacy Results at 16 Weeks in Study Ps-I
Number of Subjects (%)
|HUMIRA 40 mg every other week
N = 814
N = 398
|PGA: Clear or minimal*||506 (62%)||17 (4%)|
|PASI 75||578 (71%)||26 (7%)|
|* Clear = no plaque elevation, no scale, plus or minus
hyperpigmentation or diffuse pink or red coloration
Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration
Table 16: Efficacy
Results at 16 Weeks in Study Ps-II Number of Subjects (%)
|HUMIRA 40 mg every other week
N = 99
N = 48
|PGA: Clear or minimal*||70 (71%)||5 (10%)|
|PASI 75||77 (78%)||9 (19%)|
|* Clear = no plaque
elevation, no scale, plus or minus hyperpigmentation or diffuse pink or red coloration
Minimal = possible but difficult to ascertain whether there is slight elevation of plaque above normal skin, plus or minus surface dryness with some white coloration, plus or minus up to red coloration
Additionally, in Study Ps-I, subjects on HUMIRA who maintained a PASI 75 were re-randomized to HUMIRA (N = 250) or placebo (N = 240) at Week 33. After 52 weeks of treatment with HUMIRA, more subjects on HUMIRA maintained efficacy when compared to subjects who were re-randomized to placebo based on maintenance of PGA of “clear” or “minimal” disease (68% vs. 28%) or a PASI 75 (79% vs. 43%).
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. During the withdrawal period, no subject experienced transformation to either pustular or erythrodermic psoriasis. A total of 178 subjects who relapsed re-initiated treatment with 80 mg of HUMIRA, then 40 mg eow beginning at week 1. At week 16, 69% (123/178) of subjects had a response of PGA “clear” or “minimal”.
Two randomized, double-blind, placebo-controlled studies (Studies HS-I and II) evaluated the safety and efficacy of HUMIRA in a total of 633 adult subjects with moderate to severe hidradenitis suppurativa (HS) with Hurley Stage II or III disease and with at least 3 abscesses or inflammatory nodules. In both studies, subjects 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 and continued through Week 11. Subjects used topical antiseptic wash daily. Concomitant oral antibiotic use was allowed in Study HS-II.
Both studies evaluated Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12. HiSCR was defined as at least a 50% reduction in total abscess and inflammatory nodule count with no increase in abscess count and no increase in draining fistula count relative to baseline (see Table 17). 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.
In both studies, a higher proportion of HUMIRA- than placebo-treated subjects achieved HiSCR (see Table 17).
Table 17: Efficacy Results at 12 Weeks in Subjects
with Moderate to Severe Hidradenitis Suppurativa
|HS Study I||HS Study II*|
|Placebo||Humira 40 mg Weekly||Placebo||Humira 40 mg Weekly|
|Hidradenitis Suppurativa Clinical Response (HiSCR)||N = 154
|N = 153
|*19.3% of subjects in Study HS-II continued baseline oral antibiotic therapy during the study.|
In both studies, from Week 12 to Week 35 (Period B), subjects who had received HUMIRA were re-randomized to 1 of 3 treatment groups (HUMIRA 40 mg every week, HUMIRA 40 mg every other week, or placebo). Subjects who had been randomized to placebo were assigned to receive HUMIRA 40 mg every week (Study HS-I) or placebo (Study HS-II).
During Period B, flare of HS, defined as ≥ 25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from HUMIRA treatment following the primary efficacy timepoint in two studies.
2.Hyams JS, Ferry GD, Mandel FS, et al. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr. 1991;12:439-447.
Last reviewed on RxList: 9/23/2015
This monograph has been modified to include the generic and brand name in many instances.
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