Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB05

Mechanism of action

Cimzia has a high affinity for human TNFα and binds with a dissociation constant (KD) of 90 pM.
TNFα is a key pro-inflammatory cytokine with a central role in inflammatory processes. Cimzia selectively neutralises TNFα (IC90 of 4 ng/ml for inhibition of human TNFα in the in vitro L929 murine fibrosarcoma cytotoxicity assay) but does not neutralise lymphotoxin α (TNFβ).

Cimzia was shown to neutralise membrane associated and soluble human TNFα in a dose-dependent manner. Incubation of monocytes with Cimzia resulted in a dose-dependent inhibition of lipopolysaccharide (LPS)-induced TNFα and IL1β production in human monocytes.

Cimzia does not contain a fragment crystallisable (Fc) region, which is normally present in a complete antibody, and therefore does not fix complement or cause antibody-dependent cell- mediated cytotoxicity in vitro. It does not induce apoptosis in vitro in human peripheral blood- derived monocytes or lymphocytes, or neutrophil degranulation.

Biological activities ascribed to TNFα include the upregulation of cellular adhesion molecules and chemokines, upregulation of major histocompatibility complex (MHC) class I and class II molecules, and direct leukocyte activation. TNFα stimulates the production of downstream inflammatory mediators, including interleukin-1, prostaglandins, platelet activating factor, and nitric oxide. Elevated levels of TNFα have been implicated in the pathology of Crohn’s disease and rheumatoid arthritis. Certolizumab pegol binds to TNFα, inhibiting its role as a key mediator of inflammation. TNFα is strongly expressed in the bowel wall in areas involved by Crohn’s disease and fecal concentrations of TNFα in patients with Crohn’s disease have been shown to reflect clinical severity of the disease. After treatment with certolizumab pegol, patients with Crohn’s disease demonstrated a decrease in the levels of C-reactive protein (CRP). Increased TNFα levels are found in the synovial fluid of rheumatoid arthritis patients and play an important role in the joint destruction that is a hallmark of this disease.

Clinical efficacy

Rheumatoid arthritis
The efficacy and safety of Cimzia have been assessed in 2 randomised, placebo-controlled, double- blind clinical trials in patients ≥ 18 years of age with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria, RA-I (RAPID 1) and RA-II (RAPID 2).
Patients had ≥ 9 swollen and tender joints each and had active RA for at least 6 months prior to baseline. Cimzia was administered subcutaneously in combination with oral MTX for a minimum of 6 months with stable doses of at least 10 mg weekly for 2 months in both trials. There is no experience with Cimzia in combination with DMARDs other than MTX.

Table 2 Clinical trial description
Study           Patient      Active dose regimen                             Study objectives number          numbers
RA-I            982         400 mg (0,2,4 weeks) Evaluation for treatment of signs and (52 weeks)                          with MTX        symptoms and inhibition of structural 200 mg or 400 mg every 2              damage.
weeks with MTX       Co-primary endpoints: ACR 20 at
Week 24 and change from baseline in mTSS at Week 52
RA-II           619        400 mg (0,2,4 weeks)   Evaluation for treatment of signs and (24 weeks)                        with MTX          symptoms and inhibition of structural 200 mg or 400 mg every 2               damage.
weeks with MTX        Primary endpoint: ACR 20 at Week
24.
mTSS: modified Total Sharp Score

Signs and symptoms
The results of clinical trials RA-I and RA-II are shown in Table 3. Statistically significantly greater ACR 20 and ACR 50 responses were achieved from Week 1 and Week 2, respectively, in both clinical trials compared to placebo. Responses were maintained through Weeks 52 (RA-I) and 24 (RA-II).
Of the 783 patients initially randomised to active treatment in RA-I, 508 completed 52 weeks of placebo-controlled treatment and entered the open-label extension study. Of these, 427 completed 2 years of open-label follow-up and thus had a total exposure to Cimzia of 148 weeks overall. The observed ACR 20 response rate at this timepoint was 91%. The reduction (RA-I) from Baseline in DAS28 (ESR) also was significantly greater (p<0.001) at Week 52 (RA-I) and Week 24 (RA-II) compared to placebo and maintained through 2 years in the open-label extension trial to RA-I.



Table 3     ACR response in clinical trials RA-I and RA-II
Study RA-I                                Study RA-II
Methotrexate                               Methotrexate combination                                combination
(24 and 52 weeks)                                (24 weeks)
Response         Placebo + MTX         Cimzia 200 mg        Placebo + MTX      Cimzia 200 mg + MTX                                   + MTX every 2 weeks                           every 2 weeks

N=199                N=393              N=127                 N=246
ACR 20
Week 24              14%                59%**                 9%                  57%** Week 52              13%                53%**                 N/A                   N/A ACR 50
Week 24               8%                37%**                 3%                  33%** Week 52               8%                38%**                 N/A                   N/A ACR 70
Week 24               3%                21%**                 1%                   16%* Week 52               4%                21%**                 N/A                   N/A Major                 1%                13%**
Clinical
Responsea.
Cimzia vs. placebo: *p≤0.01, ** p<0.001 a.
Major clinical response is defined as achieving ACR 70 response at every assessment over a continuous 6-month period
Wald p-values are quoted for the comparison of treatments using logistic regression with factors for treatment and region.
Percentage response based upon number of subjects contributing data (n) to that endpoint and time point which may differ from N

Radiographic response
In RA-I, structural joint damage was assessed radiographically and expressed as change in mTSS and its components, the erosion score and joint space narrowing (JSN) score, at Week 52, compared to baseline. Cimzia patients demonstrated significantly less radiographic progression than patients receiving placebo at Week 24 and Week 52 (see Table 4). In the placebo group, 52% of patients experienced no radiographic progression (mTSS ≤ 0.0) at Week 52 compared to 69% in the Cimzia 200 mg treatment group.

Table 4        Changes over 12 months in RA-I
Placebo + MTX          Cimzia 200 mg + MTX           Cimzia 200 mg + MTX – N=199                     N=393                     Placebo + MTX
Mean (SD)                  Mean (SD)                Mean Difference mTSS
Week 52                 2.8 (7.8)                  0.4 (5.7)                     -2.4 Erosion Score
Week 52                 1.5 (4.3)                  0.1 (2.5)                     -1.4 JSN Score
Week 52                 1.4 (5.0)                  0.4 (4.2)                     -1.0 p-values were < 0.001 for both mTSS and erosion score and ≤0.01 for JSN score. An ANCOVA was fitted to the ranked change from baseline for each measure with region and treatment as factors and rank baseline as a covariate.


Of the 783 patients initially randomised to active treatment in RA-I, 508 completed 52 weeks of placebo-controlled treatment and entered the open-label extension study. Sustained inhibition of progression of structural damage was demonstrated in a subset of 449 of these patients who completed at least 2 years of treatment with Cimzia (RA-I and open-label extension study) and had evaluable data at the 2-year timepoint.

Physical function response and health-related outcomes
In RA-I and RA-II, Cimzia-treated patients reported significant improvements in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI) and in tiredness (fatigue) as reported by the Fatigue Assessment Scale (FAS) from Week 1 through to the end of the studies compared to placebo. In both clinical trials, Cimzia-treated patients reported significantly greater improvements in the SF-36 Physical and Mental Component Summaries and all domain scores. Improvements in physical function and HRQoL were maintained through 2 years in the open- label extension to RA-I. Cimzia-treated patients reported statistically significant improvements in the Work Productivity Survey compared to placebo.

DoseFlex clinical trial
The efficacy and safety of 2 dose regimens (200 mg every 2 weeks and 400 mg every 4 weeks) of Cimzia versus placebo were assessed in an 18-week, open-label, run-in, and 16-week randomised, double-blind, placebo-controlled clinical trial in adult patients with active rheumatoid arthritis diagnosed according to the ACR criteria who had inadequate response to MTX.

Patients received loading doses of Cimzia 400 mg at weeks 0, 2, and 4 followed by Cimzia 200 mg every 2 weeks during the initial open label period. Responders (achieved ACR 20) at week 16 were randomized at week 18 to Cimzia 200 mg every 2 weeks, Cimzia 400 mg every 4 weeks, or placebo in combination with MTX for an additional 16 weeks (total trial length: 34 weeks). These 3 groups were well balanced with regards to clinical response following the active run-in period (ACR 20: 83- 84% at week 18).

The primary endpoint of the study was the ACR 20 responder rate at week 34. The results at week 34 are shown in Table 5. Both Cimzia regimens showed sustained clinical response and were statistically significant compared to placebo at week 34. The ACR 20 endpoint was achieved for both Cimzia 200 mg every 2 weeks and 400 mg every 4 weeks.

Table 5    ACR response in DoseFlex clinical trial at week 34
Treatment regimen week 0 to    Cimzia 400 mg + MTX at week 0, 2 and 4, followed by 16                                      Cimzia 200 mg + MTX every 2 weeks 
Randomised, double-blind            Placebo + MTX              Cimzia                Cimzia treatment regimen week 18                                  200 mg + MTX          400 mg + MTX to 34                                                       every 2 weeks         every 4 weeks 
N=69                  N=70                   N=69
ACR 20                                    45%                   67%                    65% p-value*                                  N/A                   0.009                  0.017 ACR 50                                     30%                  50%                    52% p-value*                                   N/A                  0.020                  0.010 ACR 70                                     16%                  30%                    38% p-value*                                   N/A                  0.052                  0.005 N/A: Not Applicable
*Wald p-values for Cimzia 200 mg vs. placebo and Cimzia 400 mg vs. placebo comparisons are estimated from a logistic regression model with factors for treatment.



Axial spondyloarthritis (non-radiographic axial spondyloarthritis and ankylosing spondylitis subpopulations)
AS001
The efficacy and safety of Cimzia were assessed in one multicenter, randomized, double-blind, placebo-controlled trial (AS001) in 325 patients ≥18 years of age with adult-onset active axial spondyloarthritis for at least 3 months as defined by the Assessment of Spondyloarthritis International Society (ASAS) Classification Criteria for axial spondyloarthritis. The axial spondyloarthritis overall population included subpopulations with and without (non-radiographic axial spondyloarthritis [nr- axSpA]) radiographic evidence for ankylosing spondylitis (AS) (also known as radiographic axial spondyloarthritis). Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4, spinal pain ≥ 4 on a 0 to 10 Numerical Rating Scale (NRS) and increased CRP or current evidence of sacroiliitis on Magnetic Resonance Imaging (MRI). Patients must have been intolerant to or had an inadequate response to at least one NSAID. Overall, 16% of patients had prior TNF-antagonist exposure. Patients were treated with a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either 200 mg of Cimzia every 2 weeks or 400 mg of Cimzia every 4 weeks or placebo. 87.7% of patients received concomitant NSAIDs. The primary efficacy endpoint was the ASAS20 response rate at Week 12. The 24-week double-blind, placebo-controlled treatment period of the study was followed by a 24-week dose-blind treatment period, and a 156-week open-label treatment period. The maximum duration of the study was 204 weeks. All patients received Cimzia in both the dose-blind and open-label follow-up periods.
A total of 199 subjects (61.2% of randomized subjects) completed the study through Week 204.

Key efficacy outcomes
In AS001 clinical trial, at Week 12 ASAS20 responses were achieved by 58% of patients receiving Cimzia 200 mg every 2 weeks and 64% of patients receiving Cimzia 400 mg every 4 weeks as compared to 38% of patients receiving placebo (p<0.01). In the overall population, the percentage of ASAS20 responders was clinically relevant and significantly higher for the Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group at every visit from Week 1 through Week 24 (p≤0.001 at each visit). At Weeks 12 and 24, the percentage of subjects with an ASAS40 response was greater in the Cimzia-treated groups compared to placebo.

Similar results were achieved in both the ankylosing spondylitis and non-radiographic axial spondyloarthritis subpopulations. In women, ASAS20 responses were not statistically significantly different from placebo until after the Week 12 time point.

Improvements in ASAS5/6, Partial Remission and BASDAI-50 were statistically signficant at Week 12 and Week 24 and were sustained up to Week 48 in the overall population as well as in the subpopulations. Key efficacy outcomes from the AS001 clinical trial are shown in Table 6. Among patients remaining in the study, improvements in all afore-mentioned key efficacy outcomes were maintained through Week 204 in the overall population as well as in the subpopulations.

`



Table 6        Key efficacy outcomes in AS001 clinical trial (percent of patients) Ankylosing spondylitis       Non-radiographic                 Axial axial               spondyloarthritis
Parameters                                         spondyloarthritits         Overall Population Placebo         Cimzia        Placebo     Cimzia all    Placebo      Cimzia all N=57          all dosing      N=50         dosing      N=107          dosing regimens(a)                 regimens(a)                regimens(a)
N=121                        N=97                      N=218
ASAS20(b,c)
Week 12                   37%           60%*           40%         61%*          38%          61%** Week 24                   33%          69%**           24%        68%**          29%          68%** ASAS40(c,d)
Week 12                   19%          45%**           16%        47%**          18%          46%** Week 24                   16%          53%**           14%        51%**          15%          52%** ASAS 5/6(c,d)
Week 12                    9%          42%**            8%        44%**           8%          43%** Week 24                    5%          40%**            4%        45%**           5%          42%** Partial remission(c,d)           2%          20%**            6%        29%**           4%          24%** Week 12                    7%          28%**           10%        33%**           9%          30%** Week 24
BASDAI 50(c,d)
Week 12                   11%          41%**           16%        49%**          13%          45%** Week 24                   16%          49%**           20%        57%**          18%          52%** (a)
Cimzia all dosing regimen = data from Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 plus Cimzia 400 mg administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 (b)
Results are from the randomized set
(c)
Wald p-values are quoted for the comparison of treatments using logistic regression with factors for treatment and region.
(d)
Full Analysis Set
NA = not available
*p≤0.05, Cimzia vs placebo
**p<0.001, Cimzia vs placebo

Spinal mobility
Spinal mobility was assessed in the double-blind, placebo-controlled period by using BASMI at several time points including Baseline, Week 12 and Week 24. Clinically meaningful and statistically significant differences in Cimzia-treated patients compared with placebo-treated patients were demonstrated at each post-baseline visit. The difference from placebo tended to be greater in nr- axSpA than in the AS subpopulation which may be due to less chronic structural damage in nr-axSpA patients.
The improvement in BASMI linear score achieved at Week 24 was maintained through Week 204 for patients who remained in the study.

Physical function response and health-related outcomes
In the AS001 clinical trial, Cimzia-treated patients reported significant improvements in physical function as assessed by the BASFI and in pain as assessed by the Total and Nocturnal Back Pain NRS scales as compared to placebo. Cimzia-treated patients reported significant improvements in tiredness (fatigue) as reported by the BASDAI-fatigue item and in health-related quality of life as measured by the ankylosing spondylitis QoL (ASQoL) and the SF-36 Physical and Mental Component Summaries and all domain scores as compared to placebo. Cimzia-treated patients reported significant improvements in axial spondyloarthritis-related productivity at work and within household, as reported by the Work Productivity Survey as compared to placebo. For patients remaining in the study, improvements in all afore-mentioned outcomes were largely maintained 
through Week 204.

Inhibition of inflammation in Magnetic Resonance Imaging (MRI)
In an imaging sub-study including 153 patients, signs of inflammation were assessed by MRI at week 12 and expressed as change from baseline in SPARCC (Spondyloarthritis Research Consortium of Canada) score for sacroiliac joints and ASspiMRI-a score in the Berlin modifications for the spine.
At week 12, significant inhibition of inflammatory signs in both sacroiliac joints and the spine was observed in the Cimzia-treated patients (all dose group), in the overall axial spondyloarthritis population as well as in the sub-populations of ankylosing spondylitis and non-radiographic axial spondyloarthritis. Among patients remaining in the study, who had both baseline values and week 204 values, inhibition of inflammatory signs in both the sacroiliac joints (n=72) and spine (n=82) was largely maintained through Week 204 in the overall axial spondyloarthritis population as well as in both the AS and the nr-axSpA subpopulations.

Non-radiographic axial spondyloarthritis (nr-axSpA)
The efficacy and safety of Cimzia were assessed in a 52 weeks multicenter, randomized, double- blind, placebo-controlled study (AS0006) in 317 patients ≥18 years of age with adult-onset axial spondyloarthritis and back pain for at least 12 months. Patients had to fulfil ASAS criteria for nr- axSpA (not including family history and good response to NSAIDs), and have had objective signs of inflammation indicated by C-reactive protein (CRP) levels above the upper limit of normal and/or sacroiliitis on magnetic resonance imaging (MRI), indicative of inflammatory disease [positive CRP (> ULN) and/or positive MRI], but without definitive radiographic evidence of structural damage on sacroiliac joints. Patients had active disease as defined by the BASDAI ≥4, and spinal pain ≥4 on a 0 to 10 NRS. Patients must have been intolerant to or had an inadequate response to at least two NSAIDs. Patients were treated with placebo or a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4 followed by 200 mg of Cimzia every 2 weeks. Utilization and dose adjustment of standard of care medication (SC) (e.g., NSAIDs, DMARDs, corticosteroids, analgesics) were permitted at any time.
The primary efficacy variable was the Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI) response at Week 52. ASDAS-MI response was defined as an ASDAS reduction (improvement) ≥ 2.0 relative to baseline or as reaching the lowest possible score. ASAS 40 was a secondary endpoint.
At baseline, 37 % and 41% of patients had high disease activity (ASDAS ≥2.1, ≤3.5) and 62% and 58% of patient had very high disease activity (ASDAS >3.5) in the CIMZIA group and placebo group respectively.
Clinical response
Study AS0006, performed in subjects without radiographic signs of inflammation in the SI joints, confirmed the effect previously demonstrated in this subgroup in the AS001 study.
At Week 52, a statistically significant greater proportion of patients treated with Cimzia achieved ASDAS-MI response compared to patients treated with placebo. Cimzia-treated patients also had improvements compared to placebo in multiple components of axial spondyloarthritis disease activity, including CRP. At both Week 12 and 52, ASAS 40 responses were significantly greater than placebo. Key results are presented in Table 7.

Table 7     ASDAS-MI and ASAS 40 responses in AS0006 (percent of patients) Parameters     Placebo                   Cimziaa 200 mg every 2 weeks N= 158                    N= 159
ASDAS-MI
Week 52               7%                             47%*

ASAS 40
Week 12               11%                            48%*

Week 52               16%                            57%*
a Cimzia administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4 * p<0.001
All percents reflect the proportion of patients who responded in the full analysis set.


At Week 52, the percentage of patients achieving ASDAS inactive disease (ASDAS < 1.3) was 36.4 % for the Cimzia group compared to 11.8 % for the placebo group.

At Week 52, patients treated with Cimzia showed a clinical meaningful improvement in the MASES compared to placebo (LS mean change from baseline -2.4; -0.2 respectively).

Crohn's disease
The efficacy and safety of Cimzia were assessed in two double-blind, randomized, placebo-controlled studies in patients aged 18 years and older with moderately to severely active Crohn’s disease, as 1 defined by a Crohn’s Disease Activity Index (CDAI ) of 220 to 450 points, inclusive. Cimzia was administered subcutaneously at a dose of 400 mg in both studies. Stable concomitant medications for Crohn’s disease were permitted.

Study CD1
Study CD1 was a randomized placebo-controlled study in 662 patients with active Crohn’s disease.
Cimzia or placebo was administered at Weeks 0, 2, and 4 and then every four weeks to Week 24. Assessments were done at Weeks 6 and 26. Clinical response was defined as at least a 100-point reduction in CDAI score compared to baseline, and clinical remission was defined as an absolute CDAI score of 150 points or lower.
The results for Study CD1 are provided in Table 8. At Week 6, the proportion of clinical responders was statistically significantly greater for Cimzia-treated patients compared to controls. The difference in clinical remission rates was not statistically significant at Week 6. The difference in the proportion of patients who were in clinical response at both Weeks 6 and 26 was also statistically significant, demonstrating maintenance of clinical response.


Table 8        Study CD1 – Clinical Response and Remission, Overall Study Population % Response or Remission (95% CI)
Timepoint                   Placebo                Cimzia 400 mg
(N = 328)                  (N = 331)
Week 6
Clinical Response#                  27% (22%, 32%)              35% (30%, 40%)* #
Clinical Remission                  17% (13%, 22%)               22% (17%, 26%) Week 26
Clinical Response                   27% (22%, 31%)              37% (32%, 42%)* Clinical Remission                  18% (14%, 22%)              29% (25%, 34%)* Both Weeks 6 & 26
Clinical Response                     16% (12%, 20%)             23% (18%, 28%)* Clinical Remission                     10% (7%, 13%)              14% (11%, 18%) * p-value < 0.05 logistic regression test
#
Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI ≤ 150 points

Study CD2
Study CD2 was a randomized treatment-withdrawal study in patients with active Crohn’s disease.
All patients who entered the study were dosed initially with Cimzia 400 mg at Weeks 0, 2, and 4 and then assessed for clinical response at Week 6 (as defined by at least a 100-point reduction in CDAI score). At Week 6, a group of 428 clinical responders was randomized to receive either Cimzia 400 mg or placebo, every four weeks starting at Week 8, as maintenance therapy through Week 24. Non- responders at Week 6 were withdrawn from the study. Final evaluation was based on the CDAI score at Week 26. Patients who withdrew or who received rescue therapy were considered not to be in clinical response. Three randomized responders received no study injections, and were excluded from the ITT analysis.
The results for clinical response and remission are shown in Table 9. At Week 26, a statistically significantly greater proportion of Week 6 responders were in clinical response and in clinical remission in the Cimzia-treated group compared to the group treated with placebo.

Table 9      Study CD2 – Clinical Response and Clinical Remission
% Response or Remission (95% CI)
Cimzia 400 mg x3 +             Cimzia
Placebo                   400 mg
N = 210                  N = 215
Week 26
Clinical Response#                  36% (30%, 43%)              63% (56%, 69%)* Clinical Remission#                 29% (22%, 35%)              48% (41%, 55%)* * p < 0.05
#
Clinical response is defined as decrease in CDAI of at least 100 points, and clinical remission is defined as CDAI ≤ 150 points

Baseline use of immunosuppressants or corticosteroids had no impact on the clinical response to Cimzia.

Plaque psoriasis
The efficacy and safety of Cimzia were assessed in two placebo-controlled studies (CIMPASI-1 and CIMPASI-2) and one placebo- and active-controlled study (CIMPACT) in patients ≥18 years of age with moderate to severe chronic plaque psoriasis for at least 6 months. Patients had a Psoriasis Area and Severity Index (PASI) score ≥ 12, body surface area (BSA) involvement of ≥ 10%, Physician Global Assessment (PGA) of ≥ 3, and were candidates for systemic therapy and/or phototherapy and/or chemophototherapy. Patients who were ‘primary’ non-responders on any prior biologic therapy (defined as no response within the first 12 weeks of treatment) were excluded from the phase III studies (CIMPASI-1, CIMPASI-2 and CIMPACT). The efficacy and safety of Cimzia were evaluated versus etanercept in the CIMPACT study.

In studies CIMPASI-1 and CIMPASI-2 the co-primary efficacy endpoints were the proportion of patients achieving PASI 75 and PGA “clear” or “almost clear” (with at least a 2-point reduction from baseline) at Week 16. In the CIMPACT study, the primary efficacy endpoint was the proportion of patients achieving PASI 75 at Week 12. PASI75 and PGA at Week 16 were key secondary endpoints.
PASI 90 at Week 16 was a key secondary endpoint in all 3 studies.

CIMPASI-1 and CIMPASI-2 evaluated 234 patients and 227 patients respectively. In both studies patients were randomized to receive placebo or Cimzia 200 mg every 2 weeks (following a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4) or Cimzia 400 mg every 2 weeks. At week 16, patients randomized to Cimzia who achieved a PASI 50 response continued to receive Cimzia up to Week 48 at the same randomized dose. Patients originally randomized to placebo that achieved a PASI 50 response but not a PASI 75 response at Week 16 received Cimzia 200 mg every 2 weeks (with a loading dose of Cimzia 400 mg at Weeks 16, 18, and 20). Patients with an inadequate response at Week 16 (PASI 50 non-responders) were eligible to receive Cimzia 400 mg every 2 weeks in an open-label manner for a maximum of 128 weeks.



The CIMPACT study evaluated 559 patients. Patients were randomized to receive placebo, or Cimzia 200 mg every 2 weeks (following a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4), or Cimzia
400 mg every 2 weeks up to Week 16, or etanercept 50 mg twice weekly, up to Week 12. Patients originally randomized to Cimzia who achieved a PASI75 response at Week 16 were re-randomized based on their original dosing schedule. Patients on Cimzia 200 mg every 2 weeks were re- randomized to Cimzia 200 mg every 2 weeks, Cimzia 400 mg every 4 weeks or placebo. Patient on Cimzia 400 mg every 2 weeks were re-randomized to Cimzia 400 mg every 2 weeks, Cimzia 200 mg every 2 weeks, or placebo. Patients were evaluated in a double-blind placebo-controlled manner through Week 48. All subjects who did not achieve a PASI 75 response at Week 16 entered an escape arm and received Cimzia 400 mg every 2 weeks in an open-label manner for a maximum of 128 weeks.

In all three studies, the blinded 48-week maintenance period was followed by a 96-week open-label treatment period for the patients who were PASI 50 responders at Week 48. All these patients, including those receiving Cimzia 400 mg every 2 weeks, started the open-label period at Cimzia 200 mg every 2 weeks.

Patients were predominantly men (64%) and Caucasian (94%), with a mean age of 45.7 years (18 to 80 years); of these, 7.2% were ≥ 65 years of age. Of the 850 patients randomized to receive placebo or Cimzia in these placebo-controlled studies, 29% of patients were naïve to prior systemic therapy for the treatment of psoriasis. 47% had received prior phototherapy or chemophototherapy, and 30% had received prior biologic therapy for the treatment of psoriasis. Of the 850 patients, 14% had received at least one TNF-antagonist, 13% had received an anti-IL-17, and 5% had received an anti- IL 12/ 23. Eighteen percent of patients reported a history of psoriatic arthritis at baseline. The mean PASI score at baseline was 20 and ranged from 12 to 69. The baseline PGA score ranged from moderate (70%) to severe (30%). Mean baseline BSA was 25% and ranged from 10% to 96%.

Clinical response at Week 16 and 48
The key results of CIMPASI-1 and CIMPASI-2 studies are presented in Table 10.

Table 10 Clinical response in studies CIMPASI-1 and CIMPASI-2 at Week 16 and Week 48 Week 16                           Week 48
CIMPASI-1
Placebo      Cimzia 200 mg Cimzia 400 mg Cimzia 200 mg Cimzia 400 mg
Q2W a)         Q2W           Q2W           Q2W
N=51            N=95          N=88         N=95          N=88
PGA clear or        4.2%           47.0%*        57.9%*        52.7%         69.5% almost clearb)
PASI 75             6.5%            66.5%*            75.8%*            67.2%             87.1% PASI 90             0.4%            35.8%*            43.6%*            42.8%             60.2% CIMPASI-2
Placebo      Cimzia 200 mg Cimzia 400 mg Cimzia 200 mg Cimzia 400 mg
Q2W a)         Q2W           Q2W           Q2W
N=49            N=91          N=87         N= 91         N= 87
PGA clear or        2.0%           66.8%*        71.6%*        72.6%         66.6% almost clearb)
PASI 75             11.6%           81.4%*             82.6%*             78.7%           81.3% PASI 90             4.5%            52.6%*             55.4%*             59.6%           62.0% a)
Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Week 0, 2, 4.
b)
PGA 5 category scale. Treatment success of “clear” (0) or “almost clear”(1) consisted of no signs of psoriasis or normal to pink coloration of lesions, no thickening of the plaque, and none to minimal focal scaling.
* Cimzia vs placebo: p< 0.0001.
Response rates and p-values for PASI and PGA were estimated based on a logistic regression model where missing data were imputed using multiple imputation based on the MCMC method. Subject who escaped or withdrew (based on not achieving PASI 50 response) were treated as non-responders at Week 48.
Results are from the Randomized Set.

The key results of the CIMPACT trial are presented in Table 11.

Table 11    Clinical response in CIMPACT study at Week 12 and Week 16 Week 12                                           Week 16
Placebo Cimzia 200 Cimzia 400 Etanercept      Placebo              Cimzia 200      Cimzia 400 N=57      mg Q2W a)   mg Q2W     50 mg BiW    N=57                 mg Q2W            mg N=165      N=167       N=170                            N=165           Q2W N=167
PASI 75              5%        61.3%*,§       66.7%*,§§        53.3%          3.8%       68.2%*      74.7%* PASI 90             0.2%        31.2%*         34.0%*          27.1%          0.3%       39.8%*      49.1%* PGA clear or
1.9%       39.8%**         50.3%*          39.2%          3.4%       48.3%*        58.4%* almost clear b) a)
Cimzia 200 mg administered every 2 weeks preceded by a loading dose of 400 mg at Week 0, 2, 4.
b)
PGA 5 category scale. Treatment success of “clear” (0) or “almost clear”(1) consisted of no signs of psoriasis or normal to pink coloration of lesions, no thickening of the plaque, and none to minimal focal scaling.
* Cimzia vs placebo: p< 0.0001.
§
Cimzia 200 mg every 2 weeks versus etanercept 50 mg twice weekly demonstrated non-inferiority (difference between etanercept and Cimzia 200 mg every 2 weeks was 8.0%, 95% CI -2.9, 18.9, based on a pre-specified non-inferiority margin of 10%).
§§
Cimzia 400 mg every 2 weeks versus etanercept 50 mg twice weekly demonstrated superiority (p<0.05)
** Cimzia vs Placebo p < 0.001. Response rates and p-values based on a logistic regression model.
Missing data were imputed using multiple imputation based on the MCMC method. Results are from the Randomized Set.

In all 3 studies, the PASI 75 response rate was significantly greater for Cimzia compared to placebo starting at Week 4.

Both doses of Cimzia demonstrated efficacy compared to placebo regardless of age, gender, body weight, BMI, psoriasis disease duration, previous treatment with systemic therapies and previous treatment with biologics.

Maintenance of response
In an integrated analysis of CIMPASI-1 and CIMPASI-2, among patients who were PASI 75 responders at Week 16 and received Cimzia 400 mg every 2 weeks (N=134 of 175 randomised subjects) or Cimzia 200 mg every 2 week (N=132 of 186 randomised subjects), the maintenance of response at Week 48 was 98.0% and 87.5%, respectively. Among patients who were PGA clear or almost clear at Week 16 and received Cimzia 400 mg every 2 weeks (N=103 of 175) or Cimzia 200 mg every 2 weeks (N=95 of 186), the maintenance of response at Week 48 was 85.9% and 84.3% respectively.

After an additional 96 weeks of open-label treatment (Week 144) the maintenance of response was evaluated. Twenty-one percent of all randomised subjects were lost to follow-up before Week 144.
Approximately 27% of completer study subjects who entered the open-label treatment between weeks
48 to 144 on Cimzia 200 mg every 2 weeks had their dose increased to Cimzia 400 mg every 2 weeks for maintenance of response. In an analysis in which all patients with treatment failures were considered non-responders, the maintenance of response of the Cimzia 200 mg every 2 weeks treatment group for the respective endpoint, after an additional 96 weeks of open-label therapy, was 84.5% for PASI 75 for study subjects who were responders at Week 16 and 78.4% for PGA clear or almost clear. The maintenance of response of the Cimzia 400 mg every 2 weeks treatment group, who entered the open-label period at Cimzia 200 mg every 2 weeks, was 84.7% for PASI 75 for study subjects who were responders at Week 16 and 73.1% for PGA clear or almost clear.

These response rates were based on a logistic regression model where missing data were imputed over 48 or 144 weeks using multiple imputation (MCMC method) combined with NRI for treatment failures.

In the CIMPACT study, among PASI 75 responders at Week 16 who received Cimzia 400 mg every 2 weeks and were re-randomized to either Cimzia 400 mg every 2 weeks, Cimzia 200 mg every 2 weeks, or placebo, there was a higher percentage of PASI 75 responders at Week 48 in the Cimzia groups as compared to placebo (98.0%, 80.0%, and 36.0%, respectively). Among PASI75 responders at Week 16 who received Cimzia 200 mg every 2 weeks and were re-randomized to either Cimzia 400 mg every 4 weeks, Cimzia 200 mg every 2 weeks, or placebo, there was also a higher percentage of PASI 75 responders at Week 48 in the Cimzia groups as compared to placebo (88.6%, 79.5%, and 45.5%, respectively). Non-responder imputation was used for missing data.

Quality of life / Patient reported outcomes

Statistically significant improvements at Week 16 (CIMPASI-1 and CIMPASI-2) from baseline compared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index). Mean decreases (improvements) in DLQI from baseline ranged from -8.9 to -11.1 with Cimzia 200 mg every 2 weeks, from -9.6 to -10.0 with Cimzia 400 mg every 2 weeks, versus -2.9 to -3.3 for placebo at Week 16.

In addition, at Week 16, Cimzia treatment was associated with a greater proportion of patients achieving a DLQI score of 0 or 1 (Cimzia 400 mg every 2 weeks, 45.5% and 50.6% respectively; Cimzia 200 mg every 2 weeks, 47.4% and 46.2% respectively, versus placebo, 5.9% and 8.2% respectively).

Improvements in DLQI score were sustained or slightly decreased through Week 144.

Cimzia -treated patients reported greater improvements compared to placebo in the Hospital Anxiety and Depression Scale (HADS)-D.

Immunogenicity

The data below reflect the percentage of patients whose test results were considered positive for antibodies to Cimzia in an ELISA and later in a more sensitive method, and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to certolizumab pegol in the studies described belowwith the incidence of antibodies to other studies or to other products may be misleading.
Rheumatoid arthritis
The overall percentage of patients with antibodies to Cimzia detectable on at least 1 occasion was 9.6% in RA placebo-controlled trials. Approximately one-third of antibody-positive patients had antibodies with neutralising activity in vitro. Patients treated with concomitant immunosuppressants (MTX) had a lower rate of antibody development than patients not taking immunosuppressants at baseline. Antibody formation was associated with lowered drug plasma concentration and in some patients, reduced efficacy.
In 2 long-term (up to 5 years of exposure) open-label studies, the overall percentage of patients with antibodies to Cimzia detectable on at least one occasion was 13% (8.4% of the overall patients had transient formation of antibodies and an additional 4.7% had persistent formation of antibodies to Cimzia). The overall percentage of patients that were antibody positive with a persistent reduction of drug plasma concentration was estimated to be 9.1%. Similar to the placebo-controlled studies, antibody positivity was associated with reduced efficacy in some patients.

A pharmacodynamic model based on the Phase III trial data predicts that around 15% of the patients develop antibodies in 6 months at the recommended dose regimen (200 mg every 2 weeks following a loading dose) without MTX co-treatment. This number decreases with increasing doses of concomitant MTX treatment. These data are reasonably in agreement with observed data.

Plaque psoriasis
In the Phase III placebo- and active-controlled studies, the percentages of patients who were positive for antibodies to Cimzia on at least one occasion during treatment up to Week 48 were 8.3 % (22/265) and 19.2% (54/281) for the Cimzia 400 mg every 2 weeks and Cimzia 200 mg every 2 weeks respectively. In CIMPASI-1 and CIMPASI-2, sixty patients were antibody positive, 27 of these patients were evaluable for neutralizing antibodies and tested positive. First occurrences of antibody positivity in the open-label treatment period were observed in 2.8% (19/668) of patients. Antibody positivity was associated with lowered drug plasma concentration and in some patients with reduced efficacy.

Axial spondyloarthritis
AS001
The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to Week 24 was 4.4% in the AS001 phase III placebo controlled trial in patients with axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis subpopulations).
Antibody formation was associated with lowered drug plasma concentration.

Over the course of the entire study (up to 192 weeks), the overall percentage of patients with antibodies to Cimzia detectable on at least one occasion was 9.6% (4.8% had transient formation and an additional 4.8% had persistent formation of antibodies to Cimzia). The overall percentage of patients that were antibody positive with a persistent reduction of drug plasma concentration was estimated to be 6.8%.

AS0006
A more sensitive and drug tolerant assay was used for the first time in the AS0006 study, resulting in a greater proportion of samples having measurable antibodies to Cimzia and thus a greater incidence of patients being classed as antibody positive.
In AS0006, the overall incidence of patients who were antibody positive to Cimzia was 97% (248/255 patients) after up to 52 weeks of treatment. Only the highest titers were associated with reduced Cimzia plasma levels, however, no impact on efficacy was observed..

About 22% (54/248) of the patients in AS0006 who were anti- Cimzia antibody positive at any time, had antibodies that were classified as neutralizing.
Crohn’s disease
Patients with Crohn’s disease were tested at multiple time points for antibodies to certolizumab pegol during Studies CD1 and CD2. In patients continuously exposed to Cimzia, the overall percentage of patients who were antibody positive to Cimzia on at least one occasion was 8%; approximately 6% were neutralizing in vitro. No apparent correlation of antibody development to adverse events or efficacy was observed. Patients treated with concomitant immunosuppressants had a lower rate of antibody development than patients not taking immunosuppressants at baseline (3% and 11%, respectively). The following adverse events were reported in Crohn’s disease patients who were 
antibody-positive (N = 100) at an incidence at least 3% higher compared to antibody-negative patients (N = 1,242): abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site erythema, injection site pain, pain in extremity, and upper respiratory tract infection.
In two long-term (up to 7 years of exposure), open-label Crohn’s disease studies, overall 23% (207/903) of patients developed antibodies against certolizumab pegol on at least one occasion. Of the 207 patients who were antibody positive, 152 (73%) had a persistent reduction of drug plasma concentration, which represents 17% (152/903) of the study population. The data from these two studies do not suggest an association between the development of antibodies and adverse events.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Certolizumab pegol plasma concentrations were broadly dose-proportional. Pharmacokinetics observed in patients with rheumatoid arthritis and Crohn’s disease were consistent with those seen in healthy subjects.

Absorption
Following subcutaneous administration, peak plasma concentrations of certolizumab pegol were attained between 54 and 171 hours post-injection. Certolizumab pegol has a bioavailability (F) of approximately 80% (range 76% to 88%) following subcutaneous administration compared to intravenous administration.

Distribution
The apparent volume of distribution (V/F) was estimated at 8.01 l in a population pharmacokinetic analysis of patients with rheumatoid arthritis and at 4.71 l in a population pharmacokinetic analysis of patients with plaque psoriasis.

Biotransformation and elimination
PEGylation, the covalent attachment of PEG polymers to peptides, delays the metabolism and elimination of these entities from the circulation by a variety of mechanisms, including decreased renal clearance, decreased proteolysis, and decreased immunogenicity. Accordingly, certolizumab pegol is an antibody Fab' fragment conjugated with PEG in order to extend the terminal plasma elimination half-life of the Fab' to a value comparable with a whole antibody product. The terminal elimination phase half-life (t1/2) was approximately 14 days for all doses tested.

The clearance following IV administration to healthy subjects ranged from 9.21 mL/h to 14.38 mL/h.
The clearance following sc dosing was estimated 17 mL/h in the Crohn’s disease population PK analysis with an inter-subject variability of 38% (CV) and an inter-occasion variability of 16%.
Clearance following subcutaneous dosing was estimated as 21.0 mL/h in the rheumatoid arthritis population pharmacokinetic analysis, with an inter-subject variability of 30.8% (CV) and inter- occasion variability 22.0%. The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion. When assessed using the previous ELISA method, the presence of antibodies to certolizumab pegol resulted in an approximately three-fold increase in clearance. Compared with a 70 kg person, clearance is 29% lower and 38% higher, respectively, in individual RA patients weighing 40 kg and 120 kg. The clearance following subcutaneous dosing in patients with psoriasis was 14 ml/h with an inter-subject variability of 22.2% (CV).

The Fab' fragment comprises protein compounds and is expected to be degraded to peptides and amino acids by proteolysis. The de-conjugated PEG component is rapidly eliminated from plasma and is to an unknown extent excreted renally.

Special populations
Renal impairment
Specific clinical trials have not been performed to assess the effect of renal impairment on the pharmacokinetics of certolizumab pegol or its PEG fraction. However, population pharmacokinetic analysis based on subjects with mild renal impairment showed no effect of creatinine clearance.
There are insufficient data to provide a dosing recommendation in moderate and severe renal impairment. The pharmacokinetics of the PEG fraction of certolizumab pegol are expected to be dependent on renal function but have not been assessed in patients with renal impairment.

Hepatic impairment
Specific clinical trials have not been performed to assess the effect of hepatic impairment on the pharmacokinetics of certolizumab pegol.

Elderly patients (≥ 65 years old)
Specific clinical trials have not been performed in elderly patients subjects. However, no effect of age was observed in a population pharmacokinetic analysis in patients with rheumatoid arthritis in which 78 subjects (13.2% of the population) were aged 65 or greater and the oldest subject was aged 83 years.
No effect of age was observed in a population pharmacokinetic analysis in adult patients with plaque psoriasis.

Gender
There was no effect of gender on the pharmacokinetics of certolizumab pegol. As clearance decreases with decreasing body weight, females may generally obtain somewhat higher systemic exposure of certolizumab pegol.

Race
A specific clinical study showed no difference in pharmacokinetics between Caucasian and Japanese subjects.

Pharmacokinetic/pharmacodynamic relationship
On the basis of Phase II and Phase III clinical trial data in patients with rheumatoid arthritis, a population exposure-response relationship was established between average plasma concentration of certolizumab pegol during a dosing interval (Cavg) and efficacy (ACR 20 responder definition).
The typical Cavg that produces half the maximum probability of ACR 20 response (EC50) was 17 µg/ml (95% CI: 10-23 µg/ml). Similarly, on the basis of Phase III clinical trial data in patients with psoriasis, a population exposure-response relationship was established between plasma concentration of certolizumab pegol and PASI with an EC90 of 11.1 µg/ml.