Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: UCB Pharma S.A., Allée de la Recherche 60, B-1070, Bruxelles, Belgium
Pharmacotherapeutic group: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors
ATC code: L04AB05
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.
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.
The efficacy and safety of Cimzia was assessed in DMARD-naïve adult patients with active RA in a randomized, placebo-controlled, double-blind clinical trial (C-EARLY). In the C-EARLY trial patients were ≥18 years of age and had ≥ 4 swollen and tender joints each and must have been diagnosed with moderate to severe active and progressive RA within 1 year (as defined by the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria). Patients had a mean time since diagnosis at baseline of 2.9 months and were DMARD naïve (including MTX). For both the Cimzia and placebo arms, MTX was initiated as of Week 0 (10 mg/week), titrated up to maximum tolerated dose by Week 8 (min 15 mg/week, max 25 mg/week allowed), and maintained throughout the study (average dose of MTX after Week 8 for placebo and Cimzia was 22.3 mg/week and 21.1 mg/week respectively).
Table 2. Clinical trial description:
| Study number | Patient numbers | Active dose regimen | Study objectives |
|---|---|---|---|
| RA-I (52 weeks) | 982 | 400 mg (0,2,4 weeks) with ΜΤΧ 200mg ή 400mg every 2 weeks with MTX | Evaluation for treatment of signs and symptoms and inhibition of structural damage. Co-primary endpoints: ACR 20 at Week 24 and change from baseline in mTSS at Week 52 |
| RA-II (24 weeks) | 619 | 400 mg (0,2,4 weeks) with MTX 200 mg ή 400 mg every 2 weeks with ΜΤΧ | Evaluation for treatment of signs and symptoms and inhibition of structural damage. Primary endpoint: ACR 20 at Week 24. |
| C-EARLY (to 52 weeks) | 879 | 400 mg (0, 2, 4 weeks) with MTX 200 mg every 2 weeks with MTX | Evaluation for treatment of signs and symptoms and inhibition of structural damage in DMARD naïve patients. Primary endpoint: proportion of subjects in sustained remission* at Week 52. |
mTSS: modified Total Sharp Score
* Sustained remission at Week 52 is defined as DAS28[ESR] <2.6 at both Week 40 and Week 52.
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 Methotrexate combination (24 and 52 weeks) | Study RA-II Methotrexate combination (24 weeks) | |||
|---|---|---|---|---|
| Response | Placebo + MTX N=199 | Cimziaa 200mg + MTX every 2 weeks N=393 | Placebo + MTX N=127 | Cimzia 200 mg + MTX every 2 weeks 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 Clinical Responsea | 1% | 13%** | ||
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
The C-EARLY trial met its primary and key secondary endpoints. The key results from the study are presented in table 4.
Table 4. C-EARLY trial: percent of patients in sustained remission and sustained low disease activity at Week 52:
| Response | Placebo + MTX N=213 | Cimzia 200 mg + MTX N=655 |
|---|---|---|
| Sustained remission* (DAS28(ESR) <2.6 at both Week 40 and Week 52) | 15,0% | 28,9%6** |
| Sustained low disease activity (DAS28(ESR) ≤3,2 at both Week 40 and Week 52) | 28,6% | 43,8%** |
* Primary endpoint of C-EARLY trial (to Week 52)
Full analysis set, non-responder imputation for missing values.
** Cimzia+MTX vs placebo+MTX: p<0.001
p value was estimated from a logistic regression model with factors for treatment, region, and time since RA diagnosis at Baseline (≤4 months vs >4 months)
Patients in the Cimzia+MTX group had a greater reduction from baseline in DAS 28 (ESR) compared with the placebo+MTX group observed as early as Week 2 and continued through Week 52 (p<0.001 at each visit). Assessments on remission (DAS28(ESR) <2.6), Low Disease Activity (DAS28(ESR) ≤3.2) status, ACR50 and ACR 70 by visit demonstrated that Cimzia+MTX treatment led to faster and greater responses than PBO+MTX treatment. These results were maintained over 52 weeks of treatment in DMARD-naïve subjects.
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 5). 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 5. Changes over 12 months in RA-I:
| Placebo + MTX N=199 Mean (SD) | Cimzia 200mg + MTX N=393 Mean (SD) | Cimzia 200mg + MTX – Placebo + MTX 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.
In C-EARLY, Cimzia+ MTX inhibited the radiographic progression compared to placebo+MTX at Week 52 (see Table 6). In the placebo+MTX group, 49.7% of patients experienced no radiographic progression (change in mTSS ≤0.5) at Week 52 compared to 70.3% in the Cimzia+MTX group (p<0.001).
Table 6. Radiographic change at Week 52 in trial C-EARLY:
| Placebo + MTX N=163 Mean (SD) | Cimzia 200 mg + MTX N=528 Mean (SD) | Cimzia 200 mg + MTX – Placebo + MTX Difference* | |
|---|---|---|---|
| mTSS | |||
| Week 52 | 1,8 (4,3) | 0,2 (3,2)** | -0,978 (-1,005, -0,500) |
| Erosion score | |||
| Week 52 | 1,1 (3,0) | 0,1 (2,1)** | -0,500 (-0,508, -0,366) |
| JSN score | |||
| Week 52 | 0,7 (2,3) | 0,1 (1,7)** | 0,000 (0,000, 0,000) |
Radiographic set with linear extrapolation.
* Hodges-Lehmann point estimate of shift and 95% asymptotic (Moses) confidence interval.
** Cimzia+MTX vs placebo+MTX p<0.001. p value was estimated from an ANCOVA model on the
ranks with treatment, region, time since RA diagnosis at Baseline (≤4 months vs >4 months) as factors and Baseline rank as a covariate.
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.
In C-EARLY, Cimzia+MTX-treated patients reported significant improvements at Week 52 compared to placebo+MTX in pain as assessed by the Patient Assessment of Arthritis Pain (PAAP) – 48,5 vs – 44,0 (least square mean) (p<0.05).
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 randomised 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 7. 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 7. ACR response in DoseFlex clinical trial at week 34:
| Treatment regimen week 0 to 16 | Cimzia 400 mg + MTX at week 0, 2 and 4, followed by Cimzia 200 mg + MTX every 2 weeks | ||
|---|---|---|---|
| Randomised, double-blind treatment regimen week 18 to 34 | Placebo + MTX N=69 | Cimzia 200 mg + MTX every 2 weeks N=70 | Cimzia 400 mg + MTX every 4 weeks N=69 |
| ACR 20 p-value* | 45% N/A | 67% 0,009 | 65% 0,017 |
| ACR 50 p-value* | 30% N/A | 50% 0,020 | 52% 0,010 |
| ACR 70 p-value* | 16% N/A | 30% 0,052 | 38% 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
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.
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 popualtion as well as in the subpopulations. Key efficacy outcomes from the AS001 clinical trial are shown in Table -8. 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 8. Key efficacy outcomes in AS001 clinical trial (percent of patients):
| Parameters | Ankylosing spondylitis | Non-radiographic axial spondyloarthritits | Axial spondyloarthritis Overall Population | |||
|---|---|---|---|---|---|---|
| Placebo N=57 | Cimzia all dosing regimensa N=121 | Placebo N=50 | Cimzia all dosing regimensa N=97 | Placebo N=107 | Cimzia all dosing regimensa N=218 | |
| ASAS20b,c | ||||||
| Week 12 | 37% | 60%* | 40% | 61%* | 38% | 61%** |
| Week 24 | 33% | 69%** | 24% | 68%** | 29% | 68%** |
| ASAS40c,d | ||||||
| Week 12 | 19% | 45%** | 16% | 47%** | 18% | 46%** |
| Week 24 | 16% | 53%** | 14% | 51%** | 15% | 52%** |
| ASAS 5/6c,d | ||||||
| Week 12 | 9% | 42%** | 8% | 44%** | 8% | 43%** |
| Week 24 | 5% | 40%** | 4% | 45%** | 5% | 42%** |
| Partial remissionc,d | ||||||
| Week 12 | 2% | 20%** | 6% | 29%** | 4% | 24%** |
| Week 24 | 7% | 28%** | 10% | 33%** | 9% | 30%** |
| BASDAI 50c,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 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.
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.
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.
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.
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 9.
Table 9. ASDAS-MI and ASAS 40 responses in AS0006 (percent of patients):
| Parameters | Placebo N=158 | Cimziaa 200 mg every 2 weeks 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).
The efficacy and safety of Cimzia were assessed in a multicentre, randomised, double-blind, placebo controlled clinical trial (PsA001) in 409 patients ≥ 18 years of age with adult-onset active psoriatic arthritis for at least 6 months as defined by the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria. Patients had ≥3 swollen and tender joints and increased acute phase reactants. Patients also had active psoriatic skin lesions or a documented history of psoriasis and had failed 1 or more DMARDs. Previous treatment with one TNF-antagonist was allowed and 20% of patients had prior TNF-antagonist exposure. Patients received a loading dose of Cimzia 400 mg at Weeks 0, 2 and 4 (for both treatment arms) or placebo followed by either Cimzia 200 mg every 2 weeks or 400 mg every 4 weeks or placebo every 2 weeks. Patients receiving concomitant NSAIDs and conventional DMARDs were 72.6% and 70.2% respectively. The two primary endpoints were the percentage of patients achieving ACR 20 response at Week 12 and change from baseline in modified Total Sharp Score (mTSS) at Week 24. Efficacy and safety of Cimzia in patients with PsA whose predominant symptoms were sacroiliitis or axial spondyloarthritis have not been separately analysed.
The 24-week double-blind placebo controlled treatment period of the study was followed by a 24-week dose-blind treatment period and an 168-week open-label treatment period. The maximum duration of the study was 216 weeks. All patients received Cimzia in both the dose-blind and open-label follow-up periods. A total of 264 subjects (64.5%) completed the study through Week 216.
Cimzia-treated patients had a statistically significant higher ACR 20 response rate at Week 12 and Week 24 compared with placebo-treated patients (p<0.001). The percentage of ACR 20 responders was clinically relevant for the Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks treatment groups compared to placebo group at every visit after baseline through Week 24 (nominal p≤0.001 at each visit). Cimzia treated patients also had significant improvements in ACR 50 and 70 response rates. At week 12 and 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) were seen in the Cimzia-treated patients (nominal p-value p<0.01). Key efficacy outcomes from the PsA001 clinical trial are shown in Table 10.
Table 10. Key efficacy outcomes in PsA001 clinical trial (percent of patients):
| Response | Placebo N=136 | Cimziaa 200 mg Q2W N=138 | Cimziab 400 mg Q4W N=135 |
|---|---|---|---|
| ACR20 | |||
| Week 12 | 24% | 58%** | 52%** |
| Week 24 | 24% | 64%** | 56%** |
| ACR50 | |||
| Week 12 | 11% | 36%** | 33%** |
| Week 24 | 13% | 44%** | 40%** |
| ACR70 | |||
| Week 12 | 3% | 25%** | 13%* |
| Week 24 | 4% | 28%** | 24%** |
| Response | Placebo N=86 | Cimziaa 200 mg Q2W N=90 | Cimziab 400 mg Q4W N=76 |
| PASI 75c | |||
| Week 12 | 14% | 47%*** | 47%*** |
| Week 24 | 15% | 62%*** | 61%*** |
| Week 48 | N/A | 67% | 62% |
a Cimzia administered every 2 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
b Cimzia administered every 4 weeks preceded by a loading dose of 400 mg at Weeks 0, 2 and 4
c In subjects with at least 3% psoriasis BSA at Baseline
* p<0.01, Cimzia vs placebo
** p<0.001, Cimzia vs placebo
*** p<0.001(nominal), Cimzia vs placebo
Results are from the randomized set.Treatment Difference: Cimzia 200 mg-placebo, Cimzia 400 mg-placebo (and corresponding 95% CI and p-value) are estimated using a standard two-sided Wald asymptotic standard errors test. Non-responder Imputation (NRI) is used for patients who escaped therapy or had missing data.
Among 273 patients initially randomised to Cimzia 200 mg every 2 weeks and Cimzia 400 mg every 4 weeks, 237 (86.8%) were still on this treatment at Week 48. Of the 138 patients randomised to Cimzia 200 mg every 2 weeks, 92, 68 and 48 had an ACR 20/50/70 response, at Week 48, respectively. Of the 135 patients randomised to Cimzia 400 mg every 4 weeks, 89, 62 and 41 patients had an ACR 20/50/70 response, respectively.
Among patients remaining in the study, ACR 20, 50 and 70 response rates were maintained through Week 216. This was also the case for the other parameters of peripheral activity (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis).
In PsA001 clinical trial, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified total Sharp score (mTSS) and its components, the Erosion Score (ES) and Joint Space Narrowing score (JSN) at Week 24, compared to baseline. The mTSS Score was modified for psoriatic arthritis by addition of hand distal interphalangeal joints. Cimzia treatment inhibited the radiographic progression compared with placebo treatment at Week 24 as measured by change from baseline in total mTSS Score (LS mean [±SE] score was 0.28 [±0.07] in the placebo group compared with 0.06 [±0.06] in the Cimzia all doses group; p=0.007). Inhibition of radiographic progression was maintained with Cimzia treatment up to Week 48 in the subset of patients at higher risk of radiographic progression (patients with a Baseline mTSS score of >6). Inhibition of radiographic progression was further maintained up to Week 216 for the patients who remained in the study.
In PsA001 clinical trial, Cimzia-treated patients reported significant improvements in physical function as assessed by the Health Assessment Questionnaire – Disability Index (HAQ-DI), in pain as assessed by the PAAP and in tiredness (fatigue) as reported by the Fatigue Assessment Scale (FAS) as compared to placebo. Cimzia-treated patients reported significant improvements in health-related quality of life as measured by the psoriatic arthritis QoL (PsAQoL) and the SF-36 Physical and Mental Components and in psoriatic arthritis-related productivity at work and within household, as reported by the Work Productivity Survey compared to placebo. Improvements in all afore-mentioned outcomes were maintained through Week 216.
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 until Week 48 in an open label manner.
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.
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%.
The key results of CIMPASI-1 and CIMPASI-2 studies are presented in Table 11.
Table 11. Clinical response in studies CIMPASI-1 and CIMPASI-2 at Week 16 and Week 48:
| Week 16 | Week 48 | ||||
|---|---|---|---|---|---|
| CIMPASI-1 | |||||
| Placebo N=51 | Cimzia 200 mg Q2Wa N=95 | Cimzia 400 mg Q2W N=88 | Cimzia 200 mg Q2W N=95 | Cimzia 400 mg Q2W N=88 | |
| PGA clear or almost clearb | 4,2% | 47,0%* | 57,9%* | 52,7% | 69,5% |
| 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 N=49 | Cimzia 200 mg Q2Wa N=91 | Cimzia 400 mg Q2W N=87 | Cimzia 200 mg Q2W N=91 | Cimzia 400 mg Q2W N=87 | |
| PGA clear or almost clearb | 2,0% | 66,8%* | 71,6%* | 72,6% | 66,6% |
| 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 Table12.
Table 12. Clinical response in CIMPACT study at Week 12 and Week 16:
| Week 12 | Week 16 | ||||||
|---|---|---|---|---|---|---|---|
| Placebo N=57 | Cimzia 200 mg Q2Wa N=165 | Cimzia 400 mg Q2W N=167 | Etanercept 50 mg Q2W Ν=170 | Placebo N=57 | Cimzia 200 mg Q2W N=165 | Cimzia 400 mg 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 almost clearb | 1,9% | 39,8%** | 50,3%* | 3,4% | 48,3%* | 58,4%* | |
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.
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 or Cimzia 200 mg every other week, the maintenance response rates at Week 48 were 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 or Cimzia 200 mg every 2 weeks, the maintenance response rate at Week 48 were 85.9% and 84.3% espectively. These response rates were based on a logistic regression model where missing data were imputed using multiple imputation (MCMC method).
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.
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).
Cimzia-treated patients reported greater improvements compared to placebo in the Hospital Anxiety and Depression Scale (HADS)-D.
Improvements in all afore mentioned outcomes were maintained through Week 48.
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.
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%.
The overall percentage of patients with antibodies to Cimzia detectable on at least one occasion up to Week 24 was 11.7% in the Phase III placebo-controlled trial in patients with psoriatic arthritis. Antibody formation was associated with lowered drug plasma concentration.
Over the course of the entire study (up to 4 years of exposure), the overall percentage of patients with antibodies to Cimzia detectable on at least one occasion was 17.3% (8.7% had transient formation and an additional 8.7% 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 11.5%.
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. Antibody positivity was associated with lowered drug plasma concentration and in some patients with reduced efficacy.
The data above reflect the percentage of patients whose test results were considered positive for antibodies to Cimzia in an ELISA, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibodies in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medicinal products, and underlying disease. For these reasons, comparison of the incidence of antibodies to Cimzia with the incidence of antibodies to other TNF-antagonists is not appropriate.
In the placebo-controlled trial in patients with non-radiographic axial spondyloarthritis, using a more sensitive and drug tolerant assay than in previous trials, the overall incidence of patients who were antibody positive to certolizumab pegol was 97% (248/255 patients) after up to 52 weeks of treatment. Only the highest titers were associated with reduced certolizumab pegol plasma levels, however, no impact on efficacy was observed. About 22% (54/248) of the patients who were anti-certolizumab pegol antibody positive at any time, had antibodies that were classified as neutralizing.
Certolizumab pegol plasma concentrations were broadly dose-proportional. Pharmacokinetics observed in patients with rheumatoid arthritis and psoriasis were consistent with those seen in healthy subjects.
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.
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.
PEGylation, the covalent attachment of PEG polymers to peptides, delays the 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.
Clearance following subcutaneous dosing was estimated to be 21.0 ml/h in a rheumatoid arthritis population pharmacokinetic analysis, with an inter-subject variability of 30.8% (CV) and an inter-occasion variability of 22.0%. 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.
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.
Specific clinical trials have not been performed to assess the effect of hepatic impairment on the pharmacokinetics of certolizumab pegol.
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.
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.
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.
The pivotal non-clinical safety studies were conducted in the cynomolgus monkey. In rats and monkeys, at doses higher than those given to humans, histopathology revealed cellular vacuolation, present mainly in macrophages, in a number of organs (lymph nodes, injection sites, spleen, adrenal, uterine, cervix, choroid plexus of the brain, and in the epithelial cells of the choroid plexus). It is likely that this finding was caused by cellular uptake of the PEG moiety. In vitro functional studies of human vacuolated macrophages indicated all functions tested were retained. Studies in rats indicated that >90% of the administered PEG was eliminated in 3 months following a single dose, with the urine being the main route of excretion.
Certolizumab pegol does not cross-react with rodent TNF. Therefore, reproductive toxicology studies have been performed with a homologous reagent recognising rat TNF. The value of these data to the evaluation of human risk may be limited. No adverse effects were seen on maternal well-being or female fertility, embryo-foetal and peri- and post-natal reproductive indices in rats using a rodent anti-rat TNFα PEGylated Fab' (cTN3 PF) following sustained TNFα suppression. In male rats, reduced sperm motility and a trend of reduced sperm count were observed.
Distribution studies have demonstrated that placental and milk transfer of cTN3 PF to the foetal and neonatal circulation is negligible. Certolizumab pegol does not bind to the human neonatal Fc receptor (FcRn). Data from a human closed-circuit placental transfer model ex vivo suggest low or negligible transfer to the foetal compartment. In addition, experiments of FcRn-mediated transcytosis in cells transfected with human FcRn showed negligible transfer (see section 4.6).
No mutagenic or clastogenic effects were demonstrated in preclinical studies. Carcinogenicity studies have not been performed with certolizumab pegol.
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