Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: UCB Pharma SA Allée de la Recherche 60 B-1070 Bruxelles Belgium
Pharmacotherapeutic group: 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-dependant manner. Incubation of monocytes with Cimzia resulted in a dose-dependant 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.
Table 2 – Clinical trial description:
| Study number | Patient numbers | Dose regimen | Study objectives |
|---|---|---|---|
| RA-I (52 weeks) | 982 | 400 mg (0,2,4 weeks) with MTX | Evaluation for treatment of signs and symptoms and inhibition of structural damage. |
| 200 mg or 400 mg every 2 weeks with MTX | 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 | Evaluation for treatment of signs and symptoms and inhibition of structural damage. |
| 200 mg or 400 mg every 2 weeks with MTX | Primary endpoint: ACR 20 at Week 24. |
mTSS: modified Total Sharp Score
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 ACR20 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 | Cimzia 200 mg + 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
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 N=199 Mean (SD) | Cimzia 200 mg + MTX N=393 Mean (SD) | Cimzia 200 mg + 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 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.
The overall percentage of patients with antibodies to Cimzia detectable on at least 1 occasion was 7.7% in the Phase III RA placebo-controlled trials. Approximately one-third of antibody-positive patients (2.6% of the total population) 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.
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 data reflect the percentage of patients whose test results were considered positive for antibodies to Cimzia in an ELISA, and are highly dependant 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.
Certolizumab pegol plasma concentrations were broadly dose-proportional. Pharmacokinetics observed in patients with rheumatoid arthritis 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.
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%. 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 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.
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 (≥65 years old): Specific clinical trials have not been performed in elderly 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.
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, 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).
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. Data from a human closed-circuit placental transfer model in vitro suggest low or negligible transfer to the foetal compartment (see section 4.6).
No mutagenic or clastogenic effects were demonstrated in preclinical studies. Carcinogenicity studies have not been performed with Cimzia.
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