Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic and immunomodulating agents; immunostimulants; interferons ATC code: L03AB13

Plegridy is an interferon beta-1a conjugated with a single, linear molecule of 20,000 Da methoxy poly(ethyleneglycol)-O-2-methylpropionaldehyde (20 kDa mPEG-O-2-methylpropionaldehyde) at a degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 44 kDa of which the protein moiety constitutes approximately 23 kDa.

Mechanism of action

A definitive mechanism of action of peginterferon beta-1a in multiple sclerosis (MS) is not known. Plegridy binds to the type I interferon receptor on the surface of cells and elicits a cascade of intracellular events leading to the regulation of interferon-responsive gene expression. Biological effects that may be mediated by Plegridy include up-regulation of anti-inflammatory cytokines (e.g. IL-4, IL-10, IL-27), down-regulation of pro-inflammatory cytokines (e.g. IL-2, IL-12, IFN-γ, TNF-α) and inhibiting the migration of activated T cells across the blood brain barrier; however additional mechanisms may be involved. Whether the mechanism of action of Plegridy in MS is mediated by the same pathway(s) as the biological effects described above is not known because the pathophysiology of MS is only partially understood.

Pharmacodynamic effects

Plegridy is interferon beta-1a conjugated to a single, linear 20 kDa methoxy poly(ethyleneglycol) molecule at the alpha-amino group of the N-terminal amino acid residue.

Interferons are a family of naturally occurring proteins that are induced by cells in response to biological and chemical stimuli, and mediate numerous cellular responses that have been classified as antiviral, antiproliferative, and immunomodulatory in nature. The pharmacological properties of Plegridy are consistent with those of interferon beta-1a and are believed to be mediated by the protein portion of the molecule.

Pharmacodynamic responses were evaluated by measuring the induction of interferon-responsive genes including those encoding 2′,5′-oligoadenylate synthetase (2′,5′-OAS), myxovirus resistance protein A (MxA), and several chemokines and cytokines, as well as neopterin (D-erythro-1, 2, 3,- trihydroxypropylpterin), a product of the interferon-inducible enzyme, GTP-cyclohydrolase I. Gene induction in healthy human subjects was greater in terms of peak level and exposure (area under the effect curve) for Plegridy compared to non-pegylated interferon beta-1a (IM) when both were given at the same dose by activity (6 MIU). The duration of this response was sustained and prolonged for Plegridy, with elevations detected up to 15 days compared to 4 days for non-pegylated interferon beta-1a. Increased concentrations of neopterin were observed in both healthy subjects and multiple sclerosis patients treated with Plegridy, with a sustained and prolonged elevation over 10 days compared to 5 days observed for non-pegylated interferon beta-1a. Neopterin concentrations return to baseline after the two week dosing interval.

Clinical efficacy and safety

The efficacy and safety of Plegridy was assessed from the placebo-controlled first year of a 2 year randomised, double-blind, clinical study in patients with relapsing remitting multiple sclerosis (the ADVANCE study). 1512 patients were randomised to and dosed with 125 micrograms Plegridy injected subcutaneously every 2 (n=512) or 4 (n=500) weeks versus placebo (n=500).
The primary endpoint was the annualised relapse rate (ARR) over 1 year. The study design and patient demographics are presented in Table 2.

No data are available from clinical efficacy/safety studies directly comparing pegylated with non-pegylated interferon beta-1a, or from patients switching between non-pegylated and pegylated interferon.

Table 3: Study design
Study design
Disease history                                          Patients with RRMS, with at least 2 relapses within the prior 3 years, and 1 relapse in the prior year, with an EDSS score of ≤5.0
Follow-up                                                1 year
Study population                                         83% treatment-naïve patients 47% ≥2 relapses in prior year
38% at least 1 Gd+ lesion at baseline
92% ≥9 T2 lesions baseline
16% EDSS ≥4
17% previously treated
Baseline characteristics
Mean age (years)                                         37
Mean/Median disease duration (years)                     3.6/2.0
Mean number of relapses within the past 3 years          2.5
Mean EDSS score at baseline                              2.5
RRMS: relapsing remitting multiple sclerosis
EDSS: Expanded Disability Status Scale
Gd+: Gadolinium-enhancing

Plegridy every 2 weeks significantly reduced the annualized relapse rate (ARR) by 36% compared to placebo (p=0.0007) at one year (Table 3) with consistent reductions of the ARR noted in subgroups defined by demographic and baseline disease characteristics. Plegridy also significantly reduced the risk of relapse by 39% (p=0.0003), the risk of sustained disability progression confirmed at 12 weeks by 38% (p=0.0383) and at 24 weeks (post-hoc analysis) by 54% (p=0.0069), the number of new or newly enlarging T2 lesions by 67% (p<0.0001), the number of Gd-enhancing lesions by 86% (p<0.0001) and the number of new T1 hypointense lesions compared to placebo by 53% (p<0.0001). A treatment effect was observed as early as 6 months, with Plegridy 125 micrograms every 2 weeks demonstrating a 61% reduction (p<0.0001) in new or newly enlarging T2 lesions as compared with placebo. Across relapse and MRI endpoints Plegridy 125 micrograms every two weeks showed a numerically greater treatment effect over the Plegridy every four weeks dosing regimen at year 1.

Results over 2 years confirmed that efficacy was maintained beyond the placebo controlled first year of the study. Patients exposed to Plegridy every 2 weeks showed statistically significant reductions compared to patients exposed to Plegridy every 4 weeks over 2 years in a post-hoc analysis for endpoints including ARR (24%, p=0.0209), the risk of relapse (24%, p=0.0212), the risk of disability progression with 24 week confirmation (36%, p=0.0459), and MRI endpoints (new/enlarging T2 60%, Gd+ 71%, and new T1 hypointense lesions 53%; p<0.0001 for all). In the ATTAIN extension study, long-term efficacy with Plegridy was maintained with continuous treatment up to 4 years as shown by clinical and MRI measures of MS disease activity. Of a total of 1468 patients, 658 patients continued at least 4 years of treatment with Plegridy.

Results for this study are shown in Table 4.



Table 4: Clinical and MRI results
Placebo             Plegridy                Plegridy
125 micrograms          125 micrograms every 2 weeks           every 4 weeks
Clinical endpoints
N                                                     500                    512                 500 Annualised relapse rate                       0.397              0.256                  0.288 Rate ratio                                                 0.64                   0.72 95% CI                                                     0.50 – 0.83            0.56 – 0.93 P-value                                                    p=0.0007               p=0.0114 Proportion of subjects relapsed               0.291              0.187                  0.222 HR                                                        0.61                   0.74 95% CI                                                    0.47 – 0.80            0.57 – 0.95 P-value                                                   p=0.0003               p=0.020 Proportion with 12 week confirmed             0.105              0.068                  0.068 disability progression*
HR                                                        0.62                   0.62 95% CI                                                    0.40 – 0.97            0.40 – 0.97 P-value                                                   p=0.0383               p=0.0380 Proportion with 24-week confirmed             0.084              0.040                  0.058 disability progression*
HR                                                          0.46                   0.67 95% CI                                                      (0.26 – 0.81)          (0.41 – 1.10) P-value                                                     p=0.0069               p=0.1116 MRI endpoints
N                                                     476                    457        462 
Mean [Median] no. of new or newly             13.3 [6.0]         4.1 [1.0]              9.2 [3.0] enlarging T2 hyperintense lesions (range)     (0 – 148)          (0 – 69)               (0 – 113) Lesion mean ratio (95% CI)                                 0.33 (0.27, 0.40)      0.72 (0.60, 0.87) P-value                                                    p≤0.0001               p=0.0008 Mean [Median] no. of Gd-enhancing             1.4^ [0.0]          0.2 [0.0]               0.9 [0.0] lesions (range)                               (0 – 39)            (0 – 13)                (0 – 41) % reduction vs placebo                                     86                      36 P-value                                                    p<0.0001                p=0.0738 Mean [Median] no. of new T1 hypointense 3.8 [1.0]                 1.8 [0.0]               3.1 [1.0] lesions (range)                               (0 – 56)            (0 – 39)                (0 – 61) % reduction vs placebo                                     53                      18 P-value                                                    p<0.0001                0.0815 HR: Hazard ratio
CI: Confidence interval
* Sustained disability progression was defined as at least a 1 point increase from baseline EDSS ≥ 1 or 1.5 point increase for patients with baseline EDSS of 0, sustained for 12 / 24 weeks.
^n=477


Patients who failed previous MS treatment were not included in the study.
Subgroups of patients with higher disease activity were defined by relapse and MRI criteria as reported below, with the following efficacy results:



-    For patients with ≥1 relapse in the previous year and ≥9 T2 lesions or ≥1 Gd+ lesion (n=1401), the annual relapse rate at 1 year was 0.39 for placebo, 0.29 for Plegridy every 4 weeks and 0.25 for Plegridy every 2 weeks.
Results in this subgroup were consistent with those in the overall population.
-    For patients with ≥2 relapses in the previous year and at least 1 Gd+ lesion (n=273), the annual relapse rate at 1 year was 0.47 for placebo, 0.35 for Plegridy every 4 weeks, and 0.33 for Plegridy every 2 weeks.
Results in this subgroup were numerically consistent with those in the overall population but not statistically significant.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

The serum half-life of peginterferon beta-1a is prolonged compared with non-pegylated interferon beta-1a.
Serum concentration of peginterferon beta-1a was dose-proportional in the range of 63 to 188 micrograms as observed in a single dose and a multiple dose study in healthy subjects. Pharmacokinetics observed in multiple sclerosis patients were consistent with those seen in healthy subjects.

Absorption

Following subcutaneous administration of peginterferon beta-1a in multiple sclerosis patients, the peak concentration was reached between 1 to 1.5 days post-dose. The observed Cmax (mean±SE) was 280 ± 79 pg/mL following repeat dosing of 125 micrograms every two weeks.
Subcutaneous peginterferon beta-1a resulted in approximately 4-, 9-, and 13-fold higher exposure (AUC168h) values and approximately 2-, 3.5- and 5-fold higher Cmax, following single doses of 63 (6 MIU), 125 (12 MIU), and 188 (18 MIU) micrograms respectively, compared to intramuscular administration of 30 (6 MIU) micrograms non-pegylated beta-1a.

Distribution

Following repeat dosing of 125 micrograms doses every two weeks by subcutaneous administration, the volume of distribution uncorrected for bioavailability (mean±SE) was 481 ± 105 L.

Biotransformation and elimination

Urinary (renal) clearance is postulated to be a major excretory pathway for Plegridy. The process of covalently conjugating a PEG moiety to a protein can alter the in vivo properties of the unmodified protein, including decreased renal clearance and decreased proteolysis thus extending the circulating half-life.
Accordingly, the half-life (t1/2) of peginterferon beta-1a is approximately 2-fold longer than non-pegylated interferon beta-1a in healthy volunteers. In multiple sclerosis patients, the t1/2 mean±SE) of peginterferon beta-1a was 78 ± 15 hours at steady state. The mean steady state clearance of peginterferon beta-1a was 4.1 ± 0.4 L/hr.

Special populations

Elderly patients
Clinical experience in patients aged above 65 years is limited. However, results from a population pharmacokinetic analysis (in patients up to 65 years) suggest that age does not impact peginterferon beta-1a clearance.

Renal impairment
A single-dose study in healthy subjects and subjects with various degrees of renal impairment (mild, moderate, and severe renal impairment as well as subjects with end state renal disease) showed a fractional increase in AUC (13-62%) and Cmax (42-71%) in subjects with mild (estimated glomerular filtration rate 50 to ≤80 mL/min/1.73m2), moderate (estimated glomerular filtration rate 30 to 50 mL/min/1.73m2), and severe (estimated glomerular filtration rate <30 mL/min/1.73m2) renal impairment, compared to subjects with normal renal function (estimated glomerular filtration rate >80 mL/min/1.73m2). Subjects with end stage renal disease requiring 2-3 times haemodialysis weekly showed similar AUC and Cmax as compared to subjects with normal renal function. Each haemodialysis reduced peginterferon beta-1a concentration by approximately 24%, suggesting that haemodialysis partially removes peginterferon beta-1a from systemic circulation.

Hepatic function
The pharmacokinetics of peginterferon beta-1a has not been evaluated in patients with hepatic insufficiency.

Gender
No gender effect on the pharmacokinetics of peginterferon beta-1a was found in a population pharmacokinetic analysis.

Race
Race had no effect on the pharmacokinetics of peginterferon beta-1a in a population pharmacokinetic analysis.