Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Biogen Netherlands B.V., Prins Mauritslaan 13, 1171 LP Badhoevedorp, The Netherlands
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, immunostimulants, interferons
ATC code: L03AB13
Peginterferon beta-1a 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.
A definitive mechanism of action of peginterferon beta-1a in multiple sclerosis (MS) is not known. Peginterferon beta-1a 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 peginterferon beta-1a 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 peginterferon beta-1a 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.
Peginterferon beta-1a 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 peginterferon beta-1a 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 peginterferon beta-1a 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 peginterferon beta-1a, 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 peginterferon beta-1a, 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.
The efficacy and safety of peginterferon beta-1a 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 peginterferon beta-1a 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 .3
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
Peginterferon beta-1a every 2 weeks significantly reduced the annualized relapse rate (ARR) by 36% compared to placebo (p=0.0007) at one year (Table 4) with consistent reductions of the ARR noted in subgroups defined by demographic and baseline disease characteristics. peginterferon beta-1a 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 peginterferon beta-1a 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 peginterferon beta-1a 125 micrograms every two weeks showed a numerically greater treatment effect over the peginterferon beta-1a 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 peginterferon beta-1a every 2 weeks showed statistically significant reductions compared to patients exposed to peginterferon beta-1a 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 peginterferon beta-1a was maintained with continuous treatment up to 4 years as shown by clinical and MRI measures of MS disease activity. Of a total of 1,468 patients, 658 patients continued at least 4 years of treatment with peginterferon beta-1a.
Results for this study are shown in Table 4.
Table 4. Clinical and MRI results:
|_. <>_.Placebo|<>_.Peginterferon
beta-1a
125 micrograms
every 2 weeks|<>_.Peginterferon
beta-1a
125 micrograms
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 disability progression* | 0,105 | 0,068 | 0,068 |
| 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 disability progression* | 0,084 | 0,040 | 0,058 |
| 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 enlarging T2 hyperintense lesions (range) | 13,3 [6,0] (0-148) | 4,1 [1,0] (0-69) | 9,2 [3,0] (0-113) |
| Lesion mean ratio (95% CI) P-value | 0,33 (0,27, 0,40) p≤0,0001 | 0,72 (0,60, 0,87) 0,0008 | |
| Mean [Median] no. of Gd-enhancing lesions (range) | 1,4^ [0,0] (0-39) | 0,2 [0,0] (0-13) | 0,9 [0,0] (0-41) |
| % reduction vs placebo P-value | 86 p<0,0001 | 36 p=0,0738 | |
| Mean [Median] no. of new T1 hypointense lesions (range) | 3,8 [1,0] (0-56) | 1,8 [0,0] (0-39) | 3,1 [1,0] (0-61) |
| % reduction vs placebo P-value | 53 p<0,0001 | 18 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:
An open-label, crossover study enrolled 136 subjects to assess the bioequivalence of single doses of 125 micrograms of Plegridy administered SC and IM injection in healthy volunteers.
The serum concentration of neopterin, a marker of interferon beta activity, following administration of 125 micrograms peginterferon beta-1a IM and SC was measured for pharmacodynamic (PD) analysis.
The serum neopterin concentration versus time profiles following single doses of 125 micrograms peginterferon beta-1a SC or 125 micrograms peginterferon beta-1a IM were similar, with maximal concentrations (Epeak) reached at a median ETmax of 40.1 hours and 44.0 hours, respectively. Geometric mean neopterin levels increased from baseline to maximum concentration similarly between the 2 injection routes, with the increase from 8.0 to 22.6 nmol/L for SC, and from 8.1 to 23.2 nmol/L for IM. The overall systemic exposure to neopterin (EAUC0-336h and EAUC0-504h) were also similar between the 2 routes of administration.
Since bioequivalence was demonstrated between the IM and SC routes of administration, it is expected that IM and SC peginterferon beta-1a will have a similar efficacy profile.
The European Medicines Agency has deferred the obligation to submit the results of studies with Plegridy in one or more subsets of the paediatric population in treatment of multiple sclerosis (see section 4.2 for information on paediatric use).
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.
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.
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.
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.
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.
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.
The pharmacokinetics of peginterferon beta-1a has not been evaluated in patients with hepatic insufficiency.
No gender effect on the pharmacokinetics of peginterferon beta-1a was found in a population pharmacokinetic analysis.
Race had no effect on the pharmacokinetics of peginterferon beta-1a in a population pharmacokinetic analysis.
The pharmacokinetic (PK) profiles following single doses of 125 micrograms peginterferon beta-1a IM and 125 micrograms peginterferon beta-1a SC in healthy volunteers were similar, with maximal concentrations reached at 40.0 hours post-dose (for both SC and IM), and t1/2 values of 97.1 hours and 79.1 hours, respectively. Statistical analysis of Cmax and AUC∞ further demonstrated bioequivalence between 125 micrograms peginterferon beta-1a IM and SC. The geometric mean ratio (90% confidence interval) of IM versus SC for Cmax was 1.08 (0.98 to 1.20) and 1.09 (1.02 to 1.16) for AUC∞. These values fall within the designated 0.80 to 1.25 equivalence range.
Following repeated subcutaneous administration of peginterferon beta-1a in rhesus monkeys at doses up to 400-fold (based on exposure, AUC) the recommended therapeutic dose; no effects other than the known mild pharmacological responses by rhesus monkeys to interferon beta-1a were observed after the first and second weekly dose. Repeated dose toxicology studies were limited to 5 weeks as exposure was greatly diminished from 3 weeks onwards, due to the formation of anti-drug antibodies by rhesus monkeys to human interferon beta-1a. Therefore, the long-term safety of chronic administration of Plegridy to patients cannot be assessed on the basis of these studies.
Peginterferon beta-1a was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) test and was not clastogenic in an in vitro assay in human lymphocytes.
Peginterferon beta-1a has not been tested for carcinogenicity in animals. Based on the known pharmacology of interferon beta-1a and clinical experience with interferon beta, the potential for carcinogenicity is expected to be low.
Peginterferon beta-1a has not been tested for reproductive toxicity in pregnant animals. Fertility and developmental studies in rhesus monkeys have been carried out with non-pegylated interferon beta-1a. At very high doses, anovulatory and abortifacient effects were observed in animals. No information is available on the potential effects of peginterferon beta-1a on male fertility. Upon repeated dosing with peginterferon beta-1a of sexually mature female monkeys, effects on menstrual cycle length and progesterone levels were observed. Reversibility of the effects on menstrual cycle length was demonstrated. The validity of extrapolating these non-clinical data to humans is unknown.
Data from studies with other interferon beta compounds did not show teratogenic potential. The available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited.
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