Abstract
Peginterferon β1a is a modified form of interferon β1a with a polyethylene glycol (PEG) group attached to the α-amino group of the N terminus of the interferon molecule. This modification alters the pharmacokinetic and pharmacodynamic properties of interferon β1a, enabling reduced frequency of dosing and may also result in reduced immunogenicity of the interferon β1a molecule. The efficacy of peginterferon β1a 125 µg administered subcutaneously every 2 or 4 weeks was demonstrated at the end of the placebo-controlled period in the phase III ADVANCE study; both dosing regimens met their primary endpoint of reducing annualized relapse rate (ARR) compared with placebo. Peginterferon β1a administered every 2 weeks resulted in a more robust treatment effect on ARR, sustained disability progression and magnetic resonance imaging endpoints (new or enlarging T2 lesions and gadolinium-enhanced lesions) than peginterferon β1a every 4 weeks. Further reductions in the ARR with additional positive impact on magnetic resonance imaging outcomes were noted in year 2 of the ADVANCE study with the every 2-week dosing regimen. An adverse-effect profile similar to other interferon β formulations coupled with the advantage of a significant reduction in the number of injections, could lead to improved long-term adherence to peginterferon β1a. We review the evidence base for the role of peginterferon β1a in the treatment of relapsing–remitting multiple sclerosis.
Introduction
Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system that has both inflammatory and demyelinating components [Compston and Coles, 2008]. The majority of people with MS present with the relapsing–remitting form of the disease (RRMS). This subtype of MS responds more favorably to our currently available MS disease-modifying therapies (DMTs). The number of DMTs approved for the treatment of relapsing forms of MS continues to grow worldwide, making the selection of therapy in an individual patient a highly complex task. The decision on which DMT to choose is often based on the risk versus benefit profile of the various treatment options. Several different forms of interferon β are utilized as DMTs for RRMS [Calabresi et al. 2014; European Study Group, 1998; Jacobs et al. 1996; The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group, 1995). The various interferon β formulations have a long track record of safety and efficacy, but the frequency of injections can often be a major hurdle for patients. This factor can impact adherence to treatment and ultimately impacts its effectiveness [Cohen et al. 2015]. Injection fatigue often occurs in patients who are initially willing to do frequent injections. Unfortunately, this can ultimately lead to discontinuation of the injectable medication [Agashivala et al. 2013]. In a recent study to determine patient preferences for injectable therapies for MS, reduced injection frequency was an important attribute that influences patient preference [Poulos et al. 2016]. The development of peginterferon β1a, a formulation of interferon β that allows for infrequent administration of injections provides an alternative therapy that could help improve adherence in the setting of injection fatigue while maintaining the efficacy of this class of DMTs.
PEGylation and effect on pharmacokinetic and pharmacodynamic properties
PEGylation is a process that has been utilized previously for multiple medications prior to being used with interferon β. PEGylation involves the covalent addition of one or more polyethylene glycol (PEG) groups to a drug and is employed for the purpose of improving the toxicity profile and efficacy of the drug. PEGylation generally enhances solubility, increases the circulation time and reduces the immunogenicity of the parent drug [Zhang et al. 2014].
Peginterferon β1a is a modified form of interferon β1a that has a PEG group attached to the α-amino group of the N terminus of interferon β1a. By altering its pharmacokinetics and pharmacodynamics this approach allows for a reduced dosing frequency of interferon β1a [Kieseier and Calabresi, 2012]. Two phase I studies showed an improved pharmacokinetic and pharmacodynamic profile of peginterferon β1a compared with intramuscular interferon β1a [Hu et al. 2011, 2012].
A pharmacokinetic study utilizing intensive blood draws from patients in the ADVANCE trial demonstrated that the maximal concentration of interferon was reached at 1–1.5 days and the half life was 2–3 days [Hu et al. 2014]. As expected, the area under the curve was twice as high for the every 2 weeks dosing compared with the every 4 weeks dosing, which may help explain the added efficacy of the more frequent dosing regimen. The pharmacodynamics of peginterferon β1a were assessed using serum neopterin concentrations (a marker induced by interferon β in vivo) [Bagnato et al. 2003]. Monitoring of the levels of neopterin demonstrated that levels peaked at day 3 after injection and remained elevated for about 2 weeks. These studies demonstrate that the addition of the PEG moiety to interferon β1a results in alterations in the pharamacokinetic and pharmacodynamic profile that allow for a reduced dosing frequency.
Efficacy of peginterferon β1a
The ADVANCE study was a 2-year, randomized, double-blind, parallel group phase III study, with a 1-year placebo-controlled period, comparing placebo with subcutaneous peginterferon β1a 125 μg every 2 weeks or 4 weeks in patients with RRMS [Calabresi et al. 2014]. Patients who were aged between 18 and 65 years and had an Expanded Disability Status Scale (EDSS) less than 5.5 were randomized in a 1:1:1 fashion, stratified by site to the three study groups. At the end of the 48-week period the placebo group was randomized to either peginterferon β1a 125 ug every 2 weeks or 4 weeks for the following 48 weeks. The 48-week time point was used to analyze primary efficacy and safety, while the 96-week time point provided information on safety, immunogenicity, and sustained efficacy.
Effect on relapses
The primary endpoint of the ADVANCE trial was the annualized relapse rate (ARR) at 48 weeks. Of 1936 patients who were screened, 1516 were enrolled and randomized to either the placebo arm (n = 500), peginterferon β1a every 2 weeks (n = 512) or 4 weeks (n = 500). The adjusted ARR in the placebo group was 0.397 [95% confidence interval (CI): 0.328–481], while the ARR in the peginterferon β1a every 2-week group was 0.256 (95% CI: 0.206–0.318, p = 0.0007) and in the every 4-week group it was 0.288 (95% CI: 0.234–0.355, p = 0.0114). These data demonstrate a relative reduction in ARR of 36% in the every 2-week group and 27% in the every 4-week group compared with placebo. The absolute reduction in the ARR was around 0.15 for peginterferon β1a every 2 weeks, which translates to a number needed to treat (NNT) of seven patients a year to reduce one clinical relapse. This NNT is similar to efficacy data for other interferon formulations. Both active treatment groups also showed a reduction in the proportion of patients who had a relapse in the first 48 weeks of the trial, with the reduction being greater in the every 2-week than the every 4-week group. Additional post hoc analyses showed that the proportion of relapses associated with sustained disability progression was reduced by peginterferon β1a every 2 weeks (13.6%) and every 4 weeks (14.2%) compared with placebo (19.6%), suggesting improved recovery from relapses in patients treated with peginterferon β1a [Kieseier et al. 2014].
Data from the 96-week time point showed further reduction in the ARR in the every 2-week group to 0.178 (95% CI: 0.136–0.233) with maintenance of the ARR in the every 4-week group. A post hoc analysis examining the effect of peginterferon β1a at the 12-week time point demonstrated a relative reduction in ARR of 37.4% (p = 0.045) in the peginterferon β1a every 2-week group compared with placebo [Newsome et al. 2015b]. This suggests a rapid onset of the immunomodulatory effect of peginterferon β1a, occurring as early as the third month of treatment.
The ATTAIN study is a 2-year phase IIIb extension study of the ADVANCE trial, that includes 376 patients in the every 2-week group and 354 patients in the every 4-week group. The year 3 results of this study demonstrated a similar ARR in year 3 (0.215) as in year 2 (0.201) in the peginterferon β1a every 2-week group.
Effect on disability progression
The proportion of patients with sustained 12-week disability progression at the end of the 48 weeks was 10.5% in the placebo group while in both peginterferon β1a groups this was reduced to 6.8 % (38% reduction in both active treatment groups; p = 0.012) [Calabresi et al. 2014]. At the 96-week time point in the ADVANCE trial the proportion of patients with 12-week sustained disability progression was significantly reduced by 33% in the every 2-week group compared with patients in the delayed treatment group. Additionally, 24-week sustained disability progression at the 96-week time point was 7.7% in the every 2-week group that was 41% lower than the proportion with sustained disability progression in the delayed-treatment group: 11.9% (p = 0.013) [Kieseier et al. 2015]. There was no difference in 12-week or 24-week sustained disability progression between the every 4-week group and the delayed-treatment group at the 96-week time point [Kieseier et al. 2015]. Thus, treatment with peginterferon β1a every 2 weeks reduced the occurrence of sustained disability progression compared with placebo as early as 48 weeks on treatment and at 96 weeks this effect was maintained compared with the delayed-treatment arm.
In the ATTAIN study at year 3 there was a significant reduction (38.9%, p = 0.0091) in the proportion of patients with sustained disability progression in the every 2-week group compared with the every 4-week group.
Effect on magnetic resonance imaging outcomes
Peginterferon β1a treatment every 2 weeks (3.6, 95% CI: 3.1–4.2, p < 0.0001) resulted in a 67% reduction in the number of new or enlarging T2 lesions at 48 weeks of treatment compared with the placebo group (10.9, 95% CI: 9.6–12.5) and a 55% reduction compared with the every 4-week group (7.9, 95% CI: 6.9–9.0) [Calabresi et al. 2014]. Additionally, the peginterferon β1a every 2-week group had a reduction of 47% in the number of new T1 hypointense lesions and a reduction of 86% in gadolinium-enhanced lesions at 48 weeks compared with the placebo group (p < 0.0001 for both). While the every 4-week group had a 28% reduction in the number of new or enlarging T2 lesions compared with the placebo group (p = 0.0008), the effect on new T1 hypointense or gadolinium-enhanced lesions was not significant. No significant change was noted in any of the groups for whole-brain volume at the end of the 48-week period. At the 96-week time point in the ADVANCE trial, both treatment groups demonstrated further reductions in the number of new or enlarging T2 lesions. In the every 2-week group the number was reduced by 47% to 1.9, while for the every 4-week group it was reduced by 29% to 5.6 compared with the number of lesions seen at year 1 [Kieseier et al. 2015]. In the ATTAIN extension study, the mean number of new or enlarging T2 lesions at year 3 (1.9) in the peginterferon β1a every 2-week group was similar to that seen at year 2 (1.9). The number of new T1 hypointense lesions and new gadolinium-enhanced lesions at year 3 was also similar to the number seen at the end of year 2.
Effect on no evidence of disease activity
Another measure of efficacy of DMTs is no evidence of disease activity (NEDA). NEDA is defined as the lack of clinical (new relapse or confirmed disability progression) or magnetic resonance imaging (MRI) (new or enlarging T2 lesions or new gadolinium-enhanced lesions) disease activity. Examining the effect of peginterferon β1a on NEDA in the ADVANCE trial revealed a significantly higher proportion of participants with NEDA over the course of the entire 48-week period in the every 2-week treatment group 33.9% compared with 21.5% in the every 4-week group and 15.1% in the placebo group (p < 0.0001 for both comparisons) [Arnold et al. 2014]. This was true for both MRI and clinical portions of the NEDA criteria. Another important observation in the analysis was that the every 2-week group demonstrated an increased proportion of NEDA in the 24–48-week time period (60.2%) compared with the baseline to 24-week time period (41.0%), while a similar effect was not noted in the other two groups.
Peginterferon β1a every 2 weeks provided a higher chance of achieving NEDA compared with the other two treatment groups, in addition to providing a superior reduction in multiple MRI disease activity outcomes.
Effect on quality of life measures
Besides clinical and imaging outcomes, patient-reported outcomes that reflect health-related quality of life (HRQoL) are also important in understanding the real world effectiveness of a drug. Patient-reported outcomes can help assess for issues such as fatigue and depression which can affect treatment adherence and ultimately treatment effectiveness. A study utilized multiple HRQoL measures, including the MS Impact Scale 29 (MSIS-29), the 12-item Short Form health survey (SF-12), and the EuroQoL-5D (EQ-5D) as measures of HRQoL in the ADVANCE trial [Hobart et al. 2001; Rabin and de Charro, 2001]. The response rate to these measures was over 90% and the data were collected every 12 weeks. The MSIS-29 is a disease-specific scale and measures both the physical and psychological impact of the disease on an individual’s quality of life. Over the course of the 48 weeks, the MSIS-29 physical subscale showed a decline (i.e. negative impact) in the placebo group, although there was no significant decline seen in the two treatment groups [Newsome et al. 2015a]. The MSIS-29 psychological subscale showed an improvement in all three groups over the 48-week observation period. The total number of relapses, having a recent relapse prior to assessment of HRQoL and confirmed disability progression were all associated with worsening of HRQoL scores.
Interestingly the decline in MSIS-29 physical subscale scores associated with confirmed disability progression was greatest in the placebo group (6.04 points) and was lower in both the treatment groups: 1.88 points in every 2-week group and 3.69 points in every 4-week group. This effect was attributed to the fact that the worsening in HRQoL scores was greatest among patients who experienced incomplete recovery from relapses and this number was higher in the placebo group than the peginterferon β1a arms. Examining the effect of relapses on HRQoL scores among the different treatment groups showed that patients in the placebo group had a greater decline in their MSIS-29 psychological subscale scores (9.95 points) following a relapse than either treatment group: 3.54 points (p = 0.031) in the every 2-week group and 6.04 points (p = 0.128) in the every 4-week group. An explanation for this phenomenon could be that the placebo group had more severe relapses than the treatment group, however in the ADVANCE trial the severity of relapses as measured by the EDSS was similar across all the treatment groups.
In the ADVANCE trial, peginterferon β1a every 2 weeks significantly improved low-contrast visual acuity (2.5% chart) at week 48 compared with placebo in patients with low-baseline low-contrast visual acuity. Additionally low-contrast visual acuity scores at week 48 correlated with physical and mental impairment scores [Jia et al. 2012].
These data suggest that peginterferon β1a every 2 weeks leads to a reduction in the impact of confirmed disability progression and relapses on HRQoL measures.
Adverse event profile of peginterferon β1a
The incidence of adverse events in the first 48-week period of the ADVANCE trial was lower in the placebo group (83%) than either of the treatment groups (94% in both). Adverse events that were more common in the treatment groups than placebo included injection site reactions (56–62%), flu-like illness (47%), pyrexia (44–45%) and headache (41–44%). The incidence of serious adverse events was similar in all three groups (placebo: 11%, every 2 weeks: 18% and every 4 weeks: 16%), with relapse being the most common serious adverse event. There was no increased risk of infections or death in the peginterferon β1a treated group compared with the placebo group. There was no difference noted in the occurrence of depression or mood-related disorders between the treatment and placebo groups.
A higher percentage of patients in the peginterferon β1a groups had reductions of blood counts and elevated liver enzymes compared with the placebo group. The majority of these were not clinically significant. Leukopenia of less than 3.0 × 109 cells per liter was seen in 7% of patients in the every 2-week group, 4% in the every 4-week group and 1% in those receiving placebo. Most increases in liver enzymes were less than three times the upper limit of normal. Increases of alanine aminotransferase greater than five times the upper limit of normal were observed in 1% of patients in the placebo group and 2% of patients in both treatment groups.
The results from the ADVANCE trial at the 96-week time point showed that the incidence of adverse events was similar in both treatment groups (94%) [Kieseier et al. 2015]. The most common adverse events were the same as those noted at 48 weeks. Serious adverse events were more common in the every 4-week group (22%) than the every 2-week group (16%), with the difference being driven primarily by increased relapses in the every 4-week group. The incidence of cytopenias remained below 10% in both groups in the second year of treatment. The elevation of hepatic enzymes greater than three times the upper limit of normal occurred in only one patient in year two of ADVANCE.
The safety profile of peginterferon β1a was similar at year 3 of the ATTAIN study.
Overall, peginterferon β1a was well tolerated and its adverse-effect profile appeared to mirror that of other formulations of interferon β1a.
A study utilized the Delphi technique to obtain a consensus on the occurrence of common side effects such as flu-like symptoms and injection-site reactions with peginterferon β1a use and the strategies that are commonly recommended to ameliorate them [Halper et al. 2015]. This study polled 30 investigators who had treated 394 patients in the ADVANCE trial and the responders agreed that the incidence and duration of these adverse effects generally reduced after the first 3 months of treatment. They also reached consensus that flu-like symptoms typically last less than 24 h and have mild to moderate impact on activities of daily living. They recommended that patients should take acetaminophen/nonsteroidal anti-inflammatory drugs on a scheduled basis and change the timing of injection to manage the flu-like symptoms. Injection site rotation, injection site cooling and administering the drug at room temperature were recommended for managing injection site reactions. Moreover, patient education on these adverse effects was advocated for all patients before treatment initiation.
Immunogenicity of peginterferon β1a
Patents treated with various interferon β preparations can develop antibodies reactive to interferon over time. These antibodies may be binding or neutralizing to the interferon molecule. Studies have demonstrated that the efficacy of interferons can be reduced in patients who develop these neutralizing antibodies, especially when they persist [Kappos et al. 2005]. The immunogenicity of peginterferon β1a was examined in patients who were included in the ADVANCE trial. In addition to antibodies to interferon, antibodies to the PEG moiety were also assessed.
This study revealed that at baseline a small proportion of patients had either interferon binding (2%) or neutralizing antibodies (<1%), while a larger proportion had antibodies against PEG (5.6%). The occurrence of anti-PEG antibodies at baseline is likely secondary to the fact that PEG is seen in several products that we utilize in daily life, such as toothpaste. Assessing for treatment-emergent antibodies in patients who received 2 years of peginterferon β1a or 1 year of placebo followed by peginterferon β1a demonstrated that the incidence of interferon binding antibodies was 6% (5% every 4 weeks, 8% every 2 weeks), neutralizing antibodies was less than 1% (both groups) and anti-PEG antibodies was 7% (8% every 4 weeks, 6% every 2 weeks) [Kieseier et al. 2015]. In the trial, subjects with any of these antibodies did not appear to have a reduced efficacy of their treatment, however this analysis was limited by the small sample size in the group of patients with antibodies. In another analysis the presence of anti-PEG antibodies or anti-interferon binding antibodies did not lead to a change in pharmacokinetic or pharmacodynamic properties of peginterferon β1a [Hu et al. 2015].
These data suggest that peginterferon β1a has a low potential for immunogenicity, which may represent an additional advantage over more frequently administered interferon preparations. The reduction in immunogenicity may be due to the PEG moiety shielding the interferon molecule from the immune system [Kang et al. 2009; Kieseier et al. 2015].
Role in MS therapy
The interferons have a record of long-term safety and efficacy in patients with RRMS. As pharmacogenomic approaches advance and biomarkers of response to specific therapies are discovered, it is likely that the subset of patients who show an optimal response to interferon treatment could be identified up front. This may help choose patients who would most benefit from this therapy. As a corollary, pharmacogenomic approaches may also identify those who would be likely to have significant adverse effects and would be a high-risk population to begin interferon treatment.
Summary of clinical and imaging efficacy outcomes for peginterferon β1a.
ARR, annualized relapse rate; CI, confidence interval; Gd, gadolinium; SE, standard error.
Currently, for the majority of patients with RRMS worldwide who are newly diagnosed, the initial choice of DMT will often be an injectable therapy (interferon β1a, interferon β1b, glatiramer acetate) given the favorable risk–benefit profile of these therapies. In such a setting, the ability to reduce the number of injections could significantly help improve adherence to therapy and ultimately improve effectiveness of the treatment.
Conclusion
The current evidence base establishes peginterferon β1a 125 µg given subcutaneously every 2 weeks as a safe and effective treatment option for patients with RRMS. The reduced frequency of injections and reduced immunogenicity make it an attractive alternative to other first-line therapies for RRMS.
Trial design of the ADVANCE clinical trial.
Footnotes
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P. Bhargava receives funding from the National Multiple Sclerosis Society through an Institutional Clinician Training Award. S.D. Newsome has participated in scientific advisory boards for Biogen, Genzyme, and Novartis, and has received research support (paid directly to the institution) from Biogen, Novartis, and the National Multiple Sclerosis Society.