Peginterferon Beta-1a (Plegridy®): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Therapeutic Role in Multiple Sclerosis

Introduction and Drug Profile

The Clinical Challenge of Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic, immune-mediated, and neurodegenerative disorder of the central nervous system (CNS) that represents a significant global health challenge.[1] The pathophysiology of MS is characterized by a complex interplay of inflammation and demyelination, wherein the body's own immune system erroneously targets and attacks the myelin sheath—the protective covering of nerve fibers in the brain, spinal cord, and optic nerves.[1] This autoimmune assault disrupts the normal transmission of nerve impulses, leading to a wide spectrum of debilitating neurological symptoms. These can include, but are not limited to, profound fatigue, alterations in gait and balance, bladder and bowel dysfunction, vision disturbances, abnormal muscle spasticity, and significant mood swings, including depression.[1]

MS is one of the most common causes of non-traumatic neurological disability in young adults, with a notable predilection for women over men.[1] The clinical course of the disease is heterogeneous, but the majority of patients are initially diagnosed with a relapsing-remitting form (RRMS), characterized by acute episodes of neurological dysfunction (relapses) followed by periods of partial or complete recovery (remissions).[3] Over time, many patients with RRMS may transition to a secondary progressive phase (SPMS), marked by a steady accumulation of disability, with or without superimposed relapses.[3]

The cornerstone of modern MS management is the use of disease-modifying therapies (DMTs). These agents are not curative but are designed to alter the underlying course of the disease by modulating or suppressing the immune system.[6] The primary goals of DMTs are to reduce the frequency and severity of clinical relapses, limit the development of new inflammatory lesions in the CNS as detected by magnetic resonance imaging (MRI), and ultimately slow the progression of irreversible disability.[4] The introduction of interferon-beta therapies in the 1990s marked a paradigm shift in MS treatment, offering the first effective means to proactively manage the disease.[8] However, the need for frequent injections associated with these first-generation therapies presented challenges to patient adherence and quality of life, creating an unmet need for treatments with improved convenience and tolerability.[10]

Peginterferon Beta-1a: An Overview

Peginterferon beta-1a, marketed globally under the brand name Plegridy® by Biogen, is a biological therapeutic developed specifically to address the limitations of earlier interferon treatments for MS.[12] It is a chemically modified version of interferon beta-1a, belonging to the immunomodulator and interferon class of DMTs.[3] The key innovation of peginterferon beta-1a lies in the process of pegylation—the covalent attachment of a polyethylene glycol (PEG) molecule to the interferon protein.[10]

This strategic molecular enhancement was designed to improve the drug's pharmacokinetic profile, most notably by decreasing its rate of clearance from the body and thereby extending its circulating half-life.[19] The direct clinical consequence of this prolonged biological activity is a significantly less frequent dosing schedule. Unlike other interferon therapies that require administration several times per week or weekly, peginterferon beta-1a is administered just once every two weeks.[2] This bi-weekly regimen offers a substantial improvement in convenience for patients managing a chronic condition, potentially enhancing long-term treatment adherence and overall quality of life.[25] As the only approved pegylated interferon for MS, it represents a significant advancement within its therapeutic class, proven to reduce relapses and delay disability progression.[1]

Drug Identification and Classification

For the purposes of precise scientific and regulatory communication, peginterferon beta-1a is defined by a specific set of identifiers and classifications. These data provide an unambiguous profile of the drug, facilitating its recognition in clinical, research, and pharmaceutical databases worldwide. A summary of these key properties is presented in Table 1.

Table 1: Drug Identification and Key Properties

Property	Identifier/Value	Source(s)
Generic Name	Peginterferon beta-1a	1
Brand Name	Plegridy®	1
Drug Type	Biotech	1
Drug Class	Interferons, Immunomodulators	3
ATC Code	L03AB13	13
DrugBank ID	DB09122	1
CAS Number	1211327-92-2	13
UNII	I8309403R0	13
Manufacturer	Biogen Inc.	14

Molecular Structure and Mechanism of Action

Biochemical Composition of Interferon Beta-1a

The active protein component of peginterferon beta-1a is a recombinant form of human interferon beta-1a. It is produced using recombinant DNA technology in a mammalian cell line, specifically Chinese Hamster Ovary (CHO) cells.[20] This production method ensures that the resulting protein is a glycoprotein with a molecular structure and biological activity consistent with its natural human counterpart. The protein consists of a single polypeptide chain containing 166 amino acids, with a sequence identical to that of endogenous human interferon beta.[11] The complete amino acid sequence is as follows [27]:

MSYNLLGFLQRSSNFQCQKLWQLNGRLEYCLKDRMNFDIPEEIKQLQQFQKEDAALTIYEMLQNIFAIFRQDSSSTGWNETIVENLLANVYHQINHLKTVLEEKLEKEDFTRGKLMSSLHLKRYYGRILHYLKAKEYSHCAWTIVRVEILRNFYFINRLTGYLRN

This core protein, like other interferons, is a cytokine that plays a crucial role in the body's innate immune response, possessing antiviral, antiproliferative, and immunomodulatory properties.[20]

The Pegylation Process: A Strategic Molecular Enhancement

The defining feature of peginterferon beta-1a is its modification through a process known as pegylation, a well-established biopharmaceutical strategy used since the 1970s to enhance the therapeutic properties of proteins and small-molecule drugs.[10] The process involves the covalent attachment of one or more molecules of polyethylene glycol (PEG), a non-toxic, non-immunogenic, and highly water-soluble polymer, to the drug substance.[10]

In the case of Plegridy®, this modification is highly specific. A single, linear methoxy poly(ethylene glycol) (mPEG) molecule with a molecular weight of 20,000 Daltons (20 kDa) is conjugated to the protein.[19] The attachment occurs at a precise location: the alpha-amino group of the N-terminal amino acid residue (methionine).[19] This is achieved using reductive amination chemistry involving an -O-2-methylpropionaldehyde linker, which creates a stable covalent bond between the PEG moiety and the interferon protein.[20]

The primary purpose of this strategic molecular enhancement is to improve the drug's pharmacokinetic and pharmacodynamic profile.[21] The attachment of the large 20 kDa PEG molecule significantly increases the hydrodynamic size of the interferon beta-1a protein. This increased size has two major consequences that fundamentally alter the drug's behavior in the body. First, it sterically hinders the protein from being filtered by the glomeruli in the kidneys, thereby substantially decreasing its rate of renal clearance.[20] Second, the PEG chain acts as a protective shield, masking the protein from recognition by proteolytic enzymes, which reduces its rate of degradation.[10] The combined effect of decreased renal clearance and reduced proteolysis is a dramatically extended circulating half-life, which is the foundational principle behind the drug's less frequent dosing schedule.[19]

Pharmacodynamics and Mechanism of Action

While the definitive mechanism of action of peginterferon beta-1a in multiple sclerosis remains to be fully elucidated, its therapeutic effects are believed to be mediated by the immunomodulatory properties of the interferon beta-1a protein portion of the molecule.[1] The drug exerts its biological effects by binding with high affinity to the ubiquitous Type I interferon receptor (IFNAR) present on the surface of various cell types.[19] This binding event triggers a complex intracellular signaling cascade, primarily through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. This cascade culminates in the translocation of transcription factor complexes to the nucleus, leading to the regulation of a large number of interferon-responsive genes.[20]

The products of these genes are thought to mediate the anti-inflammatory and immunomodulatory effects observed in MS patients. Although the pathogenesis of MS is multifaceted, the therapeutic actions of peginterferon beta-1a are likely exerted through several key mechanisms targeting the autoimmune response [1]:

• Modulation of Cytokine Balance: The drug is believed to shift the cytokine profile from a pro-inflammatory state to an anti-inflammatory one. It achieves this by down-regulating the expression of pro-inflammatory cytokines such as interleukin-2 (IL-2), IL-12, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), while simultaneously up-regulating the expression of anti-inflammatory cytokines like IL-4, IL-10, and IL-27.[20]
• Inhibition of T-Cell Activity: Peginterferon beta-1a reduces the proliferation of pathogenic T-cells and decreases antigen presentation, which are critical steps in the autoimmune cascade.[1] It also helps restore the function of suppressor T-cells, which are important for maintaining immune tolerance.[1]
• Reduction of CNS Infiltration: The therapy is thought to inhibit the migration of activated immune cells, particularly T-lymphocytes, across the blood-brain barrier into the central nervous system. This is achieved in part by modifying the expression of matrix metalloproteinases (MMPs) and adhesion molecules that facilitate this infiltration.[1]

The pharmacodynamic response to peginterferon beta-1a can be quantified by measuring the induction of specific biomarkers, such as neopterin and the enzyme 2',5'-oligoadenylate synthetase (2',5'-OAS).[20] Studies have demonstrated that the pegylated form of the drug induces a more robust and, critically, a more prolonged biological response compared to non-pegylated interferon beta-1a. Following administration of peginterferon beta-1a, elevated levels of these biomarkers are sustained for up to 10 to 15 days, whereas the response to non-pegylated forms returns to baseline within 4 to 5 days.[20]

This sustained pharmacodynamic effect is a direct consequence of the drug's altered pharmacokinetic profile conferred by pegylation. The prolonged presence of the drug in the circulation allows for continuous engagement with the Type I interferon receptor, maintaining the downstream signaling and gene expression for an extended period. This provides a clear biological rationale for the efficacy of the bi-weekly (14-day) dosing interval. The duration of the pharmacodynamic response aligns almost perfectly with the dosing schedule, ensuring that a therapeutic level of immunomodulatory activity is maintained between injections. This causal link—from the specific 20 kDa mPEG chemical modification to the extended pharmacokinetic profile, which in turn drives the sustained pharmacodynamic response—is what ultimately validates the clinical convenience and efficacy of the bi-weekly regimen. The development program, which compared the bi-weekly regimen to a four-weekly regimen, further confirmed that this sustained exposure is critical for optimal efficacy.[32]

Comprehensive Pharmacokinetic (PK) Profile

Absorption, Distribution, Metabolism, and Elimination (ADME)

The pharmacokinetic profile of peginterferon beta-1a is fundamentally shaped by its pegylated structure, leading to distinct ADME characteristics compared to its non-pegylated precursor.

• Absorption: Following subcutaneous (SC) administration in patients with MS, serum concentrations of peginterferon beta-1a increase rapidly. The time to reach maximum serum concentration (Tmax) is typically between 1 and 1.5 days (24 to 36 hours) post-dose.[19] The absorption phase is followed by a characteristic plateau phase where serum concentrations remain elevated for approximately 3 to 4 days, after which they begin a gradual mono-phasic decline.[19] The observed mean maximum concentration (Cmax) after repeated dosing of 125 micrograms every two weeks is approximately 280 pg/mL.[20] The pharmacokinetics have been shown to be dose-proportional within the range of 63 to 188 micrograms, indicating linear absorption kinetics.[19]
• Distribution: Peginterferon beta-1a is widely distributed throughout the body following administration. This is evidenced by a large apparent volume of distribution (Vd) at steady state, which has been measured at approximately 481 L in MS patients receiving the 125 microgram bi-weekly dose.[20]
• Metabolism and Elimination: The clearance of peginterferon beta-1a involves two primary pathways corresponding to its two components: the protein and the PEG moiety. The interferon beta-1a protein portion is expected to undergo catabolism into smaller peptides and amino acids through standard protein degradation pathways.[20] The major route of elimination for the intact drug and the PEG moiety is renal clearance.[20] The mean steady-state clearance of peginterferon beta-1a in MS patients is approximately 4.1 L/hr.[20] The terminal half-life (t1/2) at steady state is approximately 78 hours, a significant prolongation that underpins its extended dosing interval.[20]

Comparative Pharmacokinetics: The Impact of Pegylation

The process of pegylation profoundly alters the pharmacokinetic properties of interferon beta-1a, resulting in a molecule with substantially increased systemic exposure and a longer duration of action. A direct comparison with non-pegylated interferon beta-1a quantitatively illustrates the magnitude of this effect.

The terminal half-life of peginterferon beta-1a is approximately two-fold longer than that of non-pegylated interferon beta-1a administered intramuscularly.[19] While this extension of half-life is significant, the most dramatic difference is observed in the total drug exposure, as measured by the area under the concentration-time curve (AUC). Following a single 125 microgram SC dose, peginterferon beta-1a results in an AUC that is approximately 9- to 11-fold higher than that achieved with a standard 30 microgram IM dose of non-pegylated interferon beta-1a.[19] This massive increase in total exposure is the primary driver of the drug's enhanced and sustained pharmacodynamic effects. This "high and sustained" exposure profile is central to understanding both the drug's therapeutic benefits and its tolerability profile. The greater drug exposure is directly correlated with improved efficacy, as demonstrated in exposure-efficacy models derived from clinical trial data.[19] However, this same sustained, high-level stimulation of the interferon system is also the likely contributor to the high incidence of characteristic interferon-related adverse events, such as flu-like symptoms and the need for vigilant monitoring of liver enzymes and blood cell counts.[18]

Administration Routes: Subcutaneous (SC) vs. Intramuscular (IM)

Peginterferon beta-1a was initially developed and approved for subcutaneous administration.[1] In 2021, an intramuscular (IM) route of administration was also approved by regulatory agencies, including the U.S. FDA.[1] This subsequent approval was not based on new large-scale efficacy trials but on the results of a Phase 1, open-label, crossover study in healthy adult volunteers.[26]

This study was designed to evaluate the bioequivalence of the IM and SC routes. The results demonstrated that the pharmacokinetic and pharmacodynamic profiles were comparable between the two administration methods.[26] Key PK parameters such as Cmax and AUC were shown to be bioequivalent, meaning that the systemic exposure to the drug is the same regardless of whether it is injected under the skin or into the muscle.[36] The primary rationale for developing the IM route was to improve local tolerability. The bioequivalence study confirmed that participants receiving the IM injection experienced significantly fewer injection site reactions compared to those receiving the SC injection (14.4% vs. 32.1%).[36] The approval of the IM route can be viewed as a strategic lifecycle management initiative aimed at improving the drug's overall risk-benefit balance. It offers clinicians and patients an alternative that mitigates a common and bothersome local side effect while preserving the systemic exposure profile responsible for the drug's established efficacy.

Influence of Patient Factors (Covariates)

Population pharmacokinetic analyses have been conducted to identify patient-specific factors, or covariates, that may influence the drug's disposition in the body. The most significant covariate identified for peginterferon beta-1a is body mass index (BMI).[19] The analysis revealed a negative correlation between BMI and drug exposure; that is, individuals with a higher BMI tend to have lower Cmax and AUC values. This is because BMI impacts both the clearance and the volume of distribution of the drug.[19] Despite this statistical correlation, the effect is not considered clinically significant enough to warrant dose adjustments based on body size.

Other demographic factors have been found to have no meaningful impact on the drug's pharmacokinetics. Specifically, population PK analyses have shown no effect of gender or race on the clearance of peginterferon beta-1a.[20] A dedicated post-hoc analysis of a bioequivalence study further confirmed that there were no clinically meaningful differences in the PK or PD profiles between Black and White participants, supporting the conclusion that no dose adjustments are necessary based on race.[35] Similarly, while clinical experience in patients over the age of 65 is limited, pharmacokinetic modeling suggests that age does not significantly impact drug clearance.[18]

In patients with renal impairment, systemic exposure to peginterferon beta-1a can be increased. However, for patients with end-stage renal disease, hemodialysis can partially remove the drug from circulation, reducing concentrations by approximately 24% per session.[20] The pharmacokinetics have not been formally studied in patients with hepatic impairment.[20]

Table 2: Summary of Key Pharmacokinetic Parameters

Parameter	Peginterferon beta-1a (125 mcg SC)	Peginterferon beta-1a (125 mcg IM)	Non-pegylated IFN beta-1a (30 mcg IM)
Tmax (Time to Peak Concentration)	1 – 1.5 days	Bioequivalent to SC	Later Tmax than pegylated form
Cmax (Peak Concentration)	~280 pg/mL (at steady state)	Bioequivalent to SC	Lower Cmax than pegylated form
AUC (Total Exposure)	~9- to 11-fold higher than non-pegylated form	Bioequivalent to SC	Baseline for comparison
t1/2 (Terminal Half-life)	~78 hours (at steady state)	Bioequivalent to SC	~2-fold shorter than pegylated form
Clearance (CL/F)	~4.1 L/hr (at steady state)	Bioequivalent to SC	Higher clearance than pegylated form
Vd (Volume of Distribution)	~481 L (at steady state)	Bioequivalent to SC	Not specified
Sources: 19

Clinical Efficacy in Relapsing Multiple Sclerosis

The clinical efficacy and safety of peginterferon beta-1a have been rigorously established through a comprehensive clinical development program, highlighted by the pivotal Phase 3 ADVANCE trial and its long-term extension study, ATTAIN. These studies provide the primary evidence base supporting the drug's global regulatory approvals.

The ADVANCE Trial (Pivotal Phase 3 Study)

The ADVANCE (Efficacy and Safety Study of Peginterferon Beta-1a in Participants With Relapsing Multiple Sclerosis) trial was a large-scale, two-year, randomized, double-blind, multicenter, global study that enrolled 1,512 patients with relapsing-remitting MS.[24] The design of the study was robust, with a one-year placebo-controlled period that is considered the gold standard for establishing efficacy. During this first year, patients were randomized in a 1:1:1 ratio to receive one of three treatments: placebo, peginterferon beta-1a 125 mcg administered subcutaneously every 2 weeks (Q2W), or peginterferon beta-1a 125 mcg administered subcutaneously every 4 weeks (Q4W).[24] After the first year, patients in the placebo group were re-randomized to one of the two active treatment arms for the second year of the study.[24]

The primary objective of the ADVANCE trial was to determine the efficacy of peginterferon beta-1a in reducing the annualized relapse rate (ARR) at one year compared to placebo.[19] Secondary endpoints included several other critical measures of disease activity, such as the proportion of patients who relapsed, the time to confirmed disability progression, and various MRI-based outcomes that serve as objective biomarkers of CNS inflammation.[20]

The results from the first year of the ADVANCE trial demonstrated that peginterferon beta-1a, particularly at the every-2-weeks dosing regimen, was highly effective in controlling MS disease activity. The treatment met its primary endpoint and all secondary endpoints with statistical significance. The key efficacy outcomes for the approved Q2W dose versus placebo are summarized in Table 3.

Table 3: Pivotal Efficacy Results from the ADVANCE Trial (Year 1, Every-2-Weeks vs. Placebo)

Efficacy Endpoint	Plegridy® 125 mcg every 2 weeks	Placebo	Relative Reduction (%)	p-value
Annualized Relapse Rate (ARR)	0.256	0.397	36%	0.0007
Proportion of Patients Relapsing	18.7%	29.1%	39% (risk reduction)	0.0003
Risk of 12-week Confirmed Disability Progression	6.8%	10.5%	38% (risk reduction)	0.0383
Mean Number of New Gd+ Lesions	0.2	1.4	86%	<0.0001
Mean Number of New/Newly Enlarging T2 Lesions	3.6	10.9	67%	<0.0001
Sources: 20

These results highlight the robust effect of peginterferon beta-1a on both clinical and radiological measures of MS. The profound reduction in MRI lesion activity—an 86% decrease in new gadolinium-enhancing (Gd+) lesions and a 67% decrease in new or newly enlarging T2 lesions—is particularly noteworthy. Gd+ lesions represent areas of active inflammation and breakdown of the blood-brain barrier, while T2 lesions reflect the overall burden of disease, including both acute and chronic inflammation and demyelination. The dramatic suppression of these objective biomarkers provides strong evidence of the drug's potent biological effect on the underlying inflammatory pathology of MS, complementing the significant reductions observed in clinical relapses and disability progression.

The study also provided crucial data comparing the Q2W and Q4W dosing regimens. While both active treatment arms were superior to placebo, the Q2W regimen consistently demonstrated numerically greater efficacy across all clinical and MRI endpoints.[5] This finding was instrumental in the regulatory review process, with agencies like the European Medicines Agency (EMA) concluding that the every-two-weeks dosing provided a greater benefit and was the appropriate regimen to recommend for clinical use.[5] The positive treatment effects observed in the first year were subsequently maintained throughout the second year of the study, confirming the durable efficacy of the therapy.[39]

The ATTAIN Trial (Long-Term Extension Study)

Following the completion of the two-year ADVANCE trial, eligible patients were invited to enroll in the ATTAIN (ADVANCE Extension) study, a two-year, open-label extension designed to evaluate the long-term safety and efficacy of peginterferon beta-1a.[37] This study provided an opportunity to assess the durability of the treatment effect and gather safety data over a prolonged period, with some patients receiving continuous treatment for up to nearly six years.[37]

The findings from ATTAIN confirmed the sustained efficacy of peginterferon beta-1a. Patients who continued on the Q2W regimen maintained low rates of disease activity. Over a six-year period encompassing both ADVANCE and ATTAIN, the adjusted ARR for the continuous Q2W group remained low at 0.188.[41] The benefits on MRI outcomes and disability progression were also maintained over the long term.[39] For example, through 240 weeks of treatment, 85% of patients taking Plegridy® had no worsening of physical disability.[37]

The ATTAIN study also reinforced the superiority of the Q2W dosing schedule. The long-term data showed a significantly lower ARR over six years for the Q2W group compared to the Q4W group.[41] This accumulating evidence led to a protocol amendment during the ATTAIN study, in which all remaining patients on the every-4-weeks dosing schedule were switched to the every-2-weeks regimen, effectively validating the Q2W dose as the optimal therapeutic strategy.[37]

Furthermore, analyses of the ATTAIN data explored the composite endpoint of "No Evidence of Disease Activity" (NEDA), which is defined as the absence of relapses, confirmed disability progression, and new MRI activity. A substantial proportion of patients treated with peginterferon beta-1a were able to achieve NEDA, with rates of 34.8% in year one, 54.3% in year two, and 48.7% in year three, demonstrating a durable and comprehensive control of disease activity in a large subset of patients.[39] The clinical development program for peginterferon beta-1a, therefore, serves not only as a validation of the drug's efficacy but also as a real-world experiment that systematically identified and confirmed the optimal dosing regimen for maximizing clinical benefit.

Safety, Tolerability, and Risk Management

The safety profile of peginterferon beta-1a has been well-characterized through its extensive clinical trial program and post-marketing experience. It is generally consistent with the known safety profile of the interferon-beta class of therapies, with the most common adverse events being manageable and typically decreasing over time. However, there are also several rare but serious risks that require careful monitoring and patient counseling.

Common Adverse Events and Mitigation

The most frequently reported adverse events associated with peginterferon beta-1a are flu-like symptoms and injection site reactions.[2]

• Flu-like Symptoms: These are very common and include a constellation of symptoms such as headache, muscle aches (myalgia), joint pain (arthralgia), fever (pyrexia), and chills.[13] These symptoms are most prominent at the initiation of therapy and tend to decrease in both frequency and severity with continued treatment.[18] Several strategies are employed to mitigate these effects. The most important is a mandatory dose titration schedule at the start of treatment, where patients begin with a lower dose (63 mcg) and gradually increase to the full 125 mcg dose over the first month.[2] This allows the body to acclimate to the medication. Additionally, patients are often advised to take the injection in the evening to sleep through the worst of the symptoms and to use prophylactic or concurrent over-the-counter analgesics and/or antipyretics, such as paracetamol or ibuprofen, on treatment days.[18]
• Injection Site Reactions (ISRs): As a subcutaneously or intramuscularly administered drug, local reactions at the injection site are common. These typically include redness (erythema), pain, swelling, itching (pruritus), and warmth.[13] In the ADVANCE trial, injection site erythema was the single most common adverse event, reported by 62% of patients on the Q2W regimen.[21] These reactions are usually mild to moderate in severity. Proper injection technique, including the rotation of injection sites (abdomen, thighs, back of upper arms), is crucial to minimize the occurrence and severity of ISRs.[34] In rare cases, more severe reactions such as injection site necrosis (tissue damage) can occur, which requires immediate medical attention and may necessitate discontinuation of the drug.[34] The development of the intramuscular route of administration was specifically aimed at reducing the incidence of ISRs.[36]

Serious Warnings and Precautions

While generally well-tolerated, peginterferon beta-1a carries several warnings and precautions for potentially serious adverse events that require clinical vigilance and regular monitoring.

• Hepatic Injury: Severe hepatic injury, including hepatitis, autoimmune hepatitis, and rare cases of severe hepatic failure leading to death, have been reported with interferon beta products.[29] Asymptomatic elevations in serum hepatic transaminases (liver enzymes) were also observed in clinical trials with peginterferon beta-1a.[29] Therefore, it is mandatory for patients to undergo regular monitoring of liver function tests before and during treatment. Patients should be educated on the signs and symptoms of liver dysfunction (e.g., jaundice, nausea, loss of appetite, dark urine) and instructed to report them immediately. If significant hepatic injury occurs, discontinuation of the therapy should be considered.[18]
• Depression and Suicidal Ideation: The use of interferons has been associated with an increased risk of depression and suicidal thoughts.[18] This is particularly relevant as depression is already more prevalent in the MS population. Patients, families, and caregivers should be advised to report any symptoms of new or worsening depression, suicidal ideation, or other severe psychiatric symptoms to their healthcare provider immediately. If a patient develops severe depression, discontinuation of peginterferon beta-1a should be strongly considered.[46]
• Hematological Abnormalities: Peginterferon beta-1a can cause a decrease in peripheral blood counts across all cell lines. This can manifest as leukopenia (low white blood cell count), which increases the risk of infection, and thrombocytopenia (low platelet count), which can impair blood clotting.[18] Rare cases of pancytopenia (a severe reduction in all blood cell types) have also been reported.[29] Consequently, regular monitoring of complete blood counts, with differential and platelet counts, is a required part of patient management.[18]
• Other Serious Risks: Other important warnings include the potential for congestive heart failure in patients with pre-existing cardiac disease, the occurrence of seizures (requiring caution in patients with a seizure disorder), and the rare but life-threatening risk of serious allergic reactions, including anaphylaxis.[37] Additionally, rare cases of thrombotic microangiopathy (TMA), a condition involving blood clots in small blood vessels, and nephrotic syndrome have been reported with interferon-beta products.[30]

Contraindications and Special Populations

Peginterferon beta-1a is strictly contraindicated in individuals with a known history of hypersensitivity to natural or recombinant interferon beta, peginterferon, or any other component of the formulation.[18]

The drug was also previously contraindicated in patients with current severe depression and/or suicidal ideation.[18] While this remains a critical area for monitoring, the absolute contraindication may vary by jurisdiction.

The use of peginterferon beta-1a during pregnancy was historically contraindicated. However, this has evolved based on accumulating post-marketing data. Large observational studies and registry data, including over 1,000 pregnancy outcomes, have not shown an increased risk of major congenital anomalies following exposure to interferon beta before conception or during the first trimester.[48] Based on this real-world evidence, the EMA's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion in 2019 to remove the pregnancy contraindication, allowing for the use of interferon beta therapies, including Plegridy®, during pregnancy and breastfeeding if clinically needed.[48]

The safety and efficacy in pediatric patients have not been established. Use in elderly patients (over 65 years of age) is limited, as this population was not well-represented in clinical trials.[18]

Drug-Drug Interactions

Peginterferon beta-1a has the potential for several clinically significant drug-drug interactions. Due to its immunomodulatory effects, co-administration with other immunosuppressant or immunomodulating agents (e.g., abatacept, adalimumab, alemtuzumab, aldesleukin) may increase the risk or severity of adverse effects, including infection.[1] Caution is also warranted when combining peginterferon beta-1a with myelosuppressive agents (e.g., allopurinol) due to the potential for additive effects on blood cell counts.[1] Furthermore, because interferon therapy can cause thrombocytopenia, there is an increased risk of bleeding when it is combined with anticoagulant or antiplatelet medications, such as acenocoumarol, abciximab, and acetylsalicylic acid.[1]

Table 4: Common and Serious Adverse Events

System Organ Class	Common Adverse Events (Incidence >10%)	Serious Adverse Events / Warnings & Precautions
General Disorders and Administration Site Conditions	Injection site erythema (62%), Flu-like illness (47%), Pyrexia (fever) (45%), Chills, Asthenia (weakness), Injection site pain/pruritus	Anaphylaxis and other serious allergic reactions
Nervous System Disorders	Headache (41%)	Seizures
Musculoskeletal and Connective Tissue Disorders	Myalgia (muscle pain), Arthralgia (joint pain)
Hepatobiliary Disorders		Hepatic injury (including hepatitis, autoimmune hepatitis, and rare severe hepatic failure)
Psychiatric Disorders		Depression and suicidal ideation
Blood and Lymphatic System Disorders		Decreased peripheral blood counts (leukopenia, thrombocytopenia, rare pancytopenia)
Cardiac Disorders		Congestive heart failure (in patients with pre-existing cardiac disease)
Renal and Urinary Disorders		Thrombotic Microangiopathy (TMA), Nephrotic Syndrome
Sources: 13

Dosing, Administration, and Patient Guidance

The effective and safe use of peginterferon beta-1a relies on adherence to approved indications, a specific dosing and titration schedule, and proper patient education regarding administration and storage. The manufacturer also provides a comprehensive support system to assist patients throughout their treatment journey.

Approved Indications

Peginterferon beta-1a is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis. In the United States, this indication is broad and encompasses the full spectrum of relapsing MS, including [1]:

• Clinically Isolated Syndrome (CIS): A first episode of neurological symptoms lasting at least 24 hours, which is suggestive of MS.
• Relapsing-Remitting MS (RRMS): The most common form of MS, characterized by distinct relapses and remissions.
• Active Secondary Progressive MS (SPMS): A phase of the disease characterized by progressive worsening of neurological function, with continued evidence of inflammatory relapse activity.

In the European Union, the therapeutic indication is more narrowly defined for the treatment of adult patients with relapsing-remitting multiple sclerosis.[13]

Dosage and Titration Schedule

The recommended full dose of peginterferon beta-1a is 125 micrograms administered every 14 days (two weeks) via either subcutaneous or intramuscular injection.[3]

To enhance tolerability and minimize the impact of flu-like symptoms, a mandatory dose titration schedule must be followed at the initiation of therapy. This gradual dose escalation allows the patient's body to adapt to the medication. The schedule is as follows [29]:

• Dose 1 (Day 1): 63 micrograms
• Dose 2 (Day 15): 94 micrograms
• Dose 3 (Day 29): 125 micrograms (full dose)

Thereafter, the patient continues with the full 125 microgram dose every 14 days. To facilitate this titration process, the manufacturer provides a specific Initiation Pack (or Starter Pack) that contains the first two doses in pre-filled syringes or auto-injector pens. These are color-coded for safety and ease of use: the 63 mcg dose is labeled in orange, the 94 mcg dose in blue, and the full 125 mcg maintenance dose in grey.[2]

Patient Administration and Storage

Proper administration technique and storage are critical for the efficacy and safety of peginterferon beta-1a.

• Administration: While patients can be trained to self-administer the medication at home, it is recommended that the very first injection be performed under the supervision of an appropriately qualified healthcare professional.[18] This initial supervised injection ensures the patient is comfortable and proficient with the technique. The medication is available in single-use pre-filled syringes and auto-injector pens with the needle pre-attached.[2] To minimize local skin reactions, patients must be instructed to rotate the injection site with each dose. Common sites for subcutaneous injection include the abdomen, the back of the upper arms, and the thighs.[34]
• Storage and Handling: Peginterferon beta-1a must be stored in a refrigerator at a temperature between 2°C and 8°C (36°F to 46°F).[2] It is crucial that the medication is not frozen; if it freezes, it must be discarded. It should be kept in its original carton to protect it from light. Before injection, the syringe or pen should be removed from the refrigerator and allowed to warm to room temperature for about 30 minutes. External heat sources, such as hot water, must not be used for warming.[30] If refrigeration is not available, the medication can be stored at room temperature (up to 25°C or 30°C) for a cumulative period of up to 30 days, but it must still be protected from light.[2]

Patient Support Programs

Recognizing that managing a chronic illness like MS involves challenges beyond the medication itself, the manufacturer, Biogen, has established a comprehensive patient support program called Biogen Support Services.[47] This program is designed to provide a holistic support system that addresses practical, financial, and educational needs, thereby facilitating long-term adherence and optimizing treatment outcomes. This integrated approach demonstrates an understanding that the medication is part of a larger therapeutic system. This system combines the drug's clinical benefits with user-focused product design (e.g., auto-injectors, color-coded titration packs), a proactive tolerability protocol (the titration schedule), and robust support services. This holistic paradigm is essential for successful long-term management of a chronic illness.

The services offered include:

• Financial and Insurance Assistance: Biogen Support Coordinators provide one-on-one assistance to help patients and their healthcare providers navigate the complexities of insurance coverage. They can help with understanding benefits, managing the prior authorization process, and appealing denied claims.[47] For eligible, commercially insured patients, the Biogen Copay Program can significantly reduce out-of-pocket costs, potentially to as little as $0 per prescription, subject to an annual cap.[44] The program also helps research other financial assistance options for patients who are uninsured, underinsured, or covered by government plans.[50]
• Nurse Educators: Registered nurses, many of whom are MS-certified, are available to provide personalized support to patients. They offer supplemental injection training for patients and their care partners, either in-home or virtually. They also provide education about the therapy, answer questions about what to expect during treatment, and offer practical strategies for mitigating common side effects like flu-like symptoms and injection site reactions.[47] This direct educational support empowers patients to manage their treatment more effectively.

Regulatory History and Market Context

Global Regulatory Approvals

The regulatory journey of peginterferon beta-1a reflects a process of continuous development and data-driven refinement. The initial approvals were based on the robust evidence from the ADVANCE trial, with subsequent label updates expanding its utility based on new clinical and real-world data.

• United States (FDA):
• Biogen submitted its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) in May 2013.[14]
• On August 15, 2014, the FDA granted initial approval for Plegridy® for the treatment of relapsing forms of MS, administered via subcutaneous (SC) injection.[1]
• On February 1, 2021, the FDA approved a new intramuscular (IM) route of administration. This approval was based on data from a Phase 1 bioequivalence study that demonstrated comparable systemic exposure and a more favorable local tolerability profile (fewer injection site reactions) compared to the SC route.[1]
• European Union (EMA):
• The European Commission (EC), on the recommendation of the European Medicines Agency (EMA), granted marketing authorization for Plegridy® for the treatment of adults with RRMS on July 18, 2014.[5]
• The IM route of administration was subsequently approved by the EC in December 2020, shortly before the corresponding FDA approval.[55]
• A significant regulatory evolution occurred in September 2019, when the EMA's Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion to remove the contraindication for use during pregnancy and breastfeeding for the entire interferon-beta class, including Plegridy®. This landmark decision was not based on new randomized trials but on a comprehensive review of real-world evidence from large patient registries and post-marketing data, which showed no increased risk of adverse pregnancy outcomes.[48]

This regulatory history highlights two distinct phases of innovation. The first was a pre-approval, research-and-development-driven molecular innovation—the pegylation technology itself, which enabled the convenient bi-weekly dosing. The second phase consists of post-approval, data-driven lifecycle innovations. These include the development of the IM route, a formulation change driven by patient tolerability data, and the RWE-based label expansion for use in pregnancy, a regulatory science advancement. This demonstrates how a drug's therapeutic value can continue to be enhanced long after its initial launch through both targeted product improvements and the strategic application of real-world data.

Positioning within MS Therapies

Peginterferon beta-1a entered a dynamic and evolving landscape of MS treatments. Its position is best understood in the context of both the established interferon class and the newer, often more potent, DMTs.

• Innovation within the Interferon Class: Within the class of interferon-beta therapies, peginterferon beta-1a represents a significant advancement. Older interferon products, such as interferon beta-1b and other forms of interferon beta-1a, require more frequent injections, ranging from every other day to three times per week or weekly.[8] The bi-weekly schedule of Plegridy® offers a substantial reduction in injection burden, a key factor in improving patient convenience and potentially long-term adherence.[2]
• Place in the Broader DMT Landscape: Peginterferon beta-1a is generally classified as a moderately effective DMT. Clinical trials demonstrated an annualized relapse rate reduction of approximately 36% compared to placebo.[5] This level of efficacy is comparable to other first-line injectable therapies but may be lower than that of some newer high-efficacy therapies.[57] The MS treatment landscape now includes a wide array of options with different mechanisms of action, including oral medications (e.g., dimethyl fumarate, fingolimod) and high-efficacy infusion therapies, such as monoclonal antibodies that target CD20 (e.g., ocrelizumab) or prevent lymphocyte trafficking (e.g., natalizumab).[57] These newer agents often demonstrate higher rates of relapse reduction, with some showing reductions of 50% or more.[57]

Despite the availability of more potent therapies, interferons like peginterferon beta-1a continue to hold an important place in MS management. Their primary strength lies in their extensive and well-characterized long-term safety profile.[21] Having been in clinical use for decades, the risks associated with the interferon class are well understood by clinicians, and there are established strategies for monitoring and management. This makes them a reliable and often-preferred first- or second-line treatment option, particularly for patients and physicians who prioritize a long track record of safety over the highest possible efficacy, or for whom the risks of more potent immunosuppressants are a concern.[8]

Conclusion and Future Perspectives

Synthesis of the Risk-Benefit Profile

Peginterferon beta-1a presents a well-defined and favorable risk-benefit profile for the treatment of relapsing forms of multiple sclerosis. Its clinical value is anchored in robust and durable efficacy, demonstrated through a comprehensive clinical trial program. The therapy significantly reduces the annualized relapse rate, limits the formation of new inflammatory CNS lesions, and delays the progression of physical disability. This efficacy is a direct result of its innovative molecular design—the pegylation of interferon beta-1a—which creates a unique pharmacokinetic profile characterized by a prolonged half-life and substantially increased systemic exposure. This profile, in turn, drives a sustained immunomodulatory effect that validates the drug's primary convenience advantage: a bi-weekly dosing regimen that significantly reduces injection burden compared to older interferon therapies.

The safety profile of peginterferon beta-1a is well-characterized and consistent with the extensive experience of the interferon class. The most common adverse events, flu-like symptoms and injection site reactions, are predictable, generally manageable with proactive strategies like dose titration and symptomatic treatment, and tend to diminish over time. However, the use of peginterferon beta-1a also necessitates clinical vigilance and regular laboratory monitoring for rare but serious risks, including hepatic injury, depression and suicidal ideation, and hematological abnormalities. The balance of proven, moderate efficacy against a well-understood and manageable safety profile makes it a compelling therapeutic choice.

Concluding Remarks

Peginterferon beta-1a (Plegridy®) has firmly established itself as a valuable and reliable therapeutic option in the long-term management of multiple sclerosis. It successfully addressed a key unmet need within the interferon class by offering a less frequent dosing schedule without compromising the established efficacy and safety of interferon-beta therapy. The continuous evolution of the product, including the addition of an intramuscular administration route to improve local tolerability and the data-driven revision of guidance on its use during pregnancy, has further enhanced its clinical utility and patient-centric appeal.

In an increasingly complex and crowded therapeutic landscape, which now includes numerous oral agents and high-efficacy monoclonal antibodies, peginterferon beta-1a maintains a distinct and important role. It represents a balance between moderate, durable efficacy and a long-term safety record that provides a high degree of confidence for both clinicians and patients. For many individuals with relapsing MS, particularly those for whom a long history of safety is a priority or who are initiating their first disease-modifying therapy, peginterferon beta-1a remains a cornerstone of treatment, embodying a significant and enduring innovation in the fight against multiple sclerosis.

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