Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Interferon beta-1a is a cytokine used for the treatment of multiple sclerosis (MS). It is used to treat clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and active secondary disease in adults. Treatment with interferon beta-1a aims to delay physical disability and decrease the frequency of clinical exacerbations.1,2
Interferon beta-1a is commercialized as Avonex® (by Biogen), Plegridy® (by Biogen), and Rebif® (by EMD Serono and Pfizer).1,2,3
Avonex, the leading treatment for MS, was approved in the US in 1996 and in the European Union (EU) in 1997.4 Commercialized in more than 90 countries,4 Avonex is for intramuscular use only, and the recommended dose is 30 mcg once a week.1 Three formulations are available: a single-use prefilled autoinjector, a single-use prefilled syringe, and a single-use vial with lyophilized powder.1
Rebif was approved in the EU in 1998 and in the US in 2002.5 Its recommended dosage is 22 or 44 mcg 3 times per week. A single-dose prefilled syringe and autoinjector are available for subcutaneous administration.3
Plegridy is the pegylated form of interferon beta-1a, and, similarly to Rebif, is subcutaneously administered. Initial US approval was in 2014. Plegridy’s recommended dose is 125 mcg subcutaneously administered every 14 days;3 however, its dose should be titrated. Commercial formulations exist in 63, 94, and 125 mcg in a single-dose prefilled pen.3
Interferon beta-1a Mechanism of Action
The mechanism of action by which Avonex, Plegridy, and Rebif exert their effect in MS patients is unclear.1,2,3 Research shows that interferon beta-1a decreases neuron inflammation by upregulating anti-inflammatory molecules and downregulating proinflammatory cytokines.6 It can also stimulate nerve growth factor synthesis and reduce the crossing of inflammatory cells through the blood-brain barrier (BBB).8
The use of interferon beta-1a in CIS reduces the risk of patients developing clinical definite MS.7 In the treatment of RRMS, the use of interferon beta-1a can reduce relapses frequency in about 30% of cases while also decreasing the formation of brain lesions.6
Warnings, Precautions, and Adverse Reactions
Skin reactions, including necrosis, may occur, but typically decrease as treatment continues.8 These reactions have a higher prevalence in women and are more common when administration is subcutaneous.8 It is recommended that patients rotate the place where the injections are applied.2
The most common adverse reactions (at least 5% more frequent on Avonex than on placebo and 2% more frequent with Plegridy than on placebo) are depression/suicidal ideation and flu-like symptoms, which can include chills, headache, fever, and myalgia.9 As most of these adverse effects are a consequence of the temporary increase in cytokines, such as IL-6 and tumor necrosis factor α (TNF-α), and symptoms typically subside within 12 to 24 hours.10
Additionally, the use of these drugs can also lead to hepatic injury, seizures, anaphylaxis, congestive heart failure, decreased peripheral blood counts, or autoimmune disorders.1,2,3 Patients should be monitored through blood workup regularly.8
Efficacy in Clinical Trials
Avonex was pivotally tested in a double-blind, placebo-controlled, randomized, multicenter phase III trial involving 301 patients with RRMS. Thirty mcg of Avonex were administered every week. The goal of this trial was to determine interferon beta-1a’s ability in delaying the neurological disability of RRMS.11 The primary clinical outcome for this trial was time to disability progression over 104 weeks. This outcome was measured as an increase of 1.0 on the Expanded Disability Status Scale (EDSS) maintained for 6 months (denominated as confirmed disability progression, CDP).11
Results of this study showed that Avonex significantly delayed the onset of sustained progression in disability and caused a 37% decrease in probability of CDP when compared to the placebo-treated group.11 A low number of exacerbations and lower disease activity measured by the volume of gadolinium-enhanced brain lesions were also observed for interferon beta-1a-treated patients.11 As the primary outcome was reached earlier than the 2-year follow-up scheduled, the trial ended earlier.
A second randomized, multicenter, double-blind, placebo-controlled study involving 383 patients who presented an isolated demyelinating event was conducted for up to 3 years or until a second relapse occurred in a distinct region of the central nervous system (CNS). In this CHAMPS trial, the time to a second relapse was delayed in patients treated with Avonex, and 79% of Avonex-treated individuals showed no relapses after 2 years of study.12
The clinical benefits of Avonex were further assessed in 2 long-term follow-up studies, CHAMPIONS and ASSURANCE.13,14 CHAMPIONS was a 10-year open-label, prospective follow-up of the CHAMPS study that showed a decreased probability of patients developing clinically definite multiple sclerosis (CDMS) when treated with Avonex.13 ASSURANCE trial was a 15-year multicenter, observational, single-time-point study that evaluated the effect of Avonex in the long-term disability of patients that had previously enrolled for 2 years in the pivotal study.14 ASSURANCE showed less progression on the EDSS in patients that continued treatment with Avonex14. There were no changes observed in the safety profile of Avonex during the long-term studies.
A placebo-controlled study, PRISMS, recruited 560 RRMS patients and randomized them into 3 groups.15 Two of these groups were subcutaneously administered with 22 and 184 mcg of Rebif 3 times per week for 2 years, while a third group was administered a placebo. Rebif doses were increased for the first 4 to 8 weeks until the target dose was achieved. PRISMS study showed a 2-fold delay in disability progression in Rebif-treated patients. Fewer relapses in 2 years were also observed in these patients, as well as fewer brain lesions.15
A follow-up and open-label study included 382 patients from the PRISMS study and concluded that the group of patients receiving the 44 mcg dose of interferon beta-1a showed the longest time to reach a confirmed and clinically relevant progression.16 Brain atrophy was also reduced in these patients when compared to the group of individuals receiving 22 mcg of medication.16
An extension of the PRISMS study, PRISMS-4, evaluated the long-term efficacy of interferon beta-1a in RRMS. Results showed clinical benefits for patients receiving 22 and 44 mcg of Rebif 3 times a week, when compared with the placebo group. PRISMS-4 provided additional support for early MS treatment with interferon beta-1a.17
The efficacy and safety of Plegridy were evaluated in a phase 3 randomized, double-blind, multicenter clinical trial, for patients with RRMS, ADVANCE.18 In this study, patients were randomized in a 1:1:1 ratio to receive 125 mcg of Plegridy subcutaneously injected every 2 or 4 weeks or a placebo for a total of 48 weeks. The clinical primary endpoint for this trial corresponded to the annualized relapse rate (ARR), while the secondary endpoint included the proportion of patients with CDP. Plegridy proved to reduce relapses, the risk of disability progression, and the number of brain lesions.18
A 2-year safety extension study of ADVANCE confirmed the results from the 1-year study and additionally supported the safety of Plegridy.19
1. Avonex. Package insert. Biogen; 2012. Accessed June 12, 2021.
2. Rebif. Package insert. EMD Sorono; 2014. Accessed June 12, 2021.
3. Plegridy. Package insert. Biogen; 2014. Accessed June 12, 2021.
4. First ten-year follow-up shows that treatment with Avonex® leads to long-term benefits in early multiple sclerosis patients. News release. Biogen. April 30, 2009.
5. Rebif. European Medicines Agency. Updated July 1, 2021. Accessed June 15, 2021.
6. Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011;25(6):491-502. doi:10.2165/11591110-000000000-00000
7. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517. doi:10.1016/S0140-6736(08)61620-7
8. Walther EU, Hohlfeld R. Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology. 1999;53(8):1622-1627. doi:10.1212/wnl.53.8.1622
9. Jakimovski D, Kolb C, Ramanathan M, Zivadinov R, Weinstock-Guttman B. Interferon β for multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(11):a032003. doi:10.1101/cshperspect.a032003
10. Langer-Gould A, Moses HH, Murray TJ. Strategies for managing the side effects of treatments for multiple sclerosis. Neurology. 2004;63(11 Suppl 5):S35-S41. doi:10.1212/wnl.63.11_suppl_5.s35
11. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). [published correction appears in Ann Neurol 1996 Sep;40(3):480]. Ann Neurol. 1996;39(3):285-294. doi:10.1002/ana.410390304
12. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343(13):898-904. doi:10.1056/NEJM200009283431301
13. Kinkel RP, Dontchev M, Kollman C, et al. Association between immediate initiation of intramuscular interferon beta-1a at the time of a clinically isolated syndrome and long-term outcomes: a 10-year follow-up of the controlled high-risk Avonex multiple sclerosis prevention study in ongoing neurological surveillance. Arch Neurol. 2012;69(2):183-190. doi:10.1001/archneurol.2011.1426
14. Bermel RA, Weinstock-Guttman B, Bourdette D, Foulds P, You X, Rudick RA. Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler. 2010;16(5):588-596. doi:10.1177/1352458509360549
15. Cohen BA, Rivera VM. PRISMS: the story of a pivotal clinical trial series in multiple sclerosis. [published correction appears in Curr Med Res Opin. 2010;26(8):1826. Dosage error in article text]. Curr Med Res Opin. 2010;26(4):827-838. doi:10.1185/03007991003604018
16. Kappos L, Traboulsee A, Constantinescu C, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology. 2006;67(6):944-953. doi:10.1212/01.wnl.0000237994.95410.ce
17. PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. [published correction appears in Neurology 2001;25;57(6):1146]. Neurology. 2001;56(12):1628-1636. doi:10.1212/wnl.56.12.1628
18. Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. Lancet Neurol. 2014;13(7):657-665. doi:10.1016/S1474-4422(14)70068-719.
19. Kieseier BC, Arnold DL, Balcer LJ, et al. Peginterferon beta-1a in multiple sclerosis: 2-year results from ADVANCE. Mult Scler. 2015;21(8):1025-1035. doi:10.1177/1352458514557986
Reviewed by Kyle Habet, MD, on 7/1/2021.