Interferon beta-1a (also interferon beta 1-alpha) is a cytokine in the interferon family used to treat multiple sclerosis (MS).[3] It is produced by mammalian cells, while interferon beta-1b is produced in modified E. coli.[4] Some research indicates that interferon injections may result in an 18–38% reduction in the rate of MS relapses.[5]
Interferon beta has not been shown to slow the advance of disability.[6][7][8][9] Interferons are not a cure for MS (there is no known cure); the claim is that interferons may slow the progress of the disease if started early and continued for the duration of the disease.
Medical uses
Clinically isolated syndrome
The earliest clinical presentation of relapsing-remitting multiple sclerosis is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of demyelination which should be included in the spectrum of MS phenotypes.[10] Treatment with interferons after an initial attack decreases the risk of developing clinical definite MS.[11]
Relapsing-remitting MS
Medications are modestly effective at decreasing the number of attacks in relapsing-remitting multiple sclerosis[12] and in reducing the accumulation of brain lesions, which is measured using gadolinium-enhancedmagnetic resonance imaging (MRI). Interferons reduce relapses by approximately 30% and their safe profile make them the first-line treatments.
Side effects
Interferon beta-1a is available only in injectable forms, and can cause skin reactions at the injection site that may include cutaneous necrosis. Skin reactions with interferon beta are more common with subcutaneous administration and vary greatly in their clinical presentation. They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of treatment. Skin reactions are more prevalent in women. Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy. Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop, however, this rarely occurs with interferon treatment.[17]
Interferons, a subclass of cytokines, are produced in the body during illnesses such as influenza in order to help fight the infection.They are responsible for many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches.[18] Many patients report influenza-like symptoms hours after taking interferon beta that usually improve within 24 hours, being such symptoms related to the temporary increase of cytokines.[19]
Mechanism of action
Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood brain barrier.[21] Overall, therapy with interferon beta leads to a reduction of neuron inflammation.[21] Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival.[21] In vitro, interferon beta reduces production of Th17 cells which are a subset of T lymphocytes believed to have a role in the pathophysiology of MS.[22]
Society and culture
Brand names
Avonex
Avonex was approved in the US in 1996,[23] and in the European Union in 1997, and is registered in more than 80 countries worldwide. It is the leading MS therapy in the US, with around 40% of the overall market, and in the European Union, with around 30% of the overall market. It is produced by the Biogenbiotechnology company, originally under competition protection in the US under the Orphan Drug Act.
Avonex is sold in three formulations, a lyophilized powder requiring reconstitution, a pre-mixed liquid syringe kit, and a pen; it is administered via intramuscular injection.[24]
Rebif
Research
COVID-19
Interferon beta-1a administered subcutaneously or intravenously was investigated since March 2020 as a potential treatment in patients hospitalized with COVID-19 in a multinational Solidarity trial (initially in combination with lopinavir) but it did not reduce in-hospital mortality compared to local standard of care.[35]
SNG001, an inhalation formulation of interferon beta-1a, is being developed as a treatment for COVID-19 by Synairgen.[36][37] A pilot trial in hospitalized patients showed higher odds of clinical improvement with SNG001 compared to placebo[38] and in January 2021 a phase 3 trial in this population started.[39]
External links
References
1.Avonex EPAR European Medicines Agency (EMA), 17 September 2018, retrieved 1 October 2020^
2.Rebif EPAR European Medicines Agency (EMA), 17 September 2018, retrieved 1 October 2020^
3.Spotlight on subcutaneous recombinant interferon-beta-1a (Rebif) in relapsing-remitting multiple sclerosis BioDrugs, 2005^
Nevertheless, not all the patients are responsive to these therapies.
It is known that 30% of MS patients are non-responsive to Beta interferon.[13] They can be classified in genetic, pharmacological and pathogenetic non-responders.[13] One of the factors related to non-respondance is the presence of high levels of interferon beta neutralizing antibodies.
Interferon therapy, and specially interferon beta 1b, induces the production of neutralizing antibodies, usually in the second 6 months of treatment, in 5 to 30% of treated patients.
Moreover, a subset of RRMS patients with specially active MS, sometimes called "rapidly worsening MS" are normally non-responders to interferon beta 1a.[14][15]
While more studies of the long-term effects of the drugs are needed, existing data on the effects of interferons indicate that early-initiated long-term therapy is safe and it is related to better outcomes.[16]
To help prevent injection-site reactions, patients are advised to rotate injection sites and use an aseptic injection technique. Injection devices are available to optimize the injection process. Side effects are often onerous enough that many patients ultimately discontinue taking interferons (or glatiramer acetate, a comparable disease-modifying therapy requiring regular injections).
Rebif is a disease-modifying drug (DMD) used to treat multiple sclerosis in cases of clinically isolated syndromes as well as relapsing forms of multiple sclerosis and is similar to the interferon beta protein produced by the human body.
It is co-marketed by Merck Serono and Pfizer in the US under an exception to the Orphan Drug Act.
It was approved in the European Union in 1998, and in the US in 2002; it has since been approved in more than 90 countries worldwide including Canada and Australia.
EMD Serono has had sole rights to Rebif in the US since January 2016.[25][26] Rebif is administered via subcutaneous injection.[27]
Cinnovex
Cinnovex is the brand name of recombinant Interferon beta-1a, which is manufactured as biosimilar/biogeneric in Iran.It is produced in a lyophilized form and sold with distilled water for injection.Cinnovex was developed at the Fraunhofer Society in collaboration with CinnaGen, and is the first therapeutic protein from a Fraunhofer laboratory to be approved as biogeneric / biosimilar medicine.There are several clinical studies to prove the similarity of CinnoVex and Avonex.[28] A more water-soluble variant is currently being investigated by the Vakzine Projekt Management (VPM) GmbH in Braunschweig, Germany.
Plegridy
Plegridy is a brand name of a pegylated form of Interferon beta-1a.Plegridy's advantage is it only needs injecting once every two weeks.[29]
Betaferon (interferon beta-1b)
Closely related to interferon beta-1a is interferon beta-1b, which is also indicated for MS, but is formulated with a different dose and administered with a different frequency.Each drug has a different safety/efficacy profile.[30] Interferon beta-1b is marketed only by Bayer in the US as Betaseron, and outside the US as Betaferon.
Avonex
Avonex was approved in the US in 1996,[23] and in the European Union in 1997, and is registered in more than 80 countries worldwide. It is the leading MS therapy in the US, with around 40% of the overall market, and in the European Union, with around 30% of the overall market. It is produced by the Biogenbiotechnology company, originally under competition protection in the US under the Orphan Drug Act.
Avonex is sold in three formulations, a lyophilized powder requiring reconstitution, a pre-mixed liquid syringe kit, and a pen; it is administered via intramuscular injection.[24]
Rebif
Rebif is a disease-modifying drug (DMD) used to treat multiple sclerosis in cases of clinically isolated syndromes as well as relapsing forms of multiple sclerosis and is similar to the interferon beta protein produced by the human body. It is co-marketed by Merck Serono and Pfizer in the US under an exception to the Orphan Drug Act. It was approved in the European Union in 1998, and in the US in 2002; it has since been approved in more than 90 countries worldwide including Canada and Australia. EMD Serono has had sole rights to Rebif in the US since January 2016.[25][26] Rebif is administered via subcutaneous injection.[27]
Cinnovex
Cinnovex is the brand name of recombinant Interferon beta-1a, which is manufactured as biosimilar/biogeneric in Iran.It is produced in a lyophilized form and sold with distilled water for injection.Cinnovex was developed at the Fraunhofer Society in collaboration with CinnaGen, and is the first therapeutic protein from a Fraunhofer laboratory to be approved as biogeneric / biosimilar medicine.There are several clinical studies to prove the similarity of CinnoVex and Avonex.[28] A more water-soluble variant is currently being investigated by the Vakzine Projekt Management (VPM) GmbH in Braunschweig, Germany.
Plegridy
Plegridy is a brand name of a pegylated form of Interferon beta-1a.Plegridy's advantage is it only needs injecting once every two weeks.[29]
Betaferon (interferon beta-1b)
Closely related to interferon beta-1a is interferon beta-1b, which is also indicated for MS, but is formulated with a different dose and administered with a different frequency.Each drug has a different safety/efficacy profile.[30] Interferon beta-1b is marketed only by Bayer in the US as Betaseron, and outside the US as Betaferon.
Economics
In the United States, as of 2015, the cost is between US$1,284 and US$1,386 per 30 mcg vial.[31] As of 2020, the National Average Drug Acquisition Cost (NADAC) in the United States for Avonex was $6,872.94 for a 30 mcg kit.[32]
Avonex and Rebif are on the top ten best-selling multiple sclerosis drugs of 2013.[33]
It is an example of a specialty drug that would only be available through a specialty pharmacy.This is because it requires a refrigerated chain of distribution and costs $17,000 a year.[34]
4.Neutralising antibodies to interferon beta during the treatment of multiple sclerosis Journal of Neurology, Neurosurgery, and Psychiatry, November 2002^
6.Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis JAMA, July 2012^
7.Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15 Journal of Neurology, Neurosurgery, and Psychiatry, November 2015^
8.Pegylated interferon β-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study The Lancet. Neurology, July 2014^
9.Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG) Annals of Neurology, March 1996^
10.Defining the clinical course of multiple sclerosis: the 2013 revisions Neurology, July 2014^
11.Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials Neurology, January 2011^
12.Interferon in relapsing-remitting multiple sclerosis The Cochrane Database of Systematic Reviews, 2001^
13.Interferon-beta responders and non-responders. A biological approach Neurological Sciences, September 2008^
14.Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up European Journal of Neurology, November 2007^
15.Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician The Lancet. Neurology, February 2008^
16.Long-term follow-up of clinical trials of multiple sclerosis therapies Neurology, January 2011^
17.Lipoatrophy in patients with multiple sclerosis on glatiramer acetate The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques, February 2004^
18.Understanding the symptoms of the common cold and influenza The Lancet. Infectious Diseases, November 2005^
28.Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: a double blind randomized clinical trial Clinical Neurology and Neurosurgery, September 2012^
30.A meta-analysis of the efficacy and tolerability of interferon-β in multiple sclerosis, overall and by drug and disease type Clinical Therapeutics, October 2010^
38.Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial The Lancet. Respiratory Medicine, February 2021^
