Interferon beta-1a

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.{{cite journal | vauthors = Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH | display-authors = 6 | title = Defining the clinical course of multiple sclerosis: the 2013 revisions | journal = Neurology | volume = 83 | issue = 3 | pages = 278–286 | date = July 2014 | pmid = 24871874 | pmc = 4117366 | doi = 10.1212/WNL.0000000000000560 }} Treatment with interferons after an initial attack decreases the risk of developing clinical definite MS.{{cite journal | vauthors = Bates D | title = Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials | journal = Neurology | volume = 76 | issue = 1 Suppl 1 | pages = S14–S25 | date = January 2011 | pmid = 21205678 | doi = 10.1212/WNL.0b013e3182050388 | s2cid = 362182 }}

Medications are modestly effective at decreasing the number of attacks in relapsing-remitting multiple sclerosis{{cite journal | vauthors = Rice GP, Incorvaia B, Munari L, Ebers G, Polman C, D'Amico R, Filippini G | title = Interferon in relapsing-remitting multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | volume = 2001 | issue = 4 | pages = CD002002 | date = 2001 | pmid = 11687131 | pmc = 7017973 | doi = 10.1002/14651858.CD002002 }} and in reducing the accumulation of brain lesions, which is measured using gadolinium-enhanced magnetic resonance imaging (MRI). Interferons reduce relapses by approximately 30% and their safe profile make them the first-line treatments. Nevertheless, not all the patients are responsive to these therapies. It is known that 30% of MS patients are non-responsive to Beta interferon.{{cite journal | vauthors = Bertolotto A, Gilli F | title = Interferon-beta responders and non-responders. A biological approach | journal = Neurological Sciences | volume = 29 | issue = Suppl 2 | pages = S216–S217 | date = September 2008 | pmid = 18690496 | doi = 10.1007/s10072-008-0941-2 | s2cid = 19618597 }} They can be classified in genetic, pharmacological and pathogenetic non-responders. 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.{{cite journal | vauthors = Buttinelli C, Clemenzi A, Borriello G, Denaro F, Pozzilli C, Fieschi C | title = Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up | journal = European Journal of Neurology | volume = 14 | issue = 11 | pages = 1281–1287 | date = November 2007 | pmid = 17956449 | doi = 10.1111/j.1468-1331.2007.01969.x | s2cid = 36392563 }}{{cite journal | vauthors = Boster A, Edan G, Frohman E, Javed A, Stuve O, Tselis A, Weiner H, Weinstock-Guttman B, Khan O | display-authors = 6 | title = Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician | journal = The Lancet. Neurology | volume = 7 | issue = 2 | pages = 173–183 | date = February 2008 | pmid = 18207115 | doi = 10.1016/S1474-4422(08)70020-6 | s2cid = 40367120 }}

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.{{cite journal | vauthors = Freedman MS | title = Long-term follow-up of clinical trials of multiple sclerosis therapies | journal = Neurology | volume = 76 | issue = 1 Suppl 1 | pages = S26–S34 | date = January 2011 | pmid = 21205679 | doi = 10.1212/WNL.0b013e318205051d | s2cid = 16929304 }}

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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.{{cite journal | vauthors = Edgar CM, Brunet DG, Fenton P, McBride EV, Green P | title = Lipoatrophy in patients with multiple sclerosis on glatiramer acetate | journal = The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques | volume = 31 | issue = 1 | pages = 58–63 | date = February 2004 | pmid = 15038472 | doi = 10.1017/s0317167100002845 | doi-access = free }}

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.{{cite journal | vauthors = Eccles R | title = Understanding the symptoms of the common cold and influenza | journal = The Lancet. Infectious Diseases | volume = 5 | issue = 11 | pages = 718–725 | date = November 2005 | pmid = 16253889 | pmc = 7185637 | doi = 10.1016/S1473-3099(05)70270-X }} 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.{{cite journal | vauthors = Compston A, Coles A | title = Multiple sclerosis | journal = Lancet | volume = 372 | issue = 9648 | pages = 1502–1517 | date = October 2008 | pmid = 18970977 | doi = 10.1016/S0140-6736(08)61620-7 | s2cid = 195686659 }}{{cite journal | vauthors = Walther EU, Hohlfeld R | title = Multiple sclerosis: side effects of interferon beta therapy and their management | journal = Neurology | volume = 53 | issue = 8 | pages = 1622–1627 | date = November 1999 | pmid = 10563602 | doi = 10.1212/wnl.53.8.1622 | s2cid = 30330292 }} This reaction tends to disappear after 3 months of treatment and its symptoms can be treated with over-the-counter nonsteroidal anti-inflammatory drugs, such as ibuprofen, that reduce fever and pain. Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease. Such deterioration is similar to the one produced in MS patients due to heat, fever or stress (Uhthoff's phenomenon), usually appears within 24 hours of treatment, is more common in the initial months of treatment, and may last several days. A symptom specially sensitive to worsening is spasticity. Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function. In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment. Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.

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 {{citation needed|date=March 2013}} (or glatiramer acetate, a comparable disease-modifying therapy requiring regular injections).

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.{{cite journal | vauthors = Kieseier BC | title = The mechanism of action of interferon-β in relapsing multiple sclerosis | journal = CNS Drugs | volume = 25 | issue = 6 | pages = 491–502 | date = June 2011 | pmid = 21649449 | doi = 10.2165/11591110-000000000-00000 | s2cid = 25516515 }} Overall, therapy with interferon beta leads to a reduction of neuron inflammation. Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival. 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.{{cite journal | vauthors = Mitsdoerffer M, Kuchroo V | title = New pieces in the puzzle: how does interferon-beta really work in multiple sclerosis? | journal = Annals of Neurology | volume = 65 | issue = 5 | pages = 487–488 | date = May 2009 | pmid = 19479722 | doi = 10.1002/ana.21722 | s2cid = 42050086 }}

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Avonex was approved in the US in 1996,{{cite news | title=F.D.A. Approves a Biogen Drug for Treating Multiple Sclerosis | website=The New York Times | date=8 May 1996 | url=https://www.nytimes.com/1996/05/18/business/fda-approves-a-biogen-drug-for-treating-multiple-sclerosis.html | access-date=16 January 2021 | archive-date=22 January 2021 | archive-url=https://web.archive.org/web/20210122104645/https://www.nytimes.com/1996/05/18/business/fda-approves-a-biogen-drug-for-treating-multiple-sclerosis.html | url-status=live }} and in the European Union in 1997, and is registered in more than 80 countries worldwide.{{cn|date=October 2020}} 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.{{citation needed|date=April 2015}} It is produced by the Biogen biotechnology 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.{{cite web | title=Avonex- interferon beta-1a kit Avonex Pen- interferon beta-1a injection, solution Avonex- interferon beta-1a injection, solution | website=DailyMed | date=30 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d70a39cc-de15-4c12-a1ec-8063b69ea0e1 | access-date=1 October 2020 | archive-date=25 March 2021 | archive-url=https://web.archive.org/web/20210325060926/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d70a39cc-de15-4c12-a1ec-8063b69ea0e1 | url-status=live }}

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. {{cn|date=October 2020}} 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.{{cn|date=October 2020}} EMD Serono has had sole rights to Rebif in the US since January 2016.{{Cite web|url=https://www.emdgroup.com/en/expertise/neurology-and-immunology.html|title=Neurology & Immunology|website=EMD Group|access-date=2021-08-08|archive-date=2024-04-07|archive-url=https://web.archive.org/web/20240407080938/https://www.emdgroup.com/en/expertise/neurology-and-immunology.html|url-status=live}}{{Cite press release|url=https://www.prnewswire.com/news-releases/emd-serono-takes-on-exclusive-promotion-of-rebif-interferon-beta-1a-in-the-us-300205988.html|title=EMD Serono Takes on Exclusive Promotion of Rebif (interferon beta-1a) in the US|publisher=EMD Serono|via=PR Newswire|access-date=2021-08-08|archive-date=2023-03-29|archive-url=https://web.archive.org/web/20230329045259/https://www.prnewswire.com/news-releases/emd-serono-takes-on-exclusive-promotion-of-rebif-interferon-beta-1a-in-the-us-300205988.html|url-status=live}} Rebif is administered via subcutaneous injection.{{cite web | title=Rebif- interferon beta-1a kit Rebif Rebidose- interferon beta-1a kit Rebif- interferon beta-1a injection, solution Rebif- interferon beta-1a injection, solution Rebif Rebidose- interferon beta-1a injection, solution | website=DailyMed | date=5 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fcb5d2-8fcd-44fa-a838-b84ee5f44f0f | access-date=1 October 2020 | archive-date=24 March 2021 | archive-url=https://web.archive.org/web/20210324222529/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6fcb5d2-8fcd-44fa-a838-b84ee5f44f0f | url-status=live }}

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.{{cite journal | vauthors = Nafissi S, Azimi A, Amini-Harandi A, Salami S, shahkarami MA, Heshmat R | title = 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 | journal = Clinical Neurology and Neurosurgery | volume = 114 | issue = 7 | pages = 986–989 | date = September 2012 | pmid = 22429566 | doi = 10.1016/j.clineuro.2012.02.039 | s2cid = 9236986 }} A more water-soluble variant is currently being investigated by the Vakzine Projekt Management (VPM) GmbH in Braunschweig, Germany.

{{Main|Peginterferon beta-1a}}

{{See also|Multiple_sclerosis_research#Phase_III}}

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.{{cite web | title=Plegridy- peginterferon beta-1a kit Plegridy Pen- peginterferon beta-1a kit Plegridy- peginterferon beta-1a injection, solution | website=DailyMed | date=19 July 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08f0ea03-4e6d-195d-aef4-886e32befa95 | access-date=30 March 2020 | archive-date=26 June 2020 | archive-url=https://web.archive.org/web/20200626040916/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08f0ea03-4e6d-195d-aef4-886e32befa95 | url-status=live }}

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.{{cite journal | vauthors = Nikfar S, Rahimi R, Abdollahi M | title = A meta-analysis of the efficacy and tolerability of interferon-β in multiple sclerosis, overall and by drug and disease type | journal = Clinical Therapeutics | volume = 32 | issue = 11 | pages = 1871–1888 | date = October 2010 | pmid = 21095482 | doi = 10.1016/j.clinthera.2010.10.006 }} Interferon beta-1b is marketed only by Bayer in the US as Betaseron, and outside the US as Betaferon.

In the United States, {{as of|2015|lc=yes}}, the cost is between US$1,284 and US$1,386 per 30 mcg vial.{{cite news|vauthors=Langreth R|title=Decoding Big Pharma's Secret Drug Pricing Practices|url=https://www.bloomberg.com/graphics/2016-drug-prices/|access-date=15 July 2016|publisher=Bloomberg|date=June 29, 2016|archive-date=13 July 2016|archive-url=https://web.archive.org/web/20160713133019/http://www.bloomberg.com/graphics/2016-drug-prices/|url-status=live}} 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.{{Cite web|url=https://data.medicaid.gov/Drug-Pricing-and-Payment/NADAC-as-of-2020-02-12/2ghv-q5xv|title=NADAC as of 2020-02-12 | work = Centers for Medicare and Medicaid Services|language=en|access-date=2020-02-18|archive-date=2020-02-18|archive-url=https://web.archive.org/web/20200218171241/https://data.medicaid.gov/Drug-Pricing-and-Payment/NADAC-as-of-2020-02-12/2ghv-q5xv|url-status=dead}}

Avonex and Rebif are on the top ten best-selling multiple sclerosis drugs of 2013.{{Cite web|url=https://www.fiercepharma.com/special-report/top-10-best-selling-multiple-sclerosis-drugs-of-2013|title=The top 10 best-selling multiple sclerosis drugs of 2013|website=FiercePharma|date=9 September 2014|access-date=8 August 2021|archive-date=26 February 2024|archive-url=https://web.archive.org/web/20240226115050/https://www.fiercepharma.com/special-report/top-10-best-selling-multiple-sclerosis-drugs-of-2013|url-status=live}}

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.{{cite journal | vauthors = Gleason PP, Alexander GC, Starner CI, Ritter ST, Van Houten HK, Gunderson BW, Shah ND | title = Health plan utilization and costs of specialty drugs within 4 chronic conditions | journal = Journal of Managed Care Pharmacy | volume = 19 | issue = 7 | pages = 542–548 | date = September 2013 | pmid = 23964615 | doi = 10.18553/jmcp.2013.19.7.542 | pmc = 10437312 }}

{{See also|Coronavirus disease 2019#Research|COVID-19 drug repurposing research}}

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.{{cite journal | vauthors = Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernández García C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HB, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H, Reges PP, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JA, Stevanovikj M, Tacconelli E, Tikkinen KA, Trelle S, Zaid H, Røttingen JA, Swaminathan S | display-authors = 6 | title = Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results | journal = The New England Journal of Medicine | volume = 384 | issue = 6 | pages = 497–511 | date = February 2021 | pmid = 33264556 | pmc = 7727327 | doi = 10.1056/NEJMoa2023184 }}

SNG001, an inhalation formulation of interferon beta-1a, is being developed as a treatment for COVID-19 by Synairgen.{{Cite web|url=https://www.covidtrialathome.com/|title=COVID Trial at Home - developed by Synairgen|website=Covid Trial at Home - developed by Synairgen|access-date=2021-08-08|archive-date=2022-05-07|archive-url=https://web.archive.org/web/20220507151458/https://www.covidtrialathome.com/|url-status=dead}}{{Cite web|url=https://medicalxpress.com/news/2020-05-university-led-covid19-drug-trial-home.html|title=University-led COVID19 drug trial expands into home testing|website=medicalxpress|access-date=2020-05-27|archive-date=2020-06-06|archive-url=https://web.archive.org/web/20200606011637/https://medicalxpress.com/news/2020-05-university-led-covid19-drug-trial-home.html|url-status=live}} A pilot trial in hospitalized patients showed higher odds of clinical improvement with SNG001 compared to placebo{{cite journal | vauthors = Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, Gabbay FJ, Davies DE, Holgate ST, Ho LP, Clark T, Djukanovic R, Wilkinson TM | display-authors = 6 | title = 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 | journal = The Lancet. Respiratory Medicine | volume = 9 | issue = 2 | pages = 196–206 | date = February 2021 | pmid = 33189161 | pmc = 7836724 | doi = 10.1016/S2213-2600(20)30511-7 }} and in January 2021 a phase 3 trial in this population started.{{cite web | title=Synairgen begins large-scale trial of inhaled COVID-19 treatment | website=PharmaTimes | date=13 January 2021 | url=https://www.pharmatimes.com/news/synairgen_begins_large-scale_trial_of_inhaled_covid-19_treatment_1361172 | access-date=7 August 2021 | archive-date=7 August 2021 | archive-url=https://web.archive.org/web/20210807001259/https://www.pharmatimes.com/news/synairgen_begins_large-scale_trial_of_inhaled_covid-19_treatment_1361172 | url-status=live }}

{{Reflist }}

• {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/interferon%20beta%201a | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Interferon beta-1a }}
• {{cite web | title=Interferon Beta-1a Intramuscular Injection | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a693040.html }}

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