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Interferon beta-1a

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Interferon beta-1a
Clinical data
Trade namesAvonex, Rebif, CinnoVex
Routes of
administration		Sub-cutaneous or Intramuscular Injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life10 hrs
Identifiers
  • Human interferon beta
CAS Number
DrugBank
ChemSpider
ChEMBL
Chemical and physical data
FormulaC908H1408N246O252S7
Molar mass20027.0 g/mol g·mol−1
 ☒NcheckY (what is this?)  (verify)

Interferon beta 1a (also interferon beta 1-alpha) is a drug in the interferon family used to treat multiple sclerosis (MS).[1] It is produced by mammalian cells, while interferon beta 1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses.[2] There is currently no cure for MS. Starting a course of interferons early may slow its progress.[3]

Interferon beta 1a is sold under the trade names Avonex (Biogen Idec) and Rebif (Merck Serono), (Pfizer); CinnoVex (CinnaGen) is biosimilar.

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.[4] Overall, therapy with interferon beta leads to a reduction of neuron inflammation.[4] Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival.[4]

Side effects

Injectable medications can produce irritation or bruises at injection site. The bruise depicted was produced by a subcutaneous injection.

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.[5] They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of treatment.[5] Skin reactions are more prevalent in women.[5] Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy.[5] Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop.

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 of many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches.[6] 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.[5][7] 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.[5] Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease.[5] 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.[5] A symptom specially sensitive to worsening is spasticity.[5] Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function.[5] In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment.[5] Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.[5]

The injection-site reactions can be mitigated by rotating injection sites or by using one of the medications that requires less frequent injections. Side effects are often onerous enough that many patients ultimately discontinue taking Interferons [citation needed] (or glatiramer acetate, a comparable disease-modifying therapies requiring regular injections).

Efficacy

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 but the patient does not fulfill the criteria for diagnosis of multiple sclerosis.[8] Treatment with interferons after an initial attack decreases the risk of developing clinical definite MS.[7][9]

Relapsing-remitting MS

Medications are modestly effective at decreasing the number of attacks in relapsing-remitting multiple sclerosis and in reducing the accumulation of brain lesions, which is measured using gadolinium-enhanced magnetic resonance imaging (MRI).[7] Interferons reduce relapses by approximately 30% and their safe profile make them the first-line treatments.[7] Nevertheless, not all the patients are responsive to these therapies. It is known that 30% of MS patients are non-responsive to Beta interferon.[10] They can be classified in genetic, pharmacological and pathogenetic non-responders.[10] 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.[7] Moreover, a subset of RRMS patients with specially active MS, sometimes called "rapidly worsening MS" are normally non-responders to interferon beta 1a.[11][12]

While more studies of the long-term effects of the drugs are needed,[3][7] existing data on the effects of interferons indicate that early-initiated long-term therapy is safe and it is related to better outcomes.[3]

Cost

A one week dose of Avonex can cost up to $4,704 USD(retail cost of one prefilled 30 mcg syringe. There are four syringes in one kit.

Commercial formulations

Avonex

Avonex was approved in the US in 1996, and in Europe 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 Europe, with around 30% of the overall market. It is produced by the Biogen Idec 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 once per week via intramuscular injection.

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 Europe in 1998 and in the US in 2002 and is registered in more than 80 countries worldwide. Rebif is administered via subcutaneous injection three times per week, and can be stored at room temperature for up to 30 days.

CinnoVex

Main article: CinnoVex

CinnoVex is the trade name of recombinant Interferon beta 1-a, 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 Institute in collaboration with CinnaGen, and is the first therapeutic protein from a Fraunhofer laboratory to be approved as biogeneric / biosimilar medicine. There is several clinical study to proof similarity of CinnoVex and Avonex.[13] A more water-soluble variant is currently being investigated by the Vakzine Projekt Management (VPM) GmbH in Braunschweig, Germany.

Closely related is Interferon beta 1b, also may be indicated for Multiple Sclerosis, and with a very similar drug profile. Interferon beta 1b is marketed only by Bayer in the US as Betaseron and outside the US as Betaferon.

References

  1. ^ Murdoch D, Lyseng-Williamson KA (2005). "Spotlight on subcutaneous recombinant interferon-beta-1a (Rebif) in relapsing-remitting multiple sclerosis". BioDrugs. 19 (5): 323–5. doi:10.2165/00063030-200519050-00005. PMID 16207073.
  2. ^ Stachowiak PhD., Julie (2008). "Is Avonex Right for You?". Retrieved 2008-05-07.
  3. ^ a b c Freedman, M. S. (27 December 2010). "Long-term follow-up of clinical trials of multiple sclerosis therapies". Neurology. 76 (1, Supplement 1): S26 – S34. doi:10.1212/WNL.0b013e318205051d. PMID 21205679.
  4. ^ a b c Kieseier, Bernd C. (1 June 2011). "The Mechanism of Action of Interferon-β in Relapsing Multiple Sclerosis". CNS Drugs. 25 (6): 491–502. doi:10.2165/11591110-000000000-00000. PMID 21649449.
  5. ^ a b c d e f g h i j k l Walther, EU (Nov 10, 1999). "Multiple sclerosis: side effects of interferon beta therapy and their management". Neurology. 53 (8): 1622–7. PMID 10563602. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Eccles, R (November 2005). "Understanding the symptoms of the common cold and influenza". The Lancet infectious diseases. 5 (11): 718–25. doi:10.1016/S1473-3099(05)70270-X. PMID 16253889.
  7. ^ a b c d e f Compston A, Coles A (October 2008). "Multiple sclerosis". Lancet. 372 (9648): 1502–17. doi:10.1016/S0140-6736(08)61620-7. PMID 18970977.
  8. ^ Miller D, Barkhof F, Montalban X, Thompson A, Filippi M (2005). "Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis". Lancet neurology. 4 (5): 281–8. doi:10.1016/S1474-4422(05)70071-5. PMID 15847841.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Bates, D (Jan 4, 2011). "Treatment effects of immunomodulatory therapies at different stages of multiple sclerosis in short-term trials". Neurology. 76 (1 Suppl 1): S14-25. doi:10.1212/WNL.0b013e3182050388. PMID 21205678.
  10. ^ a b Bertolotto A, Gilli F (September 2008). "Interferon-beta responders and non-responders. A biological approach". Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 29 Suppl 2: S216–7. doi:10.1007/s10072-008-0941-2. PMID 18690496.
  11. ^ Buttinelli C, Clemenzi A, Borriello G, Denaro F, Pozzilli C, Fieschi C. (2007). "Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up". European Journal of Neurology. 14 (11): 1281–7. doi:10.1111/j.1468-1331.2007.01969.x. PMID 17956449.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Boster A, Edan G, Frohman E, Javed A, Stuve O, Tselis A, Weiner H, Weinstock-Guttman B, Khan O (2008). "Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician". Lancet neurology. 7 (2): 173–83. doi:10.1016/S1474-4422(08)70020-6. PMID 18207115.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Nafissi S, Azimi A, Amini-Harandi A, Salami S, shahkarami MA, Heshmat R.,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, Clin Neurol Neurosurg. 2012 Sep;114(7) 986-9. doi: 10.1016/j.clineuro.2012.02.039. Epub 2012 Mar 18.
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