Interferon beta-1a

Interferon beta-1a
Systematic (IUPAC) name
Human interferon beta
Clinical data
Trade names Avonex, Rebif, CinnoVex
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Sub-cutaneous or Intramuscular Injection
Legal status
Pharmacokinetic data
Biological half-life 10 hrs
Identifiers
CAS Number 145258-61-3 YesY
ATC code L03AB07
IUPHAR/BPS 8339
DrugBank DB00060 YesY
ChemSpider none
ChEMBL CHEMBL1201562 N
Chemical data
Formula C908H1408N246O252S7
Molar mass 20027.0 g/mol
 NYesY (what is this?)  (verify)

Interferon beta-1a (also interferon beta 1-alpha) is a cytokine 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. Some claims have been made that Interferons produce about an 18–38% reduction in the rate of MS relapses.[2]

Interferon beta has not been shown to slow the advance of disability.[3] Interferons are not a cure for MS (there is no cure); the claim is that interferons may slow the progress of the disease if started early and continued for the duration of the disease.[4]

Manufactured forms of interferon beta-1a are sold under the trade names Avonex (Biogen) and Rebif (Merck Serono), (Pfizer); CinnoVex (CinnaGen) is biosimilar.

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 but the patient does not fulfill the criteria for diagnosis of multiple sclerosis.[5] Treatment with interferons after an initial attack decreases the risk of developing clinical definite MS.[6][7]

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).[6] Interferons reduce relapses by approximately 30% and their safe profile make them the first-line treatments.[6] Nevertheless, not all the patients are responsive to these therapies. It is known that 30% of MS patients are non-responsive to Beta interferon.[8] They can be classified in genetic, pharmacological and pathogenetic non-responders.[8] 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.[6] Moreover, a subset of RRMS patients with specially active MS, sometimes called "rapidly worsening MS" are normally non-responders to interferon beta 1a.[9][10]

While more studies of the long-term effects of the drugs are needed,[4][6] existing data on the effects of interferons indicate that early-initiated long-term therapy is safe and it is related to better outcomes.[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.[11] They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of treatment.[11] Skin reactions are more prevalent in women.[11] Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy.[11] 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 for many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches.[12] 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.[6][11] 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.[11] Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease.[11] 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.[11] A symptom specially sensitive to worsening is spasticity.[11] Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function.[11] In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment.[11] Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.[11]

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 (or glatiramer acetate, a comparable disease-modifying therapies requiring regular injections).

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.[13] Overall, therapy with interferon beta leads to a reduction of neuron inflammation.[13] Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival.[13] 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.[14]

Pharmaceutical analogs

Brand names

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 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

CinnoVex is the trade 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 Institute 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.[15] A more water-soluble variant is currently being investigated by the Vakzine Projekt Management (VPM) GmbH in Braunschweig, Germany.

Plegridy

Plegridy is the trade name of a pegylated form of Interferon beta-1a. Plegridy’s advantage is it only needs injecting once every two weeks.[16]

Betaferon (interferon beta-1b)

Closely related to interferon beta-1a is interferon beta-1b. It also may be used for Multiple Sclerosis and has a similar drug profile to the beta-1a form. Interferon beta-1b is marketed only by Bayer in the US as Betaseron, and outside the US as Betaferon.

Cost and sales

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

Avonex and Rebif are under the top 10 best-selling multiple sclerosis drugs of 2013:[17]

It is an example of a specialty drug that would only be available through specialty pharmacy. This is because it requires a refrigerated chain of distribution and costs $17,000-a-year.[18]

No. 2013 Global Sales INN Trade names Companies
1 $4.33 billion Glatiramer acetate Copaxone Teva
2 $3.00 billion Interferon beta 1a Avonex Biogen Idec
3 $2.51 billion Interferon beta 1a Rebif Merck KGaA
4 $1.93 billion Fingolimod Gilenya Novartis
5 $1.41 billion Natalizumab Tysabri Biogen Idec
6 $1.38 billion Interferon beta 1b Betaseron/Betaferon Bayer HealthCare
7 $876 million Dimethyl fumarate Tecfidera Biogen Idec
8 $303 million 4-Aminopyridine Ampyra Acorda Therapeutics
9 $250 million Adrenocorticotropic hormone H.P. Acthar Gel Questcor Pharmaceuticals
10 $221 million Teriflunomide Aubagio Sanofi

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. ↑ Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis.
  4. 1 2 3 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.
  5. ↑ 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.
  6. 1 2 3 4 5 6 Compston A, Coles A (October 2008). "Multiple sclerosis". Lancet 372 (9648): 1502–17. doi:10.1016/S0140-6736(08)61620-7. PMID 18970977.
  7. ↑ 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.
  8. 1 2 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 (S2): S216–7. doi:10.1007/s10072-008-0941-2. PMID 18690496.
  9. ↑ 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.
  10. ↑ 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.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 Walther, EU; Hohlfeld, R (Nov 10, 1999). "Multiple sclerosis: side effects of interferon beta therapy and their management.". Neurology 53 (8): 1622–7. doi:10.1212/wnl.53.8.1622. PMID 10563602.
  12. ↑ 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.
  13. 1 2 3 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.
  14. ↑ "New pieces in the puzzle: how does interferon-beta really work in multiple sclerosis?". Ann Neurol 65 (5): 487–8. May 2009. doi:10.1002/ana.21722. PMID 19479722.
  15. ↑ Nafissi, S; Azimi, A; Amini-Harandi, A; Salami, S; Shahkarami, MA; Heshmat, R (Sep 2012). "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. 114 (7): 986–9. doi:10.1016/j.clineuro.2012.02.039.
  16. ↑ Peginterferon beta-1a description National Multiple Sclerosis Society (15 August 2014). Retrieved Jan 2016
  17. ↑ Top 10 best-selling multiple sclerosis drugs of 2013; September 9, 2014
  18. ↑ Gleason, Alexander G. C.; Starner, C. I.; Ritter, S. T.; Van Houten, H. K.; Gunderson, B. W.; Shah, N. D. (September 2013). "Health plan utilization and costs of specialty drugs within 4 chronic conditions". Academy of Managed Care Pharmacy 19 (7): 542–8. PMID 23964615. Retrieved 11 October 2015.
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