Interferon beta-1a
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Interferon beta-1a (also interferon beta 1-alpha) is a
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
in the
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
family used to treat
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
(MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified ''
E. coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...
''. Some research indicates that interferon injections may result in an 18–38% reduction in the rate of MS relapses. Interferon beta has not been shown to slow the advance of disability. 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. Treatment with
interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
s after an initial attack decreases the risk of developing clinical definite MS.


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 Gadolinium is a chemical element; it has Symbol (chemistry), symbol Gd and atomic number 64. It is a silvery-white metal when oxidation is removed. Gadolinium is a malleable and ductile rare-earth element. It reacts with atmospheric oxygen or moi ...
- enhanced
magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and ...
(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. 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 An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
. 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. 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.


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 Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. The term "necrosis" came about in the mid-19th century and is commonly attributed to German pathologist Rudolf Virchow, who i ...
. 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 Lipoatrophy is the term describing the localized loss of fat tissue. This may occur as a result of subcutaneous injections of insulin in the treatment of diabetes, from the use of human growth hormone or from subcutaneous injections of copaxone u ...
, may develop, however, this rarely occurs with interferon treatment.
Interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...
s, a subclass of
cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
, are produced in the body during illnesses such as
influenza Influenza, commonly known as the flu, is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These sympto ...
in order to help fight the infection. They are responsible for many of the symptoms of influenza infections, including
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
, muscle aches,
fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...
, and
headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
s. 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. This reaction tends to disappear after 3 months of treatment and its symptoms can be treated with over-the-counter
nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents bl ...
s, such as
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It can be taken oral administration, ...
, 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 Uhthoff's phenomenon (also known as Uhthoff's syndrome, Uhthoff's sign, and Uhthoff's symptom) is the worsening of neurologic symptoms in multiple sclerosis (MS) and other demyelinating diseases when the body is overheated. This may occur due t ...
), 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 Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles. ...
. Interferon-beta can also reduce numbers of
white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s (
leukopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...
),
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s (
lymphopenia Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which r ...
) and
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
s (
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
), as well as affect
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
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 Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial ...
, 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 (or
glatiramer acetate Glatiramer acetate, sold under the brand name Copaxone among others, is an immunomodulator medication used to treat multiple sclerosis. Glatiramer acetate is approved in the United States to reduce the frequency of relapses, but not for reduci ...
, a comparable disease-modifying therapy 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 Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is compo ...
. 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 Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was ...
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.


Society and culture


Brand names


Avonex

Avonex was approved in the US in 1996, 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
Biogen Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, United States specializing in the discovery, development, and delivery of the treatment of neurological diseases to patients worldwide. Biogen ope ...
biotechnology Biotechnology is a multidisciplinary field that involves the integration of natural sciences and Engineering Science, engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists ...
company, originally under competition protection in the US under the
Orphan Drug Act The Orphan Drug Act of 1983 is a law passed in the United States to facilitate development of orphan drugs—drugs for rare diseases such as Huntington's disease, myoclonus, ALS, Tourette syndrome or muscular dystrophy which affect small numbers ...
. 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 Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be ...
.


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 Merck Serono (EMD Serono in the United States and Canada) is a pharmaceutical company headquartered in Darmstadt, Germany, and a brand and division of Merck focused on biopharmaceuticals. In September 2006, Merck KGaA announced its intent to ...
and
Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...
in the US under an exception to the
Orphan Drug Act The Orphan Drug Act of 1983 is a law passed in the United States to facilitate development of orphan drugs—drugs for rare diseases such as Huntington's disease, myoclonus, ALS, Tourette syndrome or muscular dystrophy which affect small numbers ...
. 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. Rebif is administered via
subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus (medicine), bolus into the subcutis, the layer of skin directly below the dermis and ...
.


Cinnovex

Cinnovex is the brand name of recombinant Interferon beta-1a, which is manufactured as biosimilar/biogeneric in
Iran Iran, officially the Islamic Republic of Iran (IRI) and also known as Persia, is a country in West Asia. It borders Iraq to the west, Turkey, Azerbaijan, and Armenia to the northwest, the Caspian Sea to the north, Turkmenistan to the nort ...
. It is produced in a lyophilized form and sold with
distilled water Distilled water is water that has been purified by boiling it into vapor then condensing it back into liquid in a separate container. Impurities in the original water that do not boil below or near the boiling point of water remain in the origin ...
for injection. Cinnovex was developed at the
Fraunhofer Society The Fraunhofer Society () is a German publicly-owned research organization with 76institutes spread throughout Germany, each focusing on different fields of applied science (as opposed to the Max Planck Society, which works primarily on Basic re ...
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. 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.


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. Interferon beta-1b is marketed only by
Bayer Bayer AG (English: , commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and is one of the largest pharmaceutical companies and biomedical companies in the world. Headquartered in Leverkusen, Bayer' ...
in the US as Betaseron, and outside the US as Betaferon.


Economics

In the United States, , the cost is between US$1,284 and US$1,386 per 30 mcg vial. 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. Avonex and Rebif are on the top ten best-selling multiple sclerosis drugs of 2013. It is an example of a
specialty drug Specialty drugs or specialty pharmaceuticals are a recent designation of pharmaceuticals classified as high-cost, high complexity and/or High-touch, high touch. Specialty drugs are often Biopharmaceutical, biologics—"drugs derived from living cel ...
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.


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 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...
in a multinational
Solidarity trial The Solidarity trial for treatments is a multinational Phase III-IV clinical trial organized by the World Health Organization (WHO) and partners to compare four untested treatments for hospitalized people with severe COVID-19 illness. The tria ...
(initially in combination with lopinavir) but it did not reduce in-hospital mortality compared to local standard of care. SNG001, an inhalation formulation of interferon beta-1a, is being developed as a treatment for COVID-19 by Synairgen. A pilot trial in hospitalized patients showed higher odds of clinical improvement with SNG001 compared to placebo and in January 2021 a phase 3 trial in this population started.


References


External links

* * {{DEFAULTSORT:Interferon Beta-1a Cytokines Drugs developed by Pfizer Drugs developed by Merck Immunostimulants Specialty drugs