Glatiramer acetate

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Glatiramer acetate
Glatiramer acetate.svg
Names
Trade namesCopaxone,[1] Glatopa,[2] Brabio, others
Other namesGlatiramer acetate, copolymer 1, Cop-1
Clinical data
Drug classPeptides[3]
Main usesMultiple sclerosis[4]
Side effectsPain at site of injection, rash, shortness of breath, chest pain[1]
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
use
Subcutaneous injection
Typical dose20 mg OD[1]
External links
AHFS/Drugs.comMonograph
US NLMGlatiramer acetate
MedlinePlusa603016
Legal
License data
Legal status
Chemical and physical data
FormulaC25H45N5O13
Molar mass623.657 g·mol−1

Glatiramer acetate, sold under the brand name Copaxone among others, is a medication used to treat multiple sclerosis.[4] Specifically it is used for relapsing forms of MS including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.[1] It is given by injection under the skin.[4]

Common side effects include pain at the site of injection, rash, shortness of breath, and chest pain.[1] Other side effects may include flushing, anxiety, lipoatrophy, and liver problems.[1] While there is no clear harm with use in pregnancy, such use has not been well studied.[7] It is a mixture of different sized peptides that are composed of the four amino acids, namely glutamic acid, lysine, alanine, and tyrosine.[3] It is believed to be similar to myelin basic protein (MBP) and inactivate antibodies directed against it.[3]

Glatiramer acetate was approved for medical use in the United States in 1996.[4] In the United Kingdom 4 weeks of medication costs the NHS about £515 as of 2021.[8] In the United States this amount costs about 1,200 USD.[9]

Medical uses

Glatiramer acetate is used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.[1]

A 2010 Cochrane review concluded that glatiramer acetate had partial efficacy in "relapse-related clinical outcomes" but no effect on progression of the disease.[10] As a result, it is approved by the FDA for reducing the frequency of relapses, but not for reducing the progression of disability.[1][2]

A 15-year followup of the original trial compared patients who continued with glatiramer to patients who dropped out of the trial. Patients with glatiramer had reduced relapse rates, and decreased disability progression and transition to secondary progressive MS, compared to patients who did not continue glatiramer. However, the two groups were not necessarily comparable, as it was no longer a randomized trial. There were no long-term safety issues.[11]

Dosage

It may be used at a dose of 20 mg per day or 40 mg three times per week.[1]

Side effects

Side effects may include a lump at the injection site (injection site reaction) in approximately 30% of users, and aches, fever, chills (flu-like symptoms) in approximately 10% of users.[12] Side effect symptoms are generally mild in nature. A reaction that involves flushing, shortness of breath, anxiety and rapid heartbeat has been reported soon after injection in up to 5% of patients (usually after inadvertently injecting directly into a vein). These side effects subside within thirty minutes. Over time, a visible dent at a repeat-injection site can occur due to the local destruction of fat tissue, known as lipoatrophy, that may develop.

More serious side effects have been reported for glatiramer acetate, according to the FDA's prescribing label, these include serious side effects to the cardiovascular, digestive (including the liver), hematopoietic, lymphatic, musculoskeletal, nervous, respiratory, and urogenital systems as well as special senses (in particular the eyes). Metabolic and nutritional disorders have also been reported; however a link between glatiramer acetate and these adverse effects has not been established.[1][2]

It may also cause Jessner lymphocytic infiltrate.[13]

Mechanism of action

Glatiramer acetate is a random polymer (average molecular mass 6.4 kD) composed of four amino acids found in myelin basic protein. The mechanism of action for glatiramer acetate is not fully elucidated. It is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. Administration of glatiramer acetate shifts the population of T cells from proinflammatory Th1 T-cells to regulatory Th2 T-cells that suppress the inflammatory response.[15] Given its resemblance to myelin basic protein, glatiramer acetate may act as a decoy, diverting an autoimmune response against myelin. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a condition induced in several animal species through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific regulatory T cells (Tregs) are induced and activated in the periphery, inhibiting the inflammatory reaction to myelin basic protein.[1][2]

The integrity of the blood-brain barrier, however, is not appreciably affected by glatiramer acetate, at least not in the early stages of treatment. Glatiramer acetate has been shown in clinical trials to reduce the number and severity of multiple sclerosis exacerbations.[16]

History

Glatiramer acetate was originally discovered at the Weizmann Institute of Science. Three main clinical trials followed to demonstrate safety and efficacy: The first trial was performed in a single center, double-blind, placebo controlled trial and included 50 patients.[17] The second trial was a two-year, multi-center, randomized, double-blind, placebo controlled trial and involved 251 patients.[18] The third trial was a double-blind MRI study involving participation of 239 patients.[19]

Society and culture

Marketing

Glatiramer acetate has been approved for marketing in numerous countries worldwide, including the United States, Israel, Canada and 24 European Union countries.[20][21] Approval in the U.S. was obtained in 1997.[22] Glatiramer acetate was approved for marketing in the U.K. in August 2000, and launched in December.[23] This first approval in a major European market led to approval across the European Union under the mutual recognition procedure. Iran is proceeding with domestic manufacture of glatiramer acetate.[24][25]

Patent status

Novartis subsidiary Sandoz has marketed Glatopa since 2015, a generic version of the original Teva 20 mg formulation that requires daily injection.[26]

Teva developed a long-acting 40 mg formulation, marketed since 2015, which reduced required injections to three per week.[27] In October 2017, the FDA approved a generic version, which is manufactured in India by Natco Pharma, and imported and sold by Dutch firm Mylan.[28][29] In February 2018, Sandoz received FDA approval for their generic version.[30] In parallel with the development and approval processes, the generic competitors have disputed Teva's newer patents, any of which if upheld, would prevent marketing of long-acting generics.[31]

While the patent on the chemical drug expired in 2015,[32] Teva obtained new US patents covering pharmaceutical formulations for long-acting delivery.[33] Litigation from industry competitors in 2016-2017 resulted in the new patents being judged invalid.[34][35] In October 2018, the U.S. Court of Appeals for the Federal Circuit upheld the patent invalidation for obviousness.[36][37] The case reflects the larger controversy over evergreening of generic drugs.

References

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  2. 2.0 2.1 2.2 2.3 2.4 "Glatopa- glatiramer acetate injection, solution". DailyMed. 31 July 2020. Archived from the original on 17 November 2020. Retrieved 11 November 2020.
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External links

Identifiers:
  • "Glatiramer acetate". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-03-24. Retrieved 2021-04-15.