Glatiramer

Article Author:
Arezou Babaesfahani
Article Editor:
Tushar Bajaj
Updated:
5/7/2019 10:25:10 AM
PubMed Link:
Glatiramer

Indications

Glatiramer acetate is an immune modulating medication currently used to treat relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS).

Michael Sela, Ruth Arnon, and Dvora Teitelbaum at the Weizmann Institute of Science in Rehovot, Israel originally discovered the drug in the 1960s as they were attempting to produce a synthetic antigen capable of inducing experimental autoimmune encephalomyelitis. Experimental autoimmune encephalomyelitis is the animal model of autoimmune inflammatory CNS disorders used by researchers to advance understanding of such neurological conditions. Surprisingly it was noted that the copolymer they created, Cop-1, actually reduced the incidence of encephalitis and severity of histological lesions. After testing Cop-1 on various species and achieving similar results, clinical evaluation of human subjects began in 1977.[1][2]

In 1995, Johnson et al. performed the first randomized, placebo-controlled trial of 20mg glatiramer acetate daily in the United States. The initial positive results obtained on 50 patients with RRMS led to a Phase III clinical trial expansion encompassing 251 patients with RRMS. During the two years of therapy, those patients receiving glatiramer demonstrated a statistically significant decrease in the mean number of relapses compared to those in the placebo group (1.19 vs. 1.68, p=0.0007). In Canada and Europe, Comi et al. performed MRI evaluations on 239 RRMS patients and looked at the reduction in the number of gadolinium-enhancing lesions over 9 months to assess the efficacy of treatment with glatiramer vs. placebo. A statistically significant reduction in the number of lesions was noted amongst the glatiramer receiving patients over those on placebo (26 vs. 36.7, p=0.003). These results led to the Federal Drug Administration’s clearance of the glatiramer acetate for the treatment of RRMS in 1996.[3]

In 2009, a randomized placebo-controlled trial of 20mg daily glatiramer acetate was performed on 481 patients with CIS by Comi et al. This trial deemed “PreCISE” gave rise to a statistically significant (p=0.0005) result indicating a 45% reduction in the risk of developing complete demyelinating multiple sclerosis in those patients receiving glatiramer acetate. PreCISe also resulted in a 115% prolongation of time from CIS conversion to chronic demyelinating multiple sclerosis. These results prompted same year FDA approval of glatiramer acetate in the treatment of CIS.[4]

Mechanism of Action

Glatiramer acetate is a random sized 40 to 100 amino acid polymer composed of primarily of four amino acids L-alanine, L-lysine, L-glutamic acid, and L-tyrosine in a molar ratio 4.2 to 3.4 to 1.4 to 1.0 respectively. The premise behind its mechanism of action lies in the construct that patients with multiple sclerosis have antibodies that are directed against myelin basic protein (MBP), a component of the myelin sheaths of neurons within the central nervous system.  Glatiramer acetate’s chemical construct allows for it to mimic as MBP and thus a decoy for the antibodies in these patients, thereby resulting in a decrease of the inflammatory response. Otherwise, the inflammatory response allows for the vulnerability of the blood-brain barrier to demyelination and axonal injury.[1]

The postulates from multiple clinical studies are that glatiramer acetate shifts the immune response from a pro-inflammatory state comprised of Th1 T-Cells to regulatory, non-inflammatory Th2 T-Cells. The introduction of the polymer allows it to bind to major histone compatibility (MHC) complex class II molecules on MBP-specific antigen presenting cells, preventing MBP from stimulating these cells. Instead of the usual pro-inflammatory cytokine release such as IL-2 and IL-12, anti-inflammatory cytokines such as IL-1, IL-4, and IL-10 are the cytokines dispersed.[5]

While glatiramer acetate itself cannot penetrate the blood-brain barrier, its ability to induce the peripheral Th2 cells and their subsequent crossing of the blood barrier allows reduction of further inflammation within the CNS. This mechanism of action has been dubbed as “bystander suppression.”

Additionally, in the preclinical levels thus far it has been noted that glatiramer acetate induces a neuroprotective and/or neuro-regenerative effect. The drug increases neurotrophic factors like brain-derived neurotrophic factor (BDNF) which has been discovered to be vital to neuronal and glial cell survival. There is also some evidence suggestive of glatiramer’s ability to induce remyelination and enhance neurogenesis.[5][6]  In a study of T cell lines obtained from glatiramer acetate treated multiple sclerosis patients, reactive T cells were found to secrete BDNF.[7][8]

Administration

Glatiramer acetate is to be administered by subcutaneous injection.

  • Sites approved for injection include arms, abdomen, hips, and thighs
  • Recommended to rotate injection sites to minimize the occurrence of lipoatrophy
  • Do not administer intravenously or intramuscularly
  • Glatiramer acetate comes in two dosing schedules: 20mg per mL per day or 40mg per mL three times per week with doses given at least 48 hours apart
  • Glatiramer acetate 20mg per ml and 40mg per ml are not interchangeable
  • It is recommended to allow the solution to warm to room temperature before administration

Given the positive results in reducing relapse rates with implementation of glatiramer acetate in multiple sclerosis patients, curiosity emerged regarding the effects of using the drug at a higher dosage.  

In 2007 researchers performed a phase II clinical trial comparing high dosage 40mg glatiramer acetate to the standard dosage of 20mg, encompassing 38 RRMS patients over nine months. The efficacy assessment was the number of gadolinium-enhancing lesions on MRI. Results showed increased efficacy in the patients on higher dosage glatiramer acetate 40mg as they demonstrated 2.26 lesions on MRI compared to 3.62 lesions seen on MRI in those patients on a standard dosage of 20mg. Safety profiles were comparable amongst the two groups.

The results prompted a phase III, randomized, double-blind, parallel-group trial that embodied over 1155 patients in over 136 sites across 20 different countries to compare daily administration of subQ 40mg versus 20mg glatiramer acetate in one year. Primary outcome efficacy was assessed by the relapse rate in the first year while secondary outcome efficacy was deemed by MRI findings. At the end of one year, no statistically significant difference was found between the two groups; The standard 20mg group had 0.28 mean relapse rate and the higher dosed 40mg group had a 0.27 mean relapse rate. Additionally, the mean number of new T2 lesions and percentage brain volume changes were similar amongst the two groups.[9]

In 2013, Khan et al. performed a phase III, randomized, double-blind study trial including over 1404 patients with RRMS in over 142 sites in 17 countries to compare high dose 40mg glatiramer acetate three times per week to placebo in one year. This study revealed a 34% reduction in risk of confirmed relapses in those receiving treatment compared to those receiving placebo, 0.331 vs. 0.501, p=0.0001.[10] The cumulative number of gadolinium-enhancing lesions were also statistically significantly less than placebo, p less than 0.0001. Thus in 2014, glatiramer acetate 40mg/ml three times a week was approved for RRMS by the FDA.

Adverse Effects

The number one reported side-effect of glatiramer acetate is injection site reaction which manifests as a lump at the site of the subcutaneous injection. Approximately 10% of patients will report fever, chills, and aches. Many patients note a transient episode of flushing, shortness in breath, and palpitations which self resolves within 30 minutes.

Less than 1% of patients will develop lipoatrophy, a visible dent at the injection site due to local necrosis of adipose tissue.  

Serious but rare side effects to various organ systems including cardiovascular, gastrointestinal, hematopoietic, lymphatic, musculoskeletal, nervous, and urogenital systems have been noted, as has Jessner lymphocytic infiltrate, a cutaneous condition characterized by a persistent papule or plaque eruption. 

Contraindications

  • Known hypersensitivity to glatiramer acetate or mannitol
  • Not approved for use for patients less than 18 years of age
  • Pregnancy Category B
  • Not known if nursing mothers excrete glatiramer acetate in human breast milk

Monitoring

A critical issue emerging regarding the use of immunomodulating drugs like glatiramer is the generation of antibodies to the drugs themselves. While conflicting results ensue, a sera analysis study consisting of 217 patients who participated in the treatment and placebo arms of several glatiramer acetate trials were tested for antibodies to glatiramer acetate via ELISA method. IgG antibodies, mainly IgG1, was found in the patients who received active treatment. The titers increased to a peak concentration within 3 months of initiating treatment, but then slowly tapered off. The patients with higher antibody titers seem to be more likely to be relapse free.[6]

Enhancing Healthcare Team Outcomes

Glatiramer acetate is an immunomodulating medication used in the treatment of relapsing-remitting multiple sclerosis as well as a clinically isolated syndrome. The diagnosis of relapsing and remitting multiple sclerosis may be challenging; however, it remains clear there are few medications proven to decrease exacerbations and may even offer neuroprotection. It is essential to consider a multidisciplinary approach with coordination with primary care physicians, neurologists, pharmacists, insurance companies, and other health care professionals to have this medication approved and accessible to patients. Patient education is also crucial with a necessary explanation of how the medication works and the expected clinical treatment course with outcomes.

Glatiramer therapy is best when the administration and follow-up are through a multi-disciplinary healthcare team that includes physicians, specialty-trained nurses, and pharmacists, all working collaboratively to monitor treatment and ensure optimal patient therapeutic outcomes. [Level V]


References

[1] Weinstock-Guttman B,Nair KV,Glajch JL,Ganguly TC,Kantor D, Two decades of glatiramer acetate: From initial discovery to the current development of generics. Journal of the neurological sciences. 2017 May 15;     [PubMed PMID: 28431621]
[2] Caporro M,Disanto G,Gobbi C,Zecca C, Two decades of subcutaneous glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency glatiramer acetate in relapsing-remitting multiple sclerosis treatment. Patient preference and adherence. 2014;     [PubMed PMID: 25170258]
[3] McKeage K, Glatiramer Acetate 40 mg/mL in Relapsing-Remitting Multiple Sclerosis: A Review. CNS drugs. 2015 May;     [PubMed PMID: 25906331]
[4] Comi G,Martinelli V,Rodegher M,Moiola L,Bajenaru O,Carra A,Elovaara I,Fazekas F,Hartung HP,Hillert J,King J,Komoly S,Lubetzki C,Montalban X,Myhr KM,Ravnborg M,Rieckmann P,Wynn D,Young C,Filippi M, Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2009 Oct 31;     [PubMed PMID: 19815268]
[5] Chen M,Gran B,Costello K,Johnson K,Martin R,Dhib-Jalbut S, Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Multiple sclerosis (Houndmills, Basingstoke, England). 2001 Aug;     [PubMed PMID: 11548979]
[6] Brenner T,Arnon R,Sela M,Abramsky O,Meiner Z,Riven-Kreitman R,Tarcik N,Teitelbaum D, Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. Journal of neuroimmunology. 2001 Apr 2;     [PubMed PMID: 11282165]
[7] Kerschensteiner M,Gallmeier E,Behrens L,Leal VV,Misgeld T,Klinkert WE,Kolbeck R,Hoppe E,Oropeza-Wekerle RL,Bartke I,Stadelmann C,Lassmann H,Wekerle H,Hohlfeld R, Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? The Journal of experimental medicine. 1999 Mar 1;     [PubMed PMID: 10049950]
[8] Khan O,Shen Y,Caon C,Bao F,Ching W,Reznar M,Buccheister A,Hu J,Latif Z,Tselis A,Lisak R, Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2005 Dec;     [PubMed PMID: 16320723]
[9] Tselis A,Khan O,Lisak RP, Glatiramer acetate in the treatment of multiple sclerosis. Neuropsychiatric disease and treatment. 2007 Apr;     [PubMed PMID: 19300558]
[10] Khan O,Rieckmann P,Boyko A,Selmaj K,Zivadinov R, Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Annals of neurology. 2013 Jun;     [PubMed PMID: 23686821]