Glatiramer acetate

• L-alanine -L -glutamic acid -L-lysine -L- tyrosine - polymer 6,0:1,9:4,7:1,0
• Copolymer -1

L03AX13

Immunomodulator

Template: Infobox chemical / molecular formula search available

Glatiramer acetate (brand name Copaxone ®; manufacturers to Teva Pharma ) is an immunomodulatory drug which is used to treat relapsing forms of multiple sclerosis ( MS). It is a mixture of synthetic polypeptides with unknown mechanism. Since its composition is similar to the components of the isolation of nerve cells, it is intended to reduce the inflammation appearing in the CNS in MS. As part of a drug glatiramer acetate was placed first in 1996 in the U.S. by Teva as Copaxone in the trade. The approval in the EU took place in 2001. In the United States has been running since 2008, the approval process for a generic

• 2.1 Composition
• 2.2 Mechanism of action ( pharmacodynamics )

• 3.1 History
• 3.2 studies
• 3.3 Trade names and dosage forms
• 3.4 cost

Clinical information

Approved Areas of application

Glatiramer acetate reduces the number of relapses in ambulatory patients with relapsing -remitting multiple sclerosis. Glatiramer acetate does not prevent the progression of disability in patients with MS. It is also not proven that treatment with glatiramer acetate reduces the duration or severity of the attacks.

In the EU, glatiramer acetate for the treatment of relapsing forms of multiple sclerosis has been approved for

• Reduction in frequency of relapses in ambulatory without aid patients with relapsing- remitting multiple sclerosis ( MS). This was characterized by at least two attacks of neurological dysfunction over the last 2 years in clinical trials.
• Treatment of patients with a clearly defined first clinical episode, which have a high risk of developing clinically definite multiple sclerosis. This additional indication - treatment is not yet definite MS - ​​was approved in 2009.

There is no admission for the primary or secondary progressive forms of MS.

The existing limited published data suggest that the safety profile in adolescents from 12 to 18, who received daily 20 mg glatiramer acetate subcutaneously to adults is comparable.

Type and duration of application

Glatiramer acetate daily subcutaneously, that is, in the subcutaneous tissue (subcutis ), injected. The treatment of MS requires a long-term application.

Adverse effects (side effects)

The most common cause local skin reactions such as redness, burning, itching, or hardening of the corresponding region of the subcutis. This can be mitigated by cooling the injection site before and after the injection.

Rarely, of unknown causes a side effect occur as the SPIR (immediate post injection reaction) or " Flush" is called. Immediately after the injection there is there for a short time (about 5-15 minutes), shortness of breath, anxiety, anxiety, sweating and palpitations.

Antibody

Many patients develop antibodies to glatiramer acetate; their clinical significance is unknown.

Pharmacological properties

Composition

Glatiramer acetate ( GA) is a heterogeneous mixture of synthetic polypeptides. These consist of four natural amino acids glutamic acid, lysine, alanine, and tyrosine ( " GLAT " ) which are present in a fixed molar ratio of 0.14 to 0.34 to 0.43 to 0.09. The mean molar mass of GA is located at 5000-9000 ( 4700-11000 ) Dalton.

Mechanism of action ( pharmacodynamics )

As glatiramer acetate in a position to influence the course of MS cheap, it is not clear safe; the following possible mechanisms of action are currently being discussed:

• The chemical structure of GA is that of the myelin basic medium protein ( MBP) - in particular the Peptidsequen 82-100 -, a major component of the myelin sheath, very similar. Immune cells that normally would attack the myelin layer in MS, bind to the active ingredient and can be defused.
• In addition, GA causes a shift of the ratio of TH1 to TH2 immune cells ( T-helper cells). The activated Th2 cells cross the blood- brain barrier and put in the CNS increased anti-inflammatory acting cytokines ( interleukin -4, IL -6 and interleukin -10) free. At the same time the production of proinflammatory cytokines such as IL-12 is reduced. This leads to the suppression of the pathological inflammation in the MS lesion spot. In addition, the formation of neurotrophic factors, such as the Brain Derived Neurotrophic Factor (BDNF ), funded with potentially neuroprotective effect - the loss of axons may be hampered and destroyed myelin sheath to be rebuilt.
• GA promotes the emergence of a regulatory action CD8 immune cells in untreated MS patients usually significantly reduced.
• GA promotes by activation of the transcription factor FOXP3 ( forkhead box protein 3 ) the conversion of conventional CD4 CD25 - T cells into CD4 CD25 regulatory T cells.

Other Information

History

In the 1960s, several series of experiments were at the Weizmann Institute in Israel by Michael Sela and Ruth Arnon carried out, which should clarify the minimum chemical requirements must possess a molecule to elicit an immune response of the organism, would therefore lead to the formation of antibodies. In addition, it should statements be won, how come the specificity of the immune reactions. To gelatin was equipped with short peptides of different composition, whereby the immunogenicity of the gelatin has been significantly increased as tyrosine, tryptophan, phenylalanine, or - here in to a lesser extent - cysteine ​​has been added, while covalent binding of peptides, alanine, lysine, glutamic acid, serine and proline did not drop the case was later they realized that the peptide alone shares and not gelatin were responsible for the immunogenic properties, and that such synthetic molecules from 4000 daltons represent potent antigens. Subsequently, a polypeptide was synthestisiert, the myelin basic protein (MBP, Eng. Myelin basic protein ) should be similar to (EAE ) in order to trigger an experimental autoimmune encephalomyelitis in laboratory animals, so an auto-immune reaction against MBP.

Were prepared three polypeptides, which are formed by the copolymerization, and therefore referred to as copolymers.

During EAE could be provoked by any of the polypeptides produced, was instead observed and published in 1971 that EAE was suppressed in the guinea pigs used in this test series. All three copolymers showed this protective effect when they were administered intradermally with the aid of Freund's adjuvant, a strong immunostimulatory adjuvant and lovely. An effect when injected intravenously with saline showed only the copolymer -1. This simplest of the three copolymers had the least side effects. Copolymer -1 or abbreviated Cop -1, which retained the working name until 1996, should therefore be crucial for the further development.

As a result, it could be demonstrated that this protective effect is not limited to individual animal families. Limited and was independent of the type of the trigger used for EAE.

How Stanley Scheindlin indicates that researchers were now convinced that we have instead of a pharmacological agent work found a potential drug. So was followed by additional preclinical studies of safety of the substance, laboratory animals ( mice, rats, rabbits and beagles ) different doses were administered for varying periods of time.

The commercial exploitation of research achievements and approval under the name Copaxone carried out in 1996 in the United States and in November 2001 for all Member States of the European Union by the company TEVA and Sanofi -Aventis, so it was available from January 2002, for example in Austria. Even the name Copaxone takes several times on the development history of substance reference: Cop ' for the copolymer, , ax ( on)' for nerve ( ensystem ) and 'one' for ( copolymer ) 1

Studies

In 1977, the first open-label studies were conducted with the drug in humans at the Weizmann Institute. First of four patients with far advanced multiple sclerosis, followed by four patients with Relapsing- remitting MS and twelve, who suffered from a chronic progressive disease. The results were encouraging enough to take a randomized controlled trial in attack.

The design of this pilot study took Murray B. Bornstein (1917-1995), from 1966 until his retirement in 1988 Faculty Member of the Albert Einstein College of Medicine in New York City. The primary endpoint of the study was to determine the extent to which patients would remain relapse-free. Secondary endpoints were the frequency of exacerbations and the extent of the degree of disability after the end of the study. 50 patients with Relapsing -remitting MS were randomized, was completed the study in 48 participants. Once there were still too little information on the stability of the Cop-1 is available, the patients received the drug in a frozen state, left the daily ration thaw each and injected these themselves ( after they had been trained ) once a day for two years. Under these conditions, 23 patients received a placebo ( saline) and 25 patients Cop -1. The results were published in the NEJM in 1987. In the placebo group, there were 62 exacerbations in the treatment group at 16 While the degree of disability in the placebo group deteriorated by 1.2 units, the degree of disability improved in the treatment group by 0.5 units.

In 1996, the United States Adopted Name Council in Chicago the term glatiramer, where the initials of the four amino acids involved and the suffix "- mer" ( for polymer standing) were used for the naming of the international non-proprietary name, in order to organization policy for correspond to simple and understandable terms.

Clinical efficacy in relapsing- remitting MS

In the pivotal study with 251 patients treated over a period of two years, a reduction in relapse rate of approximately 30% compared to placebo could be detected.

A long-term study that has emerged from the pivotal study has shown that the relapse rate continues to decline continuously over a long observation period. The current at the moment 15-year data from the open-label prospective study write this development continues. The relapse rate of around 1.2 per year relapses prior to treatment by more than 80 percent could be reduced to about 0.2 relapses per year in those patients who had received more than 15 years GA. At the same time, the treatment had a positive effect on neurological disability: 57 percent of patients who had been continuously treated with GA, reported after 15 years of a stable or improved value to the EDS scale on. This scale provides information on the degree of disability of MS patients. More than 80 percent remained under a EDS value of 6, so could walk at least 100 meters without aids independently. In those patients who discontinued treatment prematurely and were examined 10 years after initiation of therapy, in only 28 percent of the cases, the degree of disability had remained stable or had improved. It should be noted that the number of participants in the follow-up of originally 232 individuals who had at least once received glatiramer acetate resulted only in 100 patients, treatment after fifteen years still continues. Of the 124 patients, 50 have alighted presented again for the follow-up study after 10 years in treating clinic. It can be assumed that mainly the people who left the study, in which GA has less worked well, so it should at least be related some of the sharp drop in relapse rate. On the other hand, people may refuse further participation in the study, whose complaint freedom allows them to displace their diagnosis.

The results of a meta-analysis of three placebo-controlled double-blind studies confirm the positive effect of GA on the relapse rate .. In clinical studies, it was in those of a total of 540 study participants who were treated with the preparation, a reduction in the annualized relapse rate by 28 percent are found in the compared to those who received only a placebo. In addition, the time was extended until the first thrust by treatment with GA (322 days versus 219 days for placebo ). Also, the risk that the level of disability increases significantly, were lower with GA, with the power of the study due to the relatively short duration of the studies reviewed (24, 35, and 9 months) is limited in this respect.

In an open-label study of the therapeutic success of GA and used as standard beta - interferons in patients was compared retrospectively together with relapsing-remitting MS. These data were analyzed from 308 patients who came from a database in which the two-year course of treatment is documented: After six months of treatment, the interferons and GA were comparable in their effectiveness in terms of reducing the shear rate. After 12 and 24 months passed between the interferon preparations no differences. Treatment with GA, however, the number of relapses was significantly more reduced than under any of the investigated interferons in this period. In addition, the dropout rate below the GA was lower. For this examination, it should be noted that the validity of the results - is limited - due to the nature of the study design.

In three other recent studies - Regard, and BECOME BEYOND - different interferon beta preparations and GA were compared. During the randomized studies, were involved in a total of 3000 patients with relapsing forms of MS, similar positive effects could be observed in the interferons as well as GA with respect to time to the first flare, the relapse rate and the number of active lesions in the CNS.

Clinical efficacy in primary progressive MS

A recent controlled clinical trial evaluated the efficacy of GA on the primary progressive MS, in which no relapses occur, but the symptoms of beginning proceed chronic. During the investigation, no significant efficacy of the therapy was on the rate of progression of the entire study population. However, the progression rate was generally lower than expected, which affected the validity of the study. The results of a retrospective analysis showed a significant treatment effect in contrast to the male subpopulation of the study, in which the rate of progression was in the originally expected level.

Neuroprotective effect

In an MRI - based study, the neuroprotective effect of GA was shown. The number of lesions of scarred inflammation to irreversible axonal damage - so-called "Black Holes" - pass could be halved under the administration of GA. The protective effect of GA, however, occurs only after a treatment period of approximately six months.

The fact that GA inhibits the loss of nerve tissue is also evident from the results of a study by Omar Khan. The treated 18 patients with relapsing-remitting MS from the beginning of the illness for six years throughout with GA. More patients initially remained untreated. Regular measurements of the neural marker N- acetylaspartate (NAA ) by means of magnetic resonance spectroscopy (MRS ) showed that the ratio of creatine and NAA significantly increased in the treated patients. This in turn close to a recovery of Axonfunktion and protection against axonal damage. In the untreated patients, the NAA / creatine ratio decreased significantly from the other hand, that is, in these patients, a significant loss of axons was found. This improved after receiving the therapy.

Trade names and dosage forms

Copaxone ® 20 mg as a solution in prefilled syringes for subcutaneous injection

Because glatiramer acetate is polymerized from the four contained amino acids present only in a certain proportion randomly, the effectiveness of any coming into the trade charge must first be verified in animal experiments.

Costs

The cost of the drug amount to approximately € 19,500 ( pharmacies selling price ) per year.

The annual costs in 2011 amounted to EUR 11,600.00 (Source: Declaration of expenditure of OÖGKK )