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Glatiramer

Glatiramer acetate is a disease modifying treatment for MS. It was originally called copolymer 1 and has been marketed by the trade name of Copaxone. It was approved for use in Australia towards the end of 1999. It was discovered by accident by Israeli researchers at the Weizmann Institute of Science in 1968. These researchers were trying to make artificial substances similar to the myelin base protein with which to induce experimental autoimmune encephalomyelitis in experimental animals. Glatiramer was one of a series of mixtures of amino acids, the building blocks of proteins, which were devised to have similar properties to myelin base protein. Surprisingly, although these substances were found not to cause EAE in the animals, glatiramer somehow stopped mice getting the disease and ‘cured’ mice that already had the disease.

How Does Glatiramer Work?

It appears that glatiramer somehow re-educates the immune system because it has a similar structure to the base protein of myelin. This base protein is thought by many to be the part of the nerve which is attacked by the immune system in MS. In effect, glatiramer tricks the immune system into somehow activating certain immune cells which are normally associated with the damage in MS. These cells go into the brain, and upon reaction with myelin base protein, reduce the inflammation at the MS lesions. In a sense, it works a bit like the desensitisation injections that people with allergies to bee-stings can have. Quite a bit of work now shows that glatiramer shifts the immune system balance from a Th1 (exciting inflammation) to a Th2 (dampening down inflammation) response. That means that the drug is likely to benefit several other immune-based diseases. A 2006 study showed that it was helpful in experimental autoimmune liver disease.1

There has now been a very large scientific effort into figuring out how glatiramer works.2-7 Recently there has been considerable interest in its neuroprotective effects.8 Khan and co-workers have done studies on patients commencing glatiramer therapy and comparing them over time with people not taking glatiramer.9 They were able to use special MRI scans which allow assessment of whether axons (long nerve connections) degenerate or not in the brain. They showed that the axons of people taking glatiramer are protected and recover from injury whereas those from people not taking glatiramer tend to die from the injury.

Unlike the interferons, glatiramer doesn’t appear to have any general effect on the immune system, and it certainly doesn’t suppress the immune system. It therefore doesn’t make people more susceptible to infections or affect their blood count. And so, regular blood tests are unnecessary, because it has no measurable effect on any other body system. It also seems to reduce the production of some of the chemicals responsible for the inflammation caused by auto-immune activation.
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Glatiramer Studies

The first major study undertaken by researchers at the Albert Einstein College of Medicine in New York reported improvements in twenty-five patients treated with glatiramer compared with those treated with placebo injections for two years.10 The glatiramer treated patients had a 76 per cent reduction in relapse rate, from 1.35 attacks per year to 0.3. The percentage of patients who remained relapse-free over the two years in the treated group was more than double (56 per cent) that of the placebo group (26 per cent). It was then decided to test the drug on 106 patients with chronic progressive MS, as opposed to relapsing-remitting.11 This form of MS has been particularly difficult to treat, and glatiramer failed to show any benefit (although in one of the two centres treating patients, there was a significant difference between glatiramer and placebo).

The pivotal study was performed by researchers in Baltimore, using eleven major centres in the US. They performed a well-constructed RCT in which 251 patients with MS were either treated with glatiramer or inactive placebo for two years.12 Like the interferon studies, there were about a third (29 per cent) fewer relapses in the treated group (0.59 versus 0.84). The p value was 0.007 so the result was unlikely to have occurred by chance. Unlike most of the interferon studies, treatment with glatiramer suggested a slowing of the progression of disability. Although this was not shown with the usual measures of disability, the authors analysed the number of patients who got worse, were unchanged, or improved, and found significant benefit here for glatiramer. After two years, the glatiramer patients had improved EDSS scores by 0.05 points, whereas the placebo patients had worsened by 0.21 points.

There were relatively few side-effects and no abnormalities detected on blood tests. Most patients developed antibodies to the drug, but unlike the interferons, these antibodies did not interfere with the effect of glatiramer. In an 11-month extension of the trial, the effect of glatiramer improved, with the relapse rate reducing further by a total of 32 per cent. Follow up for more than five years showed that the effects were maintained or even increased over this time. At the end of this period, the relapse rate was reduced to 0.16 a year in those patients taking glatiramer. This represents a relapse only once every six years.

In 1999, MRI data from the pivotal study showed there was a 35 per cent reduction in the number of brain lesions. A small study of ten patients comparing the rate of new lesions with their rates pre-treatment showed uncertain improvement.13 The European-Canadian MRI study clarified this further.14 This major RCT enrolled 239 patients with relapsing-remitting MS. The patients had had MS for about eight years on average, with a mean EDSS of 2.4 and an average relapse rate in the previous two years of 2.7 per year. Patients had MRI scans every four weeks. After nine months in the study, patients taking glatiramer had 29 per cent fewer new MRI lesions, and about 50 per cent lower total MRI disease burden. The clinical relapse rates, unlike those in the interferon studies, also correlated well with the MRI changes. Patients taking glatiramer had 33 per cent fewer relapses. It took some three months before any beneficial effect was seen, and six months before this difference between glatiramer and placebo was significant. The effect seemed to increase the longer patients were on the drug.

There has now been considerable experience with glatiramer. Patients from the original 251 patient pivotal study have now been followed for six years, with interesting results.15 205 of these patients have been studied now. The longer patients remained on the drug, the greater the benefit. Patients continually on the drug for six years had an annual relapse rate in the sixth year of 0.23, or roughly one relapse every four to five years. This is markedly less than their starting relapse rate.

Of great interest, approximately 70% of patients continually on the drug for six years were either the same in terms of disability as when they started, or were somewhat better. The same research group looked at patients from the original trial of 251 patients eight years later, and compared those who started on glatiramer and continued with those who started on placebo, but at the end of the trial were started on glatiramer. This 30 month delay in starting glatiramer therapy was associated with a significantly smaller proportion of patients remaining stable in terms of their EDSS scores.16

Similarly, the European-Canadian study has been followed up long term, now for a mean time of 5.8 years for nearly two thirds of the original study group.17 In this study, the control group who originally took placebo were treated with glatiramer after 9 months along with those in the treatment group, so effectively this group had a delay of 9 months in starting treatment with glatiramer. Researchers then compared at 5.8 years these people with delayed treatment to those who had been receiving glatiramer all along. This group was significantly (p=0.034) more likely to be using a cane at this stage than those who had been on glatiramer all along. Again this points to a beneficial effect of glatiramer on disease progression.

Researchers in 2000 looking overall at clinical trials to date concluded that the chance of a relapse at one year for a patient on glatiramer was about one-sixth of that for a patient not on glatiramer.18 A 2005 MRI study showed that for patients in one of the major glatiramer trials, the reduction in lesions after treatment with glatiramer ranged from 20% to 54%.19 All of these results in combination suggest that glatiramer therapy ought to be more widely prescribed than it is.
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Side-effects

90 per cent of patients receiving glatiramer in the Baltimore study got skin reactions, and 15 per cent a transient flushing feeling, with palpitations and shortness of breath. There were no serious side-effects. These rates were somewhat lower in the European-Canadian MRI study, and again there were no serious side-effects. In particular, the flu-like symptoms, so commonly seen with the interferons, are not seen with glatiramer. Although neither the interferons nor glatiramer are recommended for use during pregnancy, we know that the interferons can definitely cause problems. Research reported to the American Academy of Neurology meeting in April 2003 suggested that this is unlikely to be the case with glatiramer. Of 215 pregnancies which occurred while patients were on glatiramer, there was no higher incidence of abnormalities than usual. This is at least reassuring for women on glatiramer who unexpectedly fall pregnant.
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Dosing

The dosing schedule for glatiramer, that is a daily injection, puts some people off, and leads them to opt for the interferons, which may be given second daily or even weekly. We are still unsure of the optimal dosing for glatiramer. There is some evidence that injecting every second day is just as effective as daily injection, and this needs to be investigated further.20 Until we have more evidence though, daily injection is recommended. A further issue about dosage that has been investigated is doubling the dose. Investigators from Ohio randomized people with MS to standard dose or double dose glatiramer given in the usual manner, subcutaneously every day.21 They found evidence suggesting the double dose to be more effective, with a longer time to first relapse and higher proportion of relapse free subjects in the double dose group.

Researchers have for some time been examining the question of whether glatiramer taken by mouth works just as well as it does when injected. Initial work in animals was highly positive, suggesting that oral glatiramer would be equally effective.22 When published in 2006, the study of 1651 patients showed no improvement at either low or high dose oral glatiramer.23 This effectively rules out oral glatiramer as a therapy for MS.
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Overview

Many authorities are now recommending glatiramer as first-line treatment for MS, equivalent in its effect to the interferons. Given that the side-effect profile is clearly superior to that of interferon, and that the studies on glatiramer were properly blinded and hence more likely to be valid than the interferon studies, my own view is that it should be considered before the interferons. I recommend that people offered interferon because of the number of relapses they have should raise the possibility of taking glatiramer instead. It is certainly likely that it will be better tolerated, and it is likely to be just as or more effective. Interferons appear to take about 1-2 months to be effective, versus 3-6 for glatiramer, and this may be an issue if the disease is particularly active, although most patients starting on these therapies have just finished a course of steroids for a relapse or first attack, and get some protection from the steroids for a period of time. Overall, glatiramer appears to be a safe and modestly effective therapy for MS, with few side effects.
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Optimal method for reducing site reactions to sub-cutaneous injections

To avoid site reactions with sub-cutaneous injections, it is important to use the correct injection technique. In this video, Prof Jelinek shows how to inject correctly.

Many people injecting sub-cutaneous (SC) medication for MS develop site reactions, like lumps, wheals, itching, redness or bruising. This is usually due to injecting too deep (into muscle) or too shallow (into the skin itself).

The right place for the medication to go is just below the skin, in the space between the skin and the underlying muscle. This space is really hard to find reliably if the skin is stretched out during injection. Picking an area where there is some fat under the skin such as the abdominal wall, the skin needs to be grasped between thumb and middle finger and lifted.

The needle is then introduced perpendicular to the top of that wad of skin and inserted all the way to the hub. If using an autoinjector, set the depth at maximal depth, as lifting that piece of skin guarantees the injection will not go to deep with a standard needle like the one on the Copaxone injection. Inject relatively slowly, as rapid injection causes pain, and once injected, remove the needle quickly, and let go of the skin.

Dispose of the syringe and needle thoughtfully. Most people do not require heat or cold packs with this technique, and very few develop any site reactions.

This video demonstration performed at one of the Gawler MS Retreats shows the technique.
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  1. Horani A, Muhanna N, Pappo O, et al. The Beneficial Effect of Glatiramer Acetate (Copaxone®) on Immune Modulation of Experimental Hepatic fibrosis. Am J Physiol Gastrointest Liver Physiol 2006
  2. Aharoni R, Teitelbaum D, Arnon R, et al. Copolymer 1 acts against the immunodominant epitope 82-100 of myelin basic protein by T cell receptor antagonism in addition to major histocompatibility complex blocking. Proc Natl Acad Sci U S A 1999; 96:634-639.
  3. Aharoni R, Teitelbaum D, Leitner O, et al. Specific Th2 cells accumulate in the central nervous system of mice protected against experimental autoimmune encephalomyelitis by copolymer 1. Proc Natl Acad Sci U S A 2000; 97:11472-11477.
  4. Brenner T, Arnon R, Sela M, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone. J Neuroimmunol 2001; 115:152-160.
  5. Duda PW, Schmied MC, Cook SL, et al. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest 2000; 105:967-976.
  6. Gran B, Tranquill LR, Chen M, et al. Mechanisms of immunomodulation by glatiramer acetate. Neurology 2000; 55:1704-1714.
  7. Miller A, Shapiro S, Gershtein R, et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation. J Neuroimmunol 1998; 92:113-121.
  8. Kreitman RR, Blanchette F. On the horizon: possible neuroprotective role for glatiramer acetate. Mult Scler 2004; 10 Suppl 1:S81-86; discussion S86-89
  9. Khan O, Shen Y, Caon C, et al. Axonal metabolic recovery and potential neuroprotective effect of glatiramer acetate in relapsing-remitting multiple sclerosis. Mult Scler 2005; 11:646-651
  10. Bornstein MB, Miller A, Slagle S, et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med 1987; 317:408-414.
  11. Bornstein MB, Miller A, Slagle S, et al. A placebo-controlled, double-blind, randomized, two-center, pilot trial of Cop 1 in chronic progressive multiple sclerosis. Neurology 1991; 41:533-539.
  12. Johnson KP, Brooks BR, Cohen JA, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998; 50:701-708.
  13. Mancardi GL, Sardanelli F, Parodi RC, et al. Effect of copolymer-1 on serial gadolinium-enhanced MRI in relapsing remitting multiple sclerosis. Neurology 1998; 50:1127-1133.
  14. Comi G, Filippi M, Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging—measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49:290-297.
  15. Johnson KP, Brooks BR, Ford CC, et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult Scler 2000; 6:255-266.
  16. Johnson KP, Ford CC, Lisak RP, et al. Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data. Acta Neurol Scand 2005; 111:42-47
  17. Rovaris M, Comi G, Rocca M, et al. Long-term follow-up of patients treated with glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-controlled, MRI-monitored trial. Mult Scler 2007; 13:502-508
  18. La Mantia L, Milanese C, D’Amico R. Meta-analysis of clinical trials with copolymer 1 in multiple sclerosis. Eur Neurol 2000; 43:189-193.
  19. Sormani MP, Bruzzi P, Comi G, et al. The distribution of the magnetic resonance imaging response to glatiramer acetate in multiple sclerosis. Mult Scler 2005; 11:447-449
  20. Flechter S, Kott E, Steiner-Birmanns B, et al. Copolymer 1 (glatiramer acetate) in relapsing forms of multiple sclerosis: open multicenter study of alternate-day administration. Clin Neuropharmacol 2002; 25:11-15.
  21. Cohen JA, Rovaris M, Goodman AD, et al. Randomized, double-blind, dose-comparison study of glatiramer acetate in relapsing-remitting MS. Neurology 2007; 68:939-944
  22. Teitelbaum D, Arnon R, Sela M. Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1. Proc Natl Acad Sci U S A 1999; 96:3842-3847.
  23. Filippi M, Wolinsky JS, Comi G. Effects of oral glatiramer acetate on clinical and MRI-monitored disease activity in patients with relapsing multiple sclerosis: a multicentre, double-blind, randomised, placebo-controlled study. Lancet Neurol 2006; 5:213-220