Monday, 31 August 2015

ClinicSpeak: glatiramer acetate experience and persistence

Glatiramer acetate, Teva's cash-cow, has plenty of life left in it! #ClinicSpeak #MSBlog #MSResearch

"I am often asked is there a future for the injectable DMTs. My knee jerk response is yes; the injectables are safe and there a large number of responders out there who will almost certainly want to stay on their current medication. Why? There is no data suggesting that if you are a responder to one class of drug that if you then move to a new class of therapy that you are likely to be a responder to the new class. Interestingly, the study below suggests that interferon-beta failures who switched to glatiramer acetate (GA) do better on GA than those starting the drug as naive to DMTs. Could this observation be telling us about the biology of MS and the DMTs we use to control the disease?"

"Another reason why GA is here to stay is the fact that its safety record in pregnancy is very favourable. This is based on large pregnancy registries that show GA is not teratogenic, i.e. it has not been shown to cause malformations in the foetus, it is not an abortifacient, i.e. increased loss of early pregnancies, it does not affect fertility, i.e. you ability to fall pregnant, it has not impact on labour and it is safe for breastfeeding. In short, out of all the currently licensed maintenance DMTs, GA is the only one that can make these claims."

"You are also probably aware that Teva, who manufacture GA, have now launched a 40 mg three times a week formulation (Copaxone-40), that looks to be as effective as the daily injection formulation (Copaxone-20). If you had an option why wouldn't you switch from the 20 mg daily formulation to the to 40 mg 3x per week formulation? You may not if it is due to affordability. In many countries generic versions of GA are about to be launched; in price-sensitive markets, which are most markets, cheaper versions of GA will disrupt the market."

"Finally, if we could only predict who will be a responder, or non-responder, to GA prior to them starting on treatment then GA will have plenty of life left in it. Who wouldn't you start GA if we could say your chances of responding to this drug (NEDA-3) are greater than 80% or 90%? It is all about risks and benefits; if only we can tip the ratio in favour of the benefits. May be I am wrong?"

Fern├índez-Fournier et al. Differential glatiramer acetate treatment persistence in treatment-naive patients compared to patients previously treated with interferon. BMC Neurol. 2015 Aug ;15:141. doi: 10.1186/s12883-015-0399-9.

BACKGROUND: In the treatment of multiple sclerosis, a change of therapy is considered after treatment failure or adverse events. Although disease modifying drugs' (DMD) efficacy and side effects have been fully analysed in clinical trials, the effects of previous therapy use are less well studied. 

AIMS: We aimed to study medication persistence with glatiramer acetate in treatment-naive patients and in patients previously treated with interferon.

METHODS: A retrospective study of relapsing-remitting multiple sclerosis patients treated with glatiramer acetate in an MS Unit of a Spanish University Hospital (January 2004 - September 2013). Treatment time on glatiramer acetate was studied. Reasons for treatment discontinuation were considered as follows: lack of efficacy, serious adverse event, injection-related side effect, pregnancy and lost to follow-up. Use of prior DMD was registered and analysed. Homogeneity of groups was analysed using Fisher's and Mann-Whitney's tests. The Kaplan Meier method and Cox regression model were used to estimate time to and risk of treatment discontinuation.

RESULTS: In total, 155 relapsing-remitting multiple sclerosis patients were treated with glatiramer acetate: 100 treatment-naive patients and 55 treated previously with interferon. At the end of the study, 76 patients (49.0 %) continued on glatiramer acetate (with an average treatment time (ATT) of 50.4 months, s.d.32.8) and 50 patients (32.3 %) had switched therapy: 27 patients (17.4 %) for inefficacy (ATT 29.2 months, s.d.17.5), 20 patients (12.9 %) for injection site reactions (ATT 16.5 months, s.d.20.3) and 3 patients (1.9 %) after serious adverse events (ATT 15.7 months, s.d.15.1). ATT in our cohort was 39 months (s.d.30.0), median follow-up 34 months. Six months after glatiramer acetate initiation, probability of persisting on GA was 91.4 %, 82.5 % after 12 months and 72.5 % after 2 years. The risk of glatiramer acetate treatment discontinuation was 2.8 [1.7 - 4.8] times greater for treatment-naive patients than for patients treated previously with interferon and this was hardly modified after adjusting for sex and age.

CONCLUSIONS: Glatiramer acetate was safe and useful with low rates of serious adverse events and low rates of break-through disease. Injection intolerance proved a major limitation to glatiramer acetate use. Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.

CoI: multiple


  1. Why the obsession with safety? My NHS neuro is south London published a paper a few years ago stating that the average life expectancy for an MSer was 30 years after the initial diagnosis. Not great if you are diagnosed in your 20s. You must see the toll this disease takes - what at MS patients like after 20 years? I'm guessing a chunk of them will be SPMS / in wheelchairs. If I invented a drug for MS which reduced relapses by 10% but was 100% safe, would this become your prescribing drug of choice? The fact that you think the injectibles still have a future makes me shudder. The real reason is too many vested interests. Given what's available now, new RRMS patients should be offered Fingolimod or Alemtuzumab. The injectibles / limited efficacy tablets should be kept in reserve for those who are risk adverse. They should come with a warning - very safe drug, but brain atrophy and disability will not be reduced. Like cigarette packets, the boxes containing injectibles should come with a picture of a shrivelled brain. How do you sleep at night prescribing sub-optimal treatments to patients - hiding behind the safety factor, but knowing the long term impact will be highly detrimental. The long term alemtuzumab follow-up showed that those who entered the spms phase was very low. Do you have such data for the injectibles which have been around for 20 plus tears?

    1. It's interesting that one of Team G's associates points to the fact that there is no statistically significant difference in the rate if progression between alemtuzimab and interferon.

      Maybe if we were to hear other voices outside of the Team G group thinkers you might come to the conclusion that not everyone wants or should be on these "highly effective " but potentially harmful drugs. It is amazing to me that the best Pharma can do is to develop drugs that are supposedly highly effective yet are contradicated for use during pregnancy. Don't they get that MS is a disease that hits young women the hardest?

      But if you want everyone on alemtuzimab it sounds like you born in the wrong generation. You may have been a be a better fit as an official in The Third Reich.

      The vast majority of Neurologists see that many people on the first line drugs do quite well. These drugs are not appropriate for those with highly aggressive disease but for the vast majority they have stabilized their disease.

      If you want to take alemtuzimab as a newly diagnosed msers who has tingling in their hands, by all means be my guest but don't force your decision on the rest of us.

    2. Dear Anon
      Selective use of details to suit your point. TeamG will say not every wants to be or should be on the highly effectives if you are NEDA-4.

      Drugs are contraindicated for use during pregnancy.....because they have not been tested during is legalese to say if you get pregnant whilst taking my drug..we will not be held responsible if something goes round.

      Your next comment is way out of line.

      Choice is just that.....if you no the facts you can make informed choices

    3. Anon 11:38:

      If the cited alemtuzumab data were the only data regarding its effect on disability progression, I would agree that we would need to be more skeptical about its use. But luckily this is not the only data. See figure 2 in the results from the second phase III trial:

      The main difference between the two trials was the rate of disability progression in the interferon group. The trial you cited was looking at newly diagnosed patients, while the second trial was looking at patients who had the disease for a longer amount of time. Only 11% of patients in the first group progressed, while more than double that number in the second group progressed. People in the alemtuzumab groups had a 30% reduction in progression in the first trial, and a 40% reduction in the second trial. The decrease was only statistically significant in the second trial, because of the differences in the baselines.

    4. Anon 11.38
      I think you are talking a lot of rubbish when you say that 'for the vast majority they have stabilised their disease' and are doing very well on the less effective DMTs. At least 20%of MSers are non responders and another large group have minimal response. I believe that you can get pregnant after you've had alemtuzumab, but you have to wait until it is out of your system.

    5. If you are going to pick and choose which data you want to believe, this is in line with Team G's approach when it supports your position. I did not cite anything, all I did was give a link to a neurologists point if view about the results.

      If you are happy on Lemtrada, good for you but what is your motivation to promote it? I understand Team G's motivation and I suspect you are just parroting their propoganda.

    6. If it's propaganda to promote the widest amount of choice of therapeutic choice for pwMS, including those that have been shown to be highly effective at stopping relapses, then guilty as charged.

    7. The message coming through by Team G was that all MSers need to be on the highly effective therapies that Team G recommends. At least this used to be the measage, but with posts like this it muddies the waters.

      Yes, if you tried first line injectables and failed maybe Lemtrada is the answer. After all you have to be persistent withe these drugs and if you aren't you can always throw your hands up in the end and proclaim these therapies are worthless.

      Hopefully at this point Lemtrada will help as long as you have not crossed over to SPMS because if you did nothing is going to help.

      So yes if you are irresponsible about adhering to your treatment maybe one of the infusion therapies would suit you better. But because the first line DMD's didn't help you it doesn't mean it won't help those that take their disease more seriously.

    8. How arrogant to say that as you didn't adhere to your first line treatment it didn't work. That is not the case. I adhered to injecting Rebif 3 x a week and still relapsed whilst on it. I take this disease very seriously indeed. Since having alemtuzumab I have not relapsed. I don't agree that alemtuzumab may do nothing to stop progression. Hopefully some with RRMS will not progress after having had this treatment, but the results won't be in for 15-20 years. Even if it delays progression it will have been worth it (and hopefully neuroprotective drugs will be available in the meantime). If you're happy on your less effective DMDs then fine , but I don't think they have the potential at all to stop progression. I hope I have the intelligence to read around the subject and not just take this blog's word for it.

    9. Anon 11.14
      As you seem to know all, tell me what is TeamG's motivation

    10. I hope that your questionably superior but highly dangerous treatment works for you. I guess we will see in 20-30 years the effect is has an cancer rates as it is known that immunosuppressive treatments reduce cancer surveillance down the road.

      If your happy being a gineua pig more power to you.

    11. If people were not willing to try new things there would be no treatments for anybody, so be very grateful for those people willing to go into trials..

    12. Yes, all those people that died when Tysabri was launched were taking a chance, but they did not expect anything as PML was not an issue in the trials. The point being you cannot take the word of experts pushing new therapies as they cannot know the problems.

      But if you educate yourself you can decide if a particular therapy is reasonable instead of blindly listening to the talking heads. I'm sure there were people that had great concerns before the Tysabri launch but you would never hear what they have to say, particularly on this blog.

    13. "I'm sure there were people that had great concerns before the Tysabri launch but you would never hear what they have to say, particularly on this blog."

      We had concerns, which sadly were proved to be correct, at least measures are now in place to reduce the risk of PML but feel free to keep grinding that axe.

  2. Do you think that people are more likely to persist if they have used beta interferon before because they are used to injections whereas the drop-outs in the naive group have injection reactions

  3. In my experience the injection site reactions on interferon are much more severe then the injection site reactions on GA. So if you switch from interferon to GA it feels like a big improvement and it is less difficult to deal with.


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