Tuesday, 22 December 2015

How do you demonstrate that a generic is the same and your expensive DMT

Anderson J, Bell C, Bishop J, Capila I, Ganguly T, Glajch J, Iyer M, Kaundinya G, Lansing J, Pradines J, Prescott J, Cohen BA, Kantor D, Sachleben R.Demonstration of equivalence of a generic glatiramer acetate (Glatopa™). J Neurol Sci. 2015;359(1-2):24-34. doi: 10.1016/j.jns.2015.10.00u7

Glatiramer acetate (GA) has been available under the brand name Copaxone® for nearly two decades. Recently, the US Food and Drug Administration (FDA) approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved; Glatopa also represents the first FDA-approved "AP-rated," substitutable generic for treating patients with MS. Glatiramer acetate is a complex mixture of polypeptides and, consequently, its characterization presented challenges not generally encountered in drug development. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerization, depolymerization, and purification; physicochemical properties; and biological and immunological properties. This article describes the rigorous overall scientific approach used to successfully establish equivalence between Glatopa and Copaxone, and presents key representative data from several of the comprehensive sets of physicochemical (structural) and biological (functional) assays that were conducted.


Copaxone is the worlds best selling MS drug at about $4 billion a year. Is this amazing because of its reported level of efficacy. Now some people will say I am doing very well on this agent. This is a fair point but some don't and choose to switch

The data is tout there for all to see and it is clear that copaxone is not the most effective at stopping the relapse rate, but some say it takes time to work, so I 
asked someone (Their idenity is not important) why they thought it was the best seller, even in Europe? 

I was shocked by their response......It was lazy neurologists......they don't want to do much. 

As Copaxone has one of the best safety profiles  then monitoring their patients is not an issue and as people with MS are happy because they are being treated without side effects and as they generally do well in terms of disability accrual early in disease, it's a win, win.

Now if this there is a shredder chomping away, as suggested by ProfG, at your neural reserve, it means that by not being on top of disease early means that your neural reserve is lost quicker. This means disability in the future. Some may point out that copaxone is reported to stimulate cells to make nerve growth factors like BDNF and be neuroprotective. Does it stop  progressive MS?

However,because Copaxone is making so much money every one wants a slice of that Pie. It is not surprsing that someone wants to make a generic. 

To limit the size of the target population, Teva have reinvented Copaxone daily to  be Copaxone 3 times a week as the copaxone daily patent has gone. So they have been shifting people onto their premium product, so I bet as this patent dies we will see Copaxone once a week:-). If the competitor lawyers get their way this will be sooner rather than later. 

Generics are copies of the original but how do you make an identical molecule, when the original is never the same as it is a random mix of amino acids that's not quite the same from batch to batch. I was told that they test each batch in animals to test for efficacy...if this is true, it is not very 3Rs. 

An IND is an Investigational new drug, which what is requested when your toxicology studies  are done and you are ready to tes your drug in humans. An NDA is a new drug application is what is applied for after your human tests are done and you are ready to sell your drug.

This paper says a few things that the FDA use to decide if the generic is worth approving and the generic glaterimer acetate
got an Abbreviated NDA. As it is open access you can read it

They say

"generics must demonstrate therapeutic equivalence (i.e., pharmaceutical equivalence and bioequivalence) to the innovator drug product". 

"Bioequivalence is defined by the Code of Federal Regulations, 21CFR320.1, as the “absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alter becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study"

Does this mean that any pro-drug is just the same as the parent?
Maybe this is why Merck is not trying to get movetro on to the agenda with the FDA in the US and are just dealing with the EMA.

However, what they say they do is a series of experiments and show that glatopia (a generic glaterimer) is like copaxone and so they go to animals.

However, if you go to animals and look at the data . The question is "Is the data is just as bad or is it just as good as the original?". 

We hear that copaxone is great at inhibiting EAE and that is it how it was developed, but if you look at the animal data, it leads a lot to be desired. 


In this paper is a good example, if we look at the top graph the effect is a delay of about 2 days and there is limited if any effect on severity of disease such that the animals end up in essentially the same place with or without treatment. So the data is not that startling. 


Is this it because they are trying to inhibit Proteolipid protein disease disease in (High EAE susceptibile) inbred SJL mice, when glaterimer is based on myelin basic protein? 


In contrast it appears to works in Myelin oligodendrocyte glycopotein in (low EAE susceptible) inbred C57BL/6 mice. 


So two individuals, it works in one and not the other. So what happens in humans, I hope it works for you, it seems to work for some and not others.

However, if we do an analysis of the published data of glaterimer acetate in animals the picture of activity if it is given subcutaneously is often like the top graph and not that impressive. 

In some studies such as found in patents this is actually toxic in the animals. 


Glaterimer works best when you mix the glaterimer acetate with the sensitizing mixture and then it can wipe out disease completelty, even in highly susceptible animals that respond to PLP. The data is there to be seen and I know I've done it. 

8 comments:

  1. "Some may point out that copaxone is reported to stimulsate cells to make nerve growth factors like BDNF and be neuroprotective. Where is the data?"

    The data is out there but if you have blinders on for immunosuppressive drugs you are not going to find it.


    http://www.ncbi.nlm.nih.gov/pubmed/16083971

    I think there is a consensus that Copaxone takes at least 6 months to become effective. For people withe highly active disease this is not fast enough, which is why EAE scientists like yourself judge a drugs effectivness by how quickly it can shut down EAE.

    But in reality EAE is not ms which is why science is still trying to understand the MOA of GA and get insight the disease itself.

    So for me the 15 year open label study that shows those on GA for 15 year continuously, 63% did not transition to SPMS and 57% had stable or improved EDSS score:

    http://m.msj.sagepub.com/content/16/3/342

    It is interesting that Team G wants to do a similar open label trial with some of their immunosuppressives that they are marketing. But since they are both open label trials, how can one be more valid than the other?

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    1. Looked at the reference.

      What do blood levels of neurotrophic factors mean as they have to be produced in the brain.

      I was refering to data in progressive MS..where the trial was stopped.

      However so 63% did not transition which is good so 37% did which is not so good.....2-4% on Alem not bad either.

      Open label trial......what's that one I haven't heard about it, do you mean the HSCT that is pretty open label. However the landscape of trials is very different today verses 15 years ago.

      I judge drugs effectiveness by effects on EAE...I don't think so other wise Natalizumab would be rubbish:-)



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    2. Also you should note that those who started opaxone with a low EDSS score (low strada of 2) were significantly less likely to progress than those who started with a higher EDSS (high strada 3.9):

      There were significant differences in the proportion of patients in the Low and High strata of the mITT cohort reaching EDSS thresholds of 4, 6, and 8 (Figure 4). In the Low stratum of the mITT cohort, 25%, 9% and 1% reached EDSS thresholds of 4, 6, and 8, respectively, and in the High EDSS stratum, 61%, 34%, and 8% reached EDSS 4, 6, and 8, respectively.

      I think this is what Team G is finding with their immunosuppressives in that if you start to late nothing is going to help.

      To me the longterm extension study is valuable and it is not something that could be done in this day with so many therapies to switch to. Is it biased in that those that do well would stay with the therapy? Maybe so but I think it gives confidence that 8t could possibly halt progression if started early enough.

      So maybe neurologists aren't lazy of "laggards". Maybe they just don't see the benefits of immunosuppressive agents for many MSers who don't have highly active disease.

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  2. "Glaterimer works best When You mix the glaterimer acetate with the sensitizing mixture And Then it can wipe out disease completelty, even in highly susceptible animals que Respond to PLP."
    MD which means that sensitizing mixture which you referred to?

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    1. The myelin antigens used to cuase the disease

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  3. "Teva have reinvented Copaxone daily to be Copaxone 3 times a week as the copaxone daily patent has gone."
    If such a 'simple' modification means a new patent can be granted, why don't generic pharma companies invent a weekly Copaxone drug once the original Copaxone is off patent? Would this be allowed? It would would good for the NHS if they can use a cheaper supplier.
    Other drugs might be similarly adapted to circumvent patent laws, or is this just too simplistic?

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    1. Yep. Assuming you could invent it but the regulators would say show me the proof that it works so you have to do a trial. So the generics companies can't afford to do this and so problem Number 1.

      Next up you have to ask. Is the work "inventive" or could a person skilled in the art have a reasonable view that it would work because if it is "obvious" it is also not patentable. We have just had this discussion so you can say it is obvious to try and so we have blown the patent. It doesn't stop you filing but it may not be granted and you may have competition lawyers trying to pull it down.

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    2. It appears Mylan which is the company that makes generic 20mg/daily is looking to market a 40mg/3xWeek formulation:

      http://newsroom.mylan.com/2015-09-02-Mylan-Confirms-the-U-S-Patent-and-Trademark-Office-Institutes-Inter-Partes-Review-Proceeding-against-Third-Copaxone-40-mg-mL-Dosing-Patent-on-All-Claims

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