Saturday, 8 November 2014

Cop-2 looks like it is no Cop


 Cop-2 looks like it is no Cop (English is such a versatile language:-)

Anneli Savinainen et al. Differentiating Plovamer Acetate and Glatiramer Acetate: Efficacy and Mechanism of Action in a Preclinical Model of Multiple Sclerosis. Differentiating Plovamer Acetate and Glatiramer Acetate: Efficacy and Mechanism of Action in a Preclinical Model of Multiple Sclerosis (P1.187). http://www.neurology.org/content/82/10_Supplement/P1.187

OBJECTIVE: To compare the response to plovamer acetate (PA) and glatiramer acetate (GA) and investigate the mechanism of action (MOA) in a preclinical model of relapsing-remitting multiple sclerosis (RRMS).

BACKGROUND: PA is a copolymer mixture of four amino acids of defined ratio, rationally designed to have improved efficacy over GA. PA competitively binds to MHC II with higher affinity than GA and drives a T-helper cell (Th)2-like response. PA is undergoing Phase II testing for RRMS.
METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in SJL/J mice. PA, GA or vehicle were administered subcutaneously either daily or three times/week, or were co-administered with PLP at EAE induction. Disease severity was measured using a standard 0-5 clinical score (CS) scale. Blood and plasma were collected weekly for hematology and cytokine production measurements, respectively. Mouse splenocytes were cultured and re-stimulated to assess proliferation and cytokine production.
RESULTS: Disease onset was delayed significantly vs. vehicle with daily PA (5 days; p<0.001), daily GA (2 days; p<0.01), PA 3x/week (6 days; p<0.001), but not GA 3x/week. In addition, PA dose-dependently decreased EAE severity when co-administered at disease induction: 10 or 30 mg/kg completely abolished disease and 3 mg/kg resulted in a 60% decrease in EAE severity. In contrast, co-administration of 3 or 10 mg/kg of GA was not efficacious; 30 mg/kg resulted in a similar decrease in CS as seen with 3 mg/kg PA, suggesting that PA was 10x more potent than GA in this preclinical model. Additional results supported previous findings that PA induces a Th2 shift.
CONCLUSIONS: When compared with GA, PA more potently delays disease onset and reduces disease severity, as demonstrated in a preclinical model of RRMS.


Yesterday ProfG posted a comment that it had been announced that there would be termination of Phase II trial of Plovamer acetate. (Cop2).This is the next generation glatierimer acetate, formally known as copaxone and Cop-1. Cop-1 is a random co-polymer of 4 animo acids found in myelin basic protein and a host of other proteins. Plovamer acetate has a different mix of amino acids and was reported to have a better blocking capapcity to the major histocompatibility complex compared to Cop-1.

 Why stop development of Cop2? 

This suggests either a strategic change by the company that maybe MS is not where they want to be or that analysis of the ongoing trial (in the thanksgiving month of turkeys), suggested that it had no chance of becoming a drug to compete with the new orally active drugs.

Maybe it wouldn't compete well againist Gaterimer acetate.

Lets look at the pre-clinical data and perhaps it is concerning how dubious the effects appeared to be in animal models.  

At the same time, it does not paint a rosey picture of glaterimer acetate, which cop2 was supposed to be better. The abstract was generated by competing company aiming to show Cop2 was better than Cop1, however I think the results on Glaterimer acetate are not that dissimilar to what is published.

Essentially when administered under the skin in mice, like used in humans, both COP1 and COP2 did not work very well. They showed a small delay of disease onset, but clearly did not stop the animals getting disease. COP2 was better than Cop1 but both not that impressive. However, they can work and this is when you give the COP at the time of sensitization. This clearly has no translational value as you do not treat MSers before they get MS. 

We should want to see that the compounds inhibit relapsing disease after it has started so it has translational value. However this data is surprsingly lacking. Whilst it may have been done and not reported, one would think this would be a minimal requirement before embarking on human trials. Maybe if this was done and it did not eliminate relapsing disease alarms bells should have run. 

Was this done with Cop-1?

There has been significant variation in the dose levels of glaterimer acetate reported to inhibit EAE, which may depend on the strain and method of disease induction

In most cases disease inhibition has been reported to be dose-dependent. However inverse dose-responses (the more you give the less effect you get) have been reported also. In some instances doses of 250μg or more glaterimer acetate in incomplete adjuvant (which is not how it is used in hunans) can have marked inhibitory effect, but can be more modest in order studies. In some instances 2-5mg (100-250mg/kg) glaterimer acetate per mouse was the optimal dose for treatment, which substantially more than administered to humans (~0.3-0.5mg/kg). 

Glaterimer acetate has had some inhibitory activity in relapsing  EAE when daily administered in solutions notably orally. However the oral route has yet to be shown to have activity in MS. 

EAEologists hold GA as an example of the translational value of the animal model,which has been used to show that it has loads of putative mechanisms of action.

Likewise I have heard that it said that it takes some months of treatment to get optimum effect and in animals treatment is for a few days in a model lasting 3-4 weeks.  


However the fact of the matter is, that GA is the biggest selling MS drug and it has efficacy in MS, so does it matter what happens in EAE, and we know that many people are satisfied.

6 comments:

  1. "Likewise I have heard that it said that it takes some months of treatment to get optimum effect and in animals treatment is for a few days in a model lasting 3-4 weeks."

    This is why immunosuppression therapies will be always view as more highly effective drugs by many in the MS research field tike Team G.

    But is quick action of a drug really a key metric for measuring efficacy?

    As a male on Copaxone, I am more optimistic about this drug than those with an immunosuppressive MOA:

    http://www.ncbi.nlm.nih.gov/pubmed/19426995

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    1. THE REFERENCE POSTED says
      The analyses conducted do not support a treatment by gender interaction for GA in either PPMS or relapsing forms of MS

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  2. Yes, but there was a statistically significant effect in the male population using the worn out RRMS endpoints. It suggests that the effectiveness may have been obvious in males since they tend to have more aggressive disease. If it shows effectiveness in an aggressive population, it seems obvious it would may effective with the new PPMS trial endpoints that are being used for "highly efective" drugs.

    It would be a shame if there was an existing therapy for PPMS that was excluded due to scientific ignorance.

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  3. GA for PPMS has been excluded due to trials being stopped.

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  4. Only the last too lines mentined that GA has efficacy in MS and many patients are satisfied, so it is overwhelmingly pathetic to spend so many lines in assessing the effects of Cop1 or Cop2 in EAE in animals. It probably matters to MouseDoctor but less so to the patients.

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    1. The data in the clinic are well known. There is a modest effect on relapse rate and MRI. The post was about pre clinical data that supports the clinica applicationl. is this afoundation of concrete or sand for plovamer it seems like sand. Is this pathetic? iIt s opinion.. To blow the trumpet of GA is also an opinion.Ill leave it for the GAers and reps to do that

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