No Evidence That (Copaxone) Slows MS Progression

[Guest guest]

For those looking for links to this new article:

http://www.pharmalive.com/News/index.cfm?articleid=186200

LONDON, ON, November 01, 2004 /PRNewswire/ -- In this week's issue of the Lancet Neurology, glatiramer acetate, known as Copaxone®, was subjected to an independent review. The systematic review, called a Cochrane Review, performed by Dr. Luca Munari and colleagues, challenges the claims of benefit from previous industry- based publications.

Same information, different sources:

http://media.netpr.pl/notatka_26080.html

http://www.globeinvestor.com/servlet/ArticleNews/story/CNW/20041102/1211027545

http://www.mwc.com/NewsfeedArticle.cfm?NewsID=5475

http://www.presseportal.ch/de/print.htx?nr=100481678

[Guest guest]

Here's a snippet from the discussion from the article(below). The

issues are quite complex. The Cochrane review is based on just 636

patients total. This Cochrane article was discussed with Teva last

year. Teva had pointed out several shortcomings in the Cochrane

review..unfortunately I dont recall the details anymore..Cochrane

Reviews have excluded all studies which were not randomized and

placebo controlled. Anyone familiar with Copa knows that the

stinging and local redness cannot be imitated by a saline placebo.

Therefore, it is impossible to have a proper placebo controlled

study. Many good studies have been excluded from analysis, see

below. I dont endorse Copa, and this is in the spirit of fairness..

" Out of 103 references identified by the search strategy, 41

abstracts were provisionally selected to be read as full published

papers. A further 24 were then excluded based on the following

criteria: eight were uncontrolled open-label studies (Abramsky 1977;

Bornstein 1982; Baumhefner 1988; Kott 1997; Meiner 1997; De Seze

2000; Duda 2000; Flechter 2002b), six reported on experimental

investigations where only laboratory endpoints have been assessed

(lymphocyte activity, cytokine outburst, uric acid increase)

(Constantinescu 2000; Qin 2000; Brenner 2001; Chen 2001; Farina

2001; Karandikar 2002), four restricted the analysis to MRI

parameters (Cohen 1995; Mancardi 1998; Wolinsky 2001; Sormani 2002),

three were comparing glatiramer acetate and beta-interferons without

any placebo group (Fusco 2001; Khan 2001; Flechter 2002a), one study

considered pretreatment data a control for the treatment effect

without randomising patient allocation as it is required in cross-

over design ( 1998), one was a re-analysis of the US phase III

study where neuropsychological test performance has been measured as

the only clinical endpoint (Weinstein 1999) and the last one re-

analysed the US phase III core trial introducing a peculiar summary

measure of the total in-trial morbidity (Liu 2000). (See table of

excluded studies). "

A

Discussion

We have undertaken this systematic review to explore the amount of

evidence currently supporting the use of glatiramer acetate in the

management of MS. Our pragmatic approach to include all MS

candidates for the administration of this agent, whatever the

disease pattern, was aimed at collecting and reviewing all available

data on this compound. Unfortunately, we should remark that 16 years

after the first randomised pilot trial (Bornstein 1987) information

on efficacy of glatiramer acetate did not move so far ahead from the

original phase III database. On the other hand, the few completed,

company-supported RCTs available are rather homogeneous in their

protocols and treatment schedules.

The primary endpoint considered in this review, i.e. disease

progression, seems unaffected by daily glatiramer acetate

administration up to two years. It should be noted that all studies

required only three months of sustained EDSS worsening to classify

patient outcome as a progression, instead of six months as it was

established in the review protocol. Even if we had to accept this

definition given in the original papers, we cannot exclude that some

patients classified as developing progression may actually have

experienced a prolonged relapse. Indeed, progression is an

irreversible state by definition. However, only 23 glatiramer

acetate-treated patients have been reported as " worsened " versus

baseline at 35 months in the pivotal trial ( 1995), although

27 were deemed " progressed " at two years.

These findings support our choice to exclude from the analysis data

on clinical worsening versus baseline. Actually, it seems unlikely

that glatiramer acetate can prevent patient deterioration over time

without affecting the risk of progression as defined by the same

disability scale (EDSS).

When average EDSS changes versus baseline are analysed, a slight

decrease in EDSS score has been shown at two years, and a half-point

improvement at about three years in RR MS. Some remarks, however,

should be taken into account. Firstly, disease progression based on

a sustained worsening in patient's disability is expected to be a

more robust endpoint than a decrease in EDSS score assessed in a

single scheduled visit. Moreover, we should balance these findings

against the reliability of blinding when evaluating glatiramer

acetate-treated patients, given a two to five fold increase in

injection-site reactions. The more sensitive the endpoint, the more

exposed to insufficient masking would be the results. Again, EDSS

score is an ordinal scale and it would be more appropriate to

analyse it as a threshold to detect disease progression rather than

calculating a mean difference. Finally, combined results on clinical

improvement are driven by a single largest trial ( 1995),

accounting itself for up to 87% of data. In summary, the above

findings do not support a beneficial role of glatiramer acetate on

the clinical status of RR MS patients over time.

Benefit of glatiramer acetate on clinical relapses also remains

questionable. Results on the risk of having at least 1 exacerbation

point to a possible relative risk reduction by 20% in the first year

of treatment. These results are driven by a small pilot study

(Bornstein 1987), supporting a significant heterogeneity among

included trials. When the average number of relapses is considered,

results are no better after correcting for heterogeneity. This

heterogeneity might reflect differences in patient selection, since

risk estimates in controls (basal risks) appear uneven across

studies. Using a random effects model, no significant decrease in

the average relapse counts can be observed at one year and two

years, while a single study suggests that the frequency of relapses

experienced at three years could be slightly reduced by less than

one, on average, in glatiramer acetate-treated patients. In this

respect, it should be noted that the weighted mean difference may

not be an appropriate measure to analyse relapse counts. Actually,

this variable seems to follow a positive asymmetric distribution

(standard deviations tend to increase with increasing mean values

across studies) rather than approximating the normal function, as it

is assumed by the weighted mean difference analysis.

As regards adverse events, no major toxicity was observed. Reactions

are predominantly localised to the injection site or self-limiting.

The most common side effect is a combination of flushing, chest

tightness, sweating, palpitations, anxiety, referred to

as " patterned reaction " and it cannot be considered a harmful event.

We have found a little higher incidence (24% of glatiramer acetate-

treated patients and 7% of those taking placebo) than reported in

the literature (15% and 5%). Rare side effects, however, cannot be

explored in phase III trial settings and deserve a careful post-

marketing surveillance (Mancardi 2000).

Secondary endpoint analysis supports a decrease in hospital

admission rates and steroid courses related to glatiramer acetate

treatment. Despite increasing speculation on process endpoints in

pharmacoeconomic models, it should be noted that

* they are strictly related to the local healthcare financing system;

* they reflect healthcare policies rather than needs;

* they ultimately depend on physician's choices. For instance,

treating neurologists may tend to manage more aggressively patients

that were not given a presumably beneficial therapy.

Therefore, both hospitalisation and virtually costless steroids are

actually of little help in estimating the economic profile of

glatiramer acetate.

It has been recently suggested that the evaluation of MRI parameters

in trials of MS may introduce an objective measure of treatment

effect (Sormani 2002). MRI parameters are still surrogates of

therapeutic efficacy and cannot represent a therapeutic goal

themselves. Moreover, according to Prentice's validity criteria

(Prentice 1989), surrogate endpoints should fully capture the net

effect of treatment on clinical outcomes, and this cannot be shown

in the absence of a significant clinical benefit.

Conclusions

Implications for practice

In conclusion, glatiramer acetate seems to have no beneficial effect

on the main outcome measures in this disease, i.e. disease

progression, and it does not substantially affect the risk of

clinical relapses over time. Therefore, there is at present

insufficient evidence to support its routine use in clinical

practice and more data from randomised clinical trials are needed.

Two major RCTs on glatiramer acetate are currently under way. A

large study to assess benefit of oral glatiramer acetate in RR MS

(CORAL) has recruited more than 1600 patients and is expected to be

completed by October, 2002 (Markowitz 2000b). An interim analysis,

however, did not show any benefit from either high (50 mg) or low (5

mg) daily doses of oral glatiramer acetate compared with inactive

placebo (Teva 2002). Another trial (PROMISE) was planned to compare

daily glatiramer acetate 20 mg given subcutaneously with placebo in

primary progressive MS patients (Markowitz 2000a) but it was stopped

for futility.

Implications for research

Looking forward to the results of ongoing trials, future studies on

glatiramer acetate should deal with the following problems:

* undertake a really blind assessment of patients treated with

subcutaneous glatiramer acetate

* develop a sensitive, comprehensive and reliable measure of patient

disability over time

* establish a unique and reliable clinical definition of patient

progression

* include patient's quality of life among primary endpoints

* make definitely clear the relationship between MRI parameters and

clinical outcomes fully accomplishing Prentice criteria (Prentice

1989).