Positive topline results for first phase 3 study of Lemtrada

[MSUK]

Sanofi and its subsidiary Genzyme announced today positive top-line results from CARE-MS I, the first of two randomized, Phase 3 clinical trials comparing the investigational drug alemtuzumab to the approved multiple sclerosis therapy Rebif(R) (high dose subcutaneous interferon beta-1a) in patients with relapsing-remitting multiple sclerosis (RRMS). Genzyme is developing alemtuzumab in MS in collaboration with Bayer HealthCare.

In the CARE-MS I trial, 2 annual cycles of alemtuzumab treatment resulted in a 55 percent reduction in relapse rate compared to Rebif(R) over the two years of the study (p<0.0001), hence satisfying the first primary endpoint, and therefore meeting the predefined protocol criteria for declaring the study a success. Statistical significance was not achieved for the second primary endpoint, time to six month sustained accumulation of disability, as compared to Rebif(R). At the two year time point, 8 percent of alemtuzumab treated patients had a sustained increase in their Expanded Disability Status Scale (EDSS) score (or worsening) as compared to 11 percent of those who received Rebif(R) (Hazard Ratio=0.70, p=0.22). The patients will have the option to be evaluated over the next 3 years as part of a separate protocol....Read More - http://www.msrc.co.uk/index.cfm/fuseact ... ageid/1307

[leetz]

i unfortunately relapsed on alemtuzumab (campath)...but did see people (2) have good results with it...it could have held me where i am now...who knows...but no improvement...

[Frank]

Do I see that correctly, that the 55% reduction in ARR (annual relapse rate) is a relative reduction?
So as Rebif is considered to to reduce ARR by about 30% then (55% of 30% = 16.5%) Campath reduces ARR by "absolute" of 46.5%?
This wouldn't seem too impressing to me...
If my calculation is correct then especially Tysabri but also Fingolimod are superior in reducing ARR.

With respect to side-effects. I read about some patients experiences when they were given Campath and that sounded to be far from being a piece of cake.

The other point that I find specially disappointing, is the fact that the disability progression was hardly better in Campath than in Rebif.
The Phase-II results were much more promising in this regards.
In recently diagnosed MS patients there was even a significant reduction in EDSS score.

Comments would be appreciated!

--Frank

[rainer]

The disability part not being reached is disappointing for sure. Although I would point out the percentages are pretty small, so picking up a change there would be difficult.

You're also right about the little numbers trick they pull to make the results sound more impressive then they are. It is unfortunately very common for drug co's to do that instead of plainly stating the results for our own interpretation.

[patientx]

I found these results a little disappointing, too - especially compared to the CAMMS223 results which showed a 74% reduced risk of relapse and 71% less risk of accumulated disability compared to Rebif.

I guess the one caveat is that the CARE-MS I trial was for people who had an onset of MS symptoms within 5 years of enrolling in the study. Given that they were early in the disease course, I wouldn't expect much accumulation of disability in either the Rebif or Campath group. Of course, that doesn't say anything about relapses. It'd be interesting to see the raw numbers, to see if the Rebif group also had an unusually low number of relapses. It will also be interesting to see the CARE-MS II results.

Frank, I'm not sure you're calculations were correct. For example (and I made up all of these numbers), if in the original Rebif trials, after 2 years the total number of relapses in the placebo group was 60, and in the Rebif group it was 40, the relative reduction in relapses is (60 - 40)/60 = 33%. And say, in the Campath trial, the total number of relapses for those given Campth after 2 years was 18. Compared to original Rebif number, this is a relative reduction of [40 -18] /40 = 55%. Compared to original placebo group, the relative reduction would be [60 -18] / 60 = 70%.

Of course, this is really a crude example. This assumes they used this method of calculating reduction in relapse rates (I know it was done this way in the Copaxone trial, but I haven't seen the papers for Rebif or CARE-MS I). But, I guess the point is, you need the raw numbers to be able to make comparisons like this. I don't think you can use the percentages.

Really, though, in order to do the Campath/Rebif/placebo comparison, the Campath trial would have needed a placebo group. Usually, trial investigators try to match participants in different treatment groups, with respect to age and sex. There was no placebo group in the Campath trial, and it's not really valid to use number from previous trials.

[Frank]

I would love to see the ARR calculations to turn out to be different and in a more favourable way than my calculation - we will certainly have to wait for the raw numbers to be published.
But then again, I think the PR machine of the pharma-company would have explicitly highlighted how to correctly understand this 55% reduction in ARR IF! it was to be interpreted in a somehow great way - but we will see .

When it comes to the disability progression - imo - the idea of the CARE-MS 1 trial was to treat early diagnosed patients BECAUSE the privious experiences with Campath treatment seemd to indicate, that when patients receive Campath early in their disease course there was little/no more disability progresse and even some reversal of EDSS.
Patients with londer disease-duration did not respond so well.

So imo. the hope was that the neuro-degenerative part of MS - that potentially would be responsible for much of the permanent disability - will not occure if you were able to stop the inflamation process early in the disease course.

If thats correct then the group of patients recruited for the CARE-MS 1 trial should be the group of MS-Patients with the best response in regards to EDSS progression...

--Frank

[patientx]

I would love to see the ARR calculations to turn out to be different and in a more favourable way than my calculation - we will certainly have to wait for the raw numbers to be published.
But then again, I think the PR machine of the pharma-company would have explicitly highlighted how to correctly understand this 55% reduction in ARR IF! it was to be interpreted in a somehow great way - but we will see .

Well, to its credit Genzyme was just reporting the results, without interpretation. I think your point was, based on these numbers, Campath doesn't look that great, especially compared to placebo. But putting the raw numbers aside, think about it like this - Rebif has shown some improvement in AAR over placebo (~30%). And Campath showed improvement over Rebif. So, compared to placbeo, Campath should show an even bigger improvement over AAR.

When it comes to the disability progression - imo - the idea of the CARE-MS 1 trial was to treat early diagnosed patients BECAUSE the privious experiences with Campath treatment seemd to indicate, that when patients receive Campath early in their disease course there was little/no more disability progresse and even some reversal of EDSS.
Patients with londer disease-duration did not respond so well.

So imo. the hope was that the neuro-degenerative part of MS - that potentially would be responsible for much of the permanent disability - will not occure if you were able to stop the inflamation process early in the disease course.

If thats correct then the group of patients recruited for the CARE-MS 1 trial should be the group of MS-Patients with the best response in regards to EDSS progression...

--Frank

That's very true - one of the ideas behind early treatment with Campath is the theory that if you stop the inflammatory component of MS, you should be able limit disability and hopefully transition to SPMS. But, keep in mind, the disability numbers in this trial, like those for AAR, were done relative to Rebif treatment. So, it could be that both groups did well in terms of disability progression. It could be a natural history thing, or it could be that Rebif has a positive effect on disability progression in those treated early. If this was the case, it wouldn't mean that Campath doesn't reduce disability progression; it would just mean that it didn't show up in this trial.

Really, to test the early treatment hypothesis, you'd probably have to track those who received Campath vs. those who got nothing over a longer period of time. But this has its own set of ethical problems.....