Antegren in acute MS relapses

[dignan]

Don't know if you've all seen this before, it came out a little while ago, but I thought it might be of interest here.


Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects.

O'Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, Sheremata WA, Vollmer TL, Stone LA; Natalizumab Multiple Sclerosis Trial Group.

St. Michael's Hospital, Toronto, Ontario, Canada. oconnorp@smh.toronto.on.ca

BACKGROUND: Relapses in multiple sclerosis (MS) can cause significant neurologic disability. Natalizumab (Antegren) is a humanized anti-alpha4-integrin antibody that inhibits the trafficking of leukocytes across endothelium by blocking binding of alpha4beta1-integrin to vascular cell adhesion molecule-1.

OBJECTIVE: To assess the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses.

METHODS: In this randomized, double-blind, multicenter trial, the effects of a single dose of IV natalizumab administered soon after the onset of MS relapses were assessed. MS patients (n = 180) in acute relapse were randomly assigned to receive a single dose of natalizumab 1 or 3 mg/kg or placebo and were followed for 14 weeks.

RESULTS: There was no difference in Expanded Disability Status Scale (EDSS) score change over time between treatment and placebo groups. In all three groups, approximately half of patients showed EDSS improvement after 2 weeks, rising to 67% by 8 weeks. EDSS improved by a mean value of 0.8 point at week 1, 1.2 points at week 4, and 1.6 points at week 8 in the natalizumab group compared with EDSS improvement of 1.0 point at week 1, 1.6 points at week 4, and 1.6 points at week 8 in the placebo group. A significant decrease in Gd-enhancing lesion volume was seen in both active treatment groups at weeks 1 and 3 compared with placebo.

CONCLUSIONS: A single dose of IV natalizumab did not hasten clinical recovery after relapse, although a significant decrease in Gd-enhancing lesion volume was observed at 1 and 3 weeks after treatment. These MRI findings are consistent with prior studies of natalizumab and support its further investigation as an agent for the treatment of MS.

http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15184611

[HarryZ]

Ironically I read this report yesterday on another MS forum.

I think what they were trying to do here was see if Antegren had any immediate effect on MS patients that had just started experiencing and exacerbation. Although it appeared to reduce the brain lesion load eventually, it did nothing to change the progress or duration of the exacerbation.

About the only drugs that have a fast effect on attacks are the steroids and steroids are not very pleasant meds to place into your system very often.

Harry

[OddDuck]

Yes, I saw this publication myself just a couple days ago. I thought "Shoot, there goes my hope that Antegren might prove more helpful on a short term basis similar to how the steroids' actions are". (Therefore, maybe providing an alternative option to taking steroids. I agree with Harry's comments regarding the steroids.)

Apparently, it doesn't appear to block T cells fast enough to interrupt sudden inflammation.

Well, another one bites the dust, as they say. (And I'm only referring to a "hypothetical situation" biting the dust. Not the whole ball of wax. I'm full of quips and quotes tonight, huh?)

Deb

[MeadowStream]

The mechanism of action would predict that short term the effect would be less apparent. The longer a patient takes antegren the better the effect - but antegren can do nothing about those long-lived cellular villains that have already migrated across the BBB. Over time, those cells die out and Antegren prevents new cells from taking their place.

MS

[OddDuck]

We hope.........

[MeadowStream]

Right - we hope so.

[HarryZ]

Meadow,

The mechanism of action would predict that short term the effect would be less apparent. The longer a patient takes antegren the better the effect - but antegren can do nothing about those long-lived cellular villains that have already migrated across the BBB. Over time, those cells die out and Antegren prevents new cells from taking their place.

Have an interesting question....Antegren prevents the VL4 "bad guy" from crossing the BB barrier and attacking the myelin but is the VL4 needed to combat any other possible disease that may decide to lurk in one's brain?

Harry

[Mman]

Have an interesting question....Antegren prevents the VL4 "bad guy" from crossing the BB barrier and attacking the myelin but is the VL4 needed to combat any other possible disease that may decide to lurk in one's brain?

Good question, and it looks like they may have been studying this all along (I guess I'm not surprised).

alpha-4 Integrins as Therapeutic Targets in Autoimmune Disease
von Andrian U. H., Engelhardt B.
Extract | Full Text | PDF
N Engl J Med 2003; 348:68-72, Jan 2, 2003. Editorials

"Chronic inhibition of 4 integrins could also have undesirable effects that are independent of the immunogenicity of the pharmacologic inhibitor. For example, in mice, an embryonic deficiency in the 4 or 1 integrin chain or in VCAM-1 is lethal before birth,3 suggesting that the use of agents that inhibit these pathways should be avoided during pregnancy. On the other hand, in the clinical trials reported by Miller et al. and Ghosh et al., the rate of adverse events did not differ significantly between the natalizumab and placebo groups.1,2 Considering the physiologic role of 4 integrins in hematopoiesis and in mucosal and humoral immunity in animals, this finding is somewhat surprising. The recipients of natalizumab had elevated levels of lymphocytes, monocytes, and eosinophils in the circulation, which is consistent with the expression of 4 integrins on these leukocytes, whereas neutrophil levels did not change.1,2 This suggests that the antibody did not interfere with neutrophil functions that are independent of 4 integrins and are necessary to combat bacterial and fungal infections. The natalizumab-treated patients with multiple sclerosis did have a higher incidence of infections, especially pharyngitis, than the patients who received placebo, but that trend was not statistically significant. Given the small number of patients and the relatively short duration of natalizumab treatment in the current phase 2 trials, firm conclusions about the safety of 4-integrin inhibition must await the results of much larger, phase 3 studies. "

According to Company press releases and NEJM January 2003 articles, side effects of Antegren have been minimal (obviously, what is minimal is dependent on the individual).

http://www.elan.com/News/full.asp?ID=641172

"Adverse events occurring in at least 5 percent of natalizumab-treated patients that were 2 percent more common than in placebo-treated patients included headache, fatigue and arthralgia. The overall incidence of infection was similar between the groups. Serious infections occurred in 1 percent of placebo-treated patients and 2 percent of natalizumab-treated patients. Serious hypersensitivity-like reactions occurred in approximately 1 percent of natalizumab-treated patients."

from the January 2003 NEJM:

A Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis
Miller D. H., Khan O. A., Sheremata W. A., Blumhardt L. D., Rice G. P.A., Libonati M. A., Willmer-Hulme A. J., Dalton C. M., Miszkiel K. A., O'Connor P. W., the International Natalizumab Multiple Sclerosis Trial Group
Abstract | Full Text | PDF
N Engl J Med 2003; 348:15-23, Jan 2, 2003. Original Articles

"Monthly infusions of natalizumab for six months were well tolerated and were associated with a safety profile similar to that of placebo. There was a trend toward an increased rate of infections in the natalizumab-treated patients, the clinical significance of which is unclear."


So, in the end, we'll see what the FDA and the P3 results show. But the fact remains that over 2800 patients, side effects noted have been minimal (according to BIIB/ELN). And reduction in relapse rates have been reported of 66% and lesion load reduction (in P2) of 90+%. WELL WORTH PURSUING, I'D SAY.

[HarryZ]

Mman,

I guess it will be interesting to see what the data shows re: infection rates after all the P3 trials are done. The P2 trials showed double (2% vs 1%) in the Antegren vs placebo for serious infections but I would imagine that would be difficult to translate into anything meaningful at the low numbers involved in the P2's.

Harry

[OddDuck]

Thanks for locating some additional findings that assist to confirm and validate my initial concerns and questions.

And since nothing has been "concluded" definitively yet regarding any of those findings that they themselves found "surprising" - same expression I used, I believe - (back in 2003), I personally hope more definitive results regarding those specific aspects will be published in the near future.

Deb