Physiologically, though, there's not much of a jolt to the system (for lack of a better term), if you stop taking a CRAB.
With Antegren, there is indication that that may not be the case! I found research that indicated that if you stop Antegren, your system rebounds - to a fairly large extent. Exacerbations suddenly get much worse, etc. So...........you also may have to factor in THAT fact, also. Do you even want to START taking Antegren if you think at all that you may want to temporarily stop it in the future in order to have a family?
Below are the FACTS about rebound effect. In summary, in the most complete study published to data there is no rebound effect. I can find no support for the statement that 'exacerbations suddenly get much worse;' I would welcome any references for this.
From the NEJM on the P2 Antegren study:
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.
http://content.nejm.org/cgi/content/ful ... lcode=nejm
From the Abstract:
Methods In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing–remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.
Results There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).
Conclusions In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
From the Text:
Safety and Tolerability
Similar numbers of patients in each group had adverse events during treatment (Table 4). Eleven serious adverse events occurred in seven patients in the placebo group, five serious events occurred in five patients who were receiving 3 mg of natalizumab per kilogram, and four such events occurred in three patients who were receiving 6 mg of natalizumab per kilogram. Four of these events were considered to be immune-mediated and related to the study drug. One patient who was receiving 3 mg of natalizumab per kilogram had an anaphylactoid reaction with urticaria and bronchospasm, which was rapidly reversed with antihistamines and corticosteroids. There were three reports of serum sickness, one in each group. Only one of these events was accompanied by a change in complement levels, and all three occurred at a single study site. These events complicated fewer than 1 in 250 infusions. Treatment was discontinued because of an adverse event in three patients in the placebo group, four in the group given 3 mg of natalizumab per kilogram, and three in the group given 6 mg of natalizumab per kilogram. One patient in the placebo group died of pleural carcinomatosis complicated by hemothorax.
When the values obtained at month 9 and month 12 were combined, the number of new enhancing lesions and scans showing activity were similar in all three groups (Table 2). After treatment, there was no significant difference among the three groups either in the total number of relapses or in those objectively confirmed (Table 3).
FWIW, there are four published Antegren studies on MS (that I am aware of):
1. A phase-1 pharmacokinetics/safety study showed that a single dose of one to three milligrams of Antegren per kilogram persisted in serum for three to eight weeks.
2. A phase-2 study showing a single infusion of Antegren did not hasten recovery from acute relapse.
3. A phase-2 study in active RRMS and SPMS of two infusions of Antegren showed reduced MRI activity and an improvement in EDSS but not relapse rate.
4. A phase-2 study in active RRMS and SPMS of six infusions of Antegren showed reduced MRI and clinical activity.
The P1 study detailed below is, I believe, the 'source' of the rebound effect comment given in the quote above, (but I cannot be sure as no citation was given in the quote).
Phase 2, Two-Dose Study in RRMS and SPMS:
N. Tubridy, P. O. Behan, R. Capildeo, A. Chaudhuri, R. Forbes, C. P. Hawkins, R. A. C. Hughes, J. Palace, B. Sharrack, R. Swingler, C. Young, I. F. Moseley, D. G. MacManus, S. Donoghue, and D. H. Miller
The effect of anti-4 integrin antibody on brain lesion activity in MS
Neurology, Aug 1999; 53: 466.
In 1999, Neurology published the results of a two-dose study of Antegren (3 mg/kg) in 72 patients with active MS; patients were followed for 24 weeks. Sixty-eight patients and 97.5% of MRI scans could be evaluated for response. Baseline MRI scans were used to determine the number of currently active lesions and an imbalance favoring placebo was noted: 1.2 active lesions/patient compared to 2.0 in the Antegren group.
The development of new lesions, following baseline correction was halved in the Antegren group during the first 12 weeks, and thus, as expected, more patients showed no new enhancing lesions in the Antegren group: 83.6%, compared to placebo at 73.1% (p=0.037). Between weeks 12 and 24, no differences between Antegren and placebo were noted, i.e. no MRI rebound occurred in the Antegren group. There was also no difference in the fate of baseline lesions, supporting data from the previously discussed study that Antegren is ineffective for ongoing inflammation. No ifferences in relapses were observed during the study, although the Antegren group suffered more relapses during the 12–24 week period than placebo, 38% versus 14%. The reason for this difference was an unexpectedly low relapse rate in the placebo group rather than an increase in the Antegren group, i.e., the relapse rate seen in the Antegren group was as
expected based on patients’ histories. It could, however, also be correlated with the leukocytosis that was observed in the Antegren group. We assume that, over extended periods of dosing, leukocytosis would resolve, and thus, if this is a causative factor for rebound—if this is indeed even an accurate description for the observation—rebound itself should be diminished. Over 24 weeks, no differences in EDSS change were
observed, although at week 12, 31% of Antegren patients had a 0.5 point improvement compared to 10% of placebo-treated patients. Further, fewer Antegren-treated patients showed a 0.5 point decline.
I hope the above facts put to rest the concerns about a rebound effect from Antegren. The larger P2 study outlined above has proved there is no rebound effect. Obviously, further studies are underway and will be done after drug approval, but the P2 data are certainly encouraging.
[Pfizer (Serono's partner in Rebif) probably referred to the Phase 1 study in their July, 2004 Earnings release and suggested a 'rebound' effect, all the while ignoring the 2003 NEJM paper and results of the P2 study on 3 times the number of patients. Talk about selective review of data! (As Serono did concerning BIIB/ELN's 8 Nov 04 Press Release). You judge for yourself whether Pfizer's release comment was ethical.]
We all await the full Antegren P3 trial results for more information. The preliminary P3 data of 66% reduction in relapses is great news for all. And note that this was a substantial improvement on P2 relapse rate reductions which were about 50%. Lets hope there is a similar improvement in P3 lesion reductions rleative to the P2 lesion reductions of 90%+.