"Any analysis that looks at rebound should not include the initial 3 months post-natalizumab when the drug is still on board and working. As you can see from the slide show that there is very little rebound activity in months 1, 2 and 3. However, in month 4, 5 and 6 and beyond there is a clear signal of rebound disease activity. Rebound coincides with desaturation of the VLA-4 antigen on the surface of lymphocytes and their retrafficking into the brain and spinal cord. You would anticipate a similar thing with fingolimod; fingolimod traps disease causing lymphocytes in lymph nodes. When fingolimod is stopped and washed out of the system these lymphocytes migrate from the lymph nodes and retraffick to the brain and spinal cord and trigger focal inflammatory events. The difference between fingolimod and natalizumab is the timing; on stopping treatment fingolimod levels drop earlier than natalizumab and hence you would expect rebound to occur earlier, which has been the observation to date. The observation that most DMTs, with the exception of fingolimod, are not effective in preventing post-natalizumab rebound is interesting. I suspect this is due to fingolimod's mode of action; trapping lymphocytes in lymph nodes prevents reconstitution of immune surveillance to the central nervous system and prevents rebound. However, for fingolimod to prevent rebound it needs to be started before natalizumab has time be cleared from the system. This is why we start it within 4 weeks of the last natalizumab infusion."
"I hope I have convinced you; rebound is not a statistical artifact but a real phenomenon with consequences. If you don't believe me read the literature or come and meet some of my patients who have suffered the consequences of rebound."
Rebound:
O'Connor et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011 May 31;76(22):1858-65.
BACKGROUND: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies.
OBJECTIVES: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS.
METHODS: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumabdosing that occurred in February 2005.
RESULTS: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted.
CONCLUSIONS: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.
Preventing rebound:
Kappos et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. Neurology. 2015 Jul 7;85(1):29-39.
OBJECTIVE: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod.
METHODS: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.
RESULTS: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6-2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred.
CONCLUSIONS: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.