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Published on: September 20, 2018
α4-integrin receptor desaturation and disease activity return after natalizumab cessation
Tobias Derfuss1, John M Kovarik1, Ludwig Kappos1
1Neurological Clinic and Policlinic (T.D.), Departments of Medicine and Biomedicine, University Hospital Basel; Novartis Pharma AG (J.M.K., M.S., D.T.), Basel; Neurological Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, Switzerland; Novartis Pharmaceuticals Corporation (Y.Z.), East Hanover, NJ; and Department of Neurology (H.W.), University of Münster, Germany; Novartis Healthcare Pvt. Ltd. (R.C.. A.T.), Hyderabad, India.
Objective:
To describe the time course of α4-integrin receptor desaturation and disease activity return in patients with relapsing-remitting MS who discontinued natalizumab and to investigate baseline and on-study predictors for the recurrence of disease activity.
Methods:
In the course of TOFINGO, a 32-week, patient- and rater-blinded multicenter, parallel-group study, we performed MRI, counted relapses, and measured α4-integrin receptor occupancy (RO) at baseline and 8, 12, 16, 20, and 24 weeks. The relationship between RO and total number of new T1 gadolinium-enhancing (Gd+) lesions was modeled using Poisson linear regression.
Results:
Patients (N = 142) were randomized (1:1:1) to 8-, 12-, or 16-week washout (WO) groups. At randomization, the median RO in the 8-, 12-, and 16-week WO groups was 94.5%, 92.4%, and 90.9%, which declined to 79.8%, 30.7%, and 8.7% after 8, 12, and 16 weeks of WO, respectively. The percentage of patients with new T1 Gd+ lesions increased with longer WO period before commencing fingolimod: 2.1% (8 weeks), 9.1% (12 weeks), and 50.0% (16 weeks). Overall, 71% of patients with first relapse between weeks 6 and 18 had RO values below the time-matched population median. Higher T2 lesion volume (LV) at baseline predicted a higher number of new T1 Gd+ lesions.
Conclusions:
A faster decline in natalizumab RO, longer WO period, and higher T2 LV at baseline were associated with an increased risk for return of inflammatory disease activity. These results provide a mechanistic rationale and, together with the main outcomes of the TOFINGO study, support initiation of fingolimod within 8 weeks of natalizumab discontinuation.
Clinicaltrialsgov Identifier:
NCT01499667.
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