α4-integrin receptor desaturation and disease activity return after natalizumab cessation

Abstract

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.

Figures

Figure 1

Receptor desaturation after the last natalizumab dose. Median α4-integrin receptor occupancy by the WO group at screening (−4 weeks), randomization (week 0), and during drug WO from weeks 8 to 32. Bars represent the IQR. A total of 137 patients (96.5%) provided at least 1 evaluable receptor occupancy measurement. IQR = interquartile range; WO = washout.

Figure 2

(A) Median-effect modeling of receptor occupancy and freedom from T1 Gd+ lesions. Scatter plot of the percentage of patients free from T1 Gd+ lesions vs median α4-integrin receptor occupancy for the 8-, 12-, and 16-week WO groups. Only patients not yet on fingolimod were included in the analysis. The curve represents the fit of the median-effect model to the data. (B) Median receptor occupancy and first reporting of T1 Gd+ lesions. Scatter plot showing the α4-integrin receptor occupancy at the visit when first T1 Gd+ lesions were reported in the context of the population median receptor desaturation curve. Gd+ = gadolinium enhancing; WO = washout.

Figure 3

Total number of T1 Gd+ lesions when the baseline volume of T2 lesions was less than (A) and greater than (B) the 75th quartile. Bottom of box is Q1 and the top of the box is Q3; upper whiskers are 1.5 × IQR of the hinge; lower whiskers are 1.5 × IQR of the hinge. Gd+ = gadolinium enhancing; IQR = interquartile range.