Table 2 Second line therapies and their effect on brain volume loss (BVL)

Kappos et al. [122]

Fingolimod orally 0.5 mg or 1.25 mg once daily vs placebo for 2 years, then FTY open-label

Phase III FREEDOMS 2 years

1272 Fingolimod 1.25 mg n = 429, Fingolimod 0.5 mg n = 425, placebo n = 418

RRMS

Significant reductions in the rate of brain volume loss were detected as early as 6 months for the 12 mg Fingolimod treatment group (PBVC values from baseline to 6 months, 1.25 mg Fingolimodvs placebo p = 0.003; 0.5 mg Fingolimodvs placebo p = 0.006) and remained significant at 24 months (P < 0.001 in all comparisons)

Kappos et al. [124]

Fingolimod orally 0.5 mg or 1.25 mg once daily (FTY open label)

Extension of Phase III FREEDOMS 2 years

RRMS

Significantly lower atrophy rates in the continuous Fingolimod groups relative to the combined switch group, over 4 years (Continuous Fingolimod 0.5 mg p = 0.0013; Continuous Fingolimod 1.25 mg p = 0.001)

Patients who switched to Fingolimod 0.5 mg during the extension study experienced significant improvements in rates of brain volume decline (Placebo—Fingolimod 0.5 mg p = 0.0084, months 24–48 vs months 0–24)

Cohen et al. [121]

Fingolimod orally 1.25 or 0.5 mgonce daily vs INF β-1a i.m. 30 μg (1 year, then open-label)

Phase III TRANSFORMS 1 year

1280 Fingolimod 1.25 mg n = 420, Fingolimod 0.5 mg n = 429, INF β-1a N = 431

RRMS

Compared to i.m. INF β-1a, patients treated with Fingolimod presented less brain volume loss, over 1 year (all p < 0.001)

Khatri et al. [125]

Fingolimod orally 1.25 or 0.5 mg once daily

Extension of Phase III TRANSFORMS 2 years

799 INF β-1a to 0.5 mg Fingolimod n = 124, INF β-1a to 1.25 mg Fingolimod n = 130. Continuous 0.5 mg Fingolimod n = 290, Continuous 1.25 mg Fingolimod n = 255

RRMS

Patients switching from INF β-1a to Fingolimod (either 1.25 or 0.5 mg) reduced their brain volume decrease (PBVC: months 13–24 vs months 0–12, p = 0.006 for the INF β-1a to 0.5 mg Fingolimod switch group p = 0·007 for the INF β-1a to 1.25 mg FTY720 switch group. No further gain in BVL for patients on continuous Fingolimod treatment (p values non-significant at months 13–24 vs months 0–12)

Calabresi et al. [120]

Fingolimod orally 1.25 or 0.5 mg once daily vs placebo

Phase III FREEDOMS II 1 year

1083 Fingolimod 1.25 mg n = 370, Fingolimod 0.5 mg n = 358, placebo n = 355

RRMS

Patients given Fingolimod had decreased brain volume loss compared with those given placebo from baseline to months 6 (Fingolimod 1.25 mg vs placebo, p = <0.0001; Fingolimod 0.50 mg vs placebo, p = 0.012) 12 (Fingolimod 1.25 mg vs placebo, p = <0.0001; Fingolimod 0.50 mg vs placebo, p = 0.004) and 24 (Fingolimod 1.25 mg vs placebo, p = <0.0001; Fingolimod 0.50 mg vs placebo, p = 0.013). (Total treatment effect on PBVC vs placebo p < 0·0001 and p = 0·0002 respectively)

Cohen et al. [123]

Fingolimod orally 1.25 or 0.5 mg once daily IFN β-1a i.m. 30 μg once a week

Extension of Phase III TRANSFORMS 4.5 years

Fingolimod 0.5 mg n = 356, IFN β-1a-switch Fingolimod 0.5 mg n = 167, Fingolimod 1.25 mg n = 330, IFN β-1a switch fingolimod 1.25 mg n = 174

RRMS

Non-significant long term benefit on mean PBVC (from baseline to 4.5 years): continuous-fingolimodvs IFN β-1a-switch group −1.01% (−0.8) vs −0.96% (−0.8); p = 0.937. The PBVC from baseline to month 12 was reduced significantly by fingolimod compare to IFN β-1a (p < 0.0001) and the low rate was maintained through the study completion

Lublin et al. [126]

Fingolimod orally 0.5 mg once daily vs placebo

Phase III INFORMS 3 years

714 Fingolimod 0.5 mg n = 293, placebo n = 421

PPMS

In patients with primary progressive MS, percentage change in brain volume did not differ between Fingolimod and placebo groups (p = 0.673)

Miller et al. [139]

Natalizumab i.v. 300 mg every 4 weeks vs placebo

Phase III AFFIRM 2 years

942 Natalizumab n = 627, placebo n = 315

RRMS

Overall, not significant effect of treatment with Natalizumabvs placebo (mean percentage change in BPF, 0.80% vs 0.82%, p = 0.822, from baseline to 2 years). During the first year, natalizumab-treated patients presented greater BVL compared to placebo (0.56% vs 0.40%, p = 0.002) but the rate of brain atrophy was significantly less in natalizumab-treated patients over the second year of treatment (0.24% vs 0.43% p = 0.004)

Radue et al. [140]

(IFN β-1a i.m.30 μg + Natalizumab i.v.300 mg every 4 weeks) vs IFN β-1a i.m. 30 μg + placebo once weekly

Phase III SENTINEL 2 years

1171 IFN β-1a + natalizumab n = 589, IFN β-1a + placebo n = 582

RRMS

From baseline to second year, no significant differences were reported between the 2 treatment arms regarding change in BPF (p = 0.926). During the first year, there was a significant reduction in BPF in the Natalizumab treated arm (p = 0.058), but lower rates during the 2nd year of treatment (– 0.31% versus – 0.40%; p = 0.020)