3.1.2. TRANSFORMS

TRANSFORMS was a Phase III clinical trial, enrolling 1292 patients, comparing efficacy of FGM to intramuscular IFNβ-1a in a 12-month, randomized, double-dummy, parallel group study in patients with active RMS over the previous 24 months [94]. The inclusion criteria included a diagnosis of RMS, EDSS ≤ 5.5. Patients were randomized 1:1:1 to oral FGM 0.5 mg or 1.25 mg once daily, or IFNβ-1a 30 μg IM once weekly, and we only report on the FGM 0.5 mg vs. IFNβ-1a results. The primary endpoint was ARR and major secondary endpoints included number of new or enlarging T2 MRI lesions at one year and 3-month CDP during the 12-month duration of the study. At 12 months, ARR was 0.16 for FGM, and 0.33 for IFNβ-1a patients (*p* < 0.001), a relative reduction in ARR of 52%. In the FGM arm time to first relapse was longer and more patients remained relapse free than the IFNβ-1a treated patients. FGM treatment was associated with a relative reduction in the mean number of new and enlarged T2 lesions (FGM 1.7 and IFNβ-1a 2.6; *p* < 0.004), a 54% relative reduction in Gd+ lesions (*p* < 0.001), a 31% relative reduction in percent brain volume loss from baseline (*p* < 0.001). In contrast, there was no significant difference observed between the treatment arms with respect to 3 month CDP.

### 3.1.3. FREEDOMS II

FREEDOMS II, a phase III trial to evaluate the efficacy and safety of FGM [95] was a 24-month, randomized, double-blind, placebo-controlled, evaluating the efficacy of FGM compared to placebo in 1083 patients. Inclusion criteria included: a diagnosis of RMS, evidence of active disease over the previous 24 months, and an EDSS ≤ 5.5. Patients were randomized in a 1:1:1 ratio to receive FGM 0.5 mg, or 1.25 mg, or placebo once daily but only the FGM 0.5 mg and placebo data are reported; patients randomized to the FGM 1.25 mg arm were switched to 0.5 mg a day at the recommendation of the data and safety committee. The primary endpoint of the trial was ARR. Secondary endpoints included the effect of FGM upon time to 3-month CDP, change in MSFC score, and effect on MRI measurements in comparison to placebo.

The ARR over 24 months was 0.21 for FGM and 0.40 for placebo (*p* < 0.0001), a relative reduction of 48%. The percent change in brain volume from baseline to 24 months, was 0.9% for FGM and 1.3% for placebo, a relative reduction of 31% (*p* < 0.001). The mean number of new and enlarged T2 lesions at 24 months was 2.3 for FGM, and 8.9 for placebo, a relative reduction of 74%; there was a 70% relative reduction in number of Gd+ lesions. There was no significant difference between FGM and placebo in 3- or 6-month CDP. The time to first confirmed relapse was longer, and more patients remained relapse-free in the FGM treated arm compared to placebo-treated patients at 24-months. MSFC scores were also improved at month 24 in the FGM versus the placebo-treated arm.

### 3.1.4. Extended TRANSFORMS

Extended TRANSFORMS reported long-term results (up to 4.5 years) for the core TRANSFORMS patients [96]. A total of 92% (*n* = 1027) of patients completing TRANSFORMS entered and 75.2% completed the extension phase. Patients randomized to FGM 0.5 mg or FGM 1.25 mg in the core study continued at the same dose in the extension study, whereas patients receiving IFNβ-1a were re-randomized 1:1 to either FGM 0.5 mg or FGM 1.25 mg daily. Following the sponsor's decision to discontinue FGM 1.25 mg in 2009, all patients subsequently received FGM 0.5 mg until completion of the extension phase. It is only the 0.5 mg FGM results vs. IFNβ-1a which are reported below.

The primary endpoint, ARR at 4.5 years, was significantly reduced in patients who initiated FGM treatment in TRANSFORMS compared to those patients switching from IFNβ-1a to FGM during Extended TRANSFORMS: (0.17 versus 0.27), a 35% relative reduction in risk of relapse (*p* < 0.001). Patients initially treated with IFNβ-1a who switched to FGM, experienced a subsequent 50% reduction in ARR, 0.4 to 0.2, by the end of the extension study. MRI outcomes in the extended TRANSFORMS revealed a 63% reduction in new or newly-enlarged T2 lesion count in the group switching from IFNβ-1a to FGM. The proportion of patients with no evidence of disease activity (NEDA: no relapses, no MRI worsening, and no sustained disability progression) increased by 50% in the first year after switching to FGM (43% to 66%). During the extension phase, there was no statistical difference in the number of patients in either group who remained without Gd+ lesions. The relative reduction in brain volume loss observed during the core study in patients continuously treated with FGM was maintained through the extension study, whereas the patients switched from IFNβ to FGM experienced a reduction in the rate of brain volume loss during the extension phase.
