Table 1 Completed trials of gantenerumab
Study name, design, and NCT | Study population | Gantenerumab dose | Primary endpoint | Other key findings |
|---|---|---|---|---|
SCarlet RoAD Phase 2/3, global double-blind placebo-controlled study (study start date: 2010) (NCT01224106) | N = 797 Prodromal ADa, 50–85 years, CSF Aβ1–42 confirmed pathology < 600 pg/mL | Gantenerumab 105 mg SC Q4W Gantenerumab 225 mg SC Q4W Placebo | Change from baseline in CDR-SB at 2 years in the gantenerumab group: 105 mg, 1.69 (P = .67) 225 mg, 1.73 (P = .45) Dosing stopped due to preplanned interim futility in 2014 Study converted to OLE in 2015 | CSF biomarkers in gantenerumab group (n = 209); change from baseline at 104 weeks: Aβ(1–42): gantenerumab 105 mg, -1.06% (P = .98); gantenerumab 225 mg, 7.55% (P = .09) t-tau: gantenerumab 105 mg, – 1.08% (P = .05); gantenerumab 225 mg, – 2.91% (P = .02) p-tau: gantenerumab 105 mg, – 5.61% (P ≤ .001); gantenerumab 225 mg, – 7.15% (P ≤ 0.001) neurogranin: gantenerumab 105 mg, – 4.58% (P = .79); gantenerumab 225 mg, – 11.76 (P = .18) PET substudy [34] (n = 115): No changes in CSF Aβ1–42 were found for either group Gantenerumab 105 mg: – 4.85% change from baseline in CSF p-tau (P < .01) at week 104; – 1.45% change from baseline in CSF t-tau (P < .01) at week 104; 0.19% change from baseline in composite standardized uptake value on amyloid PET at week 100 Gantenerumab 225 mg: – 7.52% change in CSF p-tau (P < .01) at week 104; – 2.94% change from baseline in CSF t-tau (P < .01) at week 104; – 5.37% change from baseline in composite standardized uptake value on amyloid PET at week 100 Safety One adverse event, injection site erythema, had > 5% occurrence and 2X greater than placebo: gantenerumab 105 mg, 10.7%; gantenerumab 225 mg, 13.5%; placebo, 1.1% |
Marguerite RoAD Phase 3 double-blind, placebo-controlled parallel-group study (study start date: 2014) (NCT02051608) | N = 389 50–90 years Probable mild dementiaa CSF Aβ1–42 confirmed pathology < 700 pg/mL | Gantenerumab SC Q4W uptitrated to 225 mg at week 28 if no confirmed ARIA (Fig. 3) Placebo | Change from baseline in ADAS-Cog13 scores at week 104 vs placebo Change from baseline in ADCS-ADL scores at week 104 vs placebo Terminated early following SCarlet RoAD futility analysis; study converted to OLE in 2015 Mean time on treatment = 66 weeks | CSF biomarkers in gantenerumab group (n = 12) median % from baseline at 104 weeks: Aβ(1–40): – 10.03 [– 18.08; – 2.21], P = .584 Aβ(1–42): 7.15 [– 8.52; 15.97], P = .123 t-tau: – 6.17 [– 12.72; 1.25], P = .184 p-tau: – 16.33 [– 22.84; – 4.49], P = .053 |
SCarlet RoAD Open-label extension study (study start date: 2015) (NCT01224106) | N = 154 Patients enrolled in the SCarlet RoAD study (NCT01224106) | Gantenerumab SC Q4W, uptitrated to 1200 mg based on APOE ε4 status (Fig. 3) | Safety AEs were mostly mild to moderate. 31.2% of patients experienced ISR; one patient discontinued due to ISR, which was reported as mild to moderate. | |
Marguerite RoAD Open-label extension study (study start date: 2015) (NCT02051608) | N = 225 Patients enrolled in the Marguerite RoAD study (NCT02051608) | Gantenerumab SC Q4W uptitrated to 1200 mg based on APOE ε4 carrier status (Fig. 3) | Safety AEs were mostly mild to moderate. 29.8% of patients experienced ISR; 10.7% of patients discontinued due to AE. | |
SCarlet RoAD OLE (NCT01224106) and Marguerite RoAD OLE (NCT02051608) PET substudy: exploratory analyses (study start date: 2015) | (n = 67) Prodromal ADa, 50–85 years, CSF Aβ1–42 confirmed pathology Three cohorts: 1) Pooled SR gantenerumab 105 mg or 225 mg or placebo Q4W (n = 19) 2) MR double-blind placebo (n = 27) 3) MR double-blind active gantenerumab 105 mg or 225 mg (n = 21) | Gantenerumab 1200 mg SC Q4W (Fig. 3) | Change from baseline in mean Aβ PET centiloid values 52 weeks: pooled SR, – 21; MR double-blind placebo, – 42; MR double-blind active, – 48 104 weeks: pooled SR, – 34; MR double-blind placebo, – 71; MR double-blind active, – 62 36 months: pooled SR, – 57.0; MR double-blind placebo, – 90.3; MR double-blind active, – 74.9 | At 104 weeks, 51% of patients were below the amyloid positivity threshold. At the 36-month follow-up (140 weeks total), 80% of participants were below the amyloid positivity threshold. |
DIAN-TU-001 Public-private collaboration, randomized, placebo-controlled, multi-arm phase 2/3 trial (study start date: 2012) (NCT01760005) | N = 142 Asymptomatic or mildly symptomatic participants with DIAD | Gantenerumab SC uptitrated to 1200 mg Q4W (see Fig. 3) Solanezumab uptitrated to 1600 mg Placebo | DIAN-MCE evaluated via Bayesian multivariate CPR compared with pooled placebo: Gantenerumab probability CPR < 1 = 0.144 (no treatment benefit) | No benefit with gantenerumab in the following: MMRM change from baseline in each component of DIAN-MCE MMRM change from baseline in CDR-SB MMRM change from baseline in Functional Assessment Scale Changes in biological endpoints from baseline to year 4: between-group difference (gantenerumab vs placebo) PiB-PET Aβ: 24.3% (12.7 + 11.6) decrease with gantenerumab(P < .001) CSF total Aβ42: 42.6% (19.3 + 23.3) increase with gantenerumab (P < .001) CSF total tau: 20.6% (15.3 + 5.3) decrease with gantenerumab (P < .001) Phospho-tau181: 32.8% (23.4 + 9.4) decrease with gantenerumab (P < .001) CSF NfL: 2.2% (3.9 – 1.7) slowed increase with gantenerumab (P < .05) Cortical metabolism measured with 18F-FDG-PET (no difference) Precuneus thickness and hippocampal volume (no difference) Safety The most common adverse event with gantenerumab was injection-site reactions (90%; P < .0001 vs placebo). No other adverse event occurred statistically significantly more with gantenerumab than placebo. |