Background
Selection of gantenerumab as a candidate for clinical development
Gantenerumab mechanism of action: target engagement of Aβ, especially aggregated forms, and downstream effects
Amyloid-related imaging abnormalities: a finding related to the effects of anti-amyloid monoclonal antibodies targeting fibrillar Aβ
Phase I clinical trials of gantenerumab: demonstrating target engagement and initial ARIA observations that influenced the clinical development program
Rationale for the development of a subcutaneous formulation of gantenerumab for clinical studies
SCarlet RoAD and Marguerite RoAD: the first phase 2/3 clinical trials that paved the way for the future development of gantenerumab
Clinical trial methodology considerations for Scarlet RoAD phase 2
Study name, design, and NCT | Study population | Gantenerumab dose | Primary endpoint | Other key findings |
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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) 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. |
SCarlet RoAD and Marguerite RoAD conversions to open-label extension studies: a path forward to apply lessons learned
SCarlet RoAD and Marguerite RoAD OLE PET substudy: biomarker-confirmed, exposure-dependent Aβ plaque removal
Dominantly Inherited Alzheimer Network Trials Unit
Ongoing phase 3 GRADUATE program
Study name, design, and NCT | Study population | Dose | Objective and primary endpoint | Key secondary endpoints | Estimated completion date |
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GRADUATE I and II Parallel, global, multicenter, double-blind, placebo-controlled, randomized phase 3 studies (study start date: 2018) (NCT03444870) (NCT03443973) | N = 985 (GRADUATE I) N = 981 (GRADUATE II) Early (prodromal to mild) ADa, 50–90 years, evidence of the AD pathological process confirmed by CSF tau/Aβ42 or amyloid PET scan, abnormal memory function, MMSE score ≥ 22, CDR-GS = 0.5 or 1, any APOE ε4 allele status | Gantenerumab 9-month universal dose-titration regardless of APOE ε4 allele status to 510 mg SC every 2 weeks (Fig. 3) Placebo | Objective: to evaluate the efficacy and safety of subcutaneous gantenerumab vs placebo in patients with early AD (i.e., MCI-AD to mild AD) Primary endpoint: change from baseline to week 116 in CDR-SB vs placebo | MMSE, ADAS-Cog 13, Verbal Fluency, Coding, FAQ, ADCS-ADL, safety CSF biomarkers, amyloid and tau PET, MRI, plasma biomarkers | Q4 2022 |
Open ROAD A long-term, open-label rollover safety and tolerability study of gantenerumab (study start date: 2020) (NCT04339413) | N = 116 Participants who completed Scarlet RoAD OLE (NCT01224106) or Marguerite RoAD OLE (NCT02051608) | Gantenerumab 1200 mg SC Q4W with universal titration (Fig. 3) | Objective: to define the long-term safety and tolerability of gantenerumab in patients with AD Primary endpoint: AEs, treatment discontinuation, ISR, ARIA-E, ARIA-H, ADAs | May 2025 | |
GRADUATION Multicenter, phase 2, open-label, single-arm, pharmacodynamic study (study start date: 2020) (NCT04592341) | N = 192 Probable mild dementiaa, 50–90 years, AD pathology confirmed by amyloid PET scan | Gantenerumab 255 mg SC Q1W with an option for administration by study partner or non-professional) caregivers (Fig. 3) Placebo | Objective: to evaluate the effect of a once-weekly gantenerumab dosing regimen on the change in deposited amyloid Primary endpoint: change from baseline in deposited amyloid as measured by brain amyloid PET centiloid levels | Responses to home administration questionnaire (the home administration questionnaire will capture confidence, ease of use, convenience, and overall satisfaction) Safety | November 2023 |
DIAN-TU-001 OLE (study start date: 2020) (NCT01760005) | Patients who complete DIAN-TU-001 (NCT01760005) | Gantenerumab SC uptitrated to 1500 mg Q2W Individuals in the solanezumab arm of the DIAN-TU-001 may switch to gantenerumab | Objective: to assess the effects of early and larger magnitude reduction of amyloid plaques on downstream AD processes, the clinical benefits associated with the continued removal of amyloid plaques in DIAD mutation carriers across asymptomatic and symptomatic stages of AD, and the validity of strategies to slow clinical onset of AD and its progression using gantenerumab Primary endpoint: change from baseline in: each component of DIAN-MCE; CDR-SB; Functional Assessment Scale; PiB-PET Aβ; CSF total Aβ; CSF t-tau; p-tau181 CSF NfL; precuneus thickness and hippocampal volume Safety | 2023 | |
POSTGRADUATE Open-label, multicenter, phase 3 rollover study (study start date: 2021) (NCT04374253) | Planned N = 2032 Participants who completed either GRADUATE I (NCT03444870) or II (NCT03443973) double-blind part or OLE trial | Gantenerumab 9-month universal dose-titration regardless of APOE ε4 allele status to 510 mg SC every 2 weeks (see Fig. 3) | Objective: to define the long-term safety and tolerability of gantenerumab in patients with AD Primary endpoint: AEs, SAEs, C-SSRS Score, ARIA-E, ARIA-H, ISRs | CDR, MMSE, ADAS-Cog13, Verbal fluency, Coding, FAQ, ADCS-ADL | December 2024 |
PCEx Non-interventional, patient- and caregiver-centered qualitative study (study start date: 2021) | Planned N = 100 pairs of patients and their caregivers from the GRADUATE I, GRADUATE II, and POSTGRADUATE studies | Non-interventional | Objective: to evaluate the treatment burden associated with gantenerumab for patients and their care partners to optimize the gantenerumab treatment experience in the real world Primary endpoint: survey responses of patients’ and caregivers’ experiences with gantenerumab SC administration | October 2022 | |
SKYLINE Phase 3, randomized, double-blind, placebo-controlled secondary prevention trial (estimated study start date: 2022) (NCT05256134) | Planned N = 1200 Cognitively unimpaired, 60–80 years, evidence of cerebral amyloid accumulation, CSF p-Tau181/Aβ42 ratio > 0.04 or amyloid PET visual read positive; screening includes an optional exploratory BBBM prescreening to predict Aβ positivity | Participant-centric flexible dosing Target gantenerumab dose 1200 mg SC Q1W or Q2W (Fig. 3) | Objective: to evaluate the efficacy and safety of gantenerumab in amyloid-positive, cognitively unimpaired patients who are amyloid positive and at risk for AD Primary endpoint: PACC-5 Composite endpoint to assess cognition in asymptomatic AD; logical memory from the WMS; FCSRT; coding from the WAIS-IV; MMSE; Category fluency test | CFIa, A-IADL-Q-SV, CDR-SB Safety: MRI, AEs, C-SSRS, ADAs BBBM, vMRI, amyloid and tau PET, CSF biomarkers, pharmacokinetics | October 2028 |