RO4909832 · program

Gantenerumab for Alzheimer's disease

DiscontinuedDiscontinuedF. Hoffmann-La Roche Ltd (ROG)
  • FDA Breakthrough Therapy (Alzheimer'S Disease; Granted 2021-10-08; Program Discontinued 2022)

Roche/Genentech's Phase 3 program of gantenerumab, a subcutaneous fully human anti-amyloid-beta IgG1 antibody, in Alzheimer's disease — discontinued November 2022 after the confirmatory GRADUATE I/II trials failed. The program ran three Phase 3 generations over 14 years. SCarlet RoAD (NCT01224106, prodromal AD, 105/225 mg q4w) was halted for futility on 2014-12-19; Marguerite RoAD (NCT02051608, mild AD) stopped enrollment at 389 after the same signal; both converted to open-label extensions at escalated doses (to 1200 mg) whose robust amyloid-PET removal earned FDA Breakthrough Therapy designation on 2021-10-08 and justified the GRADUATE program. GRADUATE I/II (NCT03444870/NCT03443973; n=985+980 randomized, 1,965 total; 510 mg q2w after titration) missed their primary endpoints: CDR-SB change vs placebo at week 116 was -0.31 (p=0.0954, 8% relative slowing) and -0.19 (p=0.2998, 6%), with lower-than-expected amyloid removal (28%/25% amyloid-negative at week 116) and 25% ARIA-E. Topline was announced 2022-11-14; at CTAD on 2022-11-30 Roche presented the full data and discontinued all gantenerumab studies — GRADUATION, the PostGraduate OLE, OpenRoAD and the SKYLINE secondary-prevention trial — with the registry recording 'Decision to terminate development of Gantenerumab' on each. The one continuing study, the investigator-led DIAN-TU open-label extension in dominantly inherited AD, stopped dosing in August 2023 for lack of a regulatory path; its 2025 Lancet Neurology publication showed large amyloid lowering (PiB-PET SUVR -0.71) and a suggestive halving of symptom-onset risk in the longest-treated asymptomatic carriers (HR 0.53, 95% CI 0.27-1.03) — influential evidence for the prevention hypothesis, arriving after the molecule was already dead. Roche's anti-amyloid franchise continued with the distinct Brainshuttle antibody trontinemab.

Data current as of

Development timeline

DiscontinuedNov 2022 – Mar 2025
  1. mixedDIAN-TU gantenerumab open-label extension (Lancet Neurology): amyloid PET fell profoundly (PiB-PET SUVR -0.71, p<0.0001); symptom-onset/progression risk halved in the longest-treated asymptomatic carriers (HR 0.53, 95% CI 0.27-1.03) but not overall (HR 0.79, 0.47-1.32); combined ARIA 53%, symptomatic ARIA-E 6%, no deaths.↗
  2. At CTAD (San Francisco) Roche presented the full GRADUATE data and announced discontinuation of gantenerumab development: the GRADUATION once-weekly-dosing Phase 2, the PostGraduate open-label extension, OpenRoAD, and the SKYLINE secondary-prevention Phase 3 were all halted. ClinicalTrials.gov records the terminations with whyStopped 'Decision to terminate development of Gantenerumab ... following results of a pre-planned analysis of the safety and efficacy of Gant in Grad[uate]' (SKYLINE terminated 2023-03-13; GRADUATION completed termination 2023-03-15; PostGraduate 2023-03-06). The only study allowed to continue was the investigator-led DIAN-TU open-label extension, whose dosing the sponsor stopped in August 2023 for lack of a regulatory path. No event code exists for a program discontinuation, so this row is the canonical record of it.↗
  3. Conference presentationFull GRADUATE I/II results presented at CTAD; Roche announces discontinuation of gantenerumab development↗
Phase 3Nov 2010 – Nov 2022
  1. missedGRADUATE I failed: CDR-SB difference -0.31 vs placebo at week 116 (8% relative slowing, p=0.0954); amyloid removal lower than expected; ARIA-E 25%.↗
  2. missedGRADUATE II failed: CDR-SB difference -0.19 vs placebo at week 116 (6% relative slowing, p=0.2998).↗
  3. Breakthrough TherapyFDA grants Breakthrough Therapy designation to gantenerumab for Alzheimer's disease↗
  4. missedDIAN-TU-001 gantenerumab arm missed its cognitive primary endpoint in dominantly inherited Alzheimer's disease; amyloid, tau and neurofilament biomarkers moved in the desired direction.↗
  5. GRADUATE I (NCT03444870, WN29922) started per ClinicalTrials.gov, followed by GRADUATE II (NCT03443973, WN39658) on 2018-08-22: two identically designed global Phase 3 trials of gantenerumab titrated to 510 mg SC every 2 weeks vs placebo over 116 weeks in early (prodromal-to-mild) Alzheimer's disease, primary endpoint change from baseline in CDR-SB; 1,965 randomized across 30 countries. FDA Breakthrough Therapy designation followed on 2021-10-08, and the SKYLINE secondary-prevention Phase 3 (NCT05256134) opened 2022-04-19.
  6. missedSCarlet RoAD dosing halted for futility: gantenerumab 105/225 mg q4w was unlikely to meet its CDR-SB primary endpoint in prodromal Alzheimer's disease.↗
  7. SCarlet RoAD (NCT01224106, WN25203) started per ClinicalTrials.gov: randomized, double-blind, placebo-controlled two-year study of subcutaneous gantenerumab 105 or 225 mg every 4 weeks in prodromal Alzheimer's disease (799 enrolled). Registered as Phase 3 on the registry (often described as Phase 2/3 in the literature). Phase 1 studies had run from 2008; this row starts the pivotal record.

Readouts

  • 2025-03-19ReportedFull resultsmixedNCT01760005

    DIAN-TU gantenerumab open-label extension (Lancet Neurology): amyloid PET fell profoundly (PiB-PET SUVR -0.71, p<0.0001); symptom-onset/progression risk halved in the longest-treated asymptomatic carriers (HR 0.53, 95% CI 0.27-1.03) but not overall (HR 0.79, 0.47-1.32); combined ARIA 53%, symptomatic ARIA-E 6%, no deaths. ↗

  • 2022-11-14ReportedTopline datamissedNCT03444870

    GRADUATE I failed: CDR-SB difference -0.31 vs placebo at week 116 (8% relative slowing, p=0.0954); amyloid removal lower than expected; ARIA-E 25%. ↗

  • 2022-11-14ReportedTopline datamissedNCT03443973

    GRADUATE II failed: CDR-SB difference -0.19 vs placebo at week 116 (6% relative slowing, p=0.2998). ↗

  • 2020-02-10ReportedTopline datamissedNCT01760005

    DIAN-TU-001 gantenerumab arm missed its cognitive primary endpoint in dominantly inherited Alzheimer's disease; amyloid, tau and neurofilament biomarkers moved in the desired direction. ↗

  • 2014-12-19ReportedInterim analysismissedNCT01224106

    SCarlet RoAD dosing halted for futility: gantenerumab 105/225 mg q4w was unlikely to meet its CDR-SB primary endpoint in prodromal Alzheimer's disease. ↗

Clinical trials in Alzheimer's disease

NCT05256134WN42444Phase 3Discontinuedn=25

SKYLINE — A Phase III, Multicenter, Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Gantenerumab in Participants at Risk for or at the Earliest Stages of Alzheimer's Disease (secondary prevention)

Started Apr 2022· Primary completion Mar 2023· 📍 63 sites across 10 countries (United States, Poland, United Kingdom, Canada)

NCT04374253WN42171Phase 3Discontinuedn=1382

PostGraduate — An Open-Label, Multicenter, Rollover Study to Evaluate the Safety, Tolerability, and Efficacy of Long-Term Gantenerumab Administration in Participants With Alzheimer's Disease

Started Jan 2021· Primary completion Mar 2023· 📍 268 sites across 29 countries (United States, Japan, Spain, United Kingdom)

NCT04592341WN29722Phase 2Discontinuedn=192

GRADUATION — A Phase II, Multicenter, Open-Label, Single-Arm Study to Evaluate the Pharmacodynamic Effects of Once-Weekly Administration of Gantenerumab in Participants With Early Alzheimer's Disease

Started Nov 2020· Primary completion Jan 2023· 📍 34 sites across 8 countries (United States, Poland, Spain, United Kingdom)

NCT03443973WN39658Phase 3Discontinuedn=975

GRADUATE II — A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's Disease

Started Aug 2018· Primary completion Sept 2022· 📍 155 sites across 19 countries (United States, Japan, United Kingdom, Spain)

missedprimaryChange from baseline in CDR-SB at week 116 (gantenerumab 510 mg SC q2w vs placebo) — -0.19 vs placebo (6% relative slowing of clinical decline) (0.2998)

Primary endpoint not met. Difference in CDR-SB change at week 116 was -0.19 (p=0.2998). 25% of gantenerumab participants were amyloid-PET-negative at week 116. Published with GRADUATE I in Bateman et al., N Engl J Med 2023;389:1862-1876.

NCT03444870WN29922Phase 3Discontinuedn=1053

GRADUATE I — A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's Disease

Started Jun 2018· Primary completion Dec 2022· 📍 172 sites across 15 countries (United States, China, Japan, Spain)

missedprimaryChange from baseline in CDR-SB at week 116 (gantenerumab 510 mg SC q2w vs placebo) — -0.31 vs placebo (8% relative slowing of clinical decline) (0.0954)

Primary endpoint not met. Difference in CDR-SB change at week 116 was -0.31 (p=0.0954). Amyloid removal was lower than expected: 28% of gantenerumab participants were amyloid-PET-negative at week 116. ARIA-E incidence 25% across GRADUATE, the vast majority asymptomatic (symptomatic ARIA-E 5%). Published with GRADUATE II in Bateman et al., N Engl J Med 2023;389:1862-1876.

NCT02051608WN28745Phase 3Completedn=389

Marguerite RoAD — A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Study of Gantenerumab in Patients With Mild Alzheimer Disease

Started Mar 2014· Primary completion Apr 2021· 📍 131 sites across 22 countries (United States, Canada, Japan, South Korea)

NCT01760005DIAN-TU-001Phase 2/3Activen=490

Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia (DIAN-TU-001 master protocol)

Started Dec 2012· Primary completion Apr 2028· 📍 38 sites across 15 countries (United States, France, Canada, Australia)

missedprimaryDIAN Multivariate Cognitive Endpoint over 4 years (solanezumab arm; dominantly inherited AD mutation carriers)

The solanezumab arm did not meet its cognitive primary endpoint in the Washington University-sponsored DIAN-TU platform trial (topline 2020-02-10); Lilly did not pursue a submission in dominantly inherited AD. Full results: Salloway et al. Nat Med 2021;27:1187-1196 (PMID 34155411). The master protocol remains active for other drug arms; the solanezumab arm is closed.

NCT01224106WN25203Phase 3Completedn=799

SCarlet RoAD — Multicenter, Randomized, Double-Blind, Placebo-Controlled Two-Year Study to Evaluate the Effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease

Started Nov 2010· Primary completion Sept 2020· 📍 139 sites across 24 countries (United States, Germany, France, Spain)

missedprimaryChange from baseline in CDR-SB at 2 years (gantenerumab 105 or 225 mg SC q4w vs placebo)

Dosing halted 2014-12-19 after a preplanned interim futility analysis showed the study was unlikely to meet its primary endpoint at the tested doses; exploratory analyses suggested subtherapeutic exposure with a possible benefit trend in fast progressors. The study then ran as an open-label extension titrating to 1200 mg q4w (registry completion 2020-09-10), generating the amyloid-removal data behind the 2021 Breakthrough Therapy designation. Formal per-arm efficacy statistics for the futile double-blind phase were not transcribed here (published as Ostrowitzki et al., Alzheimers Res Ther 2017).

Formulations

FormulationRouteRegimenPharmacokinetics
Gantenerumab subcutaneous injection
Subcutaneous injection; dose escalated ~10-fold across the program's lifetime as subtherapeutic exposure was recognized. SCarlet RoAD: 105 or 225 mg every 4 weeks. RoAD open-label extensions (2015 onward): titrated to 1200 mg every 4 weeks. GRADUATE I/II: titrated to 510 mg every 2 weeks (given as two 300-plus-210 style split injections; 1020 mg/month). DIAN-TU double-blind: 225 mg escalated mid-trial to 1200 mg every 4 weeks; DIAN-TU open-label extension: titrated from 120 mg every 4 weeks up to 1020-1500 mg every 2 weeks (78% reached the highest dose). SKYLINE (terminated): 255 mg weekly or 510 mg every 2 weeks.
SubcutaneousOther—

Mechanism of action (compound-wide)

Fully human IgG1 monoclonal antibody that binds a conformational epitope on aggregated amyloid-beta, spanning both the N-terminal (Abeta1-10) and central (Abeta19-26) regions of the peptide. Equilibrium binding shows strong aggregate preference: KD 0.6 nM for amyloid-beta fibrils and 1.2 nM for oligomers versus 17 nM for monomers (Bohrmann et al., 2012). In brain it preferentially decorates parenchymal and vascular aggregated amyloid and elicits cell-mediated clearance: in ex vivo human-brain-slice assays gantenerumab recruited microglia and induced Fc-receptor-mediated phagocytosis and degradation of amyloid plaques. The therapeutic hypothesis — that removing aggregated amyloid slows clinical decline — was not confirmed at the doses and disease stage tested in GRADUATE I/II, where amyloid removal was lower than expected (28% and 25% of participants amyloid-PET-negative at week 116) and CDR-SB effects were non-significant; the DIAN-TU open-label extension later showed that higher, longer exposure can drive large amyloid reductions (PiB-PET SUVR -0.71 over 3 years) with suggestive delay of symptom onset in presymptomatic mutation carriers.

TargetActionAffinity
Amyloid-beta (aggregated)primaryAPPInhibitorKd 0.6 nMⓘ

← Full RO4909832 compound page (identity, identifiers, all indications)

Sources

  1. [Ad hoc announcement pursuant to Art. 53 LR] Roche provides update on Phase III GRADUATE programme evaluating gantenerumab in early Alzheimer's disease (2022-11-14) — GRADUATE I/II miss CDR-SB primary endpoints — F. Hoffmann-La Roche Ltd
  2. [Ad hoc announcement pursuant to Art. 53 LR] Roche's anti-amyloid beta antibody gantenerumab granted FDA Breakthrough Therapy Designation in Alzheimer's disease (2021-10-08, wire copy) — F. Hoffmann-La Roche Ltd (via GlobeNewswire)
  3. Bateman RJ, et al. Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 DIAN-TU trial. Lancet Neurol. 2025;24(4):316-330 (published online 2025-03-19; open access) — The Lancet Neurology via PubMed Central
  4. Bohrmann B, et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis. 2012;28(1):49-69 — KD 0.6 nM fibrils / 1.2 nM oligomers / 17 nM monomers; HuCAL-derived; Fc-mediated microglial phagocytosis — Journal of Alzheimer's Disease / PubMed
  5. Gantenerumab — Therapeutics entry (development timeline: Phase 1 2008-2012; SCarlet RoAD futility halt 2014-12-19; RoAD OLE dose escalation to 1200 mg; GRADUATE design 510 mg q2w; DIAN-TU OLE up to 1500 mg q2w; discontinuation of all trials except the DIAN-TU OLE) — Alzforum (FBRI / Biomedical Research Forum)
  6. Lilly Announces Topline Results for Solanezumab from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Study (2020-02-10) — Eli Lilly and Company
  7. NCT01224106 (WN25203) — SCarlet RoAD, Phase 3, subcutaneous RO4909832 in prodromal Alzheimer's disease; COMPLETED 2020-09-10 (dosing halted for futility 2014, converted to open-label extension), 799 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT01760005 (DIAN-TU-001) — Dominantly Inherited Alzheimer Network Trial master protocol (Washington University School of Medicine, sponsor; Eli Lilly, collaborator) — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT02051608 (WN28745) — Marguerite RoAD, Phase 3, gantenerumab in mild Alzheimer's disease; COMPLETED 2021-04-16, 389 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT03443973 (WN39658) — GRADUATE II, Phase 3, gantenerumab vs placebo in early Alzheimer's disease; TERMINATED (decision to terminate development), 975 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. NCT03444870 (WN29922) — GRADUATE I, Phase 3, gantenerumab vs placebo in early Alzheimer's disease; TERMINATED (decision to terminate development), 1,053 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  12. NCT04374253 (WN42171) — PostGraduate, open-label rollover study of long-term gantenerumab; TERMINATED (decision to terminate development), 1,382 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  13. NCT04592341 (WN29722) — GRADUATION, Phase 2, once-weekly gantenerumab pharmacodynamics in early Alzheimer's disease; TERMINATED (decision to terminate development), 192 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  14. NCT05256134 (WN42444) — SKYLINE, Phase 3 secondary prevention of Alzheimer's disease; TERMINATED (decision to terminate development), 25 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  15. Roche discontinues clinical trials of gantenerumab, after GRADUATE studies fail to meet their primary endpoints (2022-11-30) — GRADUATION, OpenRoAD, PostGraduate and SKYLINE halted; announced at CTAD San Francisco — Alzheimer Europe
  16. Roche provides topline results from investigator-led Phase II/III trial with gantenerumab in rare inherited form of Alzheimer's disease (2020-02-10) — DIAN-TU gantenerumab arm misses primary endpoint — F. Hoffmann-La Roche Ltd