MABT5102A · program

Crenezumab for Alzheimer's disease

DiscontinuedDiscontinuedGenentech, Inc.

Genentech/Roche's program of crenezumab, AC Immune's humanized anti-amyloid-beta IgG4 antibody, in Alzheimer's disease — carrying two of the field's landmark negative results. Phase 2 ABBY (NCT01343966, n=448, mild-to-moderate AD, 300 mg SC q2w or 15 mg/kg IV q4w) and its biomarker twin BLAZE (NCT01397578, n=91) missed their primary endpoints (2014), with exploratory trends in milder patients at the highest dose that justified escalation. The Phase 3 CREAD program (CREAD 1 NCT02670083 from 2016-03-22, CREAD 2 NCT03114657 from 2017-03-29; 813+806 randomized, prodromal-to-mild AD, 60 mg/kg IV q4w) was discontinued on 2019-01-30 after the IDMC's preplanned interim analysis found crenezumab unlikely to meet its CDR-SB primary endpoint; no safety signal was observed, and the BN40031 open-label extension was terminated with the parents (published: Ostrowitzki et al., JAMA Neurology 2022). The program's second act was the Alzheimer's Prevention Initiative ADAD Colombia trial (NCT01998841, Genentech with Banner Alzheimer's Institute and the NIA, started 2013-12-20): the first anti-amyloid prevention trial in cognitively unimpaired PSEN1 E280A carriers from the Colombian kindred, n=252, treated five to eight years with doses escalated seven-fold mid-trial (300 mg SC q2w to 720 mg SC q2w to 60 mg/kg IV q4w). On 2022-06-16 Genentech and Banner announced it did not reach statistical significance on either co-primary endpoint (API ADAD composite cognitive score; FCSRT cueing index), with small numerical differences favoring crenezumab across endpoints; 94% of participants completed. That miss ended crenezumab development entirely — full results appeared in The Lancet Neurology (2026). Roche's anti-amyloid effort continued with the distinct antibodies gantenerumab (itself discontinued 2022) and trontinemab.

Data current as of

Development timeline

DiscontinuedJun 2022 – Feb 2026
  1. missedAPI ADAD Colombia full results published in The Lancet Neurology: no significant slowing of cognitive decline in PSEN1 E280A carriers treated 5-8 years; crenezumab retained a benign ARIA profile consistent with its IgG4 design.↗
  2. missedAPI ADAD Colombia prevention trial missed both co-primary endpoints in cognitively unimpaired PSEN1 E280A carriers; small numerical differences favored crenezumab but did not approach significance.↗
Phase 2Apr 2011 – Jan 2019
  1. missedCREAD 1/2 discontinued: the IDMC's preplanned interim analysis showed crenezumab 60 mg/kg IV q4w was unlikely to meet the CDR-SB primary endpoint in prodromal-to-mild Alzheimer's disease; no safety signal.↗
  2. missedABBY and BLAZE Phase 2 trials missed their primary endpoints in mild-to-moderate Alzheimer's disease; an exploratory trend in milder patients at 15 mg/kg IV motivated the CREAD dose escalation.↗
  3. API ADAD Colombia trial (NCT01998841, GN28352) started per ClinicalTrials.gov: the first-ever anti-amyloid prevention trial in autosomal-dominant Alzheimer's disease — 252 cognitively unimpaired members of the Colombian PSEN1 E280A kindred randomized to crenezumab or placebo for five to eight years, run by Genentech with Banner Alzheimer's Institute and the National Institute on Aging. ABBY and BLAZE read out in 2014 having missed their primary endpoints; dose-escalation modeling from their exploratory analyses shaped the later Phase 3 dose.
  4. ABBY (NCT01343966, ABE4869g) started per ClinicalTrials.gov: Phase 2, randomized, double-blind, placebo-controlled study of MABT5102A in 448 patients with mild-to-moderate Alzheimer's disease (300 mg SC q2w or 15 mg/kg IV q4w vs placebo). The biomarker study BLAZE (NCT01397578, ABE4955g, n=91) followed on 2011-08-31. Phase 1 studies preceded; this row starts the pivotal record.
Phase 3Mar 2016
  1. CREAD (NCT02670083, BN29552) started per ClinicalTrials.gov: Phase 3, randomized, double-blind, placebo-controlled study of crenezumab 60 mg/kg IV q4w — four times the highest Phase 2 dose — in prodromal-to-mild Alzheimer's disease (813 randomized). CREAD 2 (NCT03114657, BN29553, 806 randomized) followed on 2017-03-29, and the BN40031 open-label extension opened 2018-04-11.

Readouts

  • 2026-02-01ReportedFull resultsmissedNCT01998841

    API ADAD Colombia full results published in The Lancet Neurology: no significant slowing of cognitive decline in PSEN1 E280A carriers treated 5-8 years; crenezumab retained a benign ARIA profile consistent with its IgG4 design. ↗

  • 2022-06-16ReportedTopline datamissedNCT01998841

    API ADAD Colombia prevention trial missed both co-primary endpoints in cognitively unimpaired PSEN1 E280A carriers; small numerical differences favored crenezumab but did not approach significance. ↗

  • 2019-01-30ReportedInterim analysismissedNCT02670083

    CREAD 1/2 discontinued: the IDMC's preplanned interim analysis showed crenezumab 60 mg/kg IV q4w was unlikely to meet the CDR-SB primary endpoint in prodromal-to-mild Alzheimer's disease; no safety signal. ↗

  • 2014-07-16ReportedTopline datamissedNCT01343966

    ABBY and BLAZE Phase 2 trials missed their primary endpoints in mild-to-moderate Alzheimer's disease; an exploratory trend in milder patients at 15 mg/kg IV motivated the CREAD dose escalation. ↗

Clinical trials in Alzheimer's disease

NCT03491150BN40031Phase 3Discontinuedn=149

A Multicenter, Open-Label, Long-Term Extension of Phase III Studies (BN29552/BN29553) of Crenezumab in Patients With Alzheimer's Disease

Started Apr 2018· Primary completion May 2019· 📍 66 sites across 16 countries (United States, Spain, Canada, Mexico)

NCT03114657BN29553Phase 3Discontinuedn=806

CREAD 2 — A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer's Disease

Started Mar 2017· Primary completion Jun 2019· 📍 211 sites across 27 countries (United States, Japan, Spain, Italy)

NCT02670083BN29552Phase 3Discontinuedn=813

CREAD — A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer's Disease

Started Mar 2016· Primary completion May 2019· 📍 196 sites across 30 countries (United States, Spain, Japan, Canada)

missedprimaryChange from baseline in CDR-SB (crenezumab 60 mg/kg IV q4w vs placebo)

Study terminated 2019-01-30 after the IDMC's preplanned interim analysis indicated crenezumab was unlikely to meet the CDR-SB primary endpoint; the registry whyStopped records the same. No safety signal was observed and the overall safety profile matched previous trials. Per-arm efficacy statistics were not transcribed here; published with CREAD 2 as Ostrowitzki et al., JAMA Neurol 2022;79(11):1113-1121 (PMID 36121669), confirming no treatment effect on clinical decline and a low ARIA-E incidence consistent with the IgG4 design.

NCT01998841GN28352Phase 2Completedn=252

API ADAD Colombia — A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo (Alzheimer's Prevention Initiative; Genentech with Banner Alzheimer's Institute and the National Institute on Aging)

Started Dec 2013· Primary completion Mar 2022· 📍 4 sites across 1 country (Colombia)

missedprimaryCo-primary: rate of change in the API ADAD composite cognitive score, and in episodic memory (FCSRT cueing index), in PSEN1 E280A mutation carriers (crenezumab vs placebo, 5-8 years)

Neither co-primary endpoint reached statistical significance; small numerical differences favoring crenezumab were observed across co-primary, secondary and exploratory endpoints. 94% of the 252 participants (two-thirds mutation carriers, from the world's largest ADAD kindred) completed the trial; doses were escalated seven-fold mid-trial (300 mg SC q2w to 720 mg SC q2w to 60 mg/kg IV q4w). Announced 2022-06-15/16 by Genentech, Roche and Banner; full results presented at AAIC 2022 and published as the API ADAD Colombia Trial in Lancet Neurol 2026;25 (PMID 41579901).

NCT01397578ABE4955gPhase 2Completedn=91

BLAZE — A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase II Study to Evaluate the Impact of MABT5102A on Brain Amyloid Load and Related Biomarkers in Patients With Mild to Moderate Alzheimer's Disease

Started Aug 2011· Primary completion Apr 2014· 📍 29 sites across 3 countries (United States, Spain, France)

missedprimaryChange from baseline in brain amyloid load by florbetapir PET (crenezumab vs placebo)

Amyloid-PET primary endpoint not met; CSF amyloid-beta changes indicated peripheral and central target engagement without plaque removal. Published as Salloway et al., Alzheimers Res Ther 2018;10:96 (PMID 30231896).

NCT01343966ABE4869gPhase 2Completedn=448

ABBY — A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Phase II Study to Evaluate the Efficacy and Safety of MABT5102A in Patients With Mild to Moderate Alzheimer's Disease

Started Apr 2011· Primary completion Feb 2014· 📍 92 sites across 6 countries (United States, Canada, Germany, United Kingdom)

missedprimaryChange from baseline in ADAS-Cog12 and CDR-SB at week 73 (crenezumab 300 mg SC q2w or 15 mg/kg IV q4w vs placebo)

Co-primary endpoints not met in mild-to-moderate AD. Exploratory analyses suggested a trend toward reduced cognitive decline in milder patients receiving the higher (15 mg/kg IV) dose — the exposure-response reading that motivated the four-fold dose escalation to 60 mg/kg in CREAD. Published as Cummings et al., Neurology 2018;90(21) (PMID 29695589).

Formulations

FormulationRouteRegimenPharmacokinetics
Crenezumab subcutaneous injection
Subcutaneous injection every 2 weeks. ABBY low-dose arm: 300 mg SC q2w. API ADAD Colombia trial (initial regimen): 300 mg SC q2w, escalated to 720 mg SC q2w during the trial before the switch to 60 mg/kg IV q4w.
SubcutaneousEvery 2 weeks—
Crenezumab intravenous infusion
IV infusion every 4 weeks. ABBY/BLAZE high-dose arms: 15 mg/kg IV q4w. CREAD 1/2 and the BN40031 open-label extension: 60 mg/kg IV q4w — a four-fold escalation over Phase 2 driven by exposure modeling after the ABBY miss. The API ADAD Colombia trial switched its participants to 60 mg/kg IV q4w mid-trial as part of a seven-fold cumulative dose escalation.
IntravenousOnce monthly—

Mechanism of action (compound-wide)

Humanized monoclonal antibody against aggregated amyloid-beta, deliberately built on an IgG4 backbone: Adolfsson et al. (J Neurosci 2012) characterized it as an effector-reduced anti-amyloid antibody that binds oligomeric and fibrillar amyloid-beta (with low affinity for monomers), promotes neuroprotection against oligomer toxicity, and elicits glial engulfment of amyloid with markedly reduced Fc-gamma-receptor-mediated inflammatory activation compared with IgG1 antibodies — the design hypothesis being amyloid clearance without ARIA-driving microglial overactivation. In vivo it localizes to oligomer-rich compartments (plaque peripheries, hippocampal mossy fibers) and does not bind dense plaque cores or vascular amyloid. The hypothesis was not confirmed clinically: ABBY/BLAZE missed at up to 15 mg/kg, CREAD 1/2 were stopped for futility at 60 mg/kg IV monthly, and the API ADAD Colombia prevention trial in presymptomatic PSEN1 E280A carriers missed both co-primary endpoints — although crenezumab retained a notably benign ARIA profile throughout, consistent with the IgG4 design.

TargetActionAffinity
Amyloid-beta (aggregated)primaryAPPInhibitor—ⓘ

← Full MABT5102A compound page (identity, identifiers, all indications)

Sources

  1. Adolfsson O, et al. An effector-reduced anti-beta-amyloid (Abeta) antibody with unique Abeta binding properties promotes neuroprotection and glial engulfment of Abeta. J Neurosci. 2012;32(28):9677-89 — crenezumab's IgG4 design rationale and aggregate-preferring binding profile — Journal of Neuroscience / PubMed
  2. Crenezumab — Therapeutics entry (code names MABT5102A/RG7412; IgG4 backbone rationale; oligomer/fibril-preferring binding, low monomer affinity; dose history 300 mg SC q2w / 15 mg/kg IV to 60 mg/kg IV; CREAD termination Jan 2019; API ADAD results June 2022; development fully stopped by end-2022) — Alzforum (FBRI / Biomedical Research Forum)
  3. Cummings JL, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018;90(21):e1889-e1897 — co-primary endpoints missed; exploratory trend in milder patients at the higher dose — Neurology / PubMed
  4. Genentech Provides Update on Alzheimer's Prevention Initiative Study Evaluating Crenezumab in Autosomal Dominant Alzheimer's Disease (2022-06-15) — API ADAD Colombia co-primary endpoints not statistically significant; small numerical differences favoring crenezumab; 94% completion — Genentech, Inc. (Roche Group)
  5. NCT01343966 (ABE4869g) — ABBY, Phase 2, MABT5102A in mild-to-moderate Alzheimer's disease; COMPLETED 2014-02-28, 448 enrolled; Genentech sponsor — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT01397578 (ABE4955g) — BLAZE, Phase 2 amyloid-PET biomarker study of MABT5102A; COMPLETED 2014-04-30, 91 enrolled; Genentech sponsor — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT01998841 (GN28352) — API ADAD Colombia, Phase 2 prevention trial of crenezumab in preclinical PSEN1 E280A mutation carriers; Genentech sponsor with Banner Alzheimer's Institute and NIA collaborators; COMPLETED 2023-08-08, 252 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT02670083 (BN29552) — CREAD, Phase 3, crenezumab vs placebo in prodromal-to-mild Alzheimer's disease; TERMINATED (interim analysis: unlikely to meet primary endpoint), 813 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT03114657 (BN29553) — CREAD 2, Phase 3, crenezumab vs placebo in prodromal-to-mild Alzheimer's disease; TERMINATED (per BN29552 interim analysis), 806 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT03491150 (BN40031) — open-label long-term extension of CREAD/CREAD 2; TERMINATED (per BN29552 interim analysis), 149 enrolled — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. Roche to discontinue Phase III CREAD 1 and 2 clinical studies of crenezumab in early Alzheimer's disease (AD) - other company programmes in AD continue (2019-01-30) — IDMC preplanned interim analysis; CDR-SB primary unlikely to be met; no safety signal — F. Hoffmann-La Roche Ltd
  12. Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1 Glu280Ala mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2026 Feb — full close-out publication — The Lancet Neurology / PubMed
  13. Salloway S, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer's disease (BLAZE). Alzheimers Res Ther. 2018;10(1):96 — Alzheimer's Research & Therapy / PubMed