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. 2019 Dec 12;11(1):101.
doi: 10.1186/s13195-019-0559-z.

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis

Gregory Klein  1 , Paul Delmar  2 , Nicola Voyle  3 , Sunita Rehal  3 , Carsten Hofmann  4 , Danielle Abi-Saab  2 , Mirjana Andjelkovic  2 , Smiljana Ristic  2 , Guoqiao Wang  5 , Randall Bateman  5 , Geoffrey A Kerchner  2 , Monika Baudler  2 , Paulo Fontoura  2 , Rachelle Doody  2   6
Affiliations

Gantenerumab reduces amyloid-β plaques in patients with prodromal to moderate Alzheimer's disease: a PET substudy interim analysis

Gregory Klein et al. Alzheimers Res Ther. .

Abstract

Background: We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD).

Methods: A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale.

Results: Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold.

Conclusion: Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit.

Trial registration: ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

Keywords: Alzheimer’s disease; Amyloid-β plaque; Centiloid; Disease-modification therapies; Florbetapir; Gantenerumab; Open-label extension; Positron emission tomography.

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Conflict of interest statement

GK, PD, SRi, CH, DA-S, MA, MB, and PF are full-time employees of F. Hoffmann-La Roche Ltd. GK, CH, DA-S are shareholders in F. Hoffmann-La Roche Ltd. SRe and NV are full-time employees of Roche Products Ltd. RD is a full-time employee and shareholder in F. Hoffmann-La Roche Ltd. and Genentech Inc. GW is the statistician for the DIAN-TU study and has no competing interests to disclose. RB is a principal investigator of a therapeutic trial evaluating investigational drugs. Washington University is also the regulatory sponsor for this trial. Funding for DIAN-TU clinical trials includes the National Institute on Aging of the National Institutes of Health, Alzheimer’s Association, Eli Lilly and Co, F. Hoffmann-La Roche Ltd. and Genentech, Inc., Janssen, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous foundation. Washington University and Dr. David Holtzman, Department Head of Neurology at Washington University School of Medicine, may receive royalty income for the investigational drug, solanezumab, which is being tested in the DIAN-TU trial and was developed by Dr. Holtzman and licensed by Washington University to Eli Lilly & Company. RB also receives research funding from the DIAN-TU Pharma Consortium (AbbVie, Biogen, Eisai, Eli Lilly and Co/Avid Radiopharmaceuticals, F. Hoffmann-La Roche Ltd. and Genentech, Inc., Janssen, and United Neuroscience); and has received honoraria from Janssen, Pfizer, and F. Hoffmann-La Roche Ltd. as a speaker, Eisai as a consultant, and from Merck, F. Hoffmann-La Roche Ltd., and Pfizer as an Advisory Board member.

Figures

Fig. 1
Fig. 1
Marked and consistent reduction of amyloid load in patients receiving high-dose gantenerumab. a Marked reduction of amyloid-β plaques in patients receiving high-dose gantenerumab, and consistent reduction of amyloid-β plaques in all patient groups. b Reduction of amyloid-β plaque burden to below positivity threshold following high-dose gantenerumab. aAnalyzed using a mixed model for repeated measures
Fig. 2
Fig. 2
Amyloid-β plaque reduction with gantenerumab. Axial florbetapir brain PET images from five patients displaying reduction of amyloid-β plaques from OLE baseline to OLE week 52 and OLE week 104. Axial slices are at the level of the basal ganglia. PET images were obtained 50 min post-injection, SUVR data with the cerebellar cortex as the reference region
Fig. 3
Fig. 3
Association of PET and clinical results. a, d, g Regression analysis of CDR-SB, ADAS-Cog 11, and MMSE, respectively, shows directional slowing of clinical decline with increasing amyloid reduction. b, e, h Change in CDR-SB, ADAS-Cog 11, and MMSE for week 104 completers stratified by patients with high and low amyloid reduction at week 104 also shows directional slowing of clinical decline in the group with higher amyloid reduction. c, f, i Stratification of patients by amyloid reduction at the earlier week 52 time point shows increased clinical benefit in the high PET reduction group, suggesting a temporal lag between amyloid reduction and clinical benefit
See this image and copyright information in PMC

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