Phase 3 trials of solanezumab for mild-to-moderate alzheimer's disease

Rachelle S. Doody, Ronald G. Thomas, Martin Farlow, Takeshi Iwatsubo, Bruno Vellas, Steven Joffe, Karl Kieburtz, Rema Raman, Xiaoying Sun, Paul S. Aisen, Eric Siemers, Hong Liu-Seifert, Richard Mohs

Research output: Contribution to journalArticle

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Abstract

Background: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. Methods: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. Results: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P = 0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P = 0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P = 0.06) and 1.6 points (95% CI, -0.2 to 3.3; P = 0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P = 0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P = 0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P = 0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P = 0.49). Conclusions: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.)

Original languageEnglish
Pages (from-to)311-321
Number of pages11
JournalNew England Journal of Medicine
Volume370
Issue number4
DOIs
StatePublished - 2014

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solanezumab
Alzheimer Disease
Confidence Intervals
Activities of Daily Living
Amyloid
Antibodies, Monoclonal, Humanized
Placebos
Edema
Hemorrhage
Neurofibrillary Tangles
Aptitude
Gliosis
Amyloid Plaques
Cognition

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Doody, R. S., Thomas, R. G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., ... Mohs, R. (2014). Phase 3 trials of solanezumab for mild-to-moderate alzheimer's disease. New England Journal of Medicine, 370(4), 311-321. https://doi.org/10.1056/NEJMoa1312889

Phase 3 trials of solanezumab for mild-to-moderate alzheimer's disease. / Doody, Rachelle S.; Thomas, Ronald G.; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; Raman, Rema; Sun, Xiaoying; Aisen, Paul S.; Siemers, Eric; Liu-Seifert, Hong; Mohs, Richard.

In: New England Journal of Medicine, Vol. 370, No. 4, 2014, p. 311-321.

Research output: Contribution to journalArticle

Doody, RS, Thomas, RG, Farlow, M, Iwatsubo, T, Vellas, B, Joffe, S, Kieburtz, K, Raman, R, Sun, X, Aisen, PS, Siemers, E, Liu-Seifert, H & Mohs, R 2014, 'Phase 3 trials of solanezumab for mild-to-moderate alzheimer's disease', New England Journal of Medicine, vol. 370, no. 4, pp. 311-321. https://doi.org/10.1056/NEJMoa1312889
Doody, Rachelle S. ; Thomas, Ronald G. ; Farlow, Martin ; Iwatsubo, Takeshi ; Vellas, Bruno ; Joffe, Steven ; Kieburtz, Karl ; Raman, Rema ; Sun, Xiaoying ; Aisen, Paul S. ; Siemers, Eric ; Liu-Seifert, Hong ; Mohs, Richard. / Phase 3 trials of solanezumab for mild-to-moderate alzheimer's disease. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 4. pp. 311-321.
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TY - JOUR

T1 - Phase 3 trials of solanezumab for mild-to-moderate alzheimer's disease

AU - Doody, Rachelle S.

AU - Thomas, Ronald G.

AU - Farlow, Martin

AU - Iwatsubo, Takeshi

AU - Vellas, Bruno

AU - Joffe, Steven

AU - Kieburtz, Karl

AU - Raman, Rema

AU - Sun, Xiaoying

AU - Aisen, Paul S.

AU - Siemers, Eric

AU - Liu-Seifert, Hong

AU - Mohs, Richard

PY - 2014

Y1 - 2014

N2 - Background: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. Methods: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. Results: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P = 0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P = 0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P = 0.06) and 1.6 points (95% CI, -0.2 to 3.3; P = 0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P = 0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P = 0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P = 0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P = 0.49). Conclusions: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.)

AB - Background: Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. Methods: In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease. Results: Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was -0.8 points for the ADAS-cog11 score (95% confidence interval [CI], -2.1 to 0.5; P = 0.24) and -0.4 points for the ADCS-ADL score (95% CI, -2.3 to 1.4; P = 0.64) in EXPEDITION 1 and -1.3 points (95% CI, -2.5 to 0.3; P = 0.06) and 1.6 points (95% CI, -0.2 to 3.3; P = 0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were -1.7 points in patients with mild Alzheimer's disease (95% CI, -3.5 to 0.1; P = 0.06) and -1.5 in patients with moderate Alzheimer's disease (95% CI, -4.1 to 1.1; P = 0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P = 0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P = 0.49). Conclusions: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 and NCT00904683.)

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