A phase 3 trial of semagacestat for treatment of Alzheimer's disease

Rachelle S. Doody, Rema Raman, Martin Farlow, Takeshi Iwatsubo, Bruno Vellas, Steven Joffe, Karl Kieburtz, Feng He, Xiaoying Sun, Ronald G. Thomas, Paul S. Aisen, Eric Siemers, Gopalan Sethuraman, Richard Mohs

Research output: Contribution to journalArticle

526 Citations (Scopus)

Abstract

Background: Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. Methods: We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. Results: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P = 0.15 and P = 0.07, respectively, for the comparison with placebo). The ADCSADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P = 0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. Conclusions: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections.

Original languageEnglish
Pages (from-to)341-350
Number of pages10
JournalNew England Journal of Medicine
Volume369
Issue number4
DOIs
StatePublished - 2013

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N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide
Alzheimer Disease
Placebos
Amyloid Precursor Protein Secretases
Cognition
Therapeutics
Skin Neoplasms
Clinical Trials Data Monitoring Committees
Serum Amyloid A Protein
Aptitude
Amyloid beta-Peptides
Activities of Daily Living
Random Allocation
Infection
Uric Acid
Eosinophils
Immunoglobulins
Monocytes
Albumins

ASJC Scopus subject areas

  • Medicine(all)

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Doody, R. S., Raman, R., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., ... Mohs, R. (2013). A phase 3 trial of semagacestat for treatment of Alzheimer's disease. New England Journal of Medicine, 369(4), 341-350. https://doi.org/10.1056/NEJMoa1210951

A phase 3 trial of semagacestat for treatment of Alzheimer's disease. / Doody, Rachelle S.; Raman, Rema; Farlow, Martin; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; He, Feng; Sun, Xiaoying; Thomas, Ronald G.; Aisen, Paul S.; Siemers, Eric; Sethuraman, Gopalan; Mohs, Richard.

In: New England Journal of Medicine, Vol. 369, No. 4, 2013, p. 341-350.

Research output: Contribution to journalArticle

Doody, RS, Raman, R, Farlow, M, Iwatsubo, T, Vellas, B, Joffe, S, Kieburtz, K, He, F, Sun, X, Thomas, RG, Aisen, PS, Siemers, E, Sethuraman, G & Mohs, R 2013, 'A phase 3 trial of semagacestat for treatment of Alzheimer's disease', New England Journal of Medicine, vol. 369, no. 4, pp. 341-350. https://doi.org/10.1056/NEJMoa1210951
Doody, Rachelle S. ; Raman, Rema ; Farlow, Martin ; Iwatsubo, Takeshi ; Vellas, Bruno ; Joffe, Steven ; Kieburtz, Karl ; He, Feng ; Sun, Xiaoying ; Thomas, Ronald G. ; Aisen, Paul S. ; Siemers, Eric ; Sethuraman, Gopalan ; Mohs, Richard. / A phase 3 trial of semagacestat for treatment of Alzheimer's disease. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 4. pp. 341-350.
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AU - Raman, Rema

AU - Farlow, Martin

AU - Iwatsubo, Takeshi

AU - Vellas, Bruno

AU - Joffe, Steven

AU - Kieburtz, Karl

AU - He, Feng

AU - Sun, Xiaoying

AU - Thomas, Ronald G.

AU - Aisen, Paul S.

AU - Siemers, Eric

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AU - Mohs, Richard

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N2 - Background: Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. Methods: We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. Results: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P = 0.15 and P = 0.07, respectively, for the comparison with placebo). The ADCSADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P = 0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. Conclusions: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections.

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