A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

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

doi:10.1056/nejmoa1210951

Cited by 1,020 publications

(724 citation statements)

References 21 publications

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“…These results reveal two important messages: (1) the progression of brain dysfunction in the dementia stage of AD can be halted and even improved, and (2) the alteration of cognitive capability is independent of brain amyloid accumulation, which is consistent with previous results showing that the reduction of brain amyloid accumulation by vaccines, antibodies, or b-and c-secretase inhibitors has little beneficial effect on the cognitive ability and disease progression of AD patients [1][2][3][4]. The brain has the most abundant energy consumption in the human body, and the maintenance of its function is dependent on energy metabolism.…”

Section: Discussionsupporting

confidence: 88%

“…To date, almost all clinical trials aiming to halt or delay AD progression have failed. Particularly, multiple approaches such as vaccines, antibodies, and b or c-secretase inhibitors, have been exploited to reduce amyloid deposition in the brain but have little beneficial effect on the cognitive ability of AD patients [1][2][3][4]. Generally, the failure in cognitive improvement is attributed to the fact that these therapies were performed on patients at the dementia stage of AD, and this may be too late.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

et al. 2016

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To date, we still lack disease-modifying therapies for Alzheimer's disease (AD). Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine (300 mg daily) over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B (PiB-PET) and exhibited positive imaging with bamyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improvement as assayed by the Mini-Mental Status Examination (MMSE) with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain compared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Our study provides new insight to the development of diseasemodifying therapy.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

et al. 2016

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“…A γ-secretase inhibitor, semagacestat, was tested in a phase 2 trial and a significant reduction in plasma Aβ40 was found [21]. However, the phase 3 trial was halted after interim analysis showed worsening of cognition and increased incidence of skin cancer [8], which was predicted previously [22]. Later, a γ-secretase modulator, tarenflurbil, was tested in a 12-month phase 2 study in people with mild-to-moderate AD.…”

Section: Clinical Trial Setbacks For Drugs That Target Aβmentioning

confidence: 99%

“…Accordingly, Aβ-based therapeutics have been extensively investigated in preclinical models and clinical trials. Most prominently, phase 3 trials have been performed on drugs that lower Aβ by inhibiting its production [7,8] and lowering its levels by immunotherapy [9,10], all of which failed to reach their respective clinical endpoints. There is an urgent need, therefore, for fresh approaches to treat AD.…”

Section: Introductionmentioning

confidence: 99%

Biometals and Their Therapeutic Implications in Alzheimer's Disease

2015

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No disease modifying therapy exists for Alzheimer's disease (AD). The growing burden of this disease to our society necessitates continued investment in drug development. Over the last decade, multiple phase 3 clinical trials testing drugs that were designed to target established disease mechanisms of AD have all failed to benefit patients. There is, therefore, a need for new treatment strategies. Changes to the transition metals, zinc, copper, and iron, in AD impact on the molecular mechanisms of disease, and targeting these metals might be an alternative approach to treat the disease. Here we review how metals feature in molecular mechanisms of AD, and we describe preclinical and clinical data that demonstrate the potential for metal-based drug therapy.

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“…In vivo treatment of grafted mice with γ ‐secretase inhibitor DAPT (a pharmacological inhibitor of Notch activation) resulted in tumor‐promoting effects, depending on oncogenic ras 26. A recent clinical Phase III trial of Semagacestat, a γ ‐secretase/Notch inhibitor, was halted in part because of an increased risk of skin cancers compared with those in the placebo arm 31.…”

Section: Notch Signaling In Cutaneous Squamous Cell Carcinoma (Cscc)mentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease

Cited by 1,020 publications

References 21 publications

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

Biometals and Their Therapeutic Implications in Alzheimer's Disease

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

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