Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease

Doody, RS Rachelle S.; Thomas, RG Ronald G. Rg; Farlow, Martin R.; Iwatsubo, Takeshi; Vellas, Bruno; Joffe, Steven; Kieburtz, Karl; Raman, Rema; Sun, Xiaoying; Aisen, Paul S.; Siemers, Eric; Liu‐Seifert, Hong; Mohs, Richard C.

doi:10.1056/nejmoa1312889

Cited by 1,372 publications

(991 citation statements)

References 24 publications

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“…An increase in cardiac diseases was nonetheless seen in patients treated with solanezumab compared to those who received the placebo (3.1 vs. 1.6 %). As opposed to previous findings [60], there was no significant increase in amyloid-related imaging abnormalities with edema or hemorrhage associated with solanezumab in phase III trials [22].…”

Section: Safety Concernscontrasting

confidence: 99%

“…Solanezumab has been used by approximately 1000 AD patients in prior phase III treatment trials [22], and safety findings did not retrieve any signal that met the investigator's pre-specified criteria. An increase in cardiac diseases was nonetheless seen in patients treated with solanezumab compared to those who received the placebo (3.1 vs. 1.6 %).…”

Section: Safety Concernsmentioning

confidence: 98%

“…Finally, a widely held belief is that intervening at the dementia stage may be too late, and that putative disease-modifying agents, particularly anti-amyloid therapies, should be initiated earlier in the disease process [18][19][20][21]. The recent solanezumab trials provided some support to this theory, since there was a suggestion of beneficial treatment effects in patients with mild AD but not in those with moderate forms [22].…”

Section: Introductionmentioning

confidence: 99%

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Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

2015

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Alzheimer's disease (AD) is the most common form of dementia and is a major cause of disability and dependency amongst older people. AD drugs approved so far are symptomatic treatments and are not thought to affect the underlying disease process. Trials conducted with agents aiming to slow or stop disease progression in patients with AD have all failed, perhaps because they were tested too late in the disease process. Therefore, there has been a move towards prevention of AD. This paper presents an overview of trials testing pharmacological interventions for sporadic AD prevention. Those tested to date were initially developed for the treatment of AD or for the treatment of other conditions, rather than being specifically developed for AD prevention. Associated issues, such as evidence of 'proof-of-concept,' doses and safety, are discussed. A major shift has taken place in the methodology of AD prevention trials since the results of the first trials were published in the 1990s. New directions that are currently being considered in ongoing or future prevention trials are discussed, in terms of endpoints, target populations, and study design. The use of AD-specific drugs to prevent AD in high-risk individuals is currently limited by a lack of validated predictive and surrogate markers. Population approaches, such as lifestyle changes, are an alternative strategy that could be of public health interest, but may provide only limited benefits for individuals. The best chance of preventing AD may come from a combination of individual and population prevention approaches. Key PointsFollowing the failure of treatment trials in symptomatic Alzheimer's disease (AD), there has been a move towards prevention of AD.To date, no specific pharmacological intervention has been developed for sporadic AD prevention and trial results have been disappointing.A major shift has taken place in the methodology of AD prevention trials and new directions are being considered in terms of endpoints, target populations, and study design.

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Section: Safety Concernscontrasting

confidence: 99%

Section: Safety Concernsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

2015

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“…Solanezumab was developed by Lily, and in phase 2 clinical trials there was a significant dose-dependent increase in Aβ42 in cerebrospinal fluid but no indication of clinical benefit [20]. In phase 3, 2 trials were performed and no benefits in cognitive functions of patients with AD were found [9]. However, a secondary analysis of patients with mild AD pooled from both trials showed a significant effect on cognition, promoting the Dominantly Inherited Alzheimer Network's 5-year phase 2/3 trial (clinical trial number: NCT01760005), which is currently ongoing.…”

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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