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A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease
Open accessAbstract
OBJECTIVE: This randomized, double-blind, placebo-controlled, dose-ranging phase 2 study explored safety, efficacy, and biomarker effects of ELND005 (an oral amyloid anti-aggregation agent) in mild to moderate Alzheimer disease (AD). METHODS: A total of 353 patients were randomized to ELND005 (250, 1,000, or 2,000 mg) or placebo twice daily for 78 weeks. Coprimary endpoints were the Neuropsychological Test Battery (NTB) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale. The primary analysis compared 250 mg (n =84) to placebo (n =82) after an imbalance of infections and deaths led to early discontinuation of the 2 higher dose groups. RESULTS: The 250 mg dose demonstrated acceptable safety. The primary efficacy analysis at 78 weeks revealed no significant differences between the treatment groups on the NTB or ADCS-ADL. Brain ventricular volume showed a small but significant increase in the overall 250 mg group (p =0.049). At the 250 mg dose, scyllo-inositol concentrations increased in CSF and brain and CSF Aβx-42 was decreased significantly compared to placebo (p =0.009). CONCLUSIONS: Primary clinical efficacy outcomes were not significant. The safety and CSF biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD. CLASSIFICATION OF EVIDENCE: Due to the small sample sizes, this Class II trial provides insufficient evidence to support or refute a benefit of ELND005.
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“The oral drug, scyllo-inositol is a Aβ42 aggregation inhibitor that was studied in AD subjects (ELND005). A clinical study (phase 2) in patients with AD found no confirmation of ELND005′s clinical benefit, and the study was stopped due to severe toxicity concerns (Salloway et al., 2011).”
From An update on the novel and approved drugs for Alzheimer disease (2022) · cites this paper as Salloway et al., 2011
In the citing paper
“Further development of the agent at a lower dose has not progressed in the last 8 years.50”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [50]
In the citing paper
“A phase 2 clinical trial in patients with AD did not provide evidence to support a clinical benefit of ELND005 while severe toxicity issues (infections) forced the cessation of the study.”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [50]
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“The last Aβ42 aggregation inhibitor which was tested in humans was the oral agent scyllo-inositol (ELND005).”
From Current and Future Treatments in Alzheimer Disease: An Update (2020) · cites this paper as [50]
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“Currently, disease-modifying therapeutic strategies for AD primarily focus on reducing Aβ production using BACE- or γ-secretase inhibitors [31,32], inhibiting Aβ deposition with antiaggregation compounds that inhibit Aβ oligomerization and block Aβ toxicity [33,34], facilitating Aβ clearance with active and passive im…”
BackgroundMoonga, I., Niccolini, F., Wilson, H., Pagano, G., Politis, M., & Initiative, T. A. D. N. (2017) · European Journal of Neurology · doi:10.1111/ene.13374 · Cited by 59
Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease
Martínková, J., Quevenco, F., Karcher, H., Ferrari, A., Sandset, E. C., Szoeke, C. E. I., Hort, J., Schmidt, R., Chadha, A. S., & Ferretti, M. T. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.24124 · Cited by 65
Alzheimer’s disease and disseminated mycoses
Alonso, R., Pisa, D., Rábano, A., & Carrasco, L. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-013-2045-z · Cited by 68
Physiological Roles of Monomeric Amyloid-β and Implications for Alzheimer’s Disease Therapeutics
Jeong, H., Shin, H., Hong, S., & Kim, Y. S. (2022) · Experimental Neurobiology · doi:10.5607/en22004 · Cited by 59
Bennett, D. A., Yu, L., & Jager, P. L. D. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.037 · Cited by 54
“A number of disease modifying clinical trials have been conducted over the past decade, many focused on amyloid metabolism [34-45].”
BackgroundThe Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease
Iqbal, U., Zeng, E., & Pasinetti, G. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21144920 · Cited by 55
Drug delivery strategies with lipid-based nanoparticles for Alzheimer’s disease treatment
Jang, Y.-J., Kang, S.-J., Park, H. S., Lee, D., Kim, J. H., Kim, J.-E., Kim, D., Chung, C., Yoon, J., & Bhang, S. H. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03109-3 · Cited by 64
Hart, S. J., Visootsak, J., Tamburri, P., Phuong, P., Baumer, N., Hernandez, M., Skotko, B. G., Ochoa‐Lubinoff, C., Liogier D'Ardhuy, X., Kishnani, P. S., et al. (2017) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.38465 · Cited by 54
“A clinical trial of ELND005 in neurotypically developed adults with AD did not demonstrate significant effects on cognition or adaptive function (Salloway et al., 2011).”
BackgroundAndrade, S., Nunes, D., Dabur, M., Ramalho, M. J., Pereira, M. D. C., & Loureiro, J. A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15010212 · Cited by 55
“Scyllo-inositol Mild to moderate AD 353 78 weeks II Acceptable safety; No therapeutic effects Completed 2007 [49]”
BackgroundMethodSupraphysiologic-dose anabolic–androgenic steroid use: A risk factor for dementia?
Kaufman, M. J., Kanayama, G., Hudson, J. I., & Pope, H. G. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.02.014 · Cited by 56
“These potentially beneficial effects have prompted development of sI and close sI analogs as potential treatments for AD/ADRD (Salloway et al., 2011; Morrone et al., 2016; Lee et al., 2017; Liu et al., 2018).”
Diagnosis and Treatment of Alzheimer’s Disease:
Bomasang-Layno, E., & Bronsther, R. (2021) · Delaware Journal of Public Health · doi:10.32481/djph.2021.09.009 · Cited by 60
Small-molecule drugs development for Alzheimer's disease
Yao, W., Yang, H., & Yang, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1019412 · Cited by 54
Attar, A., & Bitan, G. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990496 · Cited by 48
“Phase-2 clinical trials for ELND-005 have been completed with mixed results, of which 9 deaths in the high-dose groups caused significant safety concerns and cognitive and functional co-primary endpoints did not achieve statistical significance [103].”
Overview of therapeutic targets in management of dementia
Malik, R., Kalra, S., Bhatia, S., Al‐Harrasi, A., Singh, G., Mohan, S., Makeen, H. A., Albratty, M., Meraya, A. M., Bahar, B., et al. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113168 · Cited by 51
What lessons can be learned from failed Alzheimer’s disease trials?
Toyn, J. H. (2015) · Expert Review of Clinical Pharmacology · doi:10.1586/17512433.2015.1034690 · Cited by 47
“Exploratory analysis, however, suggested a potential benefit in a prespecified mild AD subgroup [14].”
BackgroundCurrent Perspectives regarding Stem Cell-Based Therapy for Alzheimer’s Disease
Kwak, K.-A., Lee, S., Yang, J.-Y., & Park, Y. (2018) · Stem Cells International · doi:10.1155/2018/6392986 · Cited by 50
Fanton, S., Menezes, J., Krock, E., Sandström, A., Tour, J., Sandor, K., Jurczak, A., Hunt, M., Baharpoor, A., Kadetoff, D., et al. (2023) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2023.09.003 · Cited by 46
“, 2006), and drug trials aiming at increasing scyllo-inositol levels have been conducted in Alzheimer’s patients (Salloway et al., 2011).”
Rational heterodoxy: Cholesterol reformation of the amyloid doctrine
Castello, M. A., & Soriano, S. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2012.06.007 · Cited by 45
Watanabe, T., Shiino, A., & Akiguchi, I. (2012) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2012.01.006 · Cited by 45
C-Terminal Fragment, Aβ32–37, Analogues Protect Against Aβ Aggregation-Induced Toxicity
Bansal, S., Maurya, I. K., Yadav, N., Thota, C. K., Kumar, V., Tikoo, K., Chauhan, V. S., & Jain, R. (2016) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00006 · Cited by 45
Lai, A. Y., & McLaurin, J. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2012.07.003 · Cited by 45
“Phase 2 clinical trials, in which SI was used to treat patients withmild ormoderate AD, have recently been published: in patients with mild AD, treatment with 250 mg SI bid has shown cognitive benefit [9].”
MethodJin, M., & Selkoe, D. J. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.05.020 · Cited by 48
Zhu, L., Li, R., Jiao, S., Wei, J., Yan, Y., Wang, Z. A., Li, J., & Du, Y. (2020) · Marine Drugs · doi:10.3390/md18100488 · Cited by 44
“Scyllo-inositol, a potent Aβ aggregation inhibitor [13], failed in a phase 2 randomized trial involving 353 Alzheimer patients due to the non-significantly clinical efficacy outcomes [14].”
BackgroundAlterations in Lipid and Inositol Metabolisms in Two Dopaminergic Disorders
Schulte, E. C., Altmaier, E., Berger, H. S., Do, K. T., Kastenmüller, G., Wahl, S., Adamski, J., Peters, A., Krumsiek, J., Suhre, K., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147129 · Cited by 41
“Yet, scyllo- and chiro-inositols have been implicated as potential therapeutic agents in a number of neuropsychiatric diseases ranging from Alzheimer`s [39] to obsessive compulsive disorder [40].”
BackgroundThe TOMMORROW study: Design of an Alzheimer's disease delay‐of‐onset clinical trial
Burns, D. K., Chiang, C., Welsh-Bohmer, K. A., Brannan, S. K., Culp, M., O’Neil, J., Runyan, G., Harrigan, P., Plassman, B. L., Lutz, M. W., et al. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.09.010 · Cited by 42
Panza, F., Seripa, D., Lozupone, M., Solfrizzi, V., Imbimbo, B. P., Barulli, M. R., Tortelli, R., Capozzo, R., Bisceglia, P., Dimitri, A., et al. (2018) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2018.1389885 · Cited by 41
Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease?
Panza, F., Lozupone, M., Watling, M. I. L., & Imbimbo, B. P. (2019) · Expert Review of Neurotherapeutics · doi:10.1080/14737175.2019.1621751 · Cited by 42
“Scyllo-inositol, an Aβ aggregation inhibitor, dose-dependently increased mortality in mild-to-moderate AD patients [22].”
Background
Metadata
- Authors
- Salloway, S., Sperling, R., Keren, R., Porsteinsson, A. P., van Dyck, C. H., Tariot, P. N., Gilman, S., Arnold, D., Abushakra, S., Hernandez, C., Crans, G., Liang, E., Quinn, G., Bairu, M., Pastrak, A., Cedarbaum, J. M., & For the ELND005-AD201 Investigators
- Affiliations
- Brigham and Women's Hospital (US)
- From the Department of Neurology, Butler Hospital, and Department of Neurology, Alpert Medical School of Brown University (S.S.), Providence, RI; Center for Alzheimer Research and Treatment (R.S.), Brigham and Women's Hospital, Boston, MA; Ontario Shores Centre for Mental Health Sciences (R.K.), Whitby, Canada; Monroe Community Hospital (A.P.P.), University of Rochester Medical Center, Rochester, NY; Departments of Psychiatry and Neurobiology (C.H.v.D.), Yale University School of Medicine, New Haven...
- ORCID
- Venue
- Neurology
- Published
- 2011-09-27
- Volume
- 77
- Issue
- 13
- Pages
- 1253-1262
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3179648
- OpenAlex
- W2119197968
- Cited by
- 258
- References
- 42
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 17 · 2022: 18 · 2021: 14 · 2020: 22 · 2019: 17 · 2018: 13 · 2017: 20 · 2016: 22 · 2015: 21 · 2014: 21 · 2013: 24 · 2012: 17
- FWCI
- 14.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Elan
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- scyllo-inositol, Alzheimer's disease, amyloid-beta, cerebrospinal fluid biomarkers, activities of daily living, neuropsychological performance, dose-ranging, drug safety
- MeSH terms
- Administration, Oral, Aged, Aged, 80 and over, Alzheimer Disease, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Humans, Inositol, Magnetic Resonance Imaging, Male, Mental Status Schedule, Middle Aged, Peptide Fragments, Platelet Aggregation Inhibitors, Time Factors, Amyloid beta-Peptides, Treatment Outcome, Apolipoprotein E4
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