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|-
|- style="background:Cornsilk; color:black"
|- style="background:Cornsilk; color:black"
| Gamma Secretase Modulator/NSAID
| Selective A-Beta-42 lowering Agent
| Converts A-Beta-42 to less Toxic analogues
| Converts A-Beta-42 to less Toxic analogues
| [[MPC-7869]]<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00105547 |title = "Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2007-12-11}}</ref>.
| [[MPC-7869]]<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00105547 |title = "Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2007-12-11}}</ref>.
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| Mild-to-Moderate
| Mild-to-Moderate
| n/a
| n/a
| Earlier 45-patient Trial completed early 2007, results not released<ref>{{cite web |url = http://clinicaltrials.gov/ct/show/NCT00244322 |title = "Effects of LY450139 Dihydrate on Subjects With Mild to Moderate Alzheimer's Disease" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2007-05-24}}</ref>.
| smaller trial completed '07, data not out<ref>{{cite web |url = http://clinicaltrials.gov/ct/show/NCT00244322 |title = "Effects of LY450139 Dihydrate on Subjects With Mild to Moderate Alzheimer's Disease" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2007-05-24}}</ref>.
|- style="background:Cornsilk; color:black"
|- style="background:Cornsilk; color:black"
| Antibody to Amyloid-Beta
| Antibody to Amyloid-Beta
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|- style="background:Cornsilk; color:black"
|- style="background:Cornsilk; color:black"
| Metal-Protein Interaction Attenuation
| Metal-Protein Interaction Attenuation
| Primary Target is Copper
| Primary Targets Copper & Zinc
| [[PBT2]]<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00471211 |title = "Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2008-01-13}}</ref>.
| [[PBT2]]<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00471211 |title = "Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2008-01-13}}</ref>.
| Phase II (completed)
| Phase II (completed)
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| 120
| 120
| Mild Cognitive Impairment
| Mild Cognitive Impairment
| n/a
| Deemed a Success; Phase III to start
|- style="background:Cornsilk; color:black"
|- style="background:Cornsilk; color:black"
| Brain Cell Aptosis Inhibitor
| Blocks Mitochondrial Pores
| [[Dimebon]]<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00377715|title = "Double-Blind, Placebo-Controlled Study of Oral Dimebon in Subjects With Mild to Moderate Alzheimer's Disease" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2007-12-27}}</ref>.
| Phase II (completed)
| Sept 2006
| Nov 2007 (actual)
| 183
| Mild-to-Moderate
| n/a
| Deemed a Success; Phase III to start
|- style="background:Cornsilk; color:black"
| Natural Antibodies to A-Beta
| human plasma source limits supply
| [[IVIg]]<ref>{{cite web |url = http://clinicaltrials.gov/ct2/show/NCT00299988 |title = "Phase II Study of Intravenous Immunoglobulin (IVIg) for Alzheimer's Disease" |work = Clinical Trial |publisher = FDA/clinicaltrials.gov |date = 2007-08-03}}</ref>.
| Phase II (completed)
| Feb 2006
| June 2007
| 24
| Mild-to-Moderate
| n/a
| n/a
| Deemed a Success; Phase III to start
| Deemed a Success; Phase III to start
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| Mar 2012
| Mar 2012
| 228
| 228
| Mild Cognitive Impairment
| Mild-to-Moderate
| n/a
| n/a
| Sequel to famous AN-1792 Vaccine Trial
| Sequel to famous AN-1792 Vaccine Trial
|- style="background:Cornsilk; color:black"
|- style="background:Cornsilk; color:black"



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Revision as of 18:39, 23 March 2008

Scientists continue their extensive efforts to investigate therapies for Alzheimer's disease. As of 2008 there were more than 400 clinical trials registered on the disease, and a hundred of these were in the last phase before commercialization (phase three trials).[1]

Many different investigation approaches coexist. Amyloid beta is a common target, existing many trials which aim to reduce it with different agents such as bapineuzumab, an antibody in phase III for patients in the mild to moderate stage, MPC-7869, or acc-001, a vaccine to amyloid beta in phase II to be used in the mild stage. Other approaches are neuroprotective agents, like AL-108 (phase II completed); or metal-protein interaction attenuation, as is the case of PBT2 (phase II completed). Finally, there are also many basic investigations trying to increase the knowledge on the origin and mechanisms of the disease that in the future may help to find new treatments.

Treatments in clinical development

Several potential treatments for Alzheimer's disease are currently under investigation, including several compounds being studied in phase 3 clinical trials. Tarenflurbil (MPC-7869, formerly R-flubiprofen) is a gamma secretase modulator sometimes called a selective amyloid beta 42 lowering agent. It is believed to reduce the production of the toxic amyloid beta in favor of shorter forms of the peptide.[2]

A gamma secretase inhibitor known as LY451039 is also in Phase 3 trials[3].

Vaccines or immunotherapy for Alzheimer's, unlike typical vaccines, would be used to treat diagnosed patients rather than for disease prevention. Ongoing efforts are based on the idea that, by training the immune system to recognize and attack beta-amyloid, the immune system might reverse deposition of amyloid and thus stop the disease. Initial results using this approach in animals were promising, and clinical trials of the drug candidate AN-1792 showed results in 20% of patients. In 2002 it was reported that 6% of multi-dosed participants (18 of 300) developed symptoms resembling meningoencephalitis, and the trials were stopped. Participants in the halted trials continued to be followed, and 20% "developed high levels of antibodies to beta-amyloid" and some showed slower progression of the disease, maintaining memory-test levels while placebo-patients worsened. Micro-cererebral hemorrhages during passive immunisation and meningoencephalitis with active immunisation still remain potent threats to this strategy.[4]

Based upon this immunotherapy approach, there is an infused antibody approach known as bapineuzumab, designed as essentially identical to the natural antibody triggered by AN-1792, in Phase 3 clinical trials for both Apolipoprotein E4 gene carriers[5], and Apolipoprotein E4 gene non-carriers[6].

Simvastatin, a statin, stimulates brain vascular endothelial cells to create a beta-amyloid ejector.[7] The use of this statin may be have a causal relationship to decreased development of the disease.[8]

Several other pharmaceuticals are under investigation to treat Alzheimer's disease. A 2006 pilot study showed small but significant improvements in various cognitive rating scales in patients with Alzheimer's disease after treatment with etanercept, Tumor necrosis factor-alpha receptor fusion protein, which binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue.[9] A further study, administering to a single AD patient via perispinal infusion, showed rapid and significant improvement in Alzheimer's symptoms.[10] Laboratory studies with cells and animals continually fuel the pipeline of potential treatments. Some currently approved drugs such as statins and thiazolidinediones have also been under investigation for the treatment and prevention of Alzheimer’s.[11]

Comparative table

Table - Late-Stage Clinical Trials in Disease-Modyfing Candidates for Alzheimer's Disease
Target/Approach Notes (Theoretical) Candidate Name Trial Phase Trial Start Date Expected End Date Planned Enrollment AD population targeted (severity) AD population targeted (genetic) Comments
Gamma Secretase Modulator/NSAID Converts A-Beta-42 to less Toxic analogues MPC-7869[12]. Phase III Feb 2005 May 2008 1,600 Mild n/a 800-patient Trial also underway worldwide[13].
Gamma Secretase Inhibitor Inhibits Gamma Secretase, believed crucial to pathology LY451039[14] Phase III March 2008 March 2012 1,500 Mild-to-Moderate n/a smaller trial completed '07, data not out[15].
Antibody to Amyloid-Beta Mimics Natural Antibody triggered by AN-1792 aab-001[16] Phase III Dec 2007 Dec 2010 800 Mild-to-Moderate Apolipoprotein E4 Carriers only Identical Trial also underway in Europe
Antibody to Amyloid-Beta Mimics Natural Antibody triggered by AN-1792 aab-001[17]. Phase III Dec 2007 Dec 2010 1,250 Mild-to-Moderate Apolipoprotein E4 Non-Carriers only Identical Trial also underway in Europe
Metal-Protein Interaction Attenuation Primary Targets Copper & Zinc PBT2[18]. Phase II (completed) Dec 2006 Dec 2007 80 early Alzheimer's disease n/a Deemed a Success; Phase III to start
Fibrilization of Amyloid-Beta Prevents/Reverses Fibrilization of A-Beta AZD-103[19]. Phase II Dec 2007 May 2010 340 Mild-to-Moderate n/a Phase I was success
Neuroprotection Neuroprotective Peptide, intra-nasal AL-108[20]. Phase II (completed) Jan 2007 Jan 2008 120 Mild Cognitive Impairment n/a Deemed a Success; Phase III to start
Brain Cell Aptosis Inhibitor Blocks Mitochondrial Pores Dimebon[21]. Phase II (completed) Sept 2006 Nov 2007 (actual) 183 Mild-to-Moderate n/a Deemed a Success; Phase III to start
Natural Antibodies to A-Beta human plasma source limits supply IVIg[22]. Phase II (completed) Feb 2006 June 2007 24 Mild-to-Moderate n/a Deemed a Success; Phase III to start
Vaccine to Amyloid-Beta Injects modified A-Beta (active vaccine) acc-001[23]. Phase II Nov 2007 Mar 2012 228 Mild-to-Moderate n/a Sequel to famous AN-1792 Vaccine Trial
Notes

References

  1. ^ "Clinical Trials. Found 459 studies with search of: alzheimer". U.S National Institutes of Health. Retrieved 2008-03-23.
  2. ^ Tarenflurbil:
    • Galasko DR, Graff-Radford N, May S, Hendrix S, Cottrell BA, Sagi SA, Mather G, Laughlin M, Zavitz KH, Swabb E, Golde TE, Murphy MP, Koo EH (2007). "Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals". Alzheimer Disease and Associated Disorders. 21 (4): 292–9. doi:10.1097/WAD.0b013e31815d1048. PMID 18090435.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE (2003). "NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo". J. Clin. Invest. 112 (3): 440–9. doi:10.1172/JCI200318162. PMID 12897211.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • Christensen DD (2007). "Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies". CNS Spectrum. 12 (2): 113–116, 119–123. PMID 17277711.
  3. ^ ""Effect of LY451039 on the Long Term Progression of Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-11.
  4. ^ Vaccination:
    • Hawkes CA, McLaurin J (2007). "Immunotherapy as treatment for Alzheimer's disease". Expert Reviews of Neurotherapy. 7 (11): 1535–1548. doi:10.1586/14737175.7.11.1535. PMID 17997702.
    • Solomon B (2007). "Clinical immunologic approaches for the treatment of Alzheimer's disease". Expert Opin Investig Drugs. 16 (6): 819–828. doi:10.1517/13543784.16.6.819. PMID 17501694.
    • Woodhouse A, Dickson TC, Vickers JC (2007). "Vaccination strategies for Alzheimer's disease: A new hope?". Drugs Aging. 24 (2): 107–119. PMID 17313199.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 carriers"". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  6. ^ ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers "". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  7. ^ Whitfield JF (2007). "The road to LOAD: late-onset Alzheimer's disease and a possible way to block it". Expert Opinion on Theraputic Targets. 11 (10): 1257–1260. doi:10.1517/14728222.11.10.1257. PMID 17907956.
  8. ^ Li G, Larson EB, Sonnen JA, Shofer JB, Petrie EC, Schantz A, Peskind ER, Raskind MA, Breitner JC, Montine TJ (2007). "Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease". Neurology. 69 (9): 878–85. doi:10.1212/01.wnl.0000277657.95487.1c. PMID 17724290.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Tobinick E, Gross H, Weinberger A, Cohen H (2006). "TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study". MedGenMed. 8 (2): 25. PMID 16926764.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Tobinick EL, Gross H (2008). "Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration". Journal of Neuroinflammation. 5: 2. doi:10.1186/1742-2094-5-2. PMID 18184433.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  11. ^ Landreth G (2006). "PPARgamma agonists as new therapeutic agents for the treatment of Alzheimer's disease". Experimental Neurology. 199 (2): 245–248. doi:10.1016/j.expneurol.2006.04.006. PMID 16733054.
  12. ^ ""Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's"". Clinical Trial. FDA/clinicaltrials.gov. 2007-12-11.
  13. ^ ""Global Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's"". Clinical Trial. FDA/clinicaltrials.gov. 2007-12-11.
  14. ^ ""Effect of LY451039 on the Long Term Progression of Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-11.
  15. ^ ""Effects of LY450139 Dihydrate on Subjects With Mild to Moderate Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2007-05-24.
  16. ^ ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 carriers"". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  17. ^ ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers "". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  18. ^ ""Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-13.
  19. ^ ""ELND005 in Patients With Mild to Moderate Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  20. ^ ""Safety, Tolerability and Efficacy Study to Evaluate Subjects With Mild Cognitive Impairment"". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.
  21. ^ ""Double-Blind, Placebo-Controlled Study of Oral Dimebon in Subjects With Mild to Moderate Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2007-12-27.
  22. ^ ""Phase II Study of Intravenous Immunoglobulin (IVIg) for Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2007-08-03.
  23. ^ ""Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects"". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.
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