Alzheimer's disease clinical research

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Overview

As of 2008 there were more than 400 clinical trials underway to understand and treat Alzheimer's disease. Over one hundred of these studies 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

Multiple potential treatments for Alzheimer's disease are currently under investigation, including several compounds being studied in phase 3 clinical trials. The most important clinical research is focused on potentially treating the underlying disease pathology, for which reduction of amyloid beta is a common target of compounds under investigation.

History of immunotherapy to amyloid beta

Immunotherapy or vaccination for Alzheimer's is one anti-amyloid alternative under study. Unlike vaccines which seek to prevent disease, this therapy would be used to treat diagnosed patients, and is based upon the concept of training the immune system to recognize, attack, and reverse deposition of amyloid, thereby altering the course the disease.

Following promising pre-clinical work in genetically-altered mice which showed compelling results, the earliest small trials in humans using the vaccine known as AN-1792 suggested some promise and little safety concerns. However, in 2002 a subsequent Phase II trial using this drug reported that 6% of multi-dosed participants (18 of 300) developed serious brain inflammation symptoms resembling meningoencephalitis; as a result and the trial was stopped, and clinical development on AN-1792 was discarded.

In further years, participants in the AN-1792 trials continued to be observed, and it was determined that 20% of treated patients had developed high levels of antibodies to beta-amyloid, which was in itself an interesting result given that on average patients had received only 2 of the planned 8 drug doses. While placebo-patients and non-antibody responders worsened, these antibody-responders showed a degree of stability in cognitive levels as assessed by the neuropsychological test battery (although not by other measures), and had lower levels of the protein tau in their cerebrospinal fluid. These results may suggest reduced disease activity in the antibody-responder group.[2]

Active immunotherapy

Directly based upon the AN-1792 immunotherapy approach, in mild-to-moderate AD there are now similar so-called active vaccines being tried, so-called because they actively trigger the body's response, potentially indefinitely once amyloid beta is recognised by the immune system.

The most advanced such active vaccine, called aac-001[3], is a modified version of AN-1792, and is intended to trigger the same natural antibodies to beta-Amyloid. It is possible that meningoencephalitis-like inflammation remains a potent threats to this strategy.

Passive immunotherapy

Also derived from the AN-1792 immunotherapy program, there is an infused antibody approach termed a passive vaccine in that it does not invoke the immune system and would require regular infusions to maintain the artificial antibody levels. Micro-cererebral hemorrhages may be a threat to this process.

The most advanced such candidate is known as bapineuzumab or aab-001, and this antibody is designed as essentially identical to the natural antibody triggered by the earlier AN-1792 vaccine. The aab-001 antibody is in Phase 3 clinical trials for both Apolipoprotein E4 gene carriers,[4] and Apolipoprotein E4 gene non-carriers.[5]

Gamma secretase inhibition

Gamma secretase is a protein complex thought to be a fundamental building block in the development of the amyloid beta peptide. A gamma secretase inhibitor known as LY451039 is in Phase 3 trials.[6]

Gamma secretase modulation

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.[7]Note that of all the clinical trial programs for AD pathology, this drug candidate is the most advanced, with final results expected in 2008.

Metal-protein interaction attenuation

PBT2 is an 8-hydroxy quinoline that removes copper and zinc from cerebrospinal fluid, which are held to be necessary catalysts for amyloid beta aggregation.[8] This drug has been in a Phase II trial for early Alzheimers and which has reported preliminarily promising, but not detailed, results.

Statins

Simvastatin, a statin, stimulates brain vascular endothelial cells to create a beta-amyloid ejector.[9] The use of this statin may be have a causal relationship to decreased development of the disease.[10]

Other

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, a Tumor necrosis factor-alpha receptor fusion protein, which binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue.[11] Etanercept was administered by perispinal infusion to 15 AD patients which resulted in sustained improvement in cognitive function;[12] however it is not clear if this was temporary or not. A small trial consisting of 50 patients has commenced injecting etanercept, a TNF (tumour necrosis factor) inactivator, into the spine.[13]

Antibiotic therapy in Alzheimer's disease

Only one clinical trial has been done to investigate the efficacy of antibiotic therapy [14]. The authors of the study indicated that it was effective in delaying the progress of the disease:"In conclusion, a 3-month course of doxycycline and rifampin reduced cognitive worsening at 6 months of follow-up in patients with mild to moderate AD." [15] A re-examination of the same data using: "...AUC analysis of the pooled index showed significant treatment effect over the 12-month period".[16] Several studies using minocycline and doxycycline, in an animal model of Alzheimer's Disease, have indicated that minocycline [17] [18] and doxycycline [19] [20] exerts a protective effect in preventing neuron death and slowing the onset of the disease.

Table of advanced disease-modyfing drug (DMD) candidates

Table - Disease-Modyfing Candidates in Late-Stage Clinical Trials 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.[21] Phase III Feb 2005 May 2008 1,600 Mild n/a 800-patient Trial also underway worldwide.[22]
Gamma Secretase Inhibitor Inhibits Gamma Secretase, believed crucial to pathology LY451039[23] Phase III March 2008 March 2012 1,500 Mild-to-Moderate n/a smaller trial completed '07, data not out.[24]
Antibody to Amyloid-Beta Mimics Natural Antibody triggered by AN-1792 aab-001[25] 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.[26] 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.[27] 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.[28] Phase II Dec 2007 May 2010 340 Mild-to-Moderate n/a Phase I was success
Neuroprotection Neuroprotective Peptide, intra-nasal AL-108.[29] Phase II (completed) Jan 2007 Jan 2008 120 Mild Cognitive Impairment n/a Deemed a Success; Phase III to start
Brain Cell Apoptosis Inhibitor Blocks Mitochondrial Pores Dimebon.[30] 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.[31] 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.[32] Phase II Nov 2007 Mar 2012 228 Mild-to-Moderate n/a Sequel to famous AN-1792 Vaccine Trial
Notes

References

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  2. Vaccination:
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    • 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.
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  3. ""Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects"". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.
  4. ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 carriers"". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  5. ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers "". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  6. ""Effect of LY451039 on the Long Term Progression of Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-11.
  7. 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.
    • 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.
    • 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.
  8. Strozyk D, Launer LJ, Adlard PA; et al. (2007). "Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid". Neurobiol Aging. doi:10.1016/j.neurobiolaging.2007.10.012. PMID 18068270.
  9. 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.
  10. 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.
  11. 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.
  12. Griffin WS (2008). "Perispinal etanercept: potential as an Alzheimer therapeutic". J Neuroinflammation. 5: 3. doi:10.1186/1742-2094-5-3. PMID 18186919.
  13. Tobinick E (2007). "Perispinal etanercept for treatment of Alzheimer's disease". Curr Alzheimer Res. 4 (5): 550–2. PMID 18220520.
  14. according to www.pubmed.com
  15. Loeb MB, Molloy DW, Smieja M; et al. (2004). "A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer's disease". J Am Geriatr Soc. 52 (3): 381–7. PMID 14962152. Unknown parameter |month= ignored (help)
  16. Carusone SC, Goldsmith CH, Smieja M, Loeb M (2006). "Summary measures were a useful alternative for analyzing therapeutic clinical trial data". J Clin Epidemiol. 59 (4): 387–92. doi:10.1016/j.jclinepi.2005.05.009. PMID 16549261. Unknown parameter |month= ignored (help)
  17. Choi Y, Kim HS, Shin KY; et al. (2007). "Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models". Neuropsychopharmacology. 32 (11): 2393–404. doi:10.1038/sj.npp.1301377. PMID 17406652. Unknown parameter |month= ignored (help)
  18. Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004). "Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning". Eur. J. Neurosci. 19 (12): 3305–16. doi:10.1111/j.0953-816X.2004.03439.x. PMID 15217386. Unknown parameter |month= ignored (help)
  19. Jankowsky JL, Slunt HH, Gonzales V; et al. (2005). "Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease". PLoS Med. 2 (12): e355. doi:10.1371/journal.pmed.0020355. PMID 16279840. Unknown parameter |month= ignored (help)
  20. Khlistunova I, Biernat J, Wang Y; et al. (2006). "Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs". J. Biol. Chem. 281 (2): 1205–14. doi:10.1074/jbc.M507753200. PMID 16246844. Unknown parameter |month= ignored (help)
  21. ""Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's"". Clinical Trial. FDA/clinicaltrials.gov. 2007-12-11.
  22. ""Global Efficacy Study of MPC-7869 to Treat Patients With Alzheimer's"". Clinical Trial. FDA/clinicaltrials.gov. 2007-12-11.
  23. ""Effect of LY451039 on the Long Term Progression of Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-11.
  24. ""Effects of LY450139 Dihydrate on Subjects With Mild to Moderate Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2007-05-24.
  25. ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 carriers"". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  26. ""Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers "". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  27. ""Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-01-13.
  28. ""ELND005 in Patients With Mild to Moderate Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2008-02-29.
  29. ""Safety, Tolerability and Efficacy Study to Evaluate Subjects With Mild Cognitive Impairment"". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.
  30. ""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.
  31. ""Phase II Study of Intravenous Immunoglobulin (IVIg) for Alzheimer's Disease"". Clinical Trial. FDA/clinicaltrials.gov. 2007-08-03.
  32. ""Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects"". Clinical Trial. FDA/clinicaltrials.gov. 2008-03-11.

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