Understanding the Brain

Alzheimer's disease clinical research

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As of August 2010 there were more than 800 clinical trials under way to understand and treat Alzheimer's disease. 149 of these studies were human phase three trials, the last step before U.S. Food and Drug Administration approval and marketing. [1]

There are different approaches. One approach is to reduce Amyloid beta, for example with bapineuzumab, an antibody in phase III studies for patients in mild to moderate stage; semagacestat, a γ-secretase inhibitor, MPC-7869; and acc-001, a vaccine to amyloid beta in phase II studies used in mild stage. However, in a recent study, a vaccine cleared patients of amyloid plaques, but had no effect on their dementia, suggesting this approach won't work.[2]

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 basic investigations on the origin and mechanisms of Alzheimer's disease.

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.

Immunotherapy to amyloid beta

Immunotherapy or vaccination for Alzheimer's stimulates the immune system to attack beta-amyloid. One approach is active immunization, which would stimulate a permanent immune response.[3] The vaccine AN-1792 showed promise in mouse and early human trials, but in a 2002 Phase II trial, 6% of subjects (18 of 300) developed serious brain inflammation resembling meningoencephalitis, and the trial was stopped. In long-term followups, 20% of subjects had developed high levels of antibodies to beta-amyloid. 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. Autopsies found that immunization resulted in clearance of amyloid plaques, but did not prevent progressive neurodegeneration.[4]

A Phase IIA study of ACC-001, a modified version of AN-1792, is now recruiting subjects.[5]

One Aβ vaccine was found to be effective against inclusion body myositis in mouse models.[6]

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-cerebral 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,[7] and Apolipoprotein E4 gene non-carriers.[8]

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.[9]

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.[10] Negative results were announced regarding tarenflurbil in July 2008 and further development was canceled.

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.[11] 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.[12] The use of this statin may have a causal relationship to decreased development of the disease.[13]

Other

Several other pharmaceuticals are under investigation to treat Alzheimer's disease.

Etanercept

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.[14] Etanercept was administered by perispinal infusion to 15 AD patients which resulted in sustained improvement in cognitive function;[15] however it is not clear if this was temporary or not. A small trial consisting of 50 patients has commenced.[16] A study published in 2008 of etanercept, administered to a single AD patient via perispinal infusion, showed rapid (within 10 minutes) and significant improvement in Alzheimer's symptoms that lasted until the end of the study, which involved weekly injections.[17] [18] [19]

Methylthioninium chloride

In July 2008, researchers announced positive results from methylthioninium chloride (MTC), (trade name: rember) a drug that dissolved Tau polymers. Phase II results indicate that it is the first therapy that has success in modifying the course of disease in mild to moderate AD.[20]

Dimebon

Also in July 2008 results were announced of a study in which an antihistamine that was formerly available in Russia, Dimebon, was given to a group of AD patients. The group receiving Dimebon improved somewhat over the 6 months of the study (and this continued for the next six months), whereas those on placebo deteriorated.[21] Unfortunately the consecutive phase-III trial failed to show significant positive effects in the primary and secondary endpoints.[22] The sponsors acknowledged in March 2010 that initial results of the phase III trial showed that while the drug had been well tolerated, its outcomes did not significantly differ from the placebo control.[23]

Antibiotic therapy

Only one clinical trial is being done (at McMaster University) to investigate the efficacy of antibiotic therapy.[24] 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."[25] A re-examination of the same data using: "...AUC analysis of the pooled index showed significant treatment effect over the 12-month period".[26]

Several studies using minocycline and doxycycline, in an animal model of Alzheimer's Disease, have indicated that minocycline [27][28] and doxycycline [29][30] exerts a protective effect in preventing neuron death and slowing the onset of the disease.

Antiviral therapy

The possibility that AD could be treated with antiviral medication is suggested by a study showing colocation of herpes simplex virus with amyloid plaques.[31]

Angiotensin receptor blockers

A retrospective analysis of five million patient records with the US Department of Veterans Affairs system found that different types of commonly used anti-hypertensive medications had very different AD outcomes. Those patients taking angiotensin receptor blockers (ARBs) were 35—40% less likely to develop AD than those using other anti-hypertensives.[32]

Cannabinoids

The endocannabinoid system may have a role in AD.[33][34]

Allopregnanolone

Allopregnanolone has been identified as a potential drug agent. Levels of neurosteroids such as allopregnanolone decline in the brain in old age and AD.[35] Allopregnanolone has been shown to aid the neurogenesis that reverses cognitive deficits in a mouse model of AD.[36]

Insulin sensitizers

Recent studies suggest an association between insulin resistance and AD (fat cell sensitivity to insulin can decline with aging): In clinical trials, a certain insulin sensitizer called "rosiglitazone" improved cognition in a subset of AD patients;[37][38] in vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated[39][40]

Table of advanced disease-modifying drug (DMD) candidates

Table - Disease-Modifying 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 Shifts A-Beta production to shorter and less toxic species MPC-7869[41] Phase III Feb 2005 May 2008 1,600 Mild n/a 800-patient Trial also underway worldwide.[42]
Gamma Secretase Inhibitor Inhibits Gamma Secretase, believed crucial to pathology LY451039[43] Phase III March 2008 March 2012 1,500 Mild-to-Moderate n/a smaller trial completed '07, data not out.[44]
Antibody to Amyloid-Beta Mimics Natural Antibody triggered by AN-1792 aab-001[7] 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[45] 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[46] 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[47] Phase II Dec 2007 May 2010 340 Mild-to-Moderate n/a Phase I was success
Neuroprotection Neuroprotective Peptide, intra-nasal AL-108[48] 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[49] Phase II (completed) Sept 2006 Nov 2007 (actual) 183 Mild-to-Moderate n/a Deemed a Success; Phase III completed but failed
Natural Antibodies to A-Beta human plasma source limits supply IVIg[50] 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[5] 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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  4. Vaccination:
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  10. Tarenflurbil:
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  18. See videos at [1].
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  22. Dimebon Disappoints in Phase 3 Trial
  23. "Pfizer And Medivation Announce Results From Two Phase 3 Studies In Dimebon (latrepirdine*) Alzheimer's Disease Clinical Development Program". Press release. 3 March 2010. http://investors.medivation.com/releasedetail.cfm?ReleaseID=448818. 
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