Alzheimer's disease clinical research
Encyclopedia
As of August 2010 there were more than 800 clinical trial
s 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.
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. It has been argued that anti-Aβ therapies currently under research may be highly effective at preventing or delaying the development of the disease when administered to asymptomatic patients or at the earliest stages of the disease, but much less effective or completely uneffective in advanced stages.
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.
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.
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. 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.
A Phase IIA study of ACC-001, a modified version of AN-1792, is now recruiting subjects.
One Aβ vaccine was found to be effective against inclusion body myositis
in mouse models.
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, and Apolipoprotein E4 gene non-carriers.
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.
(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. Negative results were announced regarding tarenflurbil in July 2008 and further development was canceled.
, a statin
, stimulates brain vascular endothelial cells to create a beta-amyloid ejector. The use of this statin may have a causal relationship to decreased development of the disease.
, a Tumor necrosis factor-alpha receptor fusion protein
, which binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue. Etanercept was administered by perispinal infusion to 15 AD patients which resulted in sustained improvement in cognitive function; however it is not clear if this was temporary or not. A small trial consisting of 50 patients has commenced.
A 12 person replication study is being run by Griffith University, Australia.
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.
) 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.
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.
Unfortunately the consecutive phase-III trial failed to show significant positive effects in the primary and secondary endpoints. 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.
) to investigate the efficacy of antibiotic therapy. 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."
A re-examination of the same data using: "...AUC analysis of the pooled index
showed significant treatment effect over the 12-month period".
Several studies using minocycline
and doxycycline
, in an animal model of Alzheimer's Disease,
have indicated that minocycline
and doxycycline
exerts a protective effect in
preventing neuron death and slowing the onset of the disease.
medication is suggested by a study showing colocation of herpes simplex
virus with amyloid plaques.
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.
has been identified as a potential drug agent. Levels of neurosteroids such as allopregnanolone decline in the brain in old age
and AD. Allopregnanolone has been shown to aid the neurogenesis
that reverses cognitive deficit
s in a mouse model of AD.
In clinical trials, a certain insulin sensitizer called "rosiglitazone
" improved cognition in a subset of AD patients;
in vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s under way to understand and treat Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. 149 of these studies were human phase three trials, the last step before U.S. Food and Drug Administration approval and marketing.
There are different approaches. One approach is to reduce Amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
, for example with bapineuzumab
Bapineuzumab
Bapineuzumab is a humanized monoclonal antibody that acts on the nervous system and has potential therapeutic value for the treatment of Alzheimer's disease and possibly glaucoma....
, an antibody in phase III studies for patients in mild to moderate stage; semagacestat
Semagacestat
Semagacestat was a candidate drug for a causal therapy against Alzheimer's disease. It was originally developed by Eli Lilly and Élan, and clinical trials were conducted by Eli Lilly...
, a γ-secretase
Secretase
Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.thumb|300px|right|Processing of the amyloid precursor protein Among other roles in the cell, secretases act on the amyloid precursor protein to cleave the protein into three fragments...
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. It has been argued that anti-Aβ therapies currently under research may be highly effective at preventing or delaying the development of the disease when administered to asymptomatic patients or at the earliest stages of the disease, but much less effective or completely uneffective in advanced stages.
Other approaches are neuroprotective agents, like AL-108 (phase II completed); or metal-protein interaction attenuation, as is the case of PBT2
PBT2
PBT2 is a second-generation 8-hydroxy quinoline analog developed as a successor to Clioquinol as a potential treatment of Alzheimer's Disease....
(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 3Regulatory requirement
Regulatory requirements are part of the process of drug discovery and drug development. Regulatory requirements describe what is necessary for a new drug to be approved for marketing in any particular country. In the US, it is the function of the Food and Drug Administration to establish these...
clinical trials. The most important clinical research is focused on potentially treating the underlying disease pathology, for which reduction of amyloid beta
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
is a common target of compounds under investigation.
Immunotherapy to amyloid beta
ImmunotherapyImmunotherapy
Immunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
or vaccination
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...
for Alzheimer's stimulates the immune system to attack beta-amyloid. One approach is active immunization, which would stimulate a permanent immune response. 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
Meningoencephalitis
Meningoencephalitis is a medical condition that simultaneously resembles both meningitis, which is an infection or inflammation of the meninges, and encephalitis, which is an infection or inflammation of the brain.-Causes:...
, 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.
A Phase IIA study of ACC-001, a modified version of AN-1792, is now recruiting subjects.
One Aβ vaccine was found to be effective against inclusion body myositis
Inclusion body myositis
Inclusion body myositis is an inflammatory muscle disease, characterized by slowly progressive weakness and wasting of both distal and proximal muscles, most apparent in the muscles of the arms and legs...
in mouse models.
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
Bapineuzumab
Bapineuzumab is a humanized monoclonal antibody that acts on the nervous system and has potential therapeutic value for the treatment of Alzheimer's disease and possibly glaucoma....
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, and Apolipoprotein E4 gene non-carriers.
Gamma secretase inhibition
Gamma secretaseGamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
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.
Gamma secretase modulation
TarenflurbilR-flurbiprofen
Tarenflurbil, or R-flurbiprofen, is the single enantiomer of the racemate NSAID flurbiprofen. For several years, research and trials for the drug were conducted by Myriad Genetics, to investigate its potential as a treatment for Alzheimer's disease; that investigation concluded in June 2008 when...
(MPC-7869, formerly R-flubiprofen) is a gamma secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
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. 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. This drug has been in a Phase II trial for early Alzheimers and which has reported preliminarily promising, but not detailed, results.Statins
SimvastatinSimvastatin
Simvastatin is a hypolipidemic drug used to control elevated cholesterol, or hypercholesterolemia. Simvastatin is a member of the statin class of pharmaceuticals, is a synthetic derivate of a fermentation product of Aspergillus terreus.-Medical uses:The primary uses of simvastatin is for the...
, a statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
, stimulates brain vascular endothelial cells to create a beta-amyloid ejector. The use of this statin may have a causal relationship to decreased development of the 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 etanerceptEtanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
, a Tumor necrosis factor-alpha receptor fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
, which binds to tumor necrosis factor-alpha, and decreases its role in inflammation of nervous tissue. Etanercept was administered by perispinal infusion to 15 AD patients which resulted in sustained improvement in cognitive function; however it is not clear if this was temporary or not. A small trial consisting of 50 patients has commenced.
A 12 person replication study is being run by Griffith University, Australia.
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.
Methylthioninium chloride
In July 2008, researchers announced positive results from methylthioninium chloride (MTC), (trade name: RemberRember
Methylthioninium chloride is an investigational drug being developed by the University of Aberdeen and TauRx Therapeutics that has been shown in early clinical trials to be an inhibitor of Tau protein aggregation. The drug is of potential interest for the treatment of patients with Alzheimer's...
) 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.
Dimebon
Also in July 2008 results were announced of a study in which an antihistamineAntihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
that was formerly available in Russia, Dimebon
Dimebon
Latrepirdine , is an antihistamine drug which has been used clinically in Russia since 1983....
, 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.
Unfortunately the consecutive phase-III trial failed to show significant positive effects in the primary and secondary endpoints. 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.
Antibiotic therapy
Only one clinical trial is being done (at McMaster UniversityMcMaster University
McMaster University is a public research university whose main campus is located in Hamilton, Ontario, Canada. The main campus is located on of land in the residential neighbourhood of Westdale, adjacent to Hamilton's Royal Botanical Gardens...
) to investigate the efficacy of antibiotic therapy. 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
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
and rifampin reduced cognitive worsening at 6 months of follow-up in patients with mild to moderate AD."
A re-examination of the same data using: "...AUC analysis of the pooled index
showed significant treatment effect over the 12-month period".
Several studies using minocycline
Minocycline
Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
and doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
, in an animal model of Alzheimer's Disease,
have indicated that minocycline
Minocycline
Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
and doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
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 antiviralAntiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
medication is suggested by a study showing colocation of herpes simplex
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
virus with amyloid plaques.
Angiotensin receptor blockers
A retrospective analysis of five million patient records with the US Department of Veterans AffairsUnited States Department of Veterans Affairs
The United States Department of Veterans Affairs is a government-run military veteran benefit system with Cabinet-level status. It is the United States government’s second largest department, after the United States Department of Defense...
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.
Allopregnanolone
AllopregnanoloneAllopregnanolone
Allopregnanolone is a prototypic neurosteroid present in the blood and also the brain. It is a metabolite of progesterone and potent modulator of GABAA receptors...
has been identified as a potential drug agent. Levels of neurosteroids such as allopregnanolone decline in the brain in old age
Old age
Old age consists of ages nearing or surpassing the average life span of human beings, and thus the end of the human life cycle...
and AD. Allopregnanolone has been shown to aid the neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
that reverses cognitive deficit
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...
s in a mouse model of AD.
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
Rosiglitazone
Rosiglitazone is an antidiabetic drug in the thiazolidinedione class of drugs. It works as an insulin sensitizer, by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin...
" improved cognition in a subset of AD patients;
in vitro, beneficial effects of Rosiglitazone on primary cortical rat neurons have been demonstrated
Table of advanced disease-modifying drug (DMD) candidates
| 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 | Phase III | Feb 2005 | May 2008 | 1,600 | Mild | n/a | 800-patient Trial also underway worldwide. |
| Gamma Secretase Inhibitor | Inhibits Gamma Secretase, believed crucial to pathology | LY451039 | Phase III | March 2008 | March 2012 | 1,500 | Mild-to-Moderate | n/a | smaller trial completed '07, data not out. |
| Antibody to Amyloid-Beta | Mimics Natural Antibody triggered by AN-1792 | aab-001 | 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 | 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 PBT2 PBT2 is a second-generation 8-hydroxy quinoline analog developed as a successor to Clioquinol as a potential treatment of Alzheimer's Disease.... |
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 | Phase II | Dec 2007 | May 2010 | 340 | Mild-to-Moderate | n/a | Phase I was success |
| Neuroprotection | Neuroprotective Peptide, intra-nasal | AL-108 | 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 Dimebon Latrepirdine , is an antihistamine drug which has been used clinically in Russia since 1983.... |
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 | 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 | Phase II | Nov 2007 | Mar 2012 | 228 | Mild-to-Moderate | n/a | Sequel to famous AN-1792 Vaccine Trial |
| Notes | |||||||||