Peptides in Development for Alzheimer’s Disease
Alzheimer’s disease (AD) is an area of unmet need that places a burden on individuals, families and society as a whole with physical, psychological and economic impacts. Almost 47.5 million people worldwide have AD or another form of dementia. As the most common cause of dementia, AD contributes to approximately 60-70% of dementia cases (1). In 2015, Alzheimer’s Disease International estimated that the global costs of dementia were $818 billion representing approximately 1% of global Gross Domestic Product (2).
Consequently, there is an urgent need to identify new therapies for AD. Currently, there are five FDA approved drugs for treating AD and these are therapies that improve functioning but do not treat the disease or delay the progression of AD. In addition, it has been more than a decade since an approval for a new AD drug with the exception of the combination pill Namazaric™ in 2014(3).
Peptides may prove to be valuable new treatments for AD. Currently, there are approximately twelve peptide investigational drugs in Phase I to Phase III development for AD (Table 1). Nine of the peptides in the AD drug pipeline are therapeutic vaccines. In addition, there are at least twenty peptides known to be in preclinical development for AD.
|Product Name||Active Ingredient||Company Name||Highest Phase of Development||Mode of Action|
|CAD106||amyloid beta peptide||Cytos Biotechnology AG, Novartis AG, Amgen Inc||Phase III||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
|ACI-24||--||AC Immune SA||Phase II||Alzheimer's Disease Vaccine, Anti-Alzheimer's Agent, Antiplaque Agent, Immunostimulant, Therapeutic Vaccine|
|AL208||davunetide||Allon Therapeutics Inc||Phase II (current status unknown)||Anti-Alzheimer's Agent, Neuroprotectant, Nootropic (Cognitive Enhancer)|
|UB311||--||United Biomedical Inc, United Neuroscience Inc||Phase II||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
|AADvac1||--||Axon Neuroscience SE||Phase I||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
|ABVac40||amyloid beta 40 peptide||Araclon Biotech SL, Grifols International SA||Phase I||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
|ABVac42||amyloid beta 42 peptide||Araclon Biotech SL, Grifols International SA||Phase I||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
|ACC002||amyloid beta peptide||Pfizer Inc, Wyeth||Phase I (current status unknown)||Alzheimer's Disease Vaccine, Therapeutic Vaccine|
|ACI-35||--||AC Immune SA, Janssen Pharmaceuticals Inc||Phase I||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
|GM605||--||Genervon Biopharmaceuticals LLC||Phase I||Anti-Alzheimer's Agent, Antioxidant, Neuroprotectant, Neuroregenerant|
|RAP105||--||RAPID Pharmaceuticals AG||Phase I||Anti-Alzheimer's Agent, Neuroprotectant, Nootropic (Cognitive Enhancer)|
|V950||--||Merck & Co Inc||Phase I||Alzheimer's Disease Vaccine, Immunostimulant, Therapeutic Vaccine|
Table 1: Peptides in Phase I to III Development for AD as of December 30, 2015 (4)(5)
CAD106 is a peptide vaccine designed to induce patients’ immune systems to develop protective antibodies against β-amyloid. It consists of the immunodrug™ carrier Qb coupled with β-amyloid protein 1-6, a small peptide fragment of β-amyloid protein. In 2013, Novartis Pharmaceuticals completed a Phase II study in patients with mild AD to investigate the safety, tolerability and β-amyloid-specific antibody response following repeated intramuscular injections of Adjuvanted CAD106. In 2015, Novartis in collaboration with Amgen initiated a Phase II/III study to evaluate the efficacy of CAD106 and CNP520, a BACE1 protein inhibitor, in patients at risk for the onset of clinical symptoms associated with AD (4).
Araclon Biotech is developing two peptide vaccines for AD. ABvac40 contains the β-amyloid 1-40 fragment and ABvac42 contains the β-amyloid 1-42 fragment. In 2013, the Spanish drugs safety agency, AEM, authorized Araclon Biotech to launch a phase I clinical trial of ABvac40 in patients with mild to moderate AD. Trial completion was expected in 2015. Araclon Biotech also began a phase I trial of ABVac42 (4).
UB311 is an immunotherapeutic currently in Phase II trials. Developed by United Biomedical, the vaccine utilizes United Biomedical’s helper T cell technology and contains a site-specific epitope to target the amyloid-beta peptide (5).
AC Immune is developing ACI-24, a liposomal therapeutic vaccine containing peptide immunogens with the first 15 amino acids (beta-amyloid 1-15) of the full length beta-amyloid 1-42 peptide. This vaccine is designed to stimulate patients’ immune systems to produce antibodies that prevent plaque accumulation and enhance clearance of plaques. Currently, ACI-24 is in a phase 1/2a clinical study in patients with mild to moderate AD (4),(6).
Merck is developing V950, a multivalent β-amyloid vaccine. In 2012, Merck completed a Phase I study of V950 in patients with AD to evaluate safety, tolerability and immunogenicity. No further studies are known to be initiated after the Phase I study (4).
The vaccine ACC002 is a β-amyloid peptide conjugate in development by Pfizer. No development is reported for ACC002 after Phase I clinical trials for the treatment of Alzheimer’s disease in 2009 (4).
Axon Neuroscience SE is developing AADvac1, a vaccine containing a peptide fragment, amino acids 294 to 305 of the tau sequence, coupled to KLH. The vaccine is designed to stimulate patients’ immune systems to attack dysfunctional tau proteins and thereby stop the progression of AD. A Phase I clinical trial with AADvac1 was completed in 2015 and results from the study showed the vaccine to be safe and well tolerated in the assessed parameters. In addition, treatment with the vaccine induced a robust immune response and average cognition of patients remained stable (7).
In addition to its immunotherapy targeting β-amyloid, AC immune is developing ACI-35, an immunotherapy targeting tau. ACI-35 is a liposomal vaccine containing a phosphorylated human tau protein fragment (4). The vaccine acts by stimulating patients’ immune systems to produce antibodies against misfolded and phosphorylated forms of tau protein. In 2015, AC Immune partnered with Janssen Pharmaceuticals to develop ACI-35 and the product is currently in a Phase 1b clinical study in patients with mild to moderate AD(6).
Neuroprotection, Neuroregeneration and Cognitive Enhancers
Genervon is developing GM6, a novel endogenous, motoneuronotrophic factor (MNTF) peptide analog with neuroregenerative and neuroprotective properties. The company is currently evaluating GM6 for acute ischemic stroke, Parkinson’s disease and Amyotrophic Lateral Disease. GM6 may be a promising treatment for AD as well(8),(4).
RAP105 is a small therapeutic peptide being developed by Rapid Pharmaceuticals for AD. Phase I studies were completed but no further development has been reported. In proof of concept studies, RAP105 was shown to ameliorate some of the symptoms of confusion and memory loss in a small cohort of patients(4).
AL208 (davenutide) is a neuroprotective peptide that acts by reducing tau hyperphosphorylation. Allon was developing AL208 as an intravenous formulation of davenutide; however, no development for the AD indication is reported for AL208 after the conclusion of a Phase II clinical trial in 2008 with no published results. Allon was since acquired by Paladin Labs Inc. in 2013(4).
Peptide drug development programs for AD have focused mainly on targeting the β-Amyloid pathway. It is an exciting time in the field of AD research as new potential therapies target tau protein and more peptides targeting β-Amyloid enter the pipeline. Outcomes from clinical trials underway will show whether the peptide vaccines and other therapies in the AD drug pipeline can prevent, halt or delay the onset of AD. To support members of the AD research community along the way, Bachem offers over 190 research catalog peptides and custom synthesis services to assist with studying and developing drugs for AD (shop.www.bachem.com).
(1) World Health Organization. [Online] March 2015. [Cited: October 29, 2015.]
(2) World Alzheimer Report 2015: The Global Impact of Dementia. Alzheimer’s Disease International. [Online] August 2015. [Cited: December 30, 2015.]
(3) Actavis and Adamas Announce FDA Approval of Namzaric™, a Fixed-Dose Combination of Memantine Extended-Release and Donepezil Hydrochloride. Actavis. [Online] December 24, 2014. [Cited: December 30, 2015.]
(4) Medtrack. October 29, 2015.
(5) UB-311. United Neuroscience. [Online] 2015. [Cited: December 30, 2015.]
(6) AD Treatment and Prevention. AC Immune. [Online] 2015. [Cited: December 30, 2015.]
(7) Encouraging Results of AXON’s Tau Vaccine Advance Alzheimer’s Therapy. Axon Neuroscience. [Online] July 23, 2015. [Cited: December 29, 2015.]
(8) Therapeutic Applications. Genervon. [Online] [Cited: December 30, 2015.]
Alzheimer`s Disease – A review
Alzheimer’s disease (AD) is the most common type of dementia and accounts for an estimated 60–70% of the reported cases. It is estimated that over 47.5 million people worldwide have dementia, and this figure is expected to triple by 2050 with a trend of an aging global population. Dementia is characterized by a loss or decline in memory and other cognitive abilities. AD is an irreversible, progressive neurodegenerative disorder. A worldwide struggle is under way to find new treatments and therapies to prevent, cure or even slow the progress of Alzheimer’s disease.
Alzheimer’s brain abnormalities include but are not limited to:
- Plaques (microscopic clumps of a protein fragment called beta-amyloid (Aβ). These sticky brain plaques are known to consist mainly of Aβ and are known to build up in brain many years before the actual Alzheimer’s symptoms start.
- Tangles, twisted microscopic strands of the protein tau. Tangles destroy a vital cell transport system made of proteins.
- Loss of connections among brain cells responsible for memory, learning and communications. These connections, or synapses, transmit information from cell to cell.
- Inflammation, triggered by body’s immune system
- Eventual death of brain cells and severe tissue shrinkage leading to the brain lesions.
One indicator for the disease is the formation amyloid plaque deposits. Initially, Aβ starts as a solitary molecule and tends to come together in the form of clusters which are still soluble and are capable of free travel in the brain, and finally clusters form plaques that are the hallmark of AD. Studies show that Aβ has strong binding affinity to the receptors on nerve cells triggering an intracellular process that erodes their synapses with other nerve cells. Aβ peptides are chemically “sticky” and gradually build up into plaques. Aβ peptides are proteolytically cleaved from the membrane bound amyloid precursor protein (APP) and are major constituents of these deposits. The peptides result from the APP, which is being cut by certain enzymes to yield Aβ. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers act as seeds, which can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction. The seeds or the resulting amyloid plaques are toxic to nerve cells. Plaques as well as neurofibrillary tangles tend to spread through the cortex in a predictable pattern as AD progresses. The familial AD genetic evidence shows relation between metabolism of Aβ and AD. This progressive brain disorder damages and eventually destroys the brain cells, leading to dementia and decline in other brain functions, eventually leading to the death of brain cells.
Therefore Alzheimer’s is fatal and, unfortunately so far, there is no cure.
Aβ plays a crucial role in AD, and its high concentration (nano to micro molar) in the brain can cause neuronal death. Pico molar concentration of Aβ slow down the memory and learning process. The Aβ peptide levels in the brain are dynamically and directly influenced by synaptic activity. Low amounts of Aβ, could work as antioxidants, due to its ability to capture redox metals, such as Cu, Fe and Zn, and thus, preventing their participation in redox cycling with other ligands. Aβ peptide has neurotrophic properties and it is hence responsible for the growth and survival of neurons, in the modulation of synaptic function and defense against oxidative stress. The physiological concentrations of Aβ favor the learning and memory processes.
Image courtesy: M. del C. Cárdenas-Aguayo, M. del C. Silva-Lucero, M. Cortes-Ortiz, B. Jiménez-Ramos, L. Gómez-Virgilio, G. Ramírez-Rodríguez, E. Vera- Arroyo, R. Fiorentino-Pérez, U. García, J. Luna-Muñoz and M.A. Meraz-Ríos DOI: 10.5772/57398; click here for details.
Role of Beta Amyloid in the early detection of Alzheimer`s disease
The role of Aβ40 and Aβ42 peptides in the early pathogenesis of the AD has been frequently emphasized in the literature. These two peptides have received tremendous interest in modern AD research. Aβ40 and Aβ42 are major products of the proteolytic cleavage of multi domain integral membrane type-1 protein, APP which play important role in cell adhesion, neuronal mobility and transcriptional regulation. Among the two peptides, Aβ42 is known to be more prone to aggregation than Aβ40, even though they only differ in two (IA) amino acid residues at the C-terminal end. The metabolism of APP involves proteases/secretase processing to yield intra and extra cellular fragments that play an important role in synaptic transmission and neuronal plasticity. Amyloidogenic pathway is responsible for beta amyloids peptides through the action of beta and gamma secretases.
Aβ insoluble aggregates in the brain are the hallmark of AD and these peptides do exist as soluble aggregates as well. In vitro experiments have obtained fibrillar and different non-fibrillar aggregates. Hexafluoroisopropanol (HFIP) has been used as solvent to dissolve Aβ and other amyloidogenic peptides. HFIP has been used to obtain in vitro a highly ordered fibrillary and variety of non-fibrillar aggregates of beta amyloids. Studies at CSIR/CCMB-India show the dissolution of Aβ40 and Aβ42 in HFIP and the drying results in highly ordered aggregates. The observed alpha helical confirmation is not stable for prolonged periods. Aβ40 and Aβ42, incubated in HFIP for a longer period of time and eventually dried, led to structural transition from alpha helical to beta helical conformation. These tend to form short fibrous aggregates that further assemble into highly ordered ring like structures leading to enhancement of thioflavin T fluorescence. The researchers at CSIR-CCMB conclude that dissolution of Aβ40 and Aβ42 or other amyloidogenic fragments in HFIP leads to the formation of structures that are like annular amyloid.
Bachem offers H-7442 and H-7438 which are Beta Amyloid (1-42) and (1-40) peptides treated with HFIP.
Till date it has only been possible to detect AD in late stage when there has already been significant damage to the brain. Aβ can be detected in cerebrospinal fluid through a lumbar region puncture and PET (Positron emission tomography) scans. Both methods are expensive and not readily available everywhere.
Aβ build-up in the eyes of patients in early years has become a biomarker for this disease. The peptide build-up begins 15-20 years before the Alzheimer’s symptoms appear. Studies were conducted and concluded to find significant correlation of the levels of Aβ build-up in eyes and the Aβ build-up in the brain. An abstract prepared by the scientists for AAIC 2014 gives the results for 40 participants out of 200 totals in the study.
New Products for Alzheimer’s Disease Research
Bachem offers more than 190 Alzheimer’s disease related research products available online.
- β-Amyloid (1-43), (1-42), (1-40) and Fragments (46 peptides)
- Modified Amyloids (18 peptides)
- Modifiers of Aß-Aggregation (9 peptides)
- β-Amyloid (HFIP-treated) and Salts (HCI,TFA) (5 peptides)
- FRET β-Amyloid Substrates (15 peptides)
- Labeled Amyloid Peptides (Biotin, FITC, FAM, TAMRA) (12 peptides)
- Secretase Inhibitors (β- and γ) (11 peptides)
- β-Amyloid Mutations (19 peptides)
- β-Amyloid (APP) Precursor 770 Fragments (10 peptides)
- Related Products (59 peptides)
- AB Antagonist
- Amyloid-like Proteins
- Amyloid Bri Peptides
- Amyloid Dan Peptides
- Amyloid P-Component
- Humanins and Colivelin
- Various Related
- Recombinant Source
MEET BACHEM: Michael Scholze
What is your official job title at Bachem?
Group Leader Business Intelligence.
How long have you been with Bachem? Where did you work before Bachem?
I am with Bachem for 2 years. Prior to my Bachem time, I was working at Solvias, Switzerland as a Key Account Manager.
Briefly, what do you do at Bachem?
Management of information for industry trends in the synthetic peptides market, and deriving activities from this information.
What is your academic background?
I’m a Ph.D. chemist by education.
What do you like to do outside of work?
I enjoy spending my leisure time in swimming, hiking, travelling and listening to music.
What do you like most about your job?
The job is very multi-disciplinary, e.g. covering scientific questions, IT-related, attending trade shows and conferences.
Thank you very much Michael.
Interesting news about peptides in basic research and pharmaceutical development:
Vaccine Targets Alzheimer’s Disease-like Characteristics in People with Down Syndrome – UC San Diego Health
Hep-C Peptide Has Auspicious Antiviral Properties – GEN
New Particle Can Track Chemo – Ohio State University
Bachem peptides and biochemicals are widely cited in research publications. Congratulations to all our customers with recent publications!
Koon, N. A., Itokazu, Y. and Yu, R. K.
Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer’s Disease Model Mice.
ASN Neuro 7, (2015)
Schmidt, M., Rohou, A., Lasker, K., Yadav, J. K., Schiene-Fischer, C., Fandrich, M. and Grigorieff, N.
Peptide dimer structure in an Abeta(1-42) fibril visualized with cryo-EM.
Proc Natl Acad Sci U S A 112, 11858-11863 (2015)
Keaney, J., Walsh, D. M., O’Malley, T., Hudson, N., Crosbie, D. E., Loftus, T., Sheehan, F., McDaid, J., Humphries, M. M., Callanan, J. J., Brett, F. M., Farrell, M. A., Humphries, P. and Campbell, M.
Autoregulated paracellular clearance of amyloid-beta across the blood-brain barrier.
Sci Adv 1, e1500472 (2015)
Jeronimo-Santos, A., Vaz, S. H., Parreira, S., Rapaz-Lerias, S., Caetano, A. P., Buee-Scherrer, V., Castren, E., Valente, C. A., Blum, D., Sebastiao, A. M. and Diogenes, M. J.
Dysregulation of TrkB Receptors and BDNF Function by Amyloid-beta Peptide is Mediated by Calpain.
Cereb Cortex 25, 3107-3121 (2015)