TARGETED THERAPIES --BIOLOGICAL AND SMALL MOLECULE DRUGS
Alzheimer's is a progressive mental deterioration that can occur in middle or old age, due to generalized degeneration of the brain. It is the most common cause of premature senility. Although scientists are not absolutely sure what causes Alzheimer's plaques, tangles and inflammation are prime suspects in cell death and tissue loss in the Alzheimer brain.
There are currently 5 drugs approved for Alzheimer's, (Aricept, Razadyne, Namenda, Exelon and Namzaric). The last drug to be approved -Namzaric- was in 2014. The current Alzheimer's drugs only mask the symptoms but do not treat the underlying disease or stop or delay the cell damage that eventually leads to the worsening of symptoms. The treatment of Alzheimer's disease will require addressing the pillars of pathogenesis, namely, the advent and spread of neurotoxic oligomeric aggregates of beta-amyloid, the production of tau tangles, and chronic local inflammatory responses in the brain.
Beta-secretase drugs and monoclonal antibodies are currently being tested to target beta-amyloid. See reference 8--After a string of failed trials, drugs that target protein build-up in the brain appear to slow disease progress.
Antibodies targeting Amyloid Plaque
Aducanumab -- Biogen-- monoclonal antibody that targets aggregated forms of beta amyloid.
Gantenerumab -- Roche+/-One clinical study was stopped on December 19, 2014 after disappointing results.
Crenezumab -- Genentech and Roche --Crenezumab is a humanized monoclonal antibody against human 1-40 and 1-42 Beta amyloid, which is being investigated as a treatment of Alzheimer's disease. Crenezumab was developed by the Swiss-based biopharmaceutical company AC Immune, which licensed the drug in 2006 to Genentech, Inc.
Solanezumab -- Eli Lilly --Solanezumab, or sola, binds the amyloid-β peptides that aggregate and form plaques in the brain that are an early pathological feature of Alzheimer's disease. Sola binds the central epitope of monomeric amyloid-β, KLVFFAD, (PDB ID 4XXD) with picomolar affinity. This epitope is known as the nucleation site for Aβ oligomerization, and it is these oligomers of Aβ that are thought to be toxic to neurons.
About Beta Secretase --Beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein cleaving enzyme is an enzyme that in humans is encoded by the BACE1 gene. BACE1 is an aspartic-acid protease important in the formation of myelin sheaths in peripheral nerve cells. The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer. Generation of the 40 or 42 amino acid-long amyloid-β peptides that aggregate in the brain of Alzheimer's patients requires two sequential cleavages of the amyloid precursor protein (APP). Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since alpha-secretase cleaves APP closer to the cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by alpha-secretase rather than BACE1 prevents eventual generation of amyloid-β.
Beta Secretase inhibitors (BACE)
Small molecule BACE inhibitors
MK-8931 is a BACE inhibitor from Merck See Reference 3-- it inhibits the ability of the beta-secretase enzyme to make beta-amyloid. At the Alzheimer’s Association International Conference® 2013 (AAIC®), researchers reported that the drug significantly lowered beta-amyloid levels in people with mild-to-moderate Alzheimer’s. MK-8931 is being tested in two phase 3 clinical trials. See reference 1.
CNP520--Novartis' CNP520 is an oral drug designed to prevent the production of different forms of amyloid and has the potential to prevent, slow or delay the symptoms associated with Alzheimer's disease.
AZD3293--AstraZeneca is codeveloping with Eli Lilly AZD3293 --also known as LY3314814 is an oral beta-secretase 1 cleaving enzyme (BACE) inhibitor. A pivotal Phase II/III clinical trial of AZD3293 started in late 2014 and is planned to recruit 1,500 patients and end in May 2019. In April 2016 the company announced it would advance to phase 3 without modification.
Note: The secretase inhibitors have much higher rates of discontinued drugs and treatments that have not reported development (gamma secretase, 82%; beta secretase, 81%)-- see Reference 4.
Targeting Tau Tangles and more..
NPT088 from Neurophage binds with high affinity and specificity to aggregates of misfolded proteins, including those that form the canonical amyloid motif, which is implicated in the pathology of many serious diseases such as AD and PD. NPT088 recognizes the special conformation characteristic of amyloids, irrespective of the specific protein sequence. NPT088 which simultaneously targeting multiple misfolded proteins such as amyloid beta, tau, and alpha-synuclein at various stages of amyloid assembly in both Alzheimer's disease and Parkinson's disease. See Reference 9.
NPT088 includes the General Amyloid Interaction Motif (GAIM), a molecule that Nuerophage claims "blocks misfolded proteins from aggregating, protects cells from protein aggregate toxicity, and targets multiple types of aggregated proteins, including amyloid beta, tau and alpha-synuclein."
The researchers found that NPT088 was effective at preventing protein aggregation in laboratory-cultivated brain cells and helped brain cells survive after exposure to toxic aggregated proteins. NPT088 also had broad beneficial effects in transgenic mice with brain damage similar to that seen in Alzheimer's and Parkinson's disease, in most cases improving memory and cognition, and reducing the brain levels of amyloid beta, aggregated tau and alpha-synuclein. According to the researchers, NPT088 has successfully completed one-month exploratory monkey and rat safety studies, and is currently in the final stages of safety testing prior to the initiation of clinical trials. See Reference 10.
TRV-101-Treventis Corporation, Toronto, ON, Canada presented data on TRV 101, a new drug designed to enter the brain and inhibit protein misfolding of beta-amyloid and tau. See Reference 11.
MM-201--M3 Biotechnology is preparing for clinical trials for its Alzheimer’s drug. The Seattle company plans to begin conducting human safety trials for the treatment by the end of this year. lead compound, MM-201, which is being advanced as a first-in-class orally available treatment to reverse the course of neurodegenerative diseases such as Alzheimer's and Parkinson's Disease. -- activator of neurotrpic growth factor.
Experimental drug based on Curcumin
J147 - A new Alzheimers-reversing drug based on curcumin extract. Salk team finds molecule that slows the clock on key aspects of aging in animals---- A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease --The neurotrophic and memory-enhancing activities of J147 are associated with an increase in brain derived neurotrophic factor (BDNF) levels and the expression of BDNF responsive proteins, the enhancement of LTP, synaptic protein preservation, the reduction of markers for oxidative stress and inflammation, the reduction of amyloid plaques, and lower levels of soluble Aβ1–42 and Aβ1–40. These pleiotrophic effects of a single molecule suggest that J147 has potential for the treatment of AD. See Reference 7.
Mefenamic Acid -- University of Manchester found that mefenamic acid, a common non-steroidal anti-inflammatory drug (NSAID) that's used for period pain, completely reversed memory loss and brain inflammation in mice. See Reference 2.
Insulin resistance and the way brain cells process insulin may be linked to Alzheimer’s disease. Researchers are exploring the role of insulin in the brain and closely-related questions of how brain cells use sugar and produce energy. These investigations may reveal strategies to support cell function and stave off Alzheimer-related changes.
Progress in world's first Alzheimer's vaccine --In research findings just released in Nature's Scientific Reports journal, Flinders University experts, as part of a high-level U.S. research team at the Institute of Molecular Medicine (IMM) and University of California, Irvine (UCI), have made a successful vaccine formulation that targets the abnormal beta-amyloid and tau proteins that signal Alzheimer's disease. It is actually two separate potential vaccines, one for beta-amyloid and one for tau proteins, have been combined to form the new treatment. The second tau vaccine candidate is the most recent to be discovered and is the most effective at reversing damage in the brain. The beta-amyloid one works best if it's given as a preventative measure for those at risk of dementia. Combined, the two drugs are even more effective, based on recent tests carried out on groups of mice. See Reference 13.
C1Q BLOCKING ANTIBODY
Human form of the C1q-blocking antibody is now at an early stage of development at Annexon Biosciences, a biotech company based in San Francisco.n the mouse models of Alzheimer’s, the team found that synapse loss requires activation of the protein C1q, which “tags” synapses for elimination. C1q became visibly more abundant around vulnerable synapses in the mice. Cells known as microglia then came in and “ate” the tagged synapses, as they do during normal brain development. see Reference 12. Beth Stevens...But in the meantime, a human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences (San Francisco) and is being advanced into the clinic. The researchers believe it has potential to be used someday to protect against synapse loss in a variety of neurodegenerative diseases. The hope is that the therapeutic agent, known as ANX-005, can be used to treat a number of neurodegenerative and autoimmune conditions. Reference 12.
Readings and References