Alzheimer's is studying drug inventory: from anti-beta amyloid to gene therapy!

There are now more than 40 million people with dementia worldwide, a number that will double in 20 years.
Alzheimer's disease (AD) accounts for the majority of dementia, and for decades the only treatment available was drugs that tried to restore neurotransmitter levels in the brain, but they were only treated with moderate effect.
years, researchers have focused on the physical manifestations that AD can see in the brain, i.e. extracellular amyloid plaques and, most recently, in-cell tau protein entanglements.
It's largely an unapprefgiving task, with more than 200 projects failing, many of which entered an expensive Phase 3 testing phase before being abandoned, even though an anti-A-beta drug was picked up last year and filed a listing application with the FDA this summer for priority review.
At this year's AAIC International Conference (AAIC 2020), an analysis by UsAgainst Alzheimer's, a US non-profit organization, showed that despite the high "reduction rate", the proportion of A-beta-targeted drugs in AD post-clinical trials remained high, at about 40 per cent (13 out of 32 candidate therapies).
the remaining 19 candidate therapies can be divided into several categories, from tau-targeted therapy to a mix of other drugs to protect neurons from degeneration and block inflammation and metabolic processes associated with dementia.
However, the shift in A-beta target drugs was more pronounced in the medium-term pipeline, with 9 out of 58 projects targeting the protein, the rest targeting other pathways, 15 falling into the neurotransmitter category and only 6 targeting tau.
Alzheimer's Drug Discovery Foundation is convinced that the answer to treating AD lies in combining multiple drugs, or drugs that have multiple effects in a molecule.
this reflects that AD is an extremely complex disease with multiple causes and pathology.
1, amyloid protein targets According to the Amyloid Hypothesis, the production of beta amyloid protein (A beta) in the brain triggers a series of events that lead to clinical symptoms of AD.
drug closest to supporting this view is the aducanumab, which binds to aggregation of A-beta and removes it from the body.
years ago, based on the results of two Phase 3 trials, aducanumab seemed destined to join the garbage dumps of similar anti-A-beta products, both of which failed.
, however, after a re-analysis of the aggregate data, dramatic changes occurred at high doses, and aducanumab showed clinical improvements that could support regulatory applications.
, aducanumab is under FDA priority review.
, fda approval is far from ensuring sufficient benefits.
in one of the trials, placebos performed better numerically, and mid-course modification of the trial scheme complicated the interpretation of the data.
some critics say the effects of the drug are exaggerated.
question whether, even if approved, it represents a big step forward, or whether, like the AD drugs currently approved, the ultimate benefits are negligible and do little to ease the AD burden.
, however, the weak efficacy has not stopped the $2.5 billion peak sales of drugs such as Arisep, a treatment for the disease.
Aducanumab, if approved, will inject new enthusiasm into the A-beta target, especially in the form of a joint use with other drugs.
analysts had previously thought that if a disease-correcting AD therapy were approved, annual sales could exceed $10 billion.
, negative A-beta trials continue to appear, further undermining the A-beta hypothesis.
although its supporters say the answer lies in starting treatment early, even before symptoms appear.
In February, Roche and Lilly released results from DIAN-TU clinical trials in Gantenerumab and Solanezumab, showing no improvement in the treatment of early on-on-ongene AD for at least four years.
, the researchers studied the patient subgroup to see if the combination therapy would have any benefit to one or more of the patients.
and Lilly have not given up on these two monoantigens and are evaluating higher doses, with data expected to be released in 2022.
addition, Roche is testing another monoantigen crenezumab in a "pre-drive" or "very minor early" AD, which had previously been shelved after two Phase 3 trials failed.
At the same time, a new generation of drugs is trying to reduce A-beta through different mechanisms, including Lilly's donanemab, an active immunotherapy designed to stimulate patients' immune systems to attack and destroy A-beta, which is undergoing Phase 2 trials and will be announced in 2021.
Pfizer and Johnson and Johnson's AN-1792 were the first active immunotherapy to treat AD, but abandoned development years ago because of safety and ability.
hasn't stopped other companies from trying, even though the baton is being passed on to smaller companies.
such as Araclon's ABvac40 and United Neuroscience's UB-311, two drugs designed to remove beta without triggering inflammation in the brain, the latter phase 2a study is due to be completed in 2021.
At the same time, South Korea's AriBio is developing AR1001, an orally active PDE-5 inhibitor that increases the removal of toxic A-beta oligomers from the blood, but is also thought to inhibit neuron cell death and restore synapses lost in AD, which entered the phase 2 clinical treatment of mild to moderate AD last year.
In addition, Annovis has a drug that enters Phase 2a Clinical, which aims to target A beta and tau through a single molecule while suppressing the two targets that are thought to inhibit the "toxic cascading reaction" that causes other degenerative diseases such as AD and Parkinson's disease.
there is no denying that A-beta's status as AD's primary target has been significantly impaired, especially in about 40 percent of people over 70 who have A-beta in their brains but do not develop dementia.
2, tau targets Before the first clinical trials of the A-beta target drug produced disappointing results, researchers had begun to look at tau, a protein that normally involves substances entering and leaving neurons.
in AD, tau undergoes a chemical change called phosphate, which brings them together to form insoluble tangles that, like beta A, are toxic to nerve cells.
fastest-growing anti-tau drug project in development was TauRx's tau aggregation inhibitor LMTX, which unfortunately failed to show superior benefits over placebo when added to the arispt treatment in a Phase 3 trial reported in 2016.
, however, TauRx did not hesitate to launch a new Phase 2/3 trial LUCIDITY in 2018, treated alone with low-dose LMTX.
complete LUCIDITY data is expected to be available in 2021-2022.
AbbVie also has an antibody, ABBV-8E12, which is in phase 2 clinically, binding to abnormal tau entanglements and preventing the spread of neurons.
last year, the antibody failed clinically in stage 2 of the treatment of sexual nucleo-paralysis (PSP), but that did not affect AD's research.
the AD forum that patients in the PSP trial are in the advanced stages, while the "tau pathology" in the AD trial is at a relatively early stage, the researchers said on the AD Forum.
ABBV-8E12 in AD will be announced later this year.
same time, Yan Jian and Roche are adopting similar strategies, with their anti-tau antibodies BIIB092 and semorinemab (RO7105705) already in mid-stage trials, and Lilly and Johnson and Johnson also have early candidate therapies.
's strong belief in AD research led to two recent licensing transactions involving tau-targeted drugs, including a $45 million advance payment from Ionis-licensed antisant IONIS-MAPTRx and a $330 million advance payment from Sangamo to obtain a gene expression regulation therapy developed by Zinc finger nuclease technology, ST-501, both of which are designed to block the production of tau proteins in the central nervous system.
addition to semorinemab, Roche received a single anti-UB0107 from Ukip with an advance of $120 million to stop and reduce the accumulation of tau protein.
addition, there are many other therapies in the pipeline, including Anavex 2-73 (blarcamesine), a GSK-3b inhibitor that is clinically stage 2 and is thought to prevent tau phosphorylation.
The National Institutes of Health (NIH) is testing Novarma's Abl kinase inhibitor tasigna, which has been approved for treatment of leukemia and is clinically treated in Phase 2.
Tasigna blocks lysine acetylation, another chemical change in tau associated with disease processes.
other organizations are studying tau active immunotherapy.
Axon Neuroscience company AADvac1 in Phase 2 clinical studies have shown that they can cause an immune response, fight the modified form of tau, and reduce neurodegenerative biomarkers.
so far, the company has no data on symptoms or brain atrophy.
researchers at Temple University have also found a new way to prevent the accumulation of beta and tau in the brain, which helps brain cells identify defective proteins and stabilize or remove them before they gather.
the project is still being tested in animals, but researchers are currently working to find drugs that can solve multiple pathological processes associated with AD.
3, neuroprotegents Some scientists have steered their attention away from the A-beta and tau conundrums and turned their attention to protecting neurons from degradation.
biotech companies working in this area, Agene Bio is trying to re-use the epilepsy drug levetiracetam to treat A-beta-induced overactive brain hema.
believes that overactiveness can lead to the degeneration of nerve cells in patients with AD mild cognitive impairment.
early 2019, the company began a Phase 3 Hope4MCI trial of the AGB101 formulation, after two previous studies showed the drug improved memory scores.
Biohaven Pharma's method is to target the neurotransmitter glutamate with troriluzole, a precursor to riluzole , which is taken oral once a day.
is approved for the treatment of amyotrophic lateral sclerosis, a neurodegenerative disease associated with high levels of glutamate, which is also a feature of AD hyperactive.
Troriluzole recently failed in a Phase 3 study of extensive anxiety disorder, but is still clinically phase 2 of mild to moderate AD, and the data will be released in the first quarter of 2021.
Cognition Therapeutics drug CT1812 is thought to protect synapses from neurotoxic cascading reactions caused by A-beta by competing with sigma-2 subjects.
CT1812 is currently in Phase 2 for mild to moderate AD patients and results are expected later this year.
other participants include Neuraly, which is clinically testing the long-acting GLP-1 subject agonist NLY01, which preclinical data suggest could prevent nerve cell loss by blocking toxic activation of immune cells.
Athira Pharma is testing a small molecule drug called NDX-1017, based on peptide angiosin IV, which is said to restore lost neural connections in the brain and stimulate the growth of new ones.
company received $85 million in new funding in April to fund the two-thirds trial.
Pain Therapeutics is also developing PTI-125, an FLNA inhibitor that stabilizes a stent protein in the brain and has the potential to improve nerve function and reduce inflammation.
so far, the results have been mixed.
NIH-funded Phase 2 study received positive Phase 2a results this spring, but the Issue 2b data released in May showed that levels of AD biomarkers in the brain and cerebrospinal fluid were not reduced.
the company refused to give up, announcing in June that it planned to re-exhum patient samples to assess the cognitive abilities of patients treated with PTI-125.
Also worth mentioning is Pharmatropix's Phase 2 drug candidate P75NTF blocker LM11A-31-BHS, which reduces beta toxicity in animal models; NeuroActiva's NA-831, which is said to have a dual effect of neuroprotective protection and stimulating the growth of new neurons; and Action's Xanamem (UE2343), which is designed to block the activity of the central nervous system's stress hormone cortisol.
been considered a possible driver of AD for three decades, but interest in it as a therapeutic target has only recently skyrocketed.
, some studies have shown that patients who have been treating rheumatoid arthritis with anti-inflammatory drugs for years appear to be resistant to dementia.
, on the other hand, some data suggest that the activation of glial cells may drive chronic inflammation of AD by releasing cytokines such as leumekin-1 and tumor necrotogens.
Current anti-IL-1 and TNF drugs are too big to cross the blood-brain barrier into the central nervous system, which reduces their own chances of reducing nerve inflammation, although other drugs in the trial do not have such limitations.
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