What hope is there for the first Tau antibody clinical trial failure of the Alzheimer's Tau drug?

Ten years after the setback of the anti-amyloid drug to treat Alzheimer's disease, drug developers are turning their attention to another deadly marker of neurodegenerative disease, tau protein.
, more than 10 tau protein-targeted drug candidates are currently undergoing clinical trials and several key efficacy data are expected this year.
, however, the field could be fraught with ups and downs if the preliminary results of Genentech and its partner AC Immune's tau protein antibody semorinemab are followed.
December 10, an article published in The Reviews Drug Discovery explores some of the thinking that comes with the failure of the Semorinemab II trial.
the initial trial of semorinemab failed, and the history of anti-amyloid protein setbacks will repeat itself? In November 2020, the 13th Alzheimer's Clinical Trials (CTAD) reported that the Semorinemab in the TAURIEL PHASE II trial did not improve prognosis in patients with pre-eminent or mild Alzheimer's disease.
so far, these data have not shown any difference in cognitive decline rates in any subgroup analysis.
biomarker analysis is under way, but preliminary data do not provide much incentive.
"these results are disappointing.
," said Stephen Salloway, a test researcher at TAURIEL.
other anti-tau protein drugs may perform better (Table 1).
three other tau protein antibodies (ABBV-8E12, gosuranemab, zagotenemab) each have unique tau protein binding properties and will be available in 2021.
Tau protein-targeted vaccines, anti-tau protein antisysmatic candidates, and small molecules that regulate tau protein aggregation are also already being tested.
any positive data from these trials is welcome.
, however, in addition to the failure of semorinemab in Alzheimer's disease, two other major anti-tau protein candidates have also failed in the ongoing trial of nuclear paralytic paralysis (PSP, tau protein lesions).
negative and mixed data caused as many questions as answers were given, semorinemab's data is a good example: Did the TAURIEL trial fail because anti-tau protein drugs were not up to the task of Alzheimer's disease? Is the antibody binding to the tau protein the wrong way? Or is the trial aimed at the wrong group of patients? For some, the field seems to have forgotten the lessons of anti-amyloid protein frustration.
De Strooper, director of the Dementia Research Institute in the UK, said: "The tau protein field is now having the same problem as the amyloid field.
of these errors is the oversimplification of the biology involved.
, there are no tools in the field to quantify how any defined tau protein antibody interacts with different kinds of tau proteins in the extracellular space of the human brain.
That follows, how do the researchers determine that an experiment has tested the basic biological hypothesis of tau protein targeting strategies (that is, tau proteins spread in the brain in a prion-like manner and cause serious damage in the process)? Others disagree.
I've always thought tau protein was the best target for Alzheimer's disease," said Simon Lovestone, head of the neurodegenerative disease franchise at Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson.
I first started studying tau protein more than 30 years ago, nothing has changed my mind.
, he adds, that while drugs dedicated to amyloid protein have been clinically unsuccessful, these trials have gained hard-won insights into disease progression, biomarkers and trial design that could drive future success.
is it okay to target tau protein? The basic β of targeting amyloid is that the slow and steady accumulation of β amyloid protein in the brain over decades is toxic and can lead to cell death and disease.
similar to, but different, for tau protein.
the relationship between Tau protein damage and disease is spatially and β closer to the amyloid protein.
β amyloid protein accumulates throughout the brain, while tau protein accumulates in the brain regions most affected by the disease.
, although β levels of amyloid increased decades before symptoms of the disease appeared, tau protein pathology was more consistent with the ontology of symptoms.
Lovestone added: "Because tau protein levels are still rising in patients who are just beginning to show signs of cognitive decline, it should be easier to assess the impact of tau protein-targeted therapies on these patients."
is a good target in practical and scientific terms.
" β mechanisms for toxic effects of amyloid and tau proteins are also different, even if they appear to be synergistic.
amyloid is an extracellular protein, and amyloid plaques, which are closely related to disease, are thought to cause damage to neurons from the outside.
, tau protein is an intracular micro-tube-related protein that facilitates the transport of proteins in neurons.
in Alzheimer's disease, tau proteins are isolated from these micro tubes, modified by excessive phosphorylation or translation, and form neurofibromus entanglements (NFT) in neurons.
there is no consensus on abnormal tau proteins or how these NFTs kill cells, various mechanisms of in-cell toxicity have been proposed.
, for example, excessive phosphate tau protein may induce abnormal protein transport, and tau protein aggregation may interfere with protein removal mechanisms.
: "There is no doubt that tau proteins cause neuron dysfunction in ways that amyloid proteins do not have.
" However, tau protein pathology presents a challenge for drug developers: If the toxicity associated with tau protein stems from in-cell activity, what is the best way to suppress tau protein? To a large extent, the industry's approach is to focus on how tau proteins spread in the brain.
although tau protein is an in-cell protein, it can be in the form of free form of tau protein or extracellular vesicles into the gap between brain cells.
the Alzheimer's-related form of tau protein may spread from one neuron to another, leaving traces of abnormal tau protein and destruction.
if this hypothesis is true, the treatment that binds to the tau protein during its diffusion may delay or prevent neurodegenerative lesions.
there are at least eight antibodies clinically designed to capture extracellular tau proteins.
two vaccines that teach the immune system to produce its own antibodies against extracellular tau proteins are also being tested.
de Strooper warns that even if the diffusion hypothesis is accurate, there are weaknesses in these methods, such as: Are symptoms caused by a particular form of tau protein? Once an antibody binds to an extracellular tau protein, how do you remove it? Can drugs embedded in extracellular follicles bind to tau proteins? Crucially, is tau protein pathology really causing neurodegenerative lesions or bystander effects? "I think it's worth exploring tau protein, but the field needs to be aware of the challenges ahead," de Strooper said.
failed the "tau protein antibody TAURIEL test?" The failure of semorinemab in the first efficacy trial highlights the difficulties drug developers face in validating the anti-tau protein hypothesis.
, these also reflect the difficulties faced by anti-amyloid drugs.
that the failure of semorinemab may have been due to the antibody-targeted tau protein form.
he said: "I think the most likely explanation for failure is the wrong antigen table.
" there are six major tau protein isomers in the brain that can be widely translated and modified.
Genentech and AC Immune chose the pan-tau method for semorinemab to develop an antibody for the end of tau protein N, which binds to all full-length forms of tau protein, whether or not it has been modified after various translations.
Biogen's gosuranemab and AbbVie's ABBV-8E12, two of the most advanced tau protein antibodies under development, also bind to a table near the N end of the tau protein.
this broad approach comes at a price: the N-side can be isolated from the tau protein, and some of the truncation forms of the tau protein are associated with its propagation.
at Janssen Pharmaceuticals, Lovestone and colleagues turned their attention to a phosphate table near the tau protein center.
the JNJ-63733657 antibody they hope to produce is only a disease-caused form of tau protein.
the Tau protein vaccine ACI-35, which also includes Jansen and AC Immune, is also designed to improve response to the center-located table.
, a neuroscientist and neuroscientist at the University of British Columbia, also believes that targeting the pathogenic form of tau protein is key to success.
N-side cleavage needs to be set aside, otherwise antibodies bind to non-pathogenic forms of protein, which is a clear 'ammunition' waste, " he says.
" Cashman also believes that antibodies against aggregate rather than monobody tau proteins have the highest success rate.
In his knowledge, it wasn't until 2015 that Biogen conducted Phase III trials on aducanumab, which is highly selective for soluble β amyloid aggregates and insoluble fibers on monobodies, that drug developers finally began testing the efficacy of a correct form of amyloid drug.
Cashman is the co-founder of ProMISSciences, which is advancing antibodies against toxic forms amyloid and tau proteins clinically.
other antibody design decisions can also affect efficacy.
Semorinemab is an effect-free antibody that is carefully designed to not recruit immune gluon cells.
Genentech hopes this approach avoids the safety risks associated with antibody-induced inflammatory activation cascading effects such as angiogenesis edema observed with β amyloid antibodies.
preclinical data support this initiative, but this strategy may affect the ability of antibodies to remove tau proteins from the brain.
"It looks very safe, very good.
but it also makes you worry about how much the drug is doing. Salloway questioned.
possible explanation for TAURIEL's failure is that the trial focused on the wrong group of patients.
TAURIEL trial tested patients with pre-symptoms to mild illness in patients with low tau protein baseline levels.
Genentech and AC Immune are conducting a second trial of moderate disease patients with higher tau protein baseline levels.
, chief executive of AC Immune, said: "In this case, you can see the pathological changes and disease progression of the tau protein in less time.
believe there is still a chance of treatment for moderate Alzheimer's disease.
, in the case of amyloid antibodies, when trials fail, the dosing strategy is sometimes questioned, in part because the antibodies do not cross the blood-brain barrier well.
2015, Roche reported that its Phase III trial of the anti-β amyloid drug gantenerumab failed, but subsequent studies suggested that the antibody may have been in insufficient doses.
tests by TAURIEL show that Genentech, Roche's subsidiary, has learned the lessons of the past here.
trial of Gantenerumab is still ongoing, using four times as many drugs as in the past.
in THE TAURIEL trial, Genentech was given a dose of up to 8 g every 4 weeks, which is a high dose for antibody therapy.
progress has been made in other therapies that target tau protein? In addition to these factors, there are advocates for early use of anti-tau protein drugs.
A recent study showed that subjects with genetic mutations that cause Alzheimer's disease had elevated levels of the tau protein phosphate form (P-tau217) in the plasma about 20 years before their estimated age of mild cognitive impairment.
subsequent studies showed that plasma P-tau217 levels increased in other populations during the early preclinical stages of Alzheimer's disease, when tau-PET was not yet able to detect tau protein aggregates in the brain.
that tau-based vaccines may be particularly valuable in the early stages of these diseases.
the ACI-35 vaccine, which is currently being tested in Phase I/II, is being tested by Jansen and AC Immune.
addition, Ionis and Biogen offer a different way forward with antonym therapy for tau proteins.
antibodies and vaccines are designed to stop the spread of tau proteins in the brain, while IOMIS-MAPTRx is a oligonucleotide candidate that binds tau protein mRNAs and blocks protein production.
this method can prevent neuron death associated with intracellular tau protein pathology and reduce the spread of tau protein.
Ionis demonstrated this in a preclinical model of the disease.
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