Monthly Archives: May 2025

It slices! It dices!

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Yesterday’s post was about the clinical heterogeneity of PSP and how it prompts a theory about the cause(s) of the disease. A couple of hours after I hit “send” I saw a new paper that indirectly supports my idea.

As you probably know, PSP comes in ten known subtypes. The original type, first described in detail in 1963, is called PSP-Richardson syndrome and accounts for about half of all PSP. The other nine have been described since 2005. The new paper reports five subtypes among PSP-Richardson syndrome itself.


The study is from Dr. Mahesh Kumar, a post-doc at the Mayo Clinic, with Dr. Keith Josephs as senior author. They performed statistical tests called “network analysis” and “cluster analysis” on their 118 patients with PSP-Richardson. The five PSP-Richardson “sub-sub-types” emphasize, respectively, tremor; light sensitivity; reduced eye movement (i.e., supranuclear gaze palsy); cognitive loss and slowness/stiffness.


These are not just points on a continuous spectrum. Rather, in each of the five PSP-Richardson sub-sub-types, a group of features and their severities occurs together in individuals in a combination that would not be expected by random combination based their respective frequencies in the total PSP-RS population. For example, people with worse slowness/stiffness tended to have milder eye movement problems and worse cognition than chance would dictate.


Here’s a graphical representation of the results. The features represented by the circles in each group interact with one another in a mutually reinforcing (the black bars) or interfering (the red bars) way. The thickness of the bars represents the strength of the interaction. An explanation in the researchers’ own words follows:

From Kumar et al. Mov Dis Clin Prac 2025
Network Analysis showing 16 signs/symptoms and their associations. Each node in figure represents symptom/sign, Black edges represent positive connection, and red edges represent negative connection; thicker edges represent stronger association.
V1, Sensitivity to bright light; V2, MoCA (Cognition Score); V3, Neck Rigidity; V4, Urinary Incontinence; V5, Emotional Incontinence; V6, Upward ocular movement dysfunction; V7, Downward ocular movement dysfunction; V8, Horizontal ocular movement dysfunction; V9, Eye lid dysfunction; V10, Limb apraxia; V11, FAB (Executive Score); V12, Gait dysfunction; V13, Bradykinesia; V14, Postural tremor; V15, Kinetic tremor; V16, Rest tremor.

All this begs the question as to the basis of the specific groups of signs and symptoms. The answer will probably apply as well to the ten PSP subtypes as to the five PSP-Richardson sub-sub-types. It probably has to do with the specific combination of PSP’s menu of causative factors at work in the individual. As I pointed out in my last post, there are 14 known gene variants contributing to PSP risk and that number is growing. Exposure to toxic metals may also be a factor and those exposures could come at different times of life and in various durations, intensities and combinations. The number of genetic/toxic combinations of these factors sufficient to cause PSP would be astronomical, and the likeliest combinations might account for the likeliest PSP subtypes and sub-sub-types.


Then throw in the stochastic factors, meaning random throws of the dice. I’ll get to that in a future post.

My cure plan

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Consideration number one:


There are now ten different variants, or “phenotypes,” of PSP. The most common, PSP-Richardson syndrome, accounts for about half of those affected, and the next most common, PSP-Parkinsonism, accounts for about a third. All ten variants share the same kinds of neurofibrillary tangles, tufted astrocytes and all the other microscopic features, but their specific locations in the brain differ in emphasis. In fact, the ten have been classified into three groups: cortical PSP, subcortical PSP and PSP-RS, the last being a sort of hybrid. The differences among the ten exist only for about the first half of the disease course. After that, they all merge into what looks like PSP-RS.

What explains this (slight) diversity of anatomic predilection? We won’t know that until we know the cause of PSP, but I’ve got my theory, which I’ll tell you about after you consider this:


Consideration number two:

In 2021 I posted something about a geographical cluster of 101 people with PSP in a group of towns in northern France, which is 12 times the number expected based on surveys elsewhere. The most likely cause is the intense environmental contamination with metals dumped there by an ore processing plant. Fortunately, there have been no new cases of PSP in that area since 2016, possibly thanks to the mitigation measures taken by the local authorities starting in 2011.

In a 2015 journal publication, I did some calculations comparing the neurological features in the 92 people with PSP in the cluster at that point to those of people with “sporadic” PSP.

I found only two differences: In the cluster, the ratio of PSP-Richardson syndrome to PSP-Parkinsonism was about even, while in sporadic PSP it’s about 3:2; and the average age of symptom onset was 74.3, about a decade older than in sporadic PSP. (The area was not at all a retirement community; its age frequency structure closely resembled those of other ordinary communities in the industrialized world.) The molecular assays we performed showed no differences.


My theory:


The experts agree that the cause of most of the common neurodegenerative diseases is a genetic predisposition together with an environmental exposure. For PSP, we presently know of 14 genes, each of which has a variant in a certain percentage of the population conferring slightly elevated risk of PSP. But we don’t know how many, or what combination of those 14 are needed to set the stage for the environmental toxin. For all we know, different toxins need different numbers or combinations of PSP genetic risk factors to exert their toxicity. The only confirmed environmental risk factors for PSP are metals, but of unspecified kinds. The only other well-confirmed non-genetic PSP risk is a tendency to lesser educational attainment, which I feel is likely to act by exposing people to toxins related to manual occupations or to industrial installations or waste sites near their homes.


So, here’s how I tie all this together:


The ten PSP variants as well as the diversity of onset ages within each variant could be determined by one’s own set of PSP risk genes and by which of the possible PSP-related metals (or yet-undiscovered kinds of toxins) they encountered. The two differences between the French cluster and everyone else with PSP could be the particular types or combination of metals to which the people were exposed. That means that at its root, the cause of PSP could be an array of slightly different abnormalities at the most basic molecular level. Those differences could take the form of slightly different tau protein abnormalities across different individuals. As has already been shown, each member of the array of abnormal forms of tau (called tau “strains”) might have a predilection for a different brain area or brain cell type. That anatomic predilection would dictate the specific array of symptoms initially experienced by that individual, and that array could be different when your tau was damaged by the metals at the French site than by whatever damages tau in PSP elsewhere.


How to prove this theory:


This would take a lot of difficult research to prove, but I made a start back in 2020 with the publication of some lab experiments I suggested to a group of lab scientists at UCSF led by Dr. Aimee Kao.


She and her colleagues took stem cells from a tiny skin biopsy of a person with ordinary PSP who carried one of the known PSP risk genes. They converted the stem cells into brain cells and divided the resulting colony in two: In one half, they used the now-famous gene editing technique called CRISPR to return the variant to its normal state and left the other half with its PSP risk variant. They added chromium or nickel (the two most likely culprits at the French cluster site) to both sets of cells and found that the corrected set suffered much less damage. Furthermore, the damage involved tau aggregation and insufficient disposal of abnormal tau, just as in PSP itself.


So, now that we know 14 PSP risk genes, lab researchers could experiment with stem cells harboring different combinations thereof, along with exposure to different metals. Then, once a few such gene/metal combinations have been identified as most able to cause “PSP” in stem cells, the underlying molecular abnormalities could be worked out, drug targets identified, and drugs designed, tested, approved and prescribed.


So, you see, I’ve got it all worked out.

PSP: Some Audio Answers

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If you’ve got PSP, soon or later it gets hard to read a page of text. It typically starts with difficulty in accurately flicking the eyes down the correct distance to the next line while simultaneously moving leftward. I assume that those of you in that boat have taken advantage of audio versions of your reading matter, and I’d like to make you aware of a new resource from CurePSP.

You may have seen the booklet “PSP: Some Answers” on the CurePSP website.
It’s an eight-page description of PSP in non-technical language formatted as answers to frequently-asked questions. The document’s perfect technical level and writing style are similar to those of this blog because they share the same distinguished author, who received valuable editorial help for the 2024 update from Jessica Shurer, CurePSP’s Director of Clinical Affairs and Advocacy.

The good news today is that there’s now an audio version of PSP: Some Answers at https://www.psp.org/audiobooks. The reader is not a text-to-voice app, but a human being who pronounces everything clearly and accurately. The page at that link also has similar audio files on multiple system atrophy and corticobasal syndrome.


I hope this new resource is helpful. I’d appreciate any feedback to assist in the next update.

An insulation gene or two

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My last post reported a study demonstrating that the genetic variants (often called mutations) conferring PSP risk interact with one another to elevate the risk beyond the simple total of their individual effects. The next day brought a publication on yet another gene associated with PSP.


The current paper’s 78 authors are in Spain, Portugal and The Netherlands. The first author, Pablo García-González, is a graduate student at the International University of Catalonia in Barcelona. The senior author is Agustin Ruiz, director of the Alzheimer research center there.


The scientists analyzed 327 Iberian and 59 Dutch patients with either PSP-Richardson syndrome or with autopsy confirmation of PSP. They excluded living people with non-Richardson variants because for a significant minority of such people, the underlying condition is not actually PSP. This is the same reason most clinical PSP trials exclude people with non-Richardson variants . The advantage is less “statistical noise” from misdiagnosis. The disadvantage is that the conclusions may not apply to all variants of PSP.


The new study compares the patients and the non-PSP control subjects using 815,000 genetic markers. Variants in the markers differ with regard to which of the four nucleotides (the “letters” of the genetic code) occurs at a specific spot in the marker gene. The markers are selected because they are approximately evenly spaced along all 23 chromosomes and occur in multiple variants in the general population, a state called a polymorphism. If the frequencies of the four nucleotides at any one polymorphic location differ between the disease group and the control group to a degree unlikely to occur by chance, we call that a statistically significant allelic association. But it’s only just that – an association, and the tricky task of proving cause-and-effect begins.


The researchers confirmed previously discovered markers and found one new one nestled between two genes called NFASC and CNTN2 on chromosome 1. The proteins encoded by both genes are involved in the function of the oligodendrocytes, a major type of non-electrical brain cell. The “oligos,” as we in the business call them, produce the insulation, called myelin, around most of the axons conducting electrical impulses among the neurons

For the statistically interested: The odds ratio for the marker’s association with PSP was 0.83, with 95% confidence interval 0.78 to 0.89 and p-value 4.15 x 10-8.

The figures are from ScienceDirect.com. Above is a neuron in blue with its axon encased in myelin as insulation. The myelin occurs in sections, each of which (labeled “internode”) produced by one branch (or dendrite) from an oligodendrocyte. The green is a stylized representation of myelin starting to roll up around a section of axon.

The figures below are cross-sections of a myelinated axon as photographed by an electron microscope. The lower-power view on the left shows the axon itself with its tiny organelles surrounded by the (barely perceptible at this power) layers of myelin. In the higher-power view on the right, arrows point to the myelin layers.

The figure below shows the extent of loss of myelin from axons in the brain as imaged by three different MRI techniques listed on the left. Each column shows a different “slice” of brain. The areas shown in blue represent areas where the myelin damage in PSP exceeded that in Parkinson’s disease. In no brain area was PD worse in that regard. The scale on the right shows how the intensity of the blue represents the statistical significance of the PSP/PD difference at that anatomical point. (From Nguyen T-T et al. Frontiers in Ageing Neuroscience, 2021.)

So, at this point, what’s the evidence for a cause-and-effect relationship between these two new risk genes and PSP? One important point is that in PSP, loss of myelin and the oligos that produce and contain it are very early and important parts of the disease process. Another is that the proteins produced by the NFASC and CNTN2 genes are “co-expressed” along with two previously-discovered PSP risk genes called MOBP and SLCO1A2, both of which are also associated with oligos and myelin. Co-expression refers to a close correlation between the amounts of multiple kinds of proteins being manufactured by the cell, implying that the proteins work together to perform some specific task required by the cell at that point in time.

The discovery of these two new PSP risk genes supports the idea that the integrity of the oligos and their myelin is a very early and critical part of the PSP process. We already know a lot about that process, thanks to decades of research on multiple sclerosis, where breakdown of myelin is even more important than in PSP, but occurs for more obviously immune-related reasons. That previous research has identified many myelin-related enzymes and other kinds of molecules that might be susceptible to manipulation by drugs. Now, it’s a matter of finding the most critical such molecules and the right drugs to return their function to something like normal.

More than the sum of its parts

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The first PSP whole-genome analysis (or WGA) was published in 2011. It found that “markers” associated with each of four genes were more common among people with PSP than among controls without PSP. Those markers were themselves genes of precisely known location on their chromosome but with unknown or irrelevant function. Such a gene is useful as a marker if one specific nucleotide (the A’s, T’s, G’s and C’s of the genetic code) varies among healthy individuals. Such a phenomenon is called a “single nucleotide polymorphism” or SNP, pronounced “snip.”)

So, for example, at a certain location on, say, chromosome 1, the general population might have an A in 70% of people, a T in 20%, a G in 8% and a C in 2%. If that array of frequencies is different (to a statistically significant degree) in the population with a certain disease, it means that the marker gene is located very close to (or sometimes even within) a gene that’s actually contributing to the cause of the disease.

Since then, it has become possible to easily work out the sequence of nucleotides in every gene, which, as you’d imagine, can make it a lot easier to find genetic causes of diseases. But it’s not as easy as it sounds because it’s hard to distinguish a harmless copying error from a disease-causing error. Besides, the statistics required for sequencing studies have not yet been fully invented. So, good old marker analysis is still very important and useful.


Now let’s talk about the cause of PSP. There seems to be some sort of genetic predisposition that increases the risk but is probably not enough to actually cause the disease within a usual human lifespan. So, something else, presumably an environmental exposure, is probably needed. The only such candidate toxins discovered to date for PSP have been metals, though specific metals have not been clearly identified. (There’s also unconfirmed PSP risk for consumption of paw-paw, a fruit harboring a mitochondrial toxin; and well-confirmed incrimination of lesser educational attainment, though how that relates to environmental toxins or to PSP is unknown.)
Each of those four genes identified in 2011 and about 14 others discovered since raises the risk of PSP by only a tiny amount – in the neighborhood of 1-2%. But that figure was calculated separately for each gene. There has been no attempt to work out how the risk genes might interact to raise the PSP risk enough to allow the disease process to get started, with or without an extra boost from some mysterious environmental exposure.


Still with me? I hope so, because I’ve finally gotten to my point.

The current issue of Journal of Neurogenetics includes a paper from a research group in Bangalore, India headed by Dr. Saikat Dey of the National Institute of Mental Health and Neurosciences, with senior author Dr. Ravi Yadav. They looked only at those original four genes identified in the 2011 whole-genome marker analysis, called MAPT (encoding the tau protein), STX6 (encoding for syntaxin, which directs the movement of tiny chemical-filled balloons called vesicles in brain cells), MOPB (encoding myelin basic protein, a component of the layer of insulation around axons in the brain), and EIF2AK3 (encoding PERK, a protein that helps regulate the stress response in brain cells).


Dey et al looked for combinations of these genes’ markers occurring at a greater frequency in PSP than expected by chance given their individual frequencies. (This is called “epistatic” gene interaction.) The strongest result was between MAPT, STX6 and MOBP. The interaction between MAPT and MOBP was almost as strong, and slightly weaker interactions occurred between MOBP and STX6 and between MOBP and MAPT.


So what, you say? This is important because it can explain how gene variants, each of which raises the likelihood of developing PSP only very slightly, can nevertheless cause the disease if they occur together, perhaps even without any ancillary environmental toxin.


This can explain why PSP and other neurodegenerative diseases generally run only weakly in families: It’s unlikely that any two close relatives will share the same combination of gene variants that raise PSP risk.


Here’s a general illustration of what I’m talking about: Suppose a disease occurs with 100% likelihood in anyone with a risk mutation in each of three specific genes and that each mutation by itself has a frequency of only 1% in the population. That means that for someone to develop the disease, they’d need the unlucky combination of three 1% events. That likelihood is 1% to the third power, or 1 in a million. Now, that person’s sibling would have only a 50% chance of sharing the same form of each gene (called an “allele”). So, for each sibling of the person with the disease, the chance of sharing all three disease-causing alleles would be 0.5% to the third power, or 1¼ in 100 million.


Such gene interactions explain how a purely genetic disease could so rarely occur twice in the same family.


I’ve simplified the analysis of Dr. Dey and colleagues, and more important, there are at least another 10 PSP risk genes that their analysis didn’t consider. So, I hope they or someone else gets around to that very soon. Maybe they will find that the cause of PSP can be entirely explained by unusual combinations of mildly risk-conferring genes that can be tested for in a drop of saliva. That has some important ethical implications, but it could permit genetic counseling and could make it much easier to find volunteers with “pre-PSP” on whom to test drugs to slow or halt the disease’s progression. Furthermore, identifying a combination of protein actions that, when deficient, causes PSP could permit targeted design of new drugs.

A French Swiss Army knife

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My last post was about AADvac1, one of the three neuroprotective drugs set to inaugurate the PSP Trial Platform (PTP) later this year. Today’s post is about the second drug, AZP-2006. The third drug has not yet been finalized, but at a conference in London last week, Dr. Adam Boxer, the leader of the PTP, said it will be revealed soon.


The PTP trials are all Phase 2a, meaning that they’re designed primarily to assess safety and tolerability. However, they do include enough patients, typically about 100 or 200, to detect drug benefit if any indeed exists. The benefit would be in the form of slowing of the rate of progression of PSP as measured by a newly abridged version of the PSP Rating Scale. The PTP will recruit one placebo group to serve as a comparator for all three active-drug groups.


An unpublished Phase 1 PSP trial in 36 people with no placebo group found a 31% slowing of the PSP Rating Scale progression relative to placebo groups in previous PSP drug trials. I hasten to add that comparing the results of active drug in an uncontrolled study to the placebo group in a completely different study is a minefield. So, let’s not jump to conclusions about the efficacy of this drug. All we can say is that the result justifies further investment and study.


That said, I’ll point out that in placebo-controlled Phase 2b and Phase 3 trials, a slowing of 20% or 25% relative to the placebo group is often considered adequate to consider the drug for approval.
AZP-2006 is administered as an oral liquid, which is more convenient than the intravenous, subcutaneous or intrathecal (into the spinal fluid) routes of some of the other current experimental PSP drugs. But of course, oral liquids can be a major issue for those with PSP, though it seemed not to cause any dropouts or serious adverse effects among the 36 patients in the Phase 1 trial. I don’t know if the AZP-2006 oral solution is compatible with the commonly used gelatin- or starch-based drink thickeners. The PTP trial will be confined to patients in early to moderates stages of disability, without the more pronounced swallowing difficulty of the later stages.


Nerd Alert: The main mechanism of action of AZP-2006 is at the lysosomes, one of the cell’s garbage disposal mechanisms, where it acts specifically at the lysosome’s prosaposin and progranulin pathways. Prosaposin is the metabolic precursor (a “parent molecule” cleaved by enzymes to produce the active molecule) of the saposins, a group of proteins required for the normal breakdown of various types of lipids that are worn out or over-produced or defective from the start. Progranulin is the precursor, as you’d guess, of granulin, which, like saposin, is involved in function of the lysosomes. But progranulin addresses disposal of proteins, not lipids. In mouse experiments, the drug also enhances the production of progranulin, mitigates the abnormal inflammatory activity in tauopathy, reduces tau aggregation, and stimulates the growth or maintenance brain cell connections. The company has not published or otherwise released details of the mouse work and if they know the details of these mechanisms of action, they’re keeping them secret for now.
One hereditary type of familial frontotemporal dementia where TDP-43 is the mis-aggregating protein is caused by mutations in the progranulin gene. However, progranulin mutations seem not to be related to PSP.


AZP-2006 was developed by Alzprotect, a company headquartered in Lille, France that was started in 2007 and has no approved drugs as yet. Here’s a page from the company’s website. It includes a nice video with an artist’s conception (or a PR consultant’s dream) of how the drug works.


AZP-2006 may be the most likely to succeed among the currently announced anti-PSP candidates in or nearing clinical trials. That’s because it addresses multiple important cellular abnormalities simultaneously (see the Nerd Alert above), something that many of the experts feel will be sine qua non for any successful PSP neuroprotective drug.

A PSP shot?

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For years, I’ve looked at drug companies’ lists of tau-directed treatments in or nearing clinical trials for Alzheimer’s disease and wished that more of them would be tried for PSP. In both diseases, as most of you know, abnormalities in the tau protein are central to the brain cell damage. Of course, the prevalence of AD in the population is over 100 times that of PSP, with a correspondingly larger profit potential. But some big companies such as AbbVie, Biogen, Ferrer, GemVax & Kael, Novartis, TEVA, and UCB have given their AD drugs a shot against PSP. Even some smaller companies with lesser resources such as Allon, Amylyx, BioJiva, EmeraMed, Noscira, Sanofi, Transposon, and Woolsey have done so, and in some cases the failure of that PSP trial meant the bankruptcy of the company. Tough business.


Happily, two more companies have now taken the PSP plunge with drugs originally developed for AD. One is AADvac1, an active vaccine directed against the tau protein. An active vaccine is a component of the disease-causing protein, virus or bacterium. It stimulates the recipient’s immune system to make antibodies that then prevent, cure, or slow down the disease. You will recognize this as the mechanism for most disease-preventing vaccines like those for polio, measles and the flu. The other category of vaccines is passive, meaning that they are themselves antibodies against the relevant disease-causing molecule, virus or bacterium. Examples of passive vaccines are the rabies or tetanus shot given after an injury, and the anti-tau monoclonal antibodies from Biogen and AbbVie that have been tried unsuccessfully against PSP.


Early-phase clinical trials of AADvac1 for Alzheimer’s disease started in 2013. They were small, with only a few dozen participants, and although designed to assess safety, could have detected slowing of AD progression if it was dramatic.


The most recent such trial was published in late 2021. It showed no more side effects than placebo and excellent success in inducing anti-tau antibody formation. It was too small (117 subjects on AADvac1, 79 on placebo) to reveal less than a dramatic benefit and in fact there was no hint of benefit in its measures of dementia. However, a subsequent analysis of the trial published by a different research group in 2024 included only the 70% of the original group with high blood levels of p-tau217. That’s the most characteristic abnormal form of tau in AD, where the 217th amino acid in the protein carries a phosphate group. The re-analysis did show a strong trend toward benefit in several measures. The most dramatic effects, and the only ones reaching statistical significance, were the reduction and stabilization of blood levels of two proteins that rise in AD called neurofilament light chain and glial fibrillary acid protein. Less impressive but still favorable effects occurred in cognitive tests and imaging of brain atrophy. (Both the original and the re-analysis research groups did include important roles by employees of the drug company, Axon Neuroscience.)


I have no direct knowledge of whether the company is proceeding with a Phase 3 trial in AD based on this result, or if regulatory agencies would even allow them to do so. But I strongly suspect not, based on the absence to date of such a study from the company’s drug pipeline web page and from http://www.clinicaltrials.gov.

But PSP is another story! We now have a way for small companies like Axon Neuroscience to test a drug at relatively little expense. See my last post for some details on the PSP Trial Platform (PTP), headquartered at University of California San Francisco. Starting probably in late 2025, the PTP will perform a Phase 2 trial of AADvac1 in people with PSP in parallel with trials of the drug AZP-2006 and a third drug yet to be revealed. The three trials will share a single placebo group and coordination infrastructure, drastically reducing costs, and once things reach a steady state, reducing time delays as well.


In the Phase 2 AD trial, AADvac1 was administered as 11 subcutaneous injections, initially every four weeks and later, every three months. I suspect that the plan for the PSP trial will be very similar. The double-blind treatment period will be 12 months and the primary outcome measure will be a 15-item version of the original, 28-item PSP Rating Scale. I’ll pass along more details and contact information once these become available.


I’ll post something on the other drug planned for the PTP soon.


NERD ALERT: AADvac1 is a string of 12 amino acids from the microtubule-binding domain of tau. The full tau molecule has 352 to 441 amino acids, depending on which exons are spliced in by the cell. The two monoclonal antibodies that failed to help PSP are both directed at the N-terminal, conventionally shown as the left end (AbbVie’s tilavonemab against amino acids 25-30 and Biogen’s gosuranemab against 15-22). Subsequent research has shown that the disease-causing part of tau, however, is the middle region, which includes the microtubule-binding domain (amino acids 243 to 368). Another monoclonal antibody, bepranemab, which attacks a slightly different part of the middle region (amino acids 235-250), is currently being tested against AD and may enter a PSP trial in the next couple of years.

Two new drugs get a platform

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This could be the best news ever in the history of clinical drug development for PSP.


Last week, I attended the Global Tau meeting in London as a representative of CurePSP. Plenty of excellent research was presented, but most of it was laboratory work that would be difficult to relate to the direct concerns of most of this blog’s readers. But there were some clinical advances, and here’s a big one.

Dr. Adam Boxer of the University of California, San Francisco is the project leader for the PSP Trial Platform (PTP). My Oct. 27, 2023 post briefly mentioned that the PTP had just been funded by the NIH. A trial platform is an organization, in this case about 50 study sites throughout North America, that invites multiple pharmaceutical companies to simultaneously allow it to test their trial-ready experimental drugs. The big news last week was Dr. Boxer’s announcement identifying the first two drugs and that enrollment should begin in late 2025.

One drug to be tested will be AZP-2006, from Alzprotect, based in Lille, France. It addresses tau accumulation and neuro-inflammation. The other is AADvac1, from Axon Neuroscience, based in Bratislava, Slovakia. It is an active vaccine directed against the tau protein. More on those drugs in a future post. Both will be Phase 2a trials, meaning that the emphasis will be on safety and tolerability, though efficacy will be detectable if it’s dramatic. The PTP has a candidate for a third company/drug in the wings awaiting final contract negotiations.


The double-blind phase for each drug would be 12 months, followed by an open-label phase, where the participants on placebo will be offered active drug. The primary efficacy outcome measure will be a version of the PSP Rating Scale abridged from its original 28 items to the 15 items best suited to daily disabilities.


Advantages of platform trials over traditional single-drug trials:
• Only one central coordination, technical and statistical staff is needed. This makes drug testing more economical in terms of both money and time, lowering the bar for smaller companies to test promising treatments.
• Only one placebo group is needed and more active-drug arms can be added in the future. So, if a traditional trial offers only a 50% chance of receiving active drug, a platform trial testing three drugs would offer a 75% chance of being assigned to active drug.
• Once the platform is up and running, there is no delay for test site recruitment, contracting and training. This further reduces the costs and allows a new drug to be smoothly slotted into a vacated spot.
• It’s possible to make the three drugs’ trial protocols relatively uniform, allowing the results to be compared with greater confidence than would be possible if each had been tested in separate projects.
• The availability of a completed control group facilitates an interim analysis (a peek at the incomplete data under strict confidentiality rules) to determine if continuing that drug’s trial would be futile. If the result is unfavorable, this saves time, money and most important, drug side effect risk for future participants. Such a drug could be withdrawn from the PTP and another drug could take its place.


The other Principal Investigators working with Dr. Boxer are Dr. Anne-Marie Wills at Massachusetts General Hospital, Dr. Irene Litvan at UC San Diego and Dr. Julio Rojas of UCSF. The NIH has committed $70 million over five years to this project and the participating drug companies would also contribute substantially (though much less than if they had mounted trials on their own). Dr. Boxer told me that as of last week, in late April 2025, the NIH funding had not been affected by the recent Federal research budget cuts, but we’re all holding our breath on that.

A Flag Day activity

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Hi, everyone. Sorry for my multi-month absence — nothing more than writer’s block and competing commitments. The first seems to be un-blocking itself, though the latter continues, at least until summer.


I thought I’d pass along something verbatim from today’s email: an on line/in person informational symposium you might want to take advantage of.

Most of you are already plugged into CurePSP’s extensive information and support services, but this announcement is from an independent non-profit called the Brain Support Network, in Menlo Park, CA. It’s run by Robin Riddle, whose father had PSP and whose professional background is in marketing for tech companies in Silicon Valley. The BSN started mostly as a service for families wishing to donate their loved one’s brain to research, but has developed into an excellent source for information and support as well.


PSP-MSA-CBD Caregiving Symposium
Saturday, June 14, 2025, 10am-3pm PT
Online and In-Person (Stanford Campus)


This event is designed specifically for caregivers, partners, and family members who care for those with PSP, MSA or CBS. The in-person event is for caregivers only. Obviously, this doesn’t apply to online attendance, though the program is focused on caregiving. There is a small registration fee. Scholarships are available.

Speakers include:
• a movement disorder specialist on what caregivers can do for these three atypical Parkinsonian disorders;
• a psychologist on the caregiver’s journey;
• two social workers on the effects of neurological decline on the family unit; and
• a panel of PSP, MSA, and CBD caregivers, many of whom are Brain Support Network group members.

Attend Online:
• bit.ly/june14atypical-virtual
• Registration ends on June 14, 11am PT

Attend In Person on Stanford Campus:
• bit.ly/june14atypical-campus
• Registration ends on June 12, noon PT