Helping AI to come get PSP

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My last post, from 9/14/26, was about how AI is starting to be used for PSP care and research.  Thank you to Kristophe Diaz, PhD, CurePSP’s CEO, for sending a comment with a nice piece of news about a new source of PSP research grants with an AI emphasis:

The Rainwater Charitable Foundation (RCF) is a private philanthropy with a long record of generous support of PSP research. It has just announced a new grant program called the Learning Research Network.

Learning Research Network (LRN)

It would provide $1 million per project.  In the RCF’s own words:

“The LRN is RCF’s evolving approach to creating a more connected, reusable, and AI-enabled scientific research environment. Its goal is to make it easier for researchers and, increasingly, AI-enabled tools to build upon data, methods, analyses, software, workflows, and knowledge generated across different projects and laboratories. Rather than a single database, software platform, or AI model, the LRN is envisioned as an ecosystem of interoperable scientific resources and capabilities that can work together to accelerate discovery.”

The funded project(s) would be traditional biologically-based inquiries, usually taking place in labs, but “will combine scientific significance with a credible AI-enabled and collaborative strategy.”  That strategy would incorporate the “FAIR” principles.

Here’s an explanation of “FAIR.”  I got this from Gemini (an AI search engine) and edited it to fit this blog’s style. 

FAIR stands for “findable, accessible, interoperable, and reusable.” These are principles for managing and sharing digital information and tools such as raw patient datasets, genome sequences, or trained AI-based statistical programs.  The FAIR principle makes the on-line data easier for both humans and automated AI systems to use and to understand.

  • Findable:Data and AI models must have unique, persistent identifiers (like DOIs*) and rich metadata** so researchers and algorithms can locate them in online databases.
    • * Digital Object Identifier (DOI) is a unique, permanent string of numbers, letters, and symbols used to reliably identify an article, book, or data set online. 
    • ** Metadata is “data about data.”  For example, names of a publisher, journal, volume and page numbers, author’s contact information, or a website where information about a digital, on-line dataset can be found.  A traditional example is the masthead of a printed newspaper showing the names of the editors and the address of the publisher.
  • Accessible: Once found, users and authorized software must know how to retrieve the data or model using secure, standardized, and open communication protocols.
  • Interoperable: Information must use standard file formats, common vocabularies, and structured metadata. This allows different biomedical databases and AI programs to merge, compare, and analyze data together seamlessly.
  • Reusable: Assets must be well-documented with clear usage licenses and detailed background information (provenance) so others can safely retrain, audit, or apply the AI models in new studies.

In other words, the research results, and especially the raw data behind them and the AI programs used to obtain the data, should be made available to other researchers in a standardized way that can be easily accessed by AI programs. 

Until now, when a researcher posted their raw data on line for the use of other researchers, it has often been very time-consuming and inconvenient for the second researcher to find and use it alongside their own data.  But data produced with the help of the RCF’s new grant program would avoid those problems.

So, thanks, Rainwater Charitable Foundation, for all you’re doing and have done for PSP research!

Will PSP research benefit from AI? It already is.

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Some of you may be wondering why my blogging has fallen off lately, with only two posts in July, two in August and none so far halfway through September. Besides enjoying my summer, I’ve been writing other things:


• Two invited editorials to accompany journal publications – one on a new brain MRI technique for diagnosing PSP, the other on a set of physical exam findings with good diagnostic performance in the early years of PSP;
• A 63-slide PowerPoint lecture on the atypical Parkinsonian disorders (APDs) that I delivered last week;
• A chapter on the same topic for the 14th edition of a neurology textbook;
• A chapter on PSP for the 4th edition of a textbook on movement disorders; and
• A share of a collaborative paper on imaging, blood and skin biopsy diagnostics for the APDs.
For each task, I used the AI apps ChatGPT, Gemini and Claude to help organize my thinking and to quickly find things in the literature I may have missed. Of course, I had to double-check the results, but it was still a huge timesaver.


A couple of months ago, one of this blog’s faithful readers (Jack Phillips, Chairman of the Board of CurePSP) asked me if AI is being used in the fight against PSP. I told him how I’m using it as a writing tool, and more important, that it’s helping the search for new drugs and new diagnostic tests. Here’s a more detailed answer:


• AI apps can be taught to recognize all the parts of the brain on MRI. If they’re told which are from people with PSP and which are not, they can figure out which brain areas make that differentiation most effectively. They can then apply those insights to MRIs from future patients, particularly those whose diagnoses remain uncertain to their doctors. The type of MRI abnormality most useful here is focal atrophy – shrinkage of specific, damaged areas. But other types of changes such as scarring and iron deposition can also be recognized.


• The ten different sub-types of PSP have subtle differences in which brain areas are affected most on MRI. Using the same reasoning as for the PSP vs non-PSP task mentioned above, AI can then provide a good guess as to which sub-type is at work. This is important early in the disease course because most clinical treatment trials are confined to the PSP-Richardson syndrome subtype, which accounts for only half of all PSP. Also, the different subtypes develop differently over the years and have different survival durations – information useful to clinicians in counseling patients and families.


• The disease process of PSP spreads through the brain not uniformly like water through a dry sponge, but through routes determined by synaptic connections and kinds of contacts. What’s actually spreading is the tau protein in mis-folded form. Positron emission tomographic (PET) imaging can show the precise locations where tau is most concentrated. That can be coupled with MRI using a new AI machine-learning technique called Subtype and Stage Inference (SuStaIn). Imagine having only one tau PET scan and one MRI scan from each of hundreds of patients, each with known dates of symptom onset and of the scans. Then you have to figure out the time course and routes of the disease spread. The SuStain algorithm is told the dates of symptom onset and of the scans, measures the severity of the PET and MRI abnormalities in each of dozens of brain areas and puts all that temporal and spatial data together to create a kind of three-dimensional “movie” of the spread of the disease over time. That could allow finer assessment of differences between PSP sub-types, provide a new outcome measure for neuroprotection trials, and provide clues as to what makes some brain areas more resistant than others to the disease process.


• SuStain and similar highly sensitive measures of PSP progression could provide a much more sensitive measure of benefit of potential disease-slowing drugs. In this way, a trial could require far fewer patients and far shorter time spans than at present. I can envision a future where a trial using SuStain could require only a dozen patients and 6 months. If the drug shows a subtle slowing of the disease relative to placebo, the molecular structure of the drug could be tweaked (also with the help of AI) and another 6-month round of testing could start — a far cry from the 4 years it takes to test one drug, a combination of drugs could be evaluated, and components of the cocktail could be dropped and/or added for the next round.


• I happen to know from painful experience that extracting information from one patient’s medical records for the purpose of guiding subsequent clinical care is a major chore and doing it for dozens of patients in a research trial is worse. It’s child’s play, however, for an AI-based indexing algorithm, even when the records are in different formats or handwritten. This is especially relevant for rare diseases like PSP, where patients in a trial are likely to have been referred from multiple physicians from different health systems using different record formats.


• In 1990, the first high-resolution image of a single protein molecule was produced using cryogenic electron microscope (cryo-EM). Here’s an image of a mis-folded tau protein molecule from someone with PSP (from Shi et al. Nature 2021).

Each little bump Is an amino acid. As far as we know, the folding pattern is the same in every tau molecule in every brain cell in every part of the brain in every patient with PSP. It’s a very different folding pattern for CBD despite its frequent outward resemblance to PSP. Each little nook and cranny is a potential spot for a drug to attach to prevent this toxic form of tau from interacting with other molecules, aggregating with other, identically folded tau molecules, or templating its abnormality onto normal copies of tau. Whichever, mechanism is chose, the disease could theoretically be halted in its tracks. If given the order of amino acids in the tau molecule (which is well known), and the amino acids at each little nook and cranny (also well known), AI could design a molecule to fit. It would be a monkey wrench in the PSP works.

One thing is for sure – this graph is not going to trend down any time soon:

Censavudine hints at real neuroprotection

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Back in May 2024 I posted news about an experimental drug for PSP called TPN-101 with the generic name “censavudine.” 

The sponsoring company had just announced the results of a very small, double-blind trial showing that the drug slowed, or maybe stopped, the progressive increase of a protein in the spinal fluid that correlates with the progression of PSP.  (NfL levels are normal in Parkinson’s disease itself and in Alzheimer’s disease.)  That announcement came as a press release and a poster at a conference. Now, a peer-reviewed paper with far more detail has been published in the respected journal Movement Disorders.  The authors are mostly staff at the drug company, Transposon Therapeutics, headquartered in San Diego.

The graphs above show the change in spinal fluid NfL at the study’s baseline and at weeks 24 (left panel) and 48 (right panel, which also includes the week 0-24 data).  For the first 24 weeks, 10 patients received placebo and the 32 others were divided among three censavudine dosage levels.  The vertical axis represents the initial NfL level as 0 for all patients.  You can see that the average NfL level (in picograms per milliliter) among the placebo group (black line) increased to about 400 by week 24, the expected result.  But those on censavudine either remained unchanged (blue and yellow) or improved by about 200 (green).

Then, after it was clear that the drug was causing no important harm, all 42 patients received the top dosage level for weeks 24 to 48.  The average NfL level in the group initially on placebo improved almost back to the 0 level.  The group that had been on the high dosage level maintained that excellent result, with the NfL level still virtually unchanged from baseline.  The NfL levels in the participants on the two lower dosage levels worsened, as if those dosages lost whatever benefit they might have had after 24 weeks.

The paper explains that none of these effects reached statistical significance because of the small numbers of participants and the wide variance within each dosage group.  Still, this is very encouraging news, especially because spinal fluid levels of IL-6, a marker of inflammation, improved in similar fashion. (Failing to reach statistical significance means that the chance of this being a random fluke is more than 5%, which is the standard for medical research.) 

Unfortunately, the drug made no difference in the rate of progression in the PSP Rating Scale, which uses interview and “hands-on” examination to assess everyday things like gait, balance, speech, swallowing, eye movement, sleep, behavior and cognition. But Transposon is, and should be, encouraged to take censavudine to a Level 3 trial, where larger numbers of subjects might provide the ability to detect useful improvements in these measures. For the PSP Rating Scale to demonstrate that a trial drug slows progression by 50% relative to placebo would require 32 patients on the drug and another 32 on placebo. To demonstrate a 20% improvement would require 192 in each group.

The authors point out that other than that pesky statistical significance problem, this is the first time a treatment has been shown to slow the natural increase in NfL in PSP. NfL in the blood also increases over time in people with PSP, but more slowly than in spinal fluid (18% per year in blood, 36% in spinal fluid), which makes it more difficult to distinguish an effective treatment from placebo using blood levels. Ongoing research is working on turning NfL into a blood test usable for research or clinical care.

Censavudine works by reducing inflammation in the brain in a unique and complicated way. For a technical explanation that might make your hair hurt, see this post from November 2023.

An ALS/PSP alliance?

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A development in amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) may have welcome implications for PSP.

A tiny drug company based in Blue Bell, PA called Mitochon Pharmaceuticals just announced having won a $1 million grant from the ALS Association to mount a Phase II, double-blind trial of their drug in ALS.  The company expects the trial to kick off in early 2027, with a six-month double-blind period.  That means that the result should be available in late 2028 (my own optimistic estimate). 

The drug, known as MP-101 or 2,4-dinitrophenol, is given as an oral capsule and exerts multiple actions in the brain.  Chief among these is to correct leaks in the membrane enclosing the mitochondria, the cells’ power plants where sugar and oxygen come together to produce energy.  PSP has a similar problem with its own mitochondria.  While it’s not as important in PSP as in ALS, it’s possible that neutralizing one important such issue could have a calming effect on the whole self-reinforcing cycle of damage. That’s why Mitochon is interested in testing MP-101 in PSP as well. But so far, they have been unable to raise financing for a PSP trial and have no other drugs on the market to provide that capital.

What probably swayed the ALS Association in deciding to support the Phase II trial was spinal fluid results from Mitochon’s much smaller (10 patients) and shorter (2 weeks) ALS trial, where MP-101 reduced levels of neurofilament light chain (NfL).  That’s a protein released into the spinal fluid and blood in multiple conditions involving rapid loss of axons connecting brain cells, including those in PSP.  While the NfL level, therefore, is a diagnostic marker and not part of the problem itself, it holds promise as a sensitive way to detect benefit from an experimental drug.  Demonstrating such an effect would require far fewer patients and/or dollars than relying on any imaging procedure or neuro exam result. 

There are other biological similarities between ALS and PSP despite the fact that ALS is mostly a disease of the spinal cord and PSP is mostly a disease of the basal ganglia and brainstem:

  • Aggregates of the protein TDP-43, the equivalent of the tau aggregates of PSP, occur in the spinal cord in nearly half of all people with PSP, often in the same set of cells as in ALS.
  • Both diseases include important defects in the brain cells “garbage disposal” systems.
  • Both have problems coordinating the transport of vesicles around the cell.  Those are tiny bubbles of membrane with chemicals that are made in one part of the cell but needed elsewhere.
  • Inflammation is important in both, and in both ALS and PSP it involves the microglia, which are the “white blood cells” of the brain and spinal cord.
  • The first and most important genetic risk factor in PSP, called the tau H1 haplotype, is also associated with ALS despite the fact that the latter is not a tau-based disorder.  (The same is true for Parkinson’s disease.)
  • Both diseases can involve the frontal cortex, producing “executive dysfunction” as a cognitive symptom.

Here’s what I hope: 

  • I hope that MP-101 will be spectacularly successful in slowing the progression of ALS, which is just as disabling as PSP but starts 20 years younger, on average, and is fatal after an average of only three years.
  • I hope that funders with pockets as deep as those of the ALS Association will take a cue from that fine organization and fund a trial of MP-101 in PSP. 

For the scientists among you, here’s Mitochon’s brief but technical explanation of the mechanism of action of MP-101, lightly edited by me:

MP101 is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP), a weak acid with a dissociable proton. The pharmacology of MP101 is unique in that it involves a transfer of proton (H+) into the pH-basic mitochondrial matrix, a non-genomic event. This event involves: 1) lowering damage by reducing ROS production and calcium overload, while 2) promoting repair with the induction of cAMP production, activation of CREB and production of BDNF.

For a far more detailed review by John Geisler, PhD, co-founder and chief scientific officer of Mitochon, see this link. As you’ll read, Dr. Geisler has more ambitions for the drug than just ALS and PSP.

Disclosure: I have consulted for Mitochon in the past but have never had, and do not have, a financial interest in the success of the company.

Turning on the data tap at GP2

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A new paper in the journal JAMA Neurology presents a progress report from the Global Parkinson Genetics Program, or “GP2.” That’s a world-wide collaboration to study the genetics not only Parkinson’s disease, but also dementia with Lewy bodies, multiple system atrophy, corticobasal degeneration — and PSP.  Started in 2020, GP2 eventually plans to enroll 250,000 participants at 415 academic centers in 70 countries.  Its funding is mostly from the Sergey Brin Family Foundation to Aligning Science Across Parkinson’s (ASAP), and the complicated nuts and bolts of the project are organized by the Michael J. Fox Foundation. The paper is entitled “Pathology and Genetics in a Global Cohort of Parkinsonian Disorders,” with first author Dr. Lesley Wu and senior author Dr. Huw Morris, both of UCL Queen Square Institute of Neurology in London.

Our knowledge of the genetics of PSP, PD and the other Parkinsonian disorders remains insufficient, and the little we do know is based almost entirely on studies of white, European-derived populations.  The goal of GP2 is to extend our knowledge of the genetics of the Parkinsonian disorders to include non-European-derived populations as well.  Why?  Two reasons:

  • The most obvious justification is to allow all to benefit from tests and treatments arising from genetic knowledge. 
  • Another is to Identify genetic variants associated with the disease in previously under-studied gene pools.  That could identify previously unsuspected brain chemical processes that could in turn point to new treatment targets — not only for members of those ethnic groups or with those gene variants, but for the diseases in general, world-wide.

Examples of the groundbreaking success of this approach in neurodegenerative diseases have been a family in rural Venezuela with a mutation in the huntingtin gene causing Huntington’s disease, and one in rural southern Italy with a mutation in the alpha-synuclein gene causing a form of Parkinson’s disease.  In each case, the gene was not previously known to have any relationship to its respective disease.  In each, the genetic insight has resulted in new scientific understanding, diagnostic tests and experimental neuroprotective treatment for the disease in anyone.  Both examples, however, are based on dominant-acting mutations manifesting mostly in the young or middle-aged, where a familial pattern is obvious.  But in the vast majority of neurodegenerative diseases, any genetic component is more subtle, with each genetic “risk variant” contributing only a smidge to the overall disease likelihood, and familial patterns are often undetectable by laypersons or ordinary medical testing.

One of the first tasks for the GP2 study is to use autopsies to make sure that the people whose DNA samples have been obtained really do have the disease their neurologist has diagnosed. 

The analysis included 3,403 autopsies. Of those individuals:

• 1,171 had been diagnosed during life with PD
• 399 with Parkinson’s disease dementia (PDD)
• 227 with dementia with Lewy bodies (DLB)
• 491 with PSP
• 244 with MSA
• 76 with CBS

Here’s a table comparing the pre-mortem (or “clinical”) diagnoses with autopsy results:  The columns are the clinical diagnoses and the rows are those made at autopsy.  So, for example, of those with corticobasal syndrome diagnosed during life, 16% turned out to have Alzheimer’s disease at autopsy.

Autopsy diagnosisPercentage with Clinical Diagnosis
PDPDDDLBPSPMSACBSControls
Lewy body disease90%96%94%7%17%8%4%
Alzheimer’s1%1%3%0%0%16%1%
PSP3%2%1%88%7%36%0%
MSA3%0%0%2%75%5%0%
CBD0%0%0%1%0%24%0%
Other neuro-degen.2%1%0%2%1%12%2%
No neuro-degen.0%0%1%0%0%0%93%

Footnotes for this table:

  • “Lewy body disease” is the autopsy picture underlying the clinical spectrum that includes Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies.  Those three conditions are now widely considered to be sub-types of the same disease, just as PSP-Richardson syndrome and PSP-Parkinsonism are sub-types of PSP.
  • For visual simplicity, I’ve rounded all percentages to the nearest integer, so some of the “0%” figures are actually 0.1% to 0.4%.
  • “Other neurodegen.” comprises aging-related tau astrogliopathy, argyrophilic grain disease, chronic traumatic encephalopathy, primary age-related tauopathy, Pick disease, tauopathy not otherwise specified, and vascular pathology.

Take-homes from this table:

  • A clinical diagnosis of PSP is highly accurate, but far from optimal, with 88% confirmed at autopsy.  The next most common autopsy result in such individuals is Lewy body disease, at 7%.
  • Of those with a clinical diagnosis of CBS, only 24% proved to have CBD at autopsy.  A more typical figure from the literature is 40-50%. 
  • Of those with a clinical diagnosis of CBS, 36% proved to have PSP at autopsy.  A more typical figure from the literature is 25%.

The main point of the project, however, is the genetics.  The 20 genes analyzed in this paper were selected because of their known association with the Lewy body diseases.  However, six of them did appear in at least one of the 531 people with PSP who underwent genetic analysis.  They are:

  • The MAPT gene, which encodes the tau protein.  The H1/H1 haplotype (where each of the two copies of chromosome 17 carries the variant) occurred in 83% of people with PSP and in 48-72% of the other groups.  This was first discovered in 1998, so no news there.
  • The LRRK2 (“lark-two”) gene, which encodes an enzyme involved in breakdown of abnormal tau by the lysosomes, showed a variant in 2 people (0.4%) with PSP and in 0.8% with the Lewy body diseases.  This is also no different from previously known statistics.  The lysosomes are one of the cell’s most important mechanisms for disposing of defective, worn-out or excessive proteins such as tau.
  • 29 (16%) of the people with PSP carried one of the known disease-associated variants in the GBA1 gene.  That encodes the enzyme glucocerebrosidase, which like LRRK2, relates to the lysosomes.  This percentage was less than for LBD but did not differ from the other diseases.  Also no surprise, based on previous research.
  • Two results related to ethnicity: 
    • Ashkenazi Jews, regardless of diagnosis, were more likely than all other groups to carry variants in the GBA1 gene.  This has been known since the original description of a GBA1-Parkinson’s relationship in 1996. 
    • South Asians, regardless of genetic results, were more likely to have PSP than other ethnic groups.  This has been informally suspected, but as far as I know, this paper provides the first (admittedly meagre) actual statistics. A deeper dive into the association must now be done:  For example, are neurologists in South Asia better informed when it comes to PSP than neurologists elsewhere?  In the US, where South Asians are a relatively prosperous community with a disproportionate number of physicians, does that group tend have better access to PSP expertise than other ethnicities?  When I know, you’ll know.

  Overall take-homes:

  • This genetic analysis included only 20 genes, of which only two have been reported elsewhere to be related to PSP.  The GP2 study will eventually perform whole-genome sequencing in search of gene variations not previously known to associate with PSP and the other disorders.  To date, the number of DNA samples from under-studied populations remains too small for any results to be reported.
  • The comparison of clinical and autopsy diagnoses shows that while the positive predictive value of a clinical diagnosis of PSP is very good, it could be better.  (The PPV is the percentage of people with the clinical diagnosis who eventually prove to have the disease, in this case by autopsy.) 
  • For most of the Parkinsonian disorders, better biomarkers in living patients are urgently needed.  That, we knew.

One last take-home:  I’d say that the GP2 study shows medical science at its best, combining the latest technology with concern for – and active involvement of – populations and their physicians world-wide.  

We tauopathies have to stick together

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A post from two months ago explained why some positive results from a trial of an antisense oligonucleotide (ASO) drug for amyotrophic lateral sclerosis (ALS) is good news for PSP. Now, there’s similar but even better news about an ASO drug for Alzheimer’s disease called “diranersen.” Why better? Because unlike ALS, Alzheimer’s disease is a tau-based disorder, like PSP.

Quickie review: ASO drugs interfere with the action of messenger RNA, which is produced by a gene in the cell’s nucleus and carries it out to the ribosomes, where it’s translated into that gene’s specific protein. Trials of “neuroprotective” treatments hope to demonstrate a decline in the rate of worsening relative to placebo, affording the participant more time at each disease stage. Neuroprotective treatments like ASOs are not designed to produce improvement relative to the study’s baseline.

Yesterday (July 14, 2026) the results of a Phase 2 trial were released at the Alzheimer’s Association’s annual research conference in London. The double-blind design included 406 people with either “mild cognitive impairment” (MCI) or mild dementia caused by Alzheimer’s. (MCI does not include difficulties in performing daily activities and dementia does. For the purposes of the trial, MCI is defined as a score of 21-27 on the 30-point Mini-Mental Status Exam and dementia as 20 or less.) The participants were randomly assigned to one of three dosage levels or placebo for the 76 weeks of the double-blind period. The improvement was calculated as the difference between the first and last visit scores divided by the the first visit score.

The testing included five standard cognitive tests, tau levels in the spinal fluid, and positron emission tomography (PET) scans to image brain tau deposits. The drug, like all ASOs to date, is administered by injection into the spinal fluid space at the base of the spine, as for a spinal tap. Of those seven tests, the “primary outcome measure” was the Clinical Dementia Rating Sum of Boxes (CDR-SB), presumably because it’s the one with the most experience behind it.

Officially, the trial was negative because the CDR-SB failed to show a statistically significant slowing of the rate of worsening. But for two of the other four cognitive measures, there were statistically significant degrees of slowing of 50% in one and 42% in the other. The benefits shown by the PET and spinal fluid look equally impressive to my eyeballs, but their degree of statistical significance was not provided.

Transient pain in the head, limbs and/or back from the spinal taps were by far the most common side effects, occurring in about half of all participants, but no worse on diranersen than on placebo. The only side effect clearly worse on diranersen was a temporary confusional state (about 25% vs 5% on placbo). In all cases, it was gone within a week.

You can see and download the company’s detailed announcement here. Keep in mind that the drug company sponsor, Biogen, wrote it for public relations purposes. It is not sufficiently detailed for a research journal and has not been peer-reviewed, but Biogen has announced plans for an expensive Phase 3 trial, proving that they’re willing to put their money where their mouth is.

Biogen hasn’t parted with further details on the Phase 3, but if it starts in 2027 and is similar in design to the Phase 2 (but larger), one might expect results in 2030 and if all goes well, FDA approval shortly thereafter. Too long, I know, and besides, that’s Alzheimer’s — not PSP.

Of course, the elephant in the room is the trial of NIO-752, the ASO from Novartis, currently in a Phase 3 trial for PSP and stated for completion in mid-2029. The success to date of diranersen in Alzheimer’s, is excellent news for the prospects of a similar anti-tau ASO for PSP. As far as I know, there’s no clinically relevant difference between the two ASOs.

On behalf of the PSP community, I’ll thank Novartis for its efforts behind NIO-752 and encourage Biogen to extend its so-far-favorable Alzheimer’s program to PSP. Any other Pharma companies interested? The opportunity is ripe!

—–

Disclosure: In the past, I have consulted for both Novartis and Biogen, but have never had a financial interest in either company. The only possible exception is that Rutgers University, which owns the rights to the PSP Rating Scale because I was a professor there when I developed it, shares a fraction of its licensing fees with me.

Zoë’s extraordinary statistical analysis

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A new paper has analyzed data from 863 people with PSP from the failed Biogen and AbbVie monoclonal antibody trials from the late 2010s.  The purpose was not to re-sift the data for signs of benefit, but to characterize the participants’ cognitive deficits in detail and to measure their rate of cognitive worsening over the 12 months of the trials. 

This sort of thing has been done before, but not with as many patient or using those trials’ main cognitive measure, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a 12-component test that has become the standard cognitive test in drug trials of PSP and other diseases.  It includes tests of:

  • Immediate memory
  • Delayed memory
  • Visuospatial/constructional ability
  • Language
  • Attention. 

The present analysis also included four timed tests that other work has shown to be affected early in PSP and to be sensitive to its progression:

  • Phonemic and semantic fluency (saying as many words as possible in one minute meeting a condition such as things starting with the letter T or things found in a supermarket)
  • Wechsler Letter-Number sequencing test (connecting randomly arranged letters and digits in order: A-1-B-2, etc.)
  • Color Trails Test 1 (connecting small, randomly arranged circles in order of their enclosed numbers, ignoring their two background colors)
  • Color Trails Test 2 (similar, but alternating the background colors)  

Other features of this analysis worth noting:

  • A lot of other data about the participants’ PSP was gathered in standardized fashion, per the two trials’ protocols.  As you’d imagine, a test requiring writing and drawing could be affected by PSP’s motor and ocular deficits.  So, the statistical analysis adjusted each participant’s cognitive performance by their scores on the eye movement and/or limb movement PSP Rating Scale sections.
  • These participants were in the early-to-middle stages of PSP, at a mean of 3.3 years since symptom onset, with a standard deviation of only 1.4 years. So, one cannot assume that the conclusions of this study apply to people in earlier or later stages.  The same applies to their average age of 68.7 (sd 6.9) years.
  • The analysis combined the placebo and active-drug groups; it did not compare them to each other.  The authors felt that this would be fine because the original study’s comparison between the two groups’ responses to the drugs showed no differences, unfortunately.

The results showed that all scores worsened to a statistically significant degree over the 12 months except for story memory (immediately after the story), story recall (after a delay), list recall (immediate recitation of a word list) and list recognition (after a delay, indicating which words on a second list were also on the first).

The most rapidly progressing tasks were complex figure copying (with the original visible) and coding. (That’s where nine geometric symbols are presented beside the digits 1 to 9. The person is allowed to refer to the “code” on the same page while drawing the symbols corresponding to a list of random digits.)

The take-home for patients and families is that memory is relatively preserved in PSP, at least through the first four or five years.  This despite the habit of many laypersons of referring to any cognitive deficit as a “memory problem.”  So, cognitive activities relying on memory such as listening to music, comedy or stories may remain a source of entertainment and satisfaction for those with PSP well into the disease journey.  On the other hand, puzzles, crafts, drawing and strategy games are likely to prove frustrating.

Another use of these results is in the design of future clinical treatment trials.  The RBANS is a time-consuming, fatiguing test for both patient and clinician, requiring 45-60 minutes for those with PSP.  If the RBANS can be reduced to its most rapidly progressing, most informative components, the same (or better) information on the subject’s progression might be obtainable in a fraction of that time, without the fatigue.  This could improve the quality of the data not only on the cognitive test, but on the study’s other tests as well.  An excellent start at this was made a few years ago by scientists at Biogen.

The new paper’s first author was Zoë Cappella Cooper, a Harvard undergraduate headed for a stellar career.  (I know this because I’ve worked with her on other projects.)  The senior author was her mentor, Anne-Marie Wills, MD, a long-time colleague of mine at Harvard Medical School and Massachusetts General Hospital.

NIO-752 on the fast track

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Some encouraging news from the AD/PD Conference held this past March in Copenhagen. NIO-752 is the anti-sense oligonucleotide drug being developed by Novartis for PSP and Alzheimer’s.  It reduces the ability of the messenger RNA encoded by the tau gene to be translated into tau protein.  The news is the results of a Phase I trial designed mainly to assess safety and tolerability of various dosage levels.  But the trial also included measures of efficacy, just in case something dramatic appeared despite the trial’s small size.  The PowerPoint slides from the presentation by Dr. Günter Höglinger of Munich can be downloaded here.

NIO-752 is a large molecule that can’t cross the blood-brain barrier, so it has to be injected directly into the spinal fluid via the same sort of needle insertion used in a diagnostic spinal tap.  In this trial, 80% of the 59 subjects (45 on active drug, 14 on placebo) received injections at baseline and at months 1, 2 and 3 at ascending dosage levels.  The other 20% received it at baseline and at months 3, 6 and 9. The final assessment for all subjects occurred at 12 months.  The trial ran from February 2021 to October 2024.

The drug caused very little by way of important side effects: confusion and or lethargy in two of the 25 patients on the two highest dosage levels and some brain inflammation in one patient on the highest level as evidenced by elevated white blood cells in the spinal fluid.  This is a very modest overall burden of adverse effects, and what’s more, the frequency of milder side effects was no different between the active drug (19 of 45) and placebo (7 of 14) groups. There’s lots more information at clinicaltrials.gov.   

An important goal of Phase I trials is to demonstrate “target engagement.”  That military-style term means the ability of a drug to accomplish its job in the body’s tissues regardless of whether it actually helps the person’s symptoms or long-term outcome.  NIO-752 did well on that score, reducing the spinal fluid tau levels, especially at the highest dose level.  (The level remained unchanged in the placebo subjects.)  It also prevented any rise in levels of neurofilament light chain (NfL), while the placebo group’s NfL rose by nearly 40%.  NfL is a sign of damage to axons (the long fibers emerging from brain cells) that is elevated in PSP and several other neurodegenerative diseases.

The question in your minds is, “But what about the rate of worsening of the symptoms and disabilities”?  That wasn’t reported because there weren’t enough patients to perform a proper statistical analysis.  If the worsening in the PSP Rating Scale had been less in the 45 participants on NIO-752 than in the 14 on placebo, that would be too few to exclude the possibility of confounders (a “Type I error” or false-positive) effect.  Similarly, if this small study failed to demonstrate a benefit, Novartis would not want anyone to draw negative conclusions about the drug without a properly powered trial.

Next step: Novartis will now skip directly to a Phase III trial and just yesterday they posted details on clinicaltrials.gov.  You can get a look here, but I’ll discuss that trial in a near-future blog post. The trial’s nickname is PRESERVE.

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Full disclosure: I have consulted for Novartis on trial design in the past but not since 2023. I have no stock in the company nor any other financial interest in the success of NIO-752 or the company in general.

41 heads are better than one

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CurePSP’s Centers of Care (CoC) network has just announced this year’s four recipients of its “Collaborative Approaches to Resources, Education and Support” (CARES) grants.

The CoCs, established in 2017 with 25 sites, have grown to include 41 sites at 34 academic medical centers in the US, four in Canada and three in Europe.  All have satisfied CurePSP’s criteria for expertise in the care of people with PSP and CBS, and many have also qualified for additional certification in MSA.  The group’s mission is not traditional research, but improving the quality and quantity of clinical care. 

In pursuit of that goal, the group has collaborated in writing and publishing review articles and opinion pieces on such topics as symptomatic treatment, biomarkers, speech impairment, and delays to appointments. Its four special-interest sub- groups meet regularly to discuss ways to improve care. Sites must be re-certified every three years, at which time they must demonstrate improvement in quantitative measures and cite new, relevant programs, publications and educational activities.

CoC member sites also are eligible to apply to CurePSP for grants supporting research into improving care delivery, or for specific care delivery projects.  Brief descriptions of the newest four projects are available on the CurePSP website. The funding for this year’s crop totals $155,000.  Parkinson Canada and CurePSP are sharing support of the two projects involving Canadian sites.

An unusual aspect of the CARES grant program is its requirement for collaboration among at least two CoC sites.  The point is to encourage cross-fertilization of ideas and to encourage the newer or smaller sites to learn what has worked for the more-established ones.  

Disclosure: I helped organize the CoC network back in 2016-17 and serve on its Steering Committee as an ex officio representative of the CurePSP staff.

The takeoff of your 747 has been delayed

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I just heard that the PSP Trial Platform’s enrollment kick-off, set to happen this month, has been postponed to sometime later this year. 

You can read more about the PTP in this blog post of mine and on www.clinicaltrials.gov.  The delay, I’m told, is that the trial organizers and the sponsor of one of the three drugs have yet to nail down certain administrative issues.  That sponsor is Alzprotect, a French company, and its PSP drug is AZP-2006, an oral drug addressing abnormal tau disposal and inflammation.  The two drugs fully in place are AADvac1, a subcutaneously injected anti-tau vaccine from Axon; and LM11A-31, an orally administered nerve growth factor modulator from PharmatrophiX.   


A bit of good news is that the FDA has given the green light to the Alprotect drug to start its participation in the PTP trial.  That had been one of the causes of the delay, and now only those admin issues remain. 

So, the trial from start of this Phase II trial (the PTP) to full FDA approval, which if all goes well would have taken at least four years, will now need a few months longer.  But the PTP’s participating sites are enthusiastic, the financial support is in place, the underlying science is good, and the medical leadership is first-rate. I realize that these reassurances are scant comfort to those affected by PSP and their families, but they’re important.

I’ll pass along updates when I can.