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A dozen at the cutting edge (part 1 of 2)

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Here’s the first of two installments summarizing the original, PSP-related research presentations at the annual conference of the International Parkinson and Movement Disorder Society held in early October 2025 in Honolulu. 

The listing is in no particular order and each is followed by my own editorial opinion.  I’ve culled the 29 PSP-related presentations down to the twelve I considered most interesting considering both their scientific importance and their potential interest to this blog’s readers. 

Clinical Deficits, Quality of Life and Caregiver Burden across PSP Phenotypes

A. Cámara, I. Zaro, C. Painous, Y. Compta (Barcelona, Spain)

Caregiver burden is greater for PSP-Richardson syndrome than for other PSP subtypes, and quality of life showed a statistically non-significant trend for PSP-RS as well.  This information may be useful in counseling patients and caregivers.

LG comment: This result would be expected given the rapid progression of PSP-RS and its high prevalence of falls and dementia relative to most other PSP subtypes.  The study importantly points out that caregiver burden receives too little attention from clinicians, researchers, policy planners and insurors.

Clinical Features Suggestive of Alpha-Synucleinopathy in Progressive Supranuclear Palsy

C. Painous, A. Martínez-Reyes, J. Santamaria, M. Fernández, A. Cámara, Y. Compta (Barcelona, Spain)

Rapid eye movement behavioral disorder and reduced ability to smell are known to be very common in Parkinson’s disease and other alpha-synuclein-aggregating disorders but also occur to some extent in those with PSP.  All of this study’s patients with PD and 10% if those with clinically typical PSP had a positive spinal fluid alpha-synuclein seeding amplification assay (SAA).

LG comment: The new SAA test is not perfectly specific for synucleinopathies and could produce a false positives in people with PSP.  The same is true for RBD and reduced smell sensitivity.

Identification of Genetic Variants in Progressive Supranuclear Palsy in China

Y. Kang, W. Luo (Hangzhou, China)

Pathogenic or likely pathogenic variants consistent with their respective inheritance patterns were detected in 20% (8/40) of patients: three carried PSP-related variants (CCNF, DCTN1, POLG), while five harbored variants in neurodegeneration genes linked to PSP-like phenotypes (AARS1, TDP1, FA2H, TBP, ATXN8).  The controls were only historical controls from the literature.

LG comment: This list of genetic variants, each conferring a very slight increased PSP risk, differs from the lists reported in Western populations, which also have important differences from one another.  The differences could be related to geographically or culturally related environmental contributions (which need different genetic backgrounds to cause damage) or to differences in laboratory methods or choice of non-PSP control populations.

Unraveling the Genetic Architecture of Progressive Supranuclear Palsy in East Asians

P. Chen, R. Lin, N. Lee, J. Hsu, C. Tai, R. Wu, H. Chiang, Y. Wu, C. Lu, H. Chang, T. Lee, Y. Chang, C. Lin (Taipei, Taiwan)

Using a Taiwanese population, this study identified three likely pathogenic variants, in the genes called APP and ABCA7, and the mitochondrial genome.  It also found 39 variants of unknown significance in 37 PSP patients (20.9%), involving  other genes, many of which were already known to confer slight risk for PSP.   

LG comment: The difference in apparent genetic risk factors between Shanghai (previous abstract by Kang et al) and Taiwan underscores the possibility of differences in methodology, although ethnic differences between those two geographical areas could be contributing.  Genetic study of PSP in East Asians could benefit all ethnicities by identifying previously unsuspected cellular pathways involved in the disease.

Multimodal imaging Integrating 18F-APN-1607 and 18F-FP-DTBZ PET in Progressive Supranuclear Palsy

C. Dong, J. Ma, S. Liu (Beijing, China)

Several kinds of positron emission tomography (PET) imaging are being tested for their ability to accurately diagnose PSP.  Two of them were applied concurrently to a group of 20 participants with PSP and a control group.  One, called 18F-APN-1607, shows abnormal accumulation of the tau protein and the other, called 18F-FP-DTBZ, images the neurons that use dopamine.  The result was that 16 of the 20 were correctly identified by the 18F-APN-1607 and three of the other four were identified by the 18F-FP-DTBZ as being probable Parkinson’s disease.  The conclusion is that performing both types of PET could provide more accuracy than the tau PET alone in distinguishing PSP from PD.

LG comment: This result is consistent with the age-old medical principle that there’s no such thing as a perfectly accurate diagnostic test.  Two or more tests measuring different aspects of the same disease can work in a complementary manner to improve diagnostic accuracy.  Fortunately, PET is a nearly harmless, nearly painless test.  Its main drawbacks are time, expense and insufficient availability of many kinds of PET outside of referral centers.

Levodopa response in pathology-confirmed Parkinson’s Disease, Multiple System Atrophy and Progressive Supranuclear Palsy

V. Arca, J. Jurkeviciene, S. Wrigley, P. Cullinane, J. Parmera, Z. Jaunmuktane, T. Warner, E. de Pablo-Fernandez (London, United Kingdom)

About one in three people with PSP experiences some degree of benefit on levodopa, a statistic that prompts most neurologists to give that drug a try.  However, the benefit is often short-lived.  To measure this in a formal way, these researchers reviewed the medical records of autopsy-confirmed patients with PSP, PD or MSA.  Those responding well for over two years were 2% of those with PSP, 86% of those with PD and 8% of those with MSA.

LG comment: The short duration of useful benefit from levodopa in PSP means that each patient enjoying a benefit after the drug initiation should be re-evaluated at each subsequent visit for a continued benefit.  As levodopa can have long-term side effects such as low blood pressure, hallucinations and involuntary movements, a dosage taper carefully monitored by the physician should be considered after the first year or so of treatment.

A poem from a reader

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A reader named Delaney Moore, whose mom has PSP, sent this poem to the comments page, accompanied by a prose explanation. You can find them both there, but I thought the poem was so beautiful and meaningful that I copied/pasted it into a post on its own. It refers to my September 24 post about a new, potential approach to neuroprotective treatment entitled, “Proof of Principle and Cause for Hope.”

Proof of Principle: a Valley of Hope (by Delaney Moore)

“Proof of principle: a cause for hope”

A reason to fight; to stay afloat

They say, “life is a journey,”

that it’s long and uncertain.

Your path twists, then attacks you, all attempts to dishearten.

Then all of a sudden,

you’re falling and flailing as you crash and collide

into deep, daunting valleys,

canyons so dismal and wide.

You’re flanked by trough walls that trap you within and torment your mind.

But you don’t listen to the echoes, whispering lies to deceive you;

you know you aren’t lost, you know you’ll break through.

So you take a deep breath, drawing on bravery from within,

You refuse to surrender, to give up, to give in.

You know fear always lingers,

but courage always wins.

You start stumbling forward, slowly gaining ground.

The trek leaves you breathless; gravity beats you down.

You feel the weight of the world while the battle rages on,

But the fire within you continues to burn.

Your small, sluggish steps start to widen with ease,

It’s the fight of your life, but you begin to break free.

And, alas, you continue on your expedition of existence;

you push through, stumble forward, stagger onward, with persistence.

Until suddenly you see it, it’s in the distance, growing near.

You’ve made it out of the valley, rounded the slope – you’re free from fear.

And as you begin to catch your breath, you reflect on your trials;

the valley you conquered, despite slopes that continued for miles.

Most forget that the valley was formed over millions of years.

Brutalized by the elements, she now shapes the frontier.

The formidable sight was once a simple mound of mass,

just rugged terrain standing strong, firm, and vast.

Yes, time played its tricks, and nature dealt her cruel hand,

and the river came crashing, plundering through the land.

It cut through the valley, weathering her down,

eroding her body, leaving only slopes that had cradled the mound.

The river was violent, bringing pain, bringing change,

but as the centuries passed, the valley earned her triumphant name.

And despite the cruel torture the river unleashed,

the valley became a symbol of struggle on the journey to peace.

Proof of principle: a valley of hope.

Through trials come victory; your fight keeps you afloat.

You’ll voyage through valleys, hike mountains, climb slopes.

You’ll venture to the top, gaining strength as you cope.

And when you finally reach the peak, you’ll look back at how you’ve grown;

you’ll see that, despite climbing solo, you were never alone.

Because just like the valley, you’ve persevered through endurance and loss,

learning lessons that make you, shape you, and give you reason to pause.

To look back at your life, at each valley and slope that you’ve met,

where you’ll be awe-struck by your resilience on the journey you’ll never regret.

—

One RNA fits all?

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Maybe I’m streaming too many dramatic TV series these days.  My October 9 post ended in a cliffhanger, teasing an “oddball” molecule that could point the way to neuroprotective treatments for PSP and other neurodegenerative diseases. It’s called “lncRNA FAM151B-DT.” 

Quickly, some background.  The RNA most familiar to us is messenger RNA.  Its length can be anywhere from a few hundred to a few thousand base pairs (the genetic code’s “letters” for a single gene or a fragment thereof). The RNA is constructed (“transcribed”) in the cell’s nucleus from the code in DNA, then scoots out to the ribosomes, where it’s translated into a string of amino acids to build a specific protein.  But only about two percent of the DNA in our genome encodes the kind of RNA for making proteins, called messenger RNA.  Most of the rest, about 75 to 90 percent, encodes RNA that regulates DNA transcription or other cell functions.  A little of that “non-coding RNA” is “micro-RNA,” which has only about 20 to 25 base pairs, and the rest, with over 200 base pairs, is called “long, non-coding RNA.” 

Now I’ll get to the point. A research group at Washington University in St. Louis just published a paper entitled, “A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins.”  They used brain cells obtained at autopsy from people who had died with PSP, Alzheimer’s, or Parkinson’s disease.  They also used skin cells from a living person with a form of frontotemporal dementia with Parkinsonism (FTDP), which is caused by a mutation in the tau gene. They transformed those (slightly) specialized skin cells into unspecialized stem cells, then transformed those into highly specialized brain cells.

The lead author of the WashU study is Arun Renganathan, PhD, a staff scientist in the Department of Psychiatry.  The senior author is Celeste Karch, PhD, associate professor of psychiatry. Disclosure: Dr. Karch and I have collaborated in research in the past and she’s a member of CurePSP’s Scientific Advisory Board, which I am honored to chair.

In each of those four disease-specific brain cell cultures, the team found FAM151B-DT reduced relative to control cells and that silencing FAM151B-DT by “knocking out” its gene increased the concentration of whichever protein was aggregating in the corresponding human disease (tau for PSP, AD and FTD-P; alpha-synuclein for PD). The mechanism was a blockage of autophagy, an important component of brain cells’ “garbage disposal” system.  The researchers found that FAM151B-DT serves as a “scaffold” to allow the tau or alpha-synuclein protein and a “chaperone” molecule called HSC70 to interact with the lysosomes, a kind of bubble in the cell fluid containing protein-degrading enzymes.  

A critical piece of the new research is that increasing the cells’ production of FAM151B-DT stimulated that system to dispose of excess tau or alpha-synuclein. That means that FAM151B-DT is the “rate-limiting step” in the process.  As you’d imagine, this suggests that increasing the concentration or efficiency of FAM151B-DT could slow or halt progression of these diseases.  All four of them.

So, how does this relate to the cliffhanger from yesterday’s post about our evolving perspective on the similarities and differences between PSP and AD?  One reason to be interested in the differences between those two is that a rare disease with limited research funding like PSP could benefit from research on treatments for AD, a very common disease with much more research funding and huge commercial potential.  Besides, we in the PSP community like when drug companies try out their AD drugs on PSP first – because of their common underlying cellular and biochemical similarities. The new paper from WashU has found one more very important similarity.

It’s not only PSP and AD.  The new paper found FAM151B-DT just as relevant to PD and FTDP.  I expect to see research soon on its relevance to others forms of FTD and to ALS, dementia with Lewy bodies, corticobasal degeneration, multiple system atrophy, and many others.  Then we wouldn’t have to worry so much about making an accurate diagnosis early in the disease course– maybe one cure will fit all!

PSP and Alzheimer’s: a rocky relationship

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Back in 1987, it was discovered that the neurofibrillary tangles of PSP, like those of Alzheimer’s disease, are made of the tau protein with too many phosphate groups attached. That prompted great optimism that the two diseases could eventually share a single treatment to slow or halt the abnormal accumulation of tau.

At the time, I was a young assistant professor working on my first PSP research project — at the behest of my department chairman. It was the first epidemiological survey on that disease and my boss’s plan was for me to turn my attention to other things after that study was over.  But the new insight that the orphan disease of PSP and a huge, public health problem like AD shared an important molecular similarity helped keep part of my research effort focused on PSP.  Suddenly, it seemed a much more solvable problem than before, and one where a novice researcher like me could get in on the ground floor.

Soon thereafter, enough PSP/AD commonalities have emerged to prompt many Pharma companies to use people with PSP as a “test bed” for their new, potential blockbuster, AD drugs. Why not simply use patients with AD?  Because:

  1. The diagnostic criteria for PSP were better than those for AD in avoiding false-positive diagnoses in the patient group;
  2. The PSP Rating Scale worked better as an outcome measure for PSP than any AD-related scale did for AD; and
  3. PSP progressed faster than AD, allowing studies to be smaller and shorter, hence less expensive; and d) because a treatment directed at the tau protein might work better in a “pure tauopathy” like PSP than in AD, where another protein, beta-amyloid, accompanies tau in the brain and may affect tau’s susceptibility to the study drug in unknown and unmeasurable ways.

Then there’s another reason, which belongs in a different category and is relevant mainly in the US: If the experimental drug helps PSP only modestly (or with important side effects) it might well be approved by the FDA just because there was nothing else that worked at all. Then, Medicare, and by extension the private insurance companies, would likely agree to cover it because PSP is so rare, with about 20,000 people in the US.  But if the drug had the same lackluster benefit and important side effects in AD, with about 7 million sufferers, Medicare and insurance companies might refuse to cover it for that condition for purely financial reasons.

But back to the science:  More recently, researchers have discovered important differences between PSP and AD — enough to seriously reconsider the “test bed” strategy.  For example:

  1. The “prion-like” spread of tau through the brain proceeds more rapidly in PSP than in AD, and in a very different set of brain areas.
  2. PSP starts in the brain’s glial cells, while AD starts in neurons.
  3. The part of the brain cells’ “garbage disposal” mechanism presenting the most promising drug targets differs between PSP and AD. 
  4. Perhaps most dramatic, the new technique of cryo-electron microscopy, which can image a single tau molecule, has shown important differences between PSP and AD in how that protein mis-folds on itself.  That means that a drug could bind to tau in PSP but not in AD, or the reverse. 
  5. A practical issue related to ease of trial design: Newer imaging techniques and blood or spinal fluid tests have permitted much more accurate diagnosis and tracking of AD, while those tests are not (yet) useful in PSP.

BUT: A new discovery just published this week may re-unite PSP and AD, along with frontotemporal dementia and Parkinson’s disease, as diseases that could share the same neuroprotective treatment.  The commonality is a type of “long, non-coding RNA.” For more on that potentially groundbreaking – and definitely oddball — molecule, see the next post.

Two new drugs rarin’ to go

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Some good news for those seeking to enroll in a PSP drug trial: The PSP Platform (PTP) is scheduled to start enrolling in the first quarter of 2026. The first two drugs will be the AADvac1 and AZP-2006. The first is a vaccine that stimulates the immune system to make its own anti-tau antibodies.  The second boosts the part of the brain’s garbage disposal system most relevant to PSP.

The third drug is still being finalized with its Pharma sponsor and some points in the study protocol await approval by the FDA.  Only then could the results potentially be used to support a new drug application.  These delays explain the start-up postponement from December 1, 2025 listed in ClinicalTrials.gov to early 2026.

As described in more detail in previous posts here and here, the PTP is a group of about 50 centers in the US led by neurologists at UCSF, UCSD and Harvard.  They have created an infrastructure to test up to three drugs simultaneously, each in its own set of 110 participants.  A major advantage of such a plan is that all three trial groups share the same placebo group.  That way, each participant has only a 25% chance of being assigned to placebo.  The other obvious advantage is cost savings, which could lower the bar for a company to give its drug a go.  The trial is heavily subsidized by a grant from the NIH budgeted for about $14.5 million this year and similar amounts annually through 2029. https://reporter.nih.gov/project-details/11160498

The names and locations of the approximately 50 participating sites across the US have not been announced, but those interested should keep an eye on the ClinicalTrials.gov page https://clinicaltrials.gov/study/NCT07173803 or wait a few days and contact the study’s central enrollment center at 213-821-0569 or psp-participate@usc.edu at the University of Southern California. But perhaps the best option is simply to register with CurePSP for updates on the trial’s status.

Reality check: As for most PSP drug trials, the hope is to slow the rate of progression. The PTP is designed to be able to detect a slowing relative to the placebo group of 33% or better over the 12-month period of the trial.  The trial’s design is based on assumption that the drug would not improve the symptoms – it would at best slow down the pace at which they worsen.  But if all goes well, that could mean many months or even a couple of years of good-quality life.  An even better outcome to hope for is that one of the drugs would work well enough to prevent progression altogether (“100% slowing”), maintaining the present level of symptoms for the remainder of whatever would have been the person’s lifespan without PSP. 

A 33% slowing is a very realistic hope. That 100%-slowing scenario is only a distant hope, but one that’s theoretically possible. And hope does matter.

For once

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Some excellent news for you today.  The orally administered drug AZP-2006 has shown early signs of slowing the progression of PSP. (Yes, you heard right!)

My blog post from May 9 of this year brought news that a small, open-label, Phase 1 study of AZP-2006 seemed to have slowed the progression of PSP by 31 percent.  Now, the drug has completed a small, double-blind, Phase 2a trial with even better results: In the 11 patients receiving 60 mg per day, the worsening in the PSP Rating Scale score over the 3 months of the double-blind phase was a third slower than in the placebo group (identical to the result of the uncontrolled Phase 1) and in the 13 patients receiving a loading dose of 80 mg on the first day and then 50 mg per day, the apparent worsening was two-thirds slower.  

It’s important for you to understand, and the authors repeatedly emphasize, that these results were not statistically significant, meaning that they could be the result of a random fluke.  There were also some minor differences among the three patient groups (placebo, 60 mg, and 80 mg then 50 mg) at the study’s baseline that theoretically could have explained the results.  A larger, Phase 2b study could confirm the result while having the statistical power needed to compensate for any “baseline bias” among the treatment groups. 

The trial included a 3-month open-label extension. That’s where the participants on placebo for the first 3 months were offered the opportunity to convert to the active drug at 60 mg per day, while those initially on the active drug could opt to continue it.  Over months 4, 5 and 6, the rate of decline of the formerly-placebo group slowed down noticeably.  The other important result is that the drug showed itself to be safe and well-tolerated over the entire 6 months.

The publication’s first author is Jean-Christophe Corvol, MD, PhD, a very well-regarded, senior neurologist I know at the legendary Hôpital Pitié-Salpêtrière in Paris.  The senior (i.e., last-named) author is Luc Defebvre, MD, PhD, at Lille University. Six of the other 16 authors are staff researchers at the sponsoring drug company, AlzProtect, of Lille, France.

In this graph, the vertical axis is the worsening in terms of the 100-point PSP Rating Scale.  EOT is end of the double-blind part of the trial at Day 84.  Thereafter, all participants received active AZP-2006.  Note that both active-drug groups progressed more slowly than the placebo group over the first 3 months; and on active drug, the participants formerly on placebo may have slowed their progression rate. The vertical line segments represent standard deviations of the mean. (From:  Corvol JC, Obadia MA, Moreau C, et al. AZP2006 in progressive supranuclear palsy: outcomes from a Phase 2a multicenter, randomized trial, and open-label extension on safety, biomarkers, and disease progression. Movement  Disorders. 2025 Sep 27. doi: 10.1002/mds.70049. PMID: 41014124)

So, when will the Phase 2b study start?  My May 5, 2025 post reported on the “PSP Platform,” (PSPP) an NIH-supported collaboration among dozens of U.S. academic centers to perform Phase 2b trials on up to three drugs simultaneously using one placebo group.  One of the first three drugs, in fact, is AZP-2006.  Last I knew, the PSPP was expected to start late this year, but it’s now almost October and I’ve heard nothing further other than that some details remained to be ironed out with the FDA. That trial would take about 6-12 months to recruit and then another 12 months for the last patient to finish, then at least a couple of months to analyze the data. 

So, how does AZP-2006 work?  I’ll plagiarize my own May 9 blog post, along with its “Nerd Alert!” warning that this gets technical:

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.

Bottom line: This very small, Phase 2a trial was designed to show safety, not efficacy, and its slowing of PSP progression did not nearly achieve statistical significance nor exclude potential sources of random bias.  But the magnitude of the (apparent) effect make this excellent news for those with PSP, present and future.

Proof of principle and cause for hope

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The gene therapy company uniQure announced today that its has succeeded in slowing the rate of progression of early-stage Huntington’s disease (HD) by 75 percent.  Although the specific treatment would not work for PSP, the general principle successful in HD could be relevant to all neurodegenerative diseases.

The new research is not yet peer-reviewed nor published.  In writing this post, I used information from the company’s press release,  a news article from the BBC, and Old Reliable, ClinicalTrials.gov.

Unlike PSP, HD is a purely genetic disease.  It works on an autosomal dominant mechanism with full penetrance, which means that anyone inheriting one copy of the disease-causing version of the relevant gene from either parent will develop the disease.  The gene’s technical name is IT15 and it encodes a protein called huntingtin or HTT (notice the “-in” ending indicating a protein).  The gene defect is extra copies of a span of the three nucleotides C, A, and G. This “CAG repeat expansion” directs the cell’s protein factories (the ribosomes) to build into the HTT protein an excessively long string of the amino acid glutamine.  The normal span is 7 to 35 CAG repeats, but in people with HD, one of the person’s IT15 genes has at least 36 repeats. In people with HD, the normal version of the IT15 gene continues to make normal HTT, which means that half of their HTT is normal and half isn’t. The new treatment suppresses the brain’s production of the abnormal half.

Here’s how the trial worked: The researchers started with a kind of virus routinely used in research called AAV, which readily enters brain cells but by itself causes no harm.  They made short stretches of DNA designed to encode a type of micro-RNA corresponding to the abnormal HTT protein.  They inserted that DNA into the viruses and dubbed the result, “AMT-130.” In a 12-18-hour neurosurgical procedure, they injected the AMT-130 viruses into the caudate and putamen, the parts of the brain where HD does its main damage. The viruses released their DNA into the brain cells, which started transcribing it into RNA.  In this case the RNA was actually a “microRNA” designed to bind and disable the cells’ own abnormal RNA that would have gone on to be translated into abnormal HTT protein.   

In that way, the researchers hoped to reduce the cells’ production of abnormal HTT protein.

The trial included 29 people with HD at four study sites (Two in Warsaw, Poland and one each in London, UK and Cardiff, Wales.) Seventeen of the participants received a high dose of the virus, 12 received a low dose and all were observed for 3 years.  They were examined using the standard Unified Huntington’s Rating Scale (UHRS) and other measures of neurological function as well as spinal fluid sampling to measure levels of proteins associated with neurodegeneration.  As a control group, the trial used records of people with HD from an unrelated study of the natural history of the disease called “Enroll-HD.”

The result in the high-dose group was far better than anyone dreamed of. 

The “primary outcome measure,” the rate of worsening in the UHRS, was only 25 percent of that of similar patients from the control group.  Subsidiary measures of clinical efficacy gave similar or even better results.  Levels of neurofilament light chain (NfL), a protein released into the spinal fluid by degenerating brain cells, actually declined, while increasing in the control population. 

The low-dose group gave much less impressive results, which in a way is good because it suggests that the improvement was actually from the treatment rather than from some statistical fluke.

So, is this relevant to PSP?  Yes and no.

It’s relevant to PSP because:

  1. PSP and HD are both neurodegenerative diseases with an abnormally aggregating protein playing a critical but incompletely understood role in the loss of brain cells: tau for PSP, huntingtin (HTT) for HD.
  2. The anti-sense oligonucleotide treatment presently under development in PSP, NIO-752, works by the same principle as the AMT-130 virus.  But it’s injected into the spinal fluid and engages the tau messenger RNA directly, whereas AMT-130 releases DNA, which encodes RNA acting as the equivalent of an anti-sense oligonucleotide.

It’s not so relevant to PSP because:

  1. The tau protein aggregating in PSP is not defective from a genetic standpoint.  Yes, it’s misbehaving, but as far as we know, PSP has no common, specific, mutated form of the tau gene that could make its RNA susceptible to a targeted attack like that provided by AMT-130.  Rather, the misbehavior of tau in PSP is caused by other abnormalities in the brain cells resulting from the cumulative effect of multiple mild genetic mutations, probably along with some sort of toxic environmental exposure. 
  2. The ASO under development for PSP simply reduces the production of normal tau, and since tau has essential functions in the healthy brain, we would not want to completely eliminate its production as AMT-130 could potentially do for HTT in HD.  This means that any benefit provided by the ASO in PSP would have to be moderate at best.
  3. The damage in early HD (the stage recruited by this trial) is almost entirely in the caudate and putamen, the targets of the injections.  But in PSP, by the time a patient is diagnosed, the damage has involved many more than just two areas on each side of the brain.  This would make injecting all the involved areas extremely difficult.

Despite these reservations, the news is good for PSP because like the monoclonal anti-beta-amyloid antibodies for Alzheimer’s disease, AMT-130 sets a precedent for slowing the course of a neurodegenerative disease by attacking an aggregating protein.  But unlike the AD results, the patients receiving AMT-130 for HD suffered only mild side effects and enjoyed a dramatic benefit.

Even if this technique can’t help PSP because its tau is not genetically defective, other proteins are likely to be mutated in at least a few people with PSP.  We do know of 22 genes with some sort of genetically-related defect, but we don’t know if any are encoded into defective proteins like the HD mutation is. 

But we can hope that before too long, there will be diagnostic markers to detect PSP before it spreads beyond two or three small brain areas; and the results of genetic testing in a lone individual with PSP will allow their neurologist to order up a cocktail of injectable gene therapies to fit their own combination of mild gene mutations.  We can dream.

I’ve spent my summer in futility

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If you’ve been disappointed with the long intervals between my posts over the past few months (and I hope you are), there’s a reason.  I’ve been using much of my discretionary sitting-at-the-computer time writing a long review article on clinical trial design in PSP.

The editor of the journal Alzheimer’s and Dementia: Translational Research and Clinical Interventions invited me to write something on PSP for a special issue on a trial outcome measure called “minimum clinically important difference.”  The MCID is the smallest change in an existing, validated, accepted clinical rating scale that can be perceived by the patient as making a difference to their everyday level of disability or quality of life.  An alternative definition I’ve seen is the smallest difference that would prompt the clinician to recommend a change in treatment. The MCID has never to my knowledge been used in PSP trials, though for over a decade it has served at least as a secondary measure in trials in other conditions, including Parkinson’s disease. 

The most widely accepted outcome measure for PSP clinical trials is still the original, 28-item version of the PSP Rating Scale, which uses a point scale of 0 (best) to 100 (worst). But the original PSPRS been criticized, most prominently by the FDA, as too dependent on the neurological examination, with insufficient attention to the patient’s daily life. The European Union’s equivalent of the FDA, the European Medicines Agency (EMA), still prefers the original PSPRS. (Disclosure: I developed the PSPRS and receive a share of its licensing fees from Rutgers University, the scale’s official owner.)

I collaborated in this writing project with Ronald G. Thomas, PhD, a biostatistician at UC San Diego.  We calculated an MCID for PSP using data from the placebo groups of five published, 12-month double-blind clinical trials.  I won’t get into more details lest I plagiarize myself or invite scoops, as the manuscript was submitted only a couple of weeks ago and has not yet cleared peer review.  But I can tell you that the MCID is only a small part of our paper, which discusses many aspects of PSP trial design with an eye toward allowing trials to enroll participants faster and to become smaller, cheaper, shorter, and easier for the patient and caregiver.

Aside from obvious the patient/caregiver consideration, why is all this so important?  Because we need to lower the bar for small pharma or biotech companies to try their new drugs in PSP. One obstacle is the cost – fewer patients and shorter trial durations are simply cheaper.  Another is that during a trial, the clock is ticking on the drug’s patent protection.

A very interesting outcome of the calculations Dr. Thomas performed for our paper (again, provisional pending peer review) relates to the number of participants required for a PSP “futility trial.”  That kind of trial typically uses controls from previously published sources, thereby reducing recruitment time and costs.  It is designed to determine relatively cheaply if a drug should be abandoned or it’s worth testing in a formal, expensive, traditional trial meeting government requirements for potential approval.  A small company whose futility trial “rules out futility” (to use the formal, statistical term for success in this context) could find it easy to license or sell that drug to a larger company or to attract venture capital for a large trial of its own.

Dr. Thomas found that a futility trial needs only 100 participants on the active drug, assuming it uses placebo data from 200 people from previous trials, and has 80% power to detect a 35% slowing of progression with a statistical significance of .05. That’s not really huge news, as futility trials have been performed in PSP before, albeit using different statistical parameters than these. 

The take-home is that the unsuccessful double-blind PSP trials of the past have provided a valuable resource in the form of their placebo groups’ data, which can allow futility trials and permit many other improvement to our current clinical trial designs in PSP. That could make the clinical trial pipeline easier, faster, cheaper and less of an obstacle to small, start-up pharma companies.

Let’s pick up and dust off

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Some not-so-good news, I’m afraid: ORION trial has been discontinued for lack of benefit.

A combination of two oral drugs collectively called AMX0035 has been in a double-blind trial since late 2023. One component, sodium phenylbutyrate (brand name Buphenyl), helps brain cells get rid of misfolded, worn out or defective proteins, including tau. The other, taurursodeoxycholic acid (brain name TUDCA), stabilizes dysfunctional mitochondria. Both drugs are known to be safe in non-PSP populations, as they have long been approved and marketed for other conditions.

A few days ago, with about half of the ORION subjects having completed their 12-month double-blind observation, the sponsoring company performed an interim analysis. Their statisticians, under strict secrecy rules, “peeked” at the active drug vs. placebo assignments, comparing the groups on their degree of worsening on the PSP Rating Scale since the first visit. They found no difference, which means that allowing the remaining patients to complete their double-blind observation could never show a statistically significant improvement for the trial as a whole. Nor was there any slowing of progression on any of the secondary efficacy measures such as brain atrophy on MRI. Fortunately for the study participants, the frequency and severity of adverse effects were very low in both the active drug and placebo groups.

Where does PSP go from here, trial-wise?  Lots of places:

  • The trial of FNP-223, an oral drug that reduces abnormal phosphorylation and misfolding of tau, is nearly complete.
  • A trial of NIO-752, an anti-sense oligonucleotide injected into the spinal fluid that reduces the manufacture of tau, will start in a few months.
  • The PSP Platform Trial, which has teed up two two drugs and expects a third soon, should start later this year if changes in its NIH funding don’t stand in the way. Those are an active anti-tau vaccine called AADvac1 and AZP-2006, an oral drug that reduces inflammation and helps brain cells dispose of garbage. They will be tested separately, but using a common control group.
  • The trial of GV-1001, a subcutaneous injection that works at the RNA level to reduce brain inflammation, will probably start in 2026 or late 2025 if all goes well.  

Two drugs a bit further behind in the pipeline, based on my reading of the tea leaves, are:

  • bepranemab, an anti-tau monoclonal antibody for intravenous infusion and
  • an oral reverse transcriptase inhibitor called censavudine, where the results of the Phase I trial are sparsely reported to date.

That makes five new drugs to start trials within the next year or so — plus another one or two slightly later.

I liked the ORION trial’s idea to give two drugs simultaneously to address two different parts of PSP’s pathogenesis. Many PSP experts feel that at least that many drugs will be needed to do much to slow the progression of this complex disease. That’s what has proven necessary for things like AIDS, severe hypertension and many kinds of cancer. Those are only a few examples of multi-pronged attacks turning life-threatening, progressive diseases into chronic, manageable, non-disabling conditions.

I’m bullish on the same kind of thing happening to PSP.

Why didn’t I learn this in med school?

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“Palliative care” is too often considered to be confined to the final stages of illness: pain medications or sedatives as needed, anti-bedsore measures, adequate nutrition – and little else.  Wrong.  It’s now a medical specialty in its own right, with post-residency training programs, fat textbooks and dedicated medical center departments.  True, it’s for people with irreversible conditions, but its offerings include far more than those basics. 

Most palliative care exists in the world of oncology, of course, but it’s now gaining attention for PSP.  My PubMed search on the terms “progressive supranuclear palsy” and “palliative care” revealed 50 articles, all since 2000, of which 45 appeared since 2011.

CurePSP’s Centers of Care network has a sub-group of neurologists and site coordinators dedicated to palliative care in PSP, CBS and MSA.  Its task is to research and better understand the role of palliative care, to educate clinicians, patients, caregivers and government regulators, and to recommend changes to improve the quality and availability of such care.

That “working group,” as it’s called, took a major step this week with the publication of a paper entitled, “Serious Illness Conversation in the Care of Atypical Parkinsonian Disorders: A Practical Guide for Neurology Clinicians.” Its lead author is Dr. Michiko Bruno of The Queen’s Medical Center at the University of Hawaii.  Also playing a major role was Jessica Shurer, CurePSP’s Director of Clinical Affairs and Advocacy. (Full disclosure: I know both well, have worked with each on other projects, and vouch for their skills and dedication.)

The paper formulates four “practical guides” not confined to the traditional end-of-life role of palliative care.  They are: 1) informing the patient and family of the diagnosis and likely prognosis, 2) discussing the patient’s goals for the management of their illness given the lack of curative or very effective symptomatic treatments, 3) addressing safety, especially given the impulsivity that is a common part of PSP, and 4) guiding, ascertaining and respecting the preferences of patient and family regarding end-of-life issues.  For each, there’s a list of “dos and don’ts” that, I assure you, would be news to many neurological professionals.

How to transmit this paper to your own physicians without risking insulting them?  Maybe mention some point from the paper at an opportune moment at your next visit and cite its source. (All you need to say about the source is, “a PSP blog I read” or “doctors at CurePSP.”)  A clinician with any inclination to learn more may then ask you for a link.  Maybe the next paper from the Centers of Care should be on how patients and caregivers can diplomatically get neurologists to educate themselves on PSP.  But meanwhile, this one on palliative care will meet another important need.