Tag Archives: PSP Rating Scale

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.

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.

The scale is tilting

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The PSP Rating Scale has had quite the odyssey. I designed back in 1996 (30 years ago now!) to be used by neurologists or other clinicians working in movement disorders, and its specialized terminology reflects that.  But some people with PSP or their caregivers have attempted to apply the scale themselves.  That, and the continued importance of the scale in PSP research, prompt this update.

The scale and its tips/rules for its administration can be viewed and downloaded from the CurePSP website.

The PSPRS is intended mostly for use in routine clinical care and touches on all the common features of PSP.  It’s designed to answer the question, “So, how am I doing, Doc?” on a 100-point scale, with zero being perfectly normal.  It’s a measure of the severity of symptoms, not a set of diagnostic criteria.  The most recent such criteria, if you’re interested, are available here. They’re also pretty technical.

The PSPRS includes 28 items, 22 rated 0-4 and six rated 0-2, divided into six sections.  The first, “History” is rated via interview.  The others, all requiring a neurological exam, are Mentation, Bulbar, Ocular Motor, Limb Motor, and Midline/Gait.  (“Bulbar” means speech and swallowing, so named because the part of the brainstem where those things are controlled, the medulla oblongata, looks like a flower bulb or a fat scallion.)

The PSPRS scoring behaves thusly: The average person with PSP-Richardson syndrome, the most common PSP subtype, comprises about half of all patients) and worsens by an average of about 11 points per year, more slowly at the very start and end of their PSP journey.  PSP-Parkinsonism, accounting for about 20% of all PSP, progresses about two-thirds as quickly.  Most people entering clinical treatment trials (all with PSP-Richardson) have scores between 35 and 40, a figure heavily influenced by most trials’ rules that participants be in the early or middle disease stages.

Although I did not design it specifically for research use, the PSPRS became the world-wide standard measure in PSP research soon after its 2007 publication.  However, the time required to administer it has prevented it from attaining much popularity for its original purpose as a routine tool in patient care.  I can run through it in 10 minutes with a mildly affected patient, but physicians with less experience and patients with more complicated deficits require up to 20.  With only 20 or 30 minutes scheduled by most medical practices for follow-up visits, you can see why the PSPRS has not attained popularity outside of research projects, where the visits include many more tests and require several hours.

Another issue with the PSPRS is that some of its 28 items relate more to the neurologist’s concept of what’s going on in the patient’s brain rather than directly to daily disability, which, after all, is the primary target of both routine care and research.  Therefore, the FDA in the US has expressed a preference for its own 10-item version, which retains items only in the History, Bulbar and Midline/Gait sections and collapses some of the response options in most of the others.  Naturally, the lesser precision of the “PSPRS-10” requires that the study recruit more patients to provide the statistical power to demonstrate a given degree of drug benefit and provides no information at all on eye/eyelid movement or cognitive/behavioral deficits.  But researchers in Germany have applied a sophisticated statistical technique for drug trials called “item response theory” using all the study visits (typically about five over 12 months) rather than just the starting and ending visits.  This allows the PSPRS-10 to exceed the original in its statistical power to detect a drug benefit despite the lesser supply of information from each visit.

The anti-sense oligonucleotide (ASO) trial, called “PRESERVE” from Novartis is the first to use the FDA’s PSPRS-10 as its primary outcome measure.  The trial’s designers had little choice because as a Phase 3 trial, it is “pivotal” in the sense that it could make or break the drug in the eyes of the FDA.  However, PRESERVE will add the original 28-item version to its secondary measures. They can be considered by the FDA to clarify a weak result in the primary measure.  Its inclusion also makes life easier for future researchers seeking to integrate the study’s results into the large body of data available from previous drug trials.

Other abridged versions of the PSPRS-28 to date are:

  • A 14-item version omits the items less relevant to daily activities, with each remaining item rated 0-2.   It performs as well as the original for PSP-Richardson but not for the other variants, according to a trial by a different set of researchers.
  • A 15-item version, also a subset of the original, which uses the results of the unsuccessful PASSPORT trial to omit items less related to daily activities as well as statistically redundant items and response choices.  It offers better statistical power than the original or any of its other modified versions and is being used as the primary outcome measure in the PSP Trial Platform.  The PTP can defy the FDA’s recommendation to use its 10-item version because those are only Phase 2 trials, not the Phase 3 pivotal trials that the FDA uses to decide on a drug’s final approval. 
  • 21- and 24-item versions omitting PSPRS-28 items problematic for tele-health administration.  These have not yet reached widespread adoption for either routine practice or research, but they have excellent potential for use in pandemics or for patients with difficulty traveling to a neurologist for reasons of disability or distance.  The only potential problem is wrangling the software.

None of the PSPRS versions allows reliable administration by the patient or caregiver, but the Cortico-basal Ganglia Functional Scale (CBFS) does so.  In fact, it’s designed for use online or in the neurologist’s waiting room, with no instructions needed beyond what’s on the form. Despite its name, it has been validated for PSP as well as for corticobasal syndrome.  So, if you want to rate yourself at home, use the CBFS rather than any of the PSPRS versions, and coordinate with your neurologist so as to make best use of the results.

Despite all this, the original content and wording of the PSPRS-28 have never changed. I’ve only refined the instructions and tips published along with it.

Finally, a little perspective: Despite all this hard work on various rating scales, measuring atrophy of the brain’s frontal lob on MRI tracks progression of the disease better than any of them.  One careful analysis found that a trial designed to detect a 50% slowing of progression using the PSPRS-28 would need 112 subjects (half on active drug, half on placebo) and only 72 using the MRI measure.  Of course, the FDA would never accept such a measure in a pivotal trial, but at least one current, early-phase PSP trial is using MRI as its primary outcome measure.

I refer to the PSPRS-28 as my own work, but some of the credit belongs to my statistician colleague at Rutgers, Pamela Ohman-Strickland, PhD.  I couldn’t have validated the scale without her.  I know because I tried.

Disclosure: I (and Pam) have a financial interest in the PSPRS via a sharing policy at Rutgers University, which owns the copyright and licenses it to pharma companies for use in their drug trials.  Rutgers imposes no fee for its use in regular patient care or in research by non-profit organizations such as universities.

Neuroprotective tangles

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Prompted by a reader’s comment a few days ago, I thought I should write about the difference between “neuroprotective” and “symptomatic” treatment.  The distinction is relevant to the PSP treatment trials about to start and to one’s decisions about whether to volunteer for them.

Neurodegenerative diseases, by definition, progress over time and neuroprotective treatments attempt to slow that process, not to provide relief from existing symptoms.  In theory, such treatments could be so miraculously effective as to halt the process in its tracks, but a realistic best-case target given our current understanding of these diseases is a 40%-50% slowing of the rate of future progression. Most PSP trials are designed to detect about a 25%-30% slowing.  A trial large enough to detect more subtle degrees of slowing would be prohibitively expensive.

For a drug to improve the existing PSP symptoms or disabilities, as levodopa improves those of Parkinson’s, for example, would require replacing a molecule deficient in the brain cells that still survive and function, or stimulating the surviving cells to work harder, or modulating the activity of other, healthy, brain cells to partly compensate for the effects of the damaged cells.  Such drugs do exist for PSP, but their benefits are modest and temporary, and the underlying neurodegenerative process continues.  In Parkinson’s, levodopa gives dramatic and long-lasting symptomatic benefit, but even there, the degenerative process continues unabated.

The graph below illustrates all this:

  • The vertical axis is the PSP Rating Scale, where 100 is the worse possible score and the average rate of worsening is about 11 points per year.  At a score of about 80, fatal complications such as pneumonia or severe urinary tract infections become very common.  Note that to avoid displaying blank space, the axis starts at 30 points, not zero.
  • The horizontal axis is years since the start of the treatment (the “baseline”).  You can see that for purposes of this illustration, I’ve chosen a baseline PSPRS score of 40, which conforms to experience with previous trials and to the observation that the average person with PSP doesn’t receive that diagnosis until about three years after symptom onset.
  • The blue line represents the course of the disease untreated.  In a drug trial, there’s usually a placebo effect, but to keep things simple, the graph ignores that.  Besides, that effect would dissipate over a couple of months at most.
  • The orange line represents the course 30% slower than that of the placebo group.  Note its shallower slope.  Again, for simplicity I show the effect as starting immediately upon receiving the drug even though some neuroprotective effects may take a few months to get going.
  • The green line shows a symptomatic effect, which in this example starts immediately and lasts years.  I’ve semi-arbitrarily chosen its magnitude to be five PSPRS points and the time to maximum benefit as six months.  At that point the rate of progression of the underlying disease continues unabated, but the five-point symptomatic benefit persists.  Note that the participants on such a drug are doing better than those on the successful neuroprotective drug until a bit after the three-year point, when the lines cross, and the advantage of the neuroprotection continues to widen.

HYPOTHETICAL COMPARISON OF EFFECTS OF PLACEBO,

NEUROPROTECTIVE AND SYMPTOMATIC TREATMENTS OF PSP

I’ll emphasize that while the 11 points per year rate of progression is based on real data, the 30% slowing of the rate of progression is only an illustrative example for the purpose of this instructional exercise. The five-point symptomatic improvement is analogous to the magnitude of improvement of Alzheimer’s disease treated with cholinesterase inhibitors such as donepezil, galantamine and rivastigmine.

The death of a brain cell isn’t like an incandescent light bulb suddenly burning out – it’s more like a slowly fading LED bulb.  During that “ill” phase, it might be possible for a candidate neuroprotective treatment to instead (or in addition) have a symptomatic effect. 

With all that as background, here are some conclusions:

As you’d imagine, it could be difficult to tell neuroprotective from symptomatic (or placebo) effects, as they’re both being measured by the same PSP Rating Scale.  But clinical trials in PSP try to anticipate this by testing for more objective evidence of slowing of brain cell loss, for example by assessing atrophy on MRI or spinal fluid levels of a protein called neurofilament light chain (NfL), which increases steadily in PSP and some other disorders. Placebo and symptomatic improvement would not be reflected in those diagnostic markers.

    Neuroprotection trials also perform their first repeat exams in the first few weeks and months to look for a rapidly-appearing difference in PSPRS scores between the active drug group and the placebo group. (MRI and NfL would not be useful so soon after baseline.)  However, it would be difficult to decide whether such a PSPRS improvement is placebo effect or symptomatic effect.

    There’s another way to distinguish a placebo effect from a physiologic effect (we avoid the term “real” because placebo effects are also real in their own way).  That’s to assess the participants for worsening couple of months after the trial’s end, when any symptomatic effect would have dissipated.  I haven’t seen the PRESERVE (Novartis’ NIO752 trial) protocol and its clinicaltrials.gov entry doesn’t address the matter, but I expect that it plans to do this, if only to monitor any adverse effects of the drug. 

    Bottom line: In a Phase 3 trial in a neurodegenerative disease, separating true neuroprotection from symptomatic and placebo effects is tricky. In future blog posts, I’ll try to sort out that tangle for you if I can.

    —

    PS #1: For an excellent, very recent review of the placebo effect, see this paper, which is written in language easily comprehensible to educated laypersons.

    PS #2: Disclosure: I consulted for Novartis from 2018 to 2020, but not since. I have never held stock or any other financial interest in the company. But I do hold a major emotional interest in seeing their drug work, so there’s that.

    Tele-PSP

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    Here’s great news:  The new Federal spending bill, which the president has now signed into law, includes a continuation of Medicare’s payment for tele-health visits, including  audio-only visits, through December 2027.  It essentially cancels, for now, the planned return to Medicare’s pre-Covid telehealth policy.

    This is especially important for those with PSP, where neurologists familiar with the condition are few and far between and where many of those affected have difficulty traveling, even by car.

    PSP is in a better position now than it was pre-Covid to adapt to telehealth.  Two versions of the PSP Rating Scale that omit the items difficult to perform by video were validated in 2023.  Disclosure: I was a co-author.  The original version of the PSPRS, published in 2007, has 28 items and I’ll refer to it as the “PSPRS-28.”  (Disclosure: I developed it and validated it with the help of statistician Pam Ohman-Strickland). One video-friendly modification, the PSPRS-25, omits the three items that require the “laying on of hands,” to use a term that shows my age.  The other, the PSPRS-21, omits those plus the four others relating to eye movements and dystonia.  With the sub-optimal technical situation in the patient’s home, video’s image resolution is not adequate to assess those items, even with the caregiver’s assistance. 

    The procedure applied the PSPRS-25 and PSPRS-21 to records from PSPRS-28 administration to two patient groups.  One was the placebo group from the 12-month davunetide PSP study published in 2014 .  The other was my own patients with PSP seen from 1994 to 2020, where I applied the PSPRS-28 at each visit.  The result was that there was excellent correlation with the PSPRS-28 in the 12-month trial database and with long-term prognosis in the long-term database.  That project was led by Drs. Alexander Pantelyat of Johns Hopkins and Anne-Marie Wills of Mass General. 

    Other support for video visits for PSP was provided by a study from 2020 where two neurologists independently evaluated a series of patients with various atypical Parkinsonian disorders by live video and compared diagnoses.  The degree of agreement was excellent, with a kappa score (the standard statistical test for inter-rater agreement) of 0.83.    A kappa of 1.0 is perfect agreement and anything over 0.75 or 0.80 is considered excellent. That study is from the University of Rochester, led by Drs. Christopher Tarolli and Jamie Adams.

    It’s great to know that an accurate PSP Rating Scale exam is feasible by video, and to know that neurologists almost agree on their video diagnosis of atypical Parkinsonian disorders.  But there’s a lot more to the care of someone with PSP than diagnosis and symptom rating. But hey, maybe tele-health, with a hand from AI, will learn to do all that, too.  Give it a few years.

    An unwelcome (?) addition to the family

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    You’ve all heard of the ten known PSP subtypes.  They’re classified into three groups by the general areas of the brain involved (i.e., cortical vs. subcortical).  Here’s the list:

    1. Cortical and subcortical (~50% of all PSP)
      • PSP-Richardson syndrome (PSP-RS)
    2. Cortical (~20%)
      • PSP-frontal (PSP-F)PSP-speech/language (PSP-SL)
      • PSP-corticobasal syndrome (PSP-CBS)
    3. Subcortical (~30%)
      • PSP-Parkinsonism (PSP-P)
      • PSP-progressive gait freezing (PSP-PGF)
      • PSP-postural instability (PSP-PI)
      • PSP-ocular motor (PSP-OM)
      • PSP-cerebellar (PSP-C)
      • PSP-primary lateral sclerosis (PSP-PLS)

    (As an aside: Neurodegenerative diseases are defined mostly by their pathological (i.e., microscopical) appearance, but each disease so defined may have several possible sets of outward signs and symptoms in the living person, depending on the general locations of the pathology within the brain.  We deal with this by hyphenating the names of neurodegenerative diseases, with the pathology first and the clinical picture second.) 

    Now, to the news: Researchers at the Institute of Science in Tokyo, the Mayo Clinic, and UC San Diego have refined the above subtype classification.  First author is Dr. Daisuke Ono, senior author Dr. Dennis Dickson and eight colleagues included 588 autopsy-proven cases of PSP from the Mayo brain bank without evidence of other neurodegenerative diseases.  First, they used ChatGPT’s large-language software to extract clinical data from 53,527 pages of medical records, tabulating the order of appearance and progression rate of 12 pre-specified, PSP-related symptoms in each patient. Next, they performed a statistical technique standard for this sort of thing called “cluster analysis,” coupling it with a “decision tree model.”  The first revealed groups of symptoms and progression rates that occurred together more often than would be expected by chance.  The second worked out a practical, step-by-step way for neurologists to assign an individual patient to a subtype.

    The most important result was a new subtype combining some patients with what has been defined as PSP-F with some from PSP-PI.  The analysis still found statistical justification for continuing to recognize those two familiar categories as bona fide subtypes on their own.  The new subtype, called PSP-PF (the continuous red curve), has the dubious distinction of having the most rapid progression and shortest total survival of all.  In the graph below, you can trace a vertical line from where the “median” line crosses the curve for each subtype to find the median survival on the horizontal axis.

    The median survival of PSP-PF was 6 years, with a 25-75 interquartile span (i.e., the middle two quarters of the group) of 5-7 years.  This compares to PSP-RS, with a median of 7 and a 25-75 span of 6-8.  For the subjects remaining in the PSP-PI and PSP-F groups, the median survival figures were 8 and 9 years, respectively.

    This re-shuffling isn’t just a statistical detail.  In the total group of 588 patients, 188 (32%) had PSP-PF, while only 68 (12%) had PSP-RS.  Even considering the bias of any autopsy series toward over- representation of atypical cases, it’s still remarkable that PSP-PF is far more common than the other non-RS subtypes. 

    All that should be accompanied by the standard scientific conservatism about adopting new findings as textbook-worthy, especially without independent confirmation.  Weaknesses in this study, all of which are recognized by the authors, include the following:

    • When a clinical feature wasn’t mentioned in the records, the analysis treats it as if it were known to be absent.
    • Quantitative data such as drug dosages, blood tests results, cognitive test results, and imaging details were not considered.
    • If a symptom onset date was not mentioned in the records, the date of the first relevant physician visit was used as the equivalent.

    Having recognized all that, we can still say that an AI-based procedure may have found a pattern in ordinary medical record data that human neurologists and researchers missed. 

    My title for this post tentatively calls the discovery “unwelcome” only because no one would be glad to learn that their subtype of PSP is more rapidly progressive than they thought.  (I’m referring to those people with PSP-PI and PSP-F who would fall within the definition of the new PSP-PF.)  But one upside is that the news that a large group of people with PSP has a rate of progression similar to that of PSP-Richardson could allow neurologists to better counsel patients and their families.  Another important upside is that perhaps clinical neuroprotection trials could now enroll participants with both PSP-PF and PSP-RS instead of confining themselves to the latter.  This could greatly increase the pool of eligible trial participants and shorten the time required for the recruitment and double-blind periods. 

    The main potential obstacle to enrolling participants with PSP-PF into trials is that the primary outcome measure, the PSP Rating Scale, has not yet been validated for that subtype. But that should be possible to accomplish by identifying people with PSP-PF in existing, longitudinal or retrospective observational cohorts using the decision rubric of Ono et al.  Then, one would simply assess the ability of their existing, longitudinally administered PSP Rating Scale scores to track their symptoms over time.

    So the “unwelcome” part of this won’t actually change anyone’s PSP for the worse and the upside of speeding up clinical trials would be most welcome.

    Orphans, this could be your chance

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    Back in 2023, I posted an explanation of the ten PSP subtypes.  The archetypal subtype, PSP-Richardson syndrome accounts for about half of all PSP and, in contrast to most of the other subtypes, has a rapid progression rate, a validated rating scale, and highly accurate diagnostic criteria.  All of these features have led clinical trial sponsors to maximize their trials’ sensitivity and minimize their costs by restricting admission to people with PSP-Richardson.  But developing better outcome measures for non-Richardson forms of PSP could change that practice.

    A big step toward realizing this goal was published last week in the journal Neurology by a group at the Mayo Clinic in Rochester, MN.  Led by first author Dr. Mahesh Kumar and senior authors Drs. Jennifer Whitwell and Keith Josephs, the study found that a good outcome measure for clinical neuroprotection trials in all PSP subtypes was to combine a measure of atrophy by MRI with a measure of clinical disability.  This is a major advance.

    The researchers performed brain MRIs at the start and end of a one-year period in 88 people with PSP and 32 age-matched controls.  Of those with PSP, 50 had PSP-Richardson, 18 had “PSP-cortical” (three of the other nine subtypes) and 20 had “PSP-subcortical” (the other 6 of the subtypes).  They had to lump the non-Richardson subjects using their subtypes’ general anatomical predilections because most of the subtypes were too rare to analyze on their own.

    Calculating how much each of ten important PSP-involved brain regions had atrophied over the one-year interval allowed the researchers to identify which region(s) might best serve as markers of progression for each of the three groups when coupled with standard clinical measures.  Those measures include such familiar instruments as the PSP Rating Scale and the Unified Parkinson’s Disability Rating Scale’s motor section as well as less familiar scales specific for cognition, gait, eye movement and speech.  All the scales were administered concurrently with each of the two MRIs. 

    They expressed the sensitivity to one-year progression not by some abstract statistic, but by the number of patients needed in a double-blind trial to demonstrate with at least 80% certainty that patients on active drug enjoyed a 20% slowing of progression relative to the placebo group. (These specifications are typical for PSP clinical trials.)  The better the measure’s performance, the fewer patients are needed.

    And the award for Best Performance by an Outcome Measure in a PSP Neuroprotection Trial goes to . . . a combination of the rate of atrophy of whatever brain region shrinks fastest in the patient’s specific subtype and the PSP Rating Scale score.

    The real significance of this study’s result is that using an outcome measure customized to each participant’s PSP subtype could allow trials to enroll not just people with PSP-Richardson, but also those with any of the other subtypes.  That’s because the trial’s measure of success could be to compare each patient’s rate of progression during the trial to that of patients in the placebo group with the same PSP subtype. 

    This could double the number of people eligible to enroll in PSP trials, which means cutting the enrollment period in half, with commensurate reduction in costs for the sponsor.  The hybrid measure is more sensitive to progression than the PSP Rating Scale alone, thereby reducing the number of patients required even more. 

    Both factors could lower the financial barrier confronting a company hoping to mount a trial for a promising PSP drug.  That may be the most important bottleneck right now in the development of a treatment to prevent or slow the progression of PSP.s

    That’s why this news is huge for PSP in general and for the “orphans” in particular.

    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 Trial,” (PTP) 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 PTP 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.

    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.

    Don’t try this at home

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    CurePSP recently received an inquiry from a PSP caregiver who had evaluated the individual with PSP twice over a 6-month period using the PSP Rating Scale and needed some guidance in interpreting the results.  We had to tell them that the PSPRS is designed for use only by neurologists experienced in evaluating people with movement disorders and eye movement disorders, so the scores they generated cannot be relied on.  Besides, the second score was about 30 points (on the 100-point scale) worse than the first, and no one with PSP progresses that quickly.  So, they must have administered the PSPRS incorrectly.

    People with PSP and their caregivers who ask about the PSPRS are advised to pass it along to their neurologists, who can decide if they want to use it.  The PSPRS is still the world-wide standard “outcome measure” for PSP treatment trials and the rating standard for observational research.  But it has reached only limited acceptance in ordinary neurological practice outside of academic settings because it takes 10-15 minutes to apply, and most neurologists don’t have that kind of time in a visit to devote to it.

    But don’t despair, you neurological do-it-yourself-ers.  There’s a newer scale called the Cortico-Basal Functional Scale (CBFS), which is designed to be completed by the patient and caregiver and works just as well for PSP as for CBS.  It’s not quite as precise as the PSPRS because it relies only on subjective symptoms and experiences, but it’s still quite reliable in assessing the severity of PSP and tracking its progression.  It has more potential to be adopted by neurologists for routine care because it can be completed at home the day before the visit or even in the office waiting room. You can download it via the link above, complete the 31 multiple-choice questions and bring the completed form to your next neurology visit.