Monthly Archives: May 2026

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.

    A good problem to have

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    Now, this is progress.  Novartis just yesterday announced in clinicaltrials.gov that its Phase 3 trial of NIO752 is ready to accept volunteers for screening. The name of the trial is PRESERVE.  Good name.  No, it’s not an acronym for anything.

    So far, the company has only announced three trial sites (Rochester, MN; Englewood, CO; and Ulm, Germany) but dozens more will follow, with a total recruitment goal of 300.  Here are some details of probable interest to potential volunteers:

    • The drug is an antisense oligonucleotide, which as you’ve learned from this blog, interferes with the brain cells’ ability to translate the RNA from a specific gene into its protein.  In this case, the protein is tau, which lies at the heart of PSP.
    • As a very large molecule, NIO752 cannot pass the blood-brain barrier, so it has to be injected directly into the cerebrospinal fluid in the lower spine, using the same procedure as a diagnostic spinal tap (lumbar puncture).  This will be given every three months, assuming it follows the plan of the Phase 1 study.
    • A trial of the drug for safety in 45 people with PSP showed no important or permanent adverse effects from the procedure – just harmless and transient headaches or back pain in some.  Some transient confusion or lethargy occurred in three of the 45 – an effect of the drug, not the injection procedure.
    • The trial will enroll 300 participants overall, of whom 100 will be randomly chosen to receive a placebo injection.  That treatment assignment will be double-blind — not revealed to participant or neurological staff until the whole trial is over.
    • The duration of the double-blind period will be 72 weeks – about a year and a half.  After that, all the patients will be offered the opportunity to continue receiving the drug at no cost, as long as it has not been found to be harmful, and as long as Novartis is still manufacturing it.  That “open-label extension” program may end if and when the drug works and is on the market (let us pray).

    Your big question right now should be this: Should I volunteer for the PSP Trial Platform (PTP) or PRESERVE?  The scheduled start for PTP is next month (June 2026), and those sites will roll out gradually, just like the PRESERVE sites.  So, in theory, there’s no overall difference in the timing, though a site near you might open for one study well before the other, or there may be an accessible site for one and not the other.  All the PTP drugs and NIO752 are similarly and acceptably safe, in my view.

    Right now, I’d say volunteer for PRESERVE, though by a slim margin.  Two reasons, each minor:

    • Like any large, complicated project requiring approvals from government, private companies and academic institutions, the PSP Trial Platform has been subject to unforeseen delays.  (All major drug trials require collaboration among these three, but the PTP is more complicated than most.) In fact, the company sponsoring one of the three drugs planned for the PTP has still not finalized the arrangements, according to clinicaltrials.org. If that can’t be accomplished soon, the trial will start with only two drugs.  So, a bird in the hand . . .
    • The PRESERVE trial will have an open-label extension (see the caveats above), while the PTP has not yet decided on that, and it may differ across the different drugs.  Without an open-label extension, someone completing the Phase 2 trial would have to wait until the Phase 3 is finished and the drug approved before gaining access to it.  On the other hand, the FDA has been known to approve drugs for general use after only a Phase 2 if the need is great, and for PSP, it surely is. The PTP double-blind trials are 12 months long and the PRESERVE double-blind is nearly 18 months, so assuming both offer open-label extensions, someone on placebo in PRESERVE would have to wait six months longer to receive their active drug than someone in the PTP.

    Yes, there are other drugs whose sponsors are optimistic that trials will start within the next year or so.  Those include bepranemab (a monoclonal anti-tau antibody), GV1001 (an anti-inflammatory), ARV-102 (an enhancer of abnormal tau degradation) and TPN-101 (an inhibitor of a toxic protein called LINE-1).  But the timelines there are just too uncertain for someone with PSP to consider right now.

    Maybe the most important consideration is which drug is mostly likely to work.  I honestly don’t know, and the Phase 1 data don’t answer that question.  So that simplifies things a bit.

    A difficult choice, I know, but a good problem to have. 

    ASOs: sci-fi takes a step closer to reality

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    Great news from Biogen about an antisense oligonucleotide (ASO) designed to reduce production of the tau protein. 

    First, some background: Most of you have heard about ASOs, but for a refresher, see these posts of mine from 2022 and 2026.  Here’s a slightly more technical but cutely animated explanation of ASOs from Harvard Medical School:

    The elevator version is that an ASO is a short length of RNA that binds and inactivates the brain’s messenger RNA for a specific protein – or an abnormal version thereof – to prevent it from carrying the protein’s genetic code from the DNA to the protein-manufacturing machinery.  In theory, the production of any protein involved in the cause of a disease can be reduced by designing an appropriate ASO to bind to a segment of that protein’s messenger RNA.

    The FDA has approved only one ASO so far – for a childhood muscle disorder called spinal muscular atrophy – but dozens of other ASOs are in the development pipeline for other conditions, including tauopathies. Biogen is currently testing its anti-tau ASO, called diranersen (formerly BIIB-080) against Alzheimer’s, by far the most common tauopathy.  A few days ago, they announced the results of a Phase 2 study of its safety and tolerability.  Here’s Biogen’s press release and here’s the description of the trial (without results) in clinicaltrials.gov. 

    Diranersen was well-tolerated in people with Alzheimer’s, as expected based on the Phase 1 results.  The big news was that the rate of accumulation of abnormal tau protein aggregation actually did slow down, as measured by levels of tau in the spinal fluid and by positron emission tomographic (PET) images of the tau protein’s distribution in the brain. The press release didn’t say how much slowing occurred, but it was apparently enough to convince Biogen to proceed to a Phase 3 trial and to convince the FDA to let them do so. More details will be presented at the Alzheimer’s Association International Conference in London in July 2026.

    The trial was not primarily designed to assess slowing of progression of the participants’ actual cognitive loss, but it gathered that information anyway in various forms.  The primary such test, called the “Clinical Dementia Rating Scale Sum of Boxes,” measures memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. It did not show a statistically significant slowing of progression for diranersen in Alzheimer’s, but the press release hints that there was some slight, statistically non-significant, degree of slowing.  

    That’s all about Alzheimer’s. For PSP, a different company, Novartis, is testing a different anti-tau ASO (NIO-752).  It is also well tolerated, as demonstrated by a recently-completed Phase 1 trial.  If the brain’s accumulation of abnormal tau can be slowed down in Alzheimer’s disease, as the Biogen press release claims, then presumably PSP can achieve the same result.  Novartis says it’s still (as of May 15, 2026) analyzing its Phase 1 PSP efficacy results, but those would have to be spectacular to show statistical significance in so small a study.  That company will soon start testing NIO-752 in a Phase 2 PSP trial in the US and other countries, so keep an eye on clinicaltrials.gov for enrollment instructions.

    Given these new results of one anti-tau ASO in one tauopathy, what are the prospects for a different anti-tau ASO in a different tauopathy?  I’ll duck the issue and call them promising but far from a slam dunk. That will be the topic of a future post, but what I can say right now is even these modest, preliminary signs of success with ASOs in tauopathies would have been science fiction back when I was in med school 50 years ago.

    A random walk down PSP street

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    It’s been a year since I promised you an explanation of the role of “stochastics” in PSP and other neurodegenerative diseases.  It goes to the questions I’ve heard from every patient with PSP I’ve ever treated: “Why me?”

    The cause of a disease can be boiled down to two components: etiology and pathogenesis.  Pathogenesis is about the processes in the body that produce symptoms and tissue loss – the topic of many of my blog posts, but not this one. Etiology is about causative factors originating outside the individual.  Here’s a very generic rundown of what’s known about the etiology of PSP:

    1. Variants in the genetic code inherited from one’s parents:
      • 15 gene variants are known to increase the risk of PSP, though each has only a small effect and together they probably explain less than a quarter of the total population’s PSP risk. 
      • A paper published a few days ago found that a common thread in 13 of the 15 was impairment in the microtubules, the brain cells’ internal monorail/skeletal system.  But other commonalities could exist, too.
    2. Experiences during life, such as:
      • Lesser educational attainment is associated with PSP risk.
      • Other experiences associated with other neurodegenerative diseases include minor brain injury and non-specific stress.
    3. Toxic exposures
      • Rural living and well water use, each possibly via pesticide exposure.
      • Metals, though the specific metals and the routes of exposure remain unclear. 
      • Foods such as sweetsop, soursop, and American paw-paw, with toxins affecting the mitochondria.

    But all these together, based on my seat-of-the-pants statistics, don’t explain most of the population’s risk of developing PSP.  Other than genes, experiences and toxins that have eluded detection to date, what other suspects could there be?  Stochastic events.

    That word basically means “random.”  What specific events are happening randomly to cause PSP?  A few possibilities:

    1. Random mutations in one’s DNA occurring during cell division (called “somatic” mutations, as distinguished from “germ line” mutations from mom and dad) may fail to be corrected by the brain’s error-correction machinery.
    2. Random errors in the encoding of RNA from normal DNA.
    3. Random changes to the DNA other than the nucleotide sequence (the “letters” in the genetic code) itself.  Such changes usually consist of small molecules attached to the DNA and are called “epigenetic” changes.  They occur normally as a way to regulate gene function but can also occur inappropriately, with harmful result.
    4. But the one I’ll put my money on is random tau protein misfolding

    Here’s how that works: Normal tau has no standard pattern of folding on itself.  Rather, each normal tau molecule is like a piece of overcooked spaghetti in boiling water.  But occasionally, and randomly, the loops and curls of one strand happen upon an arrangement that sticks to itself.  The brain does have an app for that – a sophisticated mechanism to recognize, tag, and dispose of such miscreants.  But some of those abnormal folding patterns have the unfortunate ability to get nearby normal copies of tau to adopt the same abnormal folds.  This process, as you’d imagine, operates as a chain reaction, with each misfolded tau molecule inducing the same change in others.  The misfolded molecules tend to form stacks, like checkers with interlocking ridges.  Those stacks are called fibrils and they’re toxic. Clusters of fibrils are called neurofibrillary tangles.

    Which brings us to the original question, “Why me”?  In the figure below, the horizontal axis is time, the vertical is the population of misfolded tau and each colored line is one brain cell. (The graph was designed by an investment advisory service called Artificall.com to describe the random behavior of stock prices, but the principle is similar. I’ve adapted the graph to present purposes. Ignore the tiny number labels.) 

    Here’s what’s happening, in my opinion: Each brain cell starts out with the same frequency of tau misfolding events, but then that frequency varies randomly.  In the vast majority of cells, the resulting number of misfolded tau molecules stays within the range that the cell’s disposal system can handle.  But very rarely, one cell’s load of misfolded tau molecules exceeds that limit (the green circle) and the process of templating more copies can proceed.

    Once that one cell on which I’ve placed the green circle has exceeded its ability to dispose of misfolded tau molecules, it can start transmitting them to nearby cells through both synapses and direct contact without synapses.  As the cell dies from the toxic effects of all those misfolded tau molecules, it will burst, allowing its misfolded tau molecules to disperse through the brain’s fluid to more distant areas, where the same process occurs.

    Where does the “randomness” come in? 

    Notice that each colored line in the figure varies randomly, its direction of variation at any given point being independent of the movements that got it there.  Sooner or later, one brain cell will, by pure chance, accumulate enough random variations in the graph’s upward direction to reach the threshold that overwhelms the cell’s defenses. (Note that an equal number of brain cells are enjoying a less-than-average frequency of tau misfolding – again randomly.)

    Where do the other causative factors come in?

    Without getting into the weeds, those things damage other cellular functions, perhaps in a very subtle way, but enough to impair the disposal mechanism a bit, thereby slightly lowering that horizontal blue line in the graph, which in turn increases the chances that one brain cell will see its disposal threshold exceeded.

    So, what’s the takeaway?

    We can’t control the laws of statistics driving the randomness.  But we can look at the mechanisms of the known factors that lower the level of that blue line, identify drug targets that neutralize those actions, and design drugs (or repurpose existing molecules) to interfere with them. 

    So, despite all the energy I’ve put into the genetics and environmental epidemiology of PSP and Parkinson’s over the course of my career, I’ll say this: Maybe it’s time to stop looking for more little contributing causes.  Instead, maybe we should devote more of our resources to designing and testing drugs that fit and influence the function of known proteins critical to the processes by which randomly misfolded tau causes damage. AI tools already exist for this purpose and are in active use. 

    Another approach the problem of low-impact risk factors is to look at them in combination. In theory, they could interact with one another to elevate PSP risk. But that would require either very large patient surveys or sophisticated laboratory models such as stem cells or mice with one or more PSP-related genetic mutations that are then exposed to pesticides or metals, etc.

    I’ll keep you apprised before another year passes.

    Anti-sense makes sense

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    Today’s New York Times had a human interest story about people with a rare, genetic form of amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) who are benefiting from a drug called tofersen (brand name, Qalsody). It was approved for clinical use in the US in 2023 and in Europe in 2024.  The drug slows the progression of that rare form of ALS by about two-thirds, a phenomenal degree of efficacy.  Today’s story was not news, just a heart-warming a review of the experiences of a few of the people benefiting.

    Tofersen is a member of a drug class called “anti-sense oligonucleotides” (ASOs).  If that sounds familiar, it’s because several other drugs with the same mechanism are being developed for PSP.  ASO’s interfere with the ability of one’s cells to manufacture a specific protein.  In the case of PSP, that protein is tau, and for ALS, it’s superoxide dismutase-1 (SOD-1).  The FDA approval and the NY Times story pertain only to the 1-2% of ALS sufferers with an inherited mutation in the SOD-1 gene.  However, a 30-subject, non-blinded trial of tofersen in people with ALS without an SOD-1 mutation (that is, the vast majority) is in progress at Washington University in St. Louis, under the direction of Dr. Timothy Miller and colleagues, the drug’s original discoverers.   That trial is scheduled to end in 2028.

    As far as PSP is concerned, the ASO furthest along the pipeline is NIO-752, from Novartis.That Phase 3 trial is scheduled to start this month (May 2026) with 300 patients with non-familial PSP (as for ALS, the vast majority). 

    Should we expect a two-thirds slowing of progression, as in ALS with SOD-1 mutations?  Probably not, for two reasons:

    1. There’s no single mutation producing abnormal tau protein in the vast majority of people with PSP. 
    2. ASOs are large molecules – to large to cross the blood-brain barrier.  So, they are injected directly into the spinal fluid using the same procedure a diagnostic spinal tap.  ALS is a disease mostly of the spinal cord, which is close to the injection site and only a fraction of an inch in diameter, so tofersen can easily soak into the cord’s full thickness. PSP, on the other hand, is mostly a disease of the brain, where a drug must penetrate a longer distance and into a much larger mass of tissue.  It has been shown to do so in monkeys, but our large human brains may be a different story.

    Despite those caveats, I’m optimistic because even if PSP derives only half of the benefit enjoyed by this genetic form of ALS, it will be a huge advance. Scientists call this “proof of principle.” That means that the general idea has been found to make sense in a similar situation.

    The list of centers slated to participate in the NIO-752 trial has not been announced, so if you’re interested, keep an eye on www.clinicaltrials.gov, www.curepsp.org or this blog. Before you volunteer, keep in mind that several other promising trials for PSP will be starting over the next few months. Check those same three sources for info on those.

    (Disclosure: I’ve done consulting for Novartis, but none since 2023, and I have no financial interest in the company.)