A bit of help with prognosis

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A paper of mine just hit the streets today.  Actually, the idea and most of the work came from an old friend and colleague at the University of Chicago, Dr. Tao Xie.  (His last name is somewhere between “she” and “chee” and his first name is perfect for a PSP researcher.)  Here’s the story of that project, from the beginning.

From 1994 to my retirement from practice in 2020, I kept a careful record of the PSP Rating Scale (PSPRS) results in all 526 patients I saw with PSP.  The database includes each patient’s sex, birth year, month/year of PSP symptom onset, and death month/year (if deceased).  For each visit, I recorded the month/year and each of the 28 PSP Rating Scale item scores.  Back in 2020, some other colleagues and I published a paper on how to use the raw PSPRS scores to help predict prognosis in individual patients.

Tao asked if he could use my database, with my formal collaboration, to find a better way of predicting long-term survival.   He said he didn’t just want to look at raw scores – he wanted to look at their magnitude and rate of progression at one critical point: the time when the person first developed difficulty looking down.  That’s easily approximated by finding the date of the visit when the score on the PSPRS item for downgaze first exceeded zero.  He would then correlate those “input variables” with, as “output variable,” the patient’s overall survival.  The progression rate would be calculated as the raw item score divided by the number of years since PSP onset.  I said, “great idea.”  

Why choose the onset of downgaze palsy as the benchmark?  That’s when the insidious pathological process of PSP has first broken out of its three places of origin in the brain: the substantia nigra, the subthalamic nucleus and the globus pallidus.  Why it starts in those three places is a mystery, but from there the abnormally folded tau protein molecules travel along the axons to other places, and pretty much their first stop is the area where downgaze is controlled, in the dorsal midbrain.  (Perhaps relevantly, downgaze palsy is by far the most “specific” feature of PSP, meaning that of all of the disease’s features, that’s the one shared with fewest other diseases.)

So, Tao figured that once the process gets to the downgaze area, it has emerged from its birthplaces and is on its unfortunate way to other parts of the brain, probably at whatever speed is specified by the individual’s particular chemical and genetic makeup.  Because that rate of transmission varies among individuals with PSP, it makes sense to measure the progression rate of PSP as of that stage of the disease rather than at a one-point-fits-all stage such as a set number of years after symptom onset.

Here’s what we found:  The shorter survival is associated with older onset age and, as of the time of initial downgaze palsy, the PSPRS item scores for 1) difficulty swallowing liquids and 2) difficulty arising from a chair.

So, what does this mean?  For care of an individual patient, the neurologist’s recommendations might be shaded to an extent by the knowledge that the patient’s future course will be more – or less – favorable than the published averages for PSP.  In a large clinical trial, the statistician analyzing the data might want to achieve a more valid comparison of the active drug and placebo groups by weighting the progression data according to these factors. 

Yes, research proceeds in small steps, but proceed it does.

A rescue operation

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It’s been 26 days since my last post.  Sorry.  I’ve been very busy with some consulting for drug companies and with co-authoring a research paper.  You’ll hear more about the fruits of those labors before too long.  But for now, I have some good news about a new drug:

Back in 2015, I reported to you on a conference presentation by the CEO of a tiny Swiss company called Asceneuron (“uh-SEH-nu-ron”).  They had a promising group of nearly identical drugs for PSP that were just entering the mouse testing stage.  Since that time, one drug has emerged from among its littermates as the leading candidate and has acquired the code name, “ASN90.”  Here’s that blog post’s maybe too-technical explanation of its mechanism of action:

“All of the OGA inhibitors being developed are small molecules suitable for oral administration. . . . [These drugs reduce] tau aggregation by inhibiting OGA (O-GlcNAcase; pronounced “oh-GLY-na-kaze”). That enzyme removes the sugar N-acetyl-beta-D-glucosamine from either serine or threonine residues of proteins. The opposing reaction, catalyzed by O-GlcNAc transferase, like other post-translational modifications, is a common way for cells to regulate proteins. In the case of tau, having that sugar in place reduces aggregation.“

In other words, ASN90 works via the ancient drug mechanism of inhibiting the action of an enzyme.

Since 2015, ASN90 has emerged from its littermates as Asceneuron’s favored OGA inhibitor.  It has passed its tests for efficacy in animals and for safety in three small trials in healthy humans and now it’s ready to be tested in people with PSP.  But Asceneuron has had trouble finding the multiple millions in funding for that, so for the past few years, poor ASN-90 has been languishing. 

But now, Asceneuron has announced that it has licensed ASN90 to a big Spanish drug company called Ferrer, which is ready to start a Phase II trial!  Cool!  That’s all I know so far, except that the drug also has potential in Alzheimer’s disease. I also know that Phase II trials in PSP typically need 6 months to organize, 6 months to fully recruit, 12 months as the double-blind treatment duration and another few months to organize the data’s loose ends and analyze the results. That’s about 2 to 2½ years — and then it takes a few months for the FDA has to scrutinize the results and issue its decision, and then it takes more time for the company to ramp up production and distribution.

Hope matters.

In case you don’t know, Phase II trials may be open-label or double-blind and serve mostly to test the safety and tolerability of the drug in people with the target disease, as opposed to healthy volunteers.  Such trials also help establish the optimal dosage needed to minimize side effects while keeping the dosage high enough to accomplish its job in the brain, based on previous lab and animal data.  Phase II trials often have a “multiple ascending dose” phase to establish the optimal dosage before proceeding with the main part of the trial using that dosage. When a Phase II trial is double-blind and sufficiently large, it can also serve as a test of efficacy.  In the past, the FDA has indicated that when it comes to PSP and other serious, rare diseases without existing treatment, a moderate-size (i.e., about 200-400 patients) Phase II trial with highly favorable safety and efficacy results would be enough for it to approve the drug. Ordinarily, for drugs targeting conditions that already have good treatments on the market, the FDA demands at least one larger Phase III trial, sometimes two.

I’ll report back the moment I know more, including the locations of study sites for Ferrer’s drug trial.

The sincerest form of flattery

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A reader just commented, “What other diseases can mimic PSP?” Below is a pretty exhaustive list of things that can cause vertical gaze palsy*, the most specific** diagnostic hallmark of PSP. Most of these disorders don’t mimic the whole classic PSP syndrome, but even PSP doesn’t do that in many cases. Keep in mind that most of these mimics have other features besides the gaze palsy, occur at much younger ages than PSP, or are exceedingly rare. For all those reasons, a good neurologist is unlikely to confuse these conditions with PSP in practice.

The disorders with specific treatment (though maybe not cures) have three asterisks ***.

*”Palsy” in general means weakness (not tremor, as popularly thought). In the setting of PSP, palsy refers to a limitation of the range of voluntary eye movements.

**The “specificity” of a diagnostic sign is technically the fraction of the people without the disease who don’t have the sign. In other words, specificity = [true negatives] divided by [true negatives + false positives].

———

DISORDERS WITH VERTICAL GAZE PALSY IN AT LEAST SOME CASES

Degenerative

  • Amyotrophic lateral sclerosis
  • Corticobasal degeneration
  • Dementia with Lewy bodies
  • Frontotemporal dementia with tau staining
  • Frontotemporal dementia with ubiquitin staining
  • Globular glial tauopathy
  • Lytico-bodig
  • Motor neuron disease with congophilic angiopathy
  • Multiple-system atrophy
  • Pallidal degeneration
  • Parkinson disease (only upgaze affected)***
  • PSP

Structural           

  • Normal-pressure hydrocephalus***
  • Pineal region masses***
  • Third ventricular enlargement***

Metabolic / Genetic          

  • B-12 deficiency***
  • Huntington disease
  • Neuronal intranuclear inclusion disease
  • Niemann-Pick disease type C***
  • Spinocerebellar ataxia type 8
  • Tay-Sachs disease, adult-onset (hypometric vertical saccades)
  • Wernicke encephalopathy***
  • Wilson disease***

Immune              

  • Anti-phospholipid syndrome***
  • Anti-IgLON4 disease***
  • Paraneoplastic syndromes***
  • Postencephalitic parkinsonism***

Vascular              

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
  • Lacunar states (“vascular PSP”)***
  • Post-aortic surgery

Infectious          

  • Whipple disease***
  • Neurosyphilis***

Toxic    

  • Guadeloupean tauopathy

Prion

  • Creutzfeldt-Jakob disease

Re-programming

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This morning I received an email from a CurePSP support group leader in Texas forwarding a local newspaper clipping about a young girl in Taiwan with a genetic metabolic defect of the brain who had received a form of gene therapy.  She asked if that approach could be of potential use against PSP.

Here’s my answer:

For decades, a routine neuroscience laboratory tool has been to inject the brain with a harmless virus, called a “vector,” carrying a gene to induce brain cells to manufacture that gene’s protein product.  This has been useful in PSP research. Before long, the same idea could become a treatment for patients with neurodegenerative diseases.  The main drawback is that it requires a neurosurgical procedure to inject the virus with the therapeutic gene into the specific spot(s) in the brain where it’s needed. 

This approach has worked in early-phase trials in people with Parkinson’s disease, where cells that make dopamine are degenerating, and is continuing safety studies in PD.  The gene in those trials encodes the enzyme AADC (aromatic amino acid decarboxylase), which controls dopamine’s rate of production.  AADC mutations do not occur in PD, but the girl in Taiwan who received the gene therapy was suffering from an inherited deficiency of AADC, causing delayed neurological development. 

This sort of gene therapy, but using MAPT, the gene for the tau protein, has been used in PSP research to produce a rat model for use in testing new treatments.  The company sponsoring the AADC deficiency trial in Taiwan is developing an MAPT gene therapy for the rare form of frontotemporal dementia caused by mutations in MAPT, called FTDP-17.  Unfortunately, PSP, unlike AADC deficiency or FTDP-17, is not caused by a single mutation in a known gene, so it would not be amenable to having that gene replaced by this sort of gene therapy.  It’s true that PSP, like PD, includes a dopamine deficiency, but PSP would not respond to AADC gene therapy for the same reason it doesn’t respond to L-DOPA (which is converted by the body into dopamine): the brain cells on which dopamine acts degenerate in PSP. 

The hopeful note, however, is that if a compound such as a growth factor protein or an anti-sense oligonucleotide (ASO) is found to help PSP, a gene for that compound could, in theory, be inserted into a viral vector and injected into the brain.  That could provide a steady, lifetime supply of the compound.

Larry

Hope

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Today is Martin Luther King Day, and here’s one of his best quotes, from 1968:

“We must accept finite disappointment, but never lose infinite hope.”

Fast-forward to the 1980s, early in my career as a neurologist mostly for patients with incurable movement disorders.  I rapidly learned that besides objective diagnosis and treatment, my agenda at patient visits should include an old-fashioned pep talk along with an update on research.  Now, I had grown up in a culture where such “touchy-feely,” subjective things were far subservient to scientific thinking, and my medical education was no different.  So, once I was out in the real world of patient care, it was kind of a revelation to discover that a simple, subjective appeal to hope could sometimes alleviate more suffering than any medication, therapy or surgery I could prescribe.

Fast-forward again to 2004, at which point I had been CurePSP’s Clinical and Scientific Director for 14 years, and a new CEO named Richard Zyne arrived.  He was an ordained minister who spent his career mostly with non-sectarian, non-profit organizations.  As a clergyman, he well knew the value of hope in helping people deal with adversity, and he quickly made “Because Hope Matters” CurePSP’s tagline.

I’ll admit I was skeptical at first.  I thought that providing hope was the doctor’s job at an individualized, “retail” level in the exam room and that CurePSP should support research, educate patients and clinicians, and help find ways to bring the best available care to all who need it.  But working with CurePSP showed me the value of a national organization with multiple communication platforms in reassuring patients and families that scientific understanding of PSP is advancing, that similar diseases are slowly yielding to new treatment, that more researchers and journal articles are devoted to PSP than ever, and that a well-run non-profit organization is in their corner. In other words, I again discovered that hope matters, but now at a more “wholesale” level.

The idea for this blog post entered my mind from the proximity of MLK Day and my post from four days ago, where I reported the failure of one PSP drug candidate but offered hope for five others currently in clinical trials.  In fact, regular readers of this blog know that I try to infuse hope into every post rather than merely reporting the news objectively.  For the ability to understand the value in that, I thank my patients, Richard Zyne – and Dr. King.

We just have to keep trying

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I have some bad news.  Another experimental drug has failed to slow the progression of PSP.  The double-blind Phase 2 trial of RT-001 in 40 participants took place in Munich, Germany.  The company, BioJiva, has given me permission to discuss this ahead of their press release.

RT-001 has a unique mechanism of action.  It’s based on the ample evidence that a major part of the problem in PSP is an attack on brain cells’ membranes by “reactive oxygen species.”  ROS, a product of dysfunction of the mitochondria, damage the fatty acids, a major component of cell membranes.  The drug is one of those fatty acids, linoleic acid, but with a twist.  Two of the hydrogen atoms in the molecule are replaced by deuterium, which is hydrogen with an extra neutron in its nucleus.  (Water made with deuterium instead of hydrogen is called “heavy water.”)  The drug is incorporated into the membranes as if it were ordinary linoleic acid, but the two deuteriums protect it against attack by the ROS. 

Sound crazy, you say?  Naïve, maybe? Well, it may actually work in another disease with too much ROS activity, amyotrophic lateral sclerosis!  BioJiva announced last year that an early-phase trial in ALS gave favorable, albeit undramatic results, with a 23% slower rate of decline relative to the placebo group.  So, the company will continue to pursue work with RT-001 in ALS, but not in PSP.

But take heart, PSP community.  There are still five PSP neuroprotection trials in progress using fasudil, TPN-101, NIO-752, sodium selenate, and AZP2006.  Then, of course, there are multiple trials of “symptomatic” treatment.  See my recent post for details.

Which of those five PSP neuroprotection candidates is most likely to work?  I wish I (or anyone) knew enough about the molecular and cellular abnormalities underlying PSP to answer that question.

Disclaimer:  I don’t own any stock in BioJiva or have any other financial relationship with them.  Their Chief Medical Officer gave a presentation on the then-ongoing trial at CurePSP’s “Neuro2022” symposium in New York in October, where I was one of the organizers and moderators.

Current clinical trials

Great PR, so-so accuracy

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Two full weeks since my last post – holiday activities, don’t you know, starting on December 21 with a solstice party at the home of an eccentric friend.   I see that my blog viewership has declined precipitously in the past week, so I’m happy that you all have better things to do at holiday time than to read about PSP.  Don’t we all wish that the disease itself would take a few days off, too?

My re-emergent thought is about the famous “hummingbird sign.”  On an MRI scan in the sagittal plane – that’s as if you sliced someone down the middle and looked at the cut surface – the brainstem sort of looks like a side view of a hummingbird. 

In the MRIs above, the nose is on the left.  In the lower images, the arrows stop just short of the indicated structures so as not to obscure them.  Note the progressively thinner, sleeker midbrain (the hummingbird’s head and beak) with retention of the plump pons (the belly, which is plumper than than that of a real hummingbird). 

Now here’s the issue.  The appearance of the hummingbird sign isn’t as closely related to PSP as has been implied by many.  There are just too many false positives and false negatives. 

The false positives mostly occur in people with normal-pressure hydrocephalus, a condition where the fluid-filled spaces in the brain (the “ventricles”) enlarge because of an obstruction in the re-absorption of the fluid into the bloodstream.  This stretches the fibers adjacent to the ventricles, impairing control of gait, cognition and the bladder.  It also presses down on the midbrain, producing the hummingbird sign.  Then there are those individuals with corticobasal degeneration where the features resemble PSP (“CBS-PSP”).  They can also have a hummingbird sign.

The false negatives occur in the first couple of years after the initial symptoms.  They also occur if the MRI is mis-aligned on the brain or the head is a little rotated, producing an allegedly midline cut that’s actually a couple of millimeters to one side.  That means that the thinnest part of the midbrain, which is in the midline, isn’t shown in the image. 

You should also know that the hummingbird sign isn’t just about a thin midbrain.  A normal pons is also part of the sign.  That’s because in multiple system atrophy and a few rarer disorders, both the midbrain and pons become thinner.  But in PSP, it’s mostly the midbrain that does so.

I think that in the next year or two, a test of the tau protein in spinal fluid, blood or a tiny punch biopsy of skin will provide a much more accurate diagnosis of PSP than the hummingbird sign.  Soon thereafter we will probably have a PET technique that does the same. Then, clinical treatment trials can be accomplished faster because they won’t have to compensate for the statistical noise produced by participants with a false positive diagnosis.  In fact, all sorts of research on PSP will become much more powerful if people without PSP can be excluded. 

All my best for the New Year.

Low-tech solutions

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I know that some of my posts are too technical for some of my readers, so I’ll make amends right now. An important paper just appeared in the journal Neurology and Therapy called “The Lived Experiences of People with Progressive Supranuclear Palsy and Their Caregivers.” 

The nine authors were led by Dr. Gesine Respondek, a well-published PSP expert formerly at Hannover Medical School in Germany and now at Roche Pharmaceuticals.  The others are a diverse group from five different European medical institutions, two patient advocacy organizations and the study’s sponsor, the Belgian drug company UCB Biopharma.  They performed one-hour interviews of 21 patient/caregiver pairs, 7 patient organization representatives, 21 nurses and 42 neurologists in France, Germany, Italy, Japan, Spain, the UK and the US.  The patients and caregivers also completed smartphone-based, 7-day diaries with photos and formal daily questionnaires.  The analysis used a qualitative approach rather than attempting to fit the subjective information into a standard statistical model used in most medical research.

The study identified barriers to optimal care, the emotional responses to being a patient or a caregiver, and major “pain points.” The areas identified as important were:

  • delays in seeking medical advice for the initial symptoms because of apathy or misattribution of the symptoms by the patient or family
  • lack of awareness of PSP by non-neurologists
  • delays in even the neurologist suspecting PSP because of delayed appearance of downgaze difficulty or other hallmarks
  • a feeling of being overwhelmed by the diagnosis and its implications
  • delays in being referred by the general neurologist to a movement disorders specialist
  • diagnostic uncertainty even by the movement disorders specialist because of the overlaps between PSP and other candidate diagnoses
  • absence of objective diagnostic tests
  • a lack of empathy by the neurologist
  • frustration in having to settle for symptomatic treatment rather than disease-modifying treatment
  • the problem of being “no longer you”
  • the loss of independence in daily activities
  • lack of consistency in the rating and monitoring of symptoms
  • lack of guidelines and quality care standards for PSP management
  • stresses in confronting the end of life
  • caregivers feeling frustrated, sad, lonely, guilty and unsupported

The most important stresses among these related to the delays in receiving a correct diagnosis.  The countries differed in some areas with Japan offering the best support, information and home care. 

The authors concluded with these recommendations:

  • More countries should create patient organizations dedicated to PSP.
  • Time allotted for consultations should be longer to allow the clinician to better educate the patient/caregiver.  If this is not possible, then providing formal follow-up time by phone or video would be a good substitute.
  • To assist in the above, one of the shorter versions of the PSP Rating Scale should be widely adopted by neurologists in order to provide patients with an quantitative measure of their status within the time allotted at the visit.
  • At-home follow-up by a nurse specialized in parkinsonism, when financially feasible, would help.
  • Closer collaboration between patient organizations and clinicians should be facilitated.
  • More information should be available on “financial support, life expectancy, nutrition and tube feeding, and preparation for end-of-life.”
  • There should be better access to support for patient and caregiver in the form of adult day programs, support groups, respite care, home health care, social work, caregiver training and psychological support.
  • Tele-health forms of occupational therapy should be available.
  • Clinicians should be honest and open with the patient and caregiver about the unpleasant truths and the uncertainties.
  • The needs of the caregiver should be as important as those of the patients to clinicians, support organizations, insurors and policymakers.

As my own editorial response, I’ll say that:

  • Many of these recommendations are for services already available in the US via CurePSP and in the UK via the PSP Association.  But funding limitations at these charities limit their reach. 
  • CurePSP and the PSPA already offer many forms of layperson and professional education where funding is not an issue. They just have to get it to the right people.
  • Creating new or more educational materials for clinicians who can read English is not a priority.  We just need to grab their attention and convince them to devote some time and energy from their busy schedules to learning the material. Providing the materials in other languages would also help.
  • CurePSP’s Centers of Care network, which is only just getting started in earnest, is attempting to address many of the deficiencies on the part of professional education and access to care.  The best example is its “Best Practices” paper advising on treatment options and published last year.
  • I hope that there can be a radical change in how most physicians and insurers see PSP.  The current, “Oh, PSP is just a disease that old people get, and you’ve got to go sometime, and there’s nothing to be done.” has to change to, “PSP is a disease that reduces the quality and quantity of one’s retirement years and its sufferers and their families can benefit in many ways — both psychological and physical — from better access to care, faster diagnosis, and delivery of well-informed and empathetic symptomatic management.”

What’s in a name? A lot.

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Maybe nothing is more boring to patients and their families than squabbles among doctors about how to classify diseases.  But here goes.

You may have read that PSP is one of the “frontotemporal dementias.”  The FTDs are an umbrella category of diseases with deficits involving degeneration of the frontal and temporal lobes.  The results are trouble planning, forming new ideas, multi-tasking, obeying rules and adapting to circumstances.  Some types of FTD also (or mostly) have problems with speech and language.  Yes, PSP includes some of those things to some degree, but unfortunately, that’s only one of many parts of PSP. 

The protein aggregating in the brain cells in the various FTDs can be tau, as in PSP, but only in a minority.  Even in those few with tau, the distribution of the aggregates is different from that of PSP.  The majority of FTDs don’t even have tau – instead, they have the proteins TDP-43, FUS or ubiquitin.  So, it has always irked me to hear PSP classified as an FTD.

But now, I’ve got backup:  In August 2022, a group of leading neuropathologists published a revised set of criteria for making a diagnosis of PSP at autopsy. 

This replaces a set of criteria from 1996, antedating modern methods of tissue staining (necessary for viewing through the microscope) certain observations about the pathology of PSP.  Now, here’s the critical part: the new criteria don’t require, or even accept, abnormalities in the temporal lobes in support of the diagnosis of PSP. 

The new criteria, called the “Rainwater Charitable Foundation Criteria” for the philanthropy funding the project, are very simple.  They require both of these:

  1. Neurofibrillary tangles or pre-tangles, at least mild in frequency, in two or more of the following regions: globus pallidus, subthalamic nucleus and substantia nigra
  2. Tufted astrocytes, at least mild in frequency, in either peri-Rolandic cortices or putamen

In English:

  • Neurofibrillary tangles: mature aggregates of tau protein
  • Pretangles: aggregates of tau protein that aren’t (yet) sufficiently well-formed to be called tangles
  • Globus pallidus: part of the basal ganglia, an important area for control of movement
  • Subthalamic nucleus: another movement-control area, a cluster of brain cells so-called because it’s just under the thalamus
  • Substantia nigra: yet another movement-control area, the one where dopamine is made; It’s also a critical one for Parkinson’s.
  • Tufted: containing a type of tau aggregate with a sort of fluffy appearance
  • Astrocytes: the main type of glia, which are non-electrical brain cells
  • Peri-Rolandic cortices: the folds of the cerebrum running down each side of the brain in front of and behind a long in-folding called the Rolandic fissure.  The pre-Rolandic cortex is part of the frontal lobe and serves motor control.  The post-Rolandic cortex is part of the parietal lobe and serves the sense of touch.
  • Putamen:  another movement control area of the basal ganglia

The fact that involvement of the temporal lobe is so mild and inconsistent in PSP as not to merit a place in the new diagnostic criteria should finally put an end to the notion that PSP should be classified as one of the fronto-temporal dementias. 

I was gratified to discover recently that the Memory and Ageing Center at UCSF, possibly the leading such institution in the world, now specifically states on its website’s home page that PSP, while sharing some symptoms with the FTDs, is not one of them.

So, why does this matter?  Because PSP is sufficiently different from the FTDs that it deserves to be researched and treated on its own.  Its sufferers and their families need a type of support not generally relevant to the FTDs.  Similarly, those serving the urgent and important needs of the FTD community should not be distracted by efforts aimed at PSP. 

Lecanemab: now for the (not that) bad news

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A bombshell hit the news yesterday (11/20/22) about a breakthrough treatment for Alzheimer’s disease.  But the drug company announced the same news two months ago in the form of a press release.  Today’s story was merely about a formal presentation of the results at an Alzheimer’s conference that added some important safety data.  Here’s my blog post from September.

The drug is called lecanemab, and as its last three letters indicate, it’s a monoclonal antibody – in this case directed against the beta-amyloid protein.  That’s present in an abnormal, aggregated form in brain cells in Alzheimer’s but not in PSP.  In the trial, the antibody solution was infused intravenously every two weeks for 18 months and compared with a group of participants receiving placebo infusions.  The news was that lecanemab slowed the rate of worsening of Alzheimer’s by 27%.  This is great news from the PSP standpoint because it’s the first time that a monoclonal antibody was shown to slow progression of any neurodegenerative condition, even if it’s a different one.  We call that a “proof of principle.”

Today’s new information on the drug’s safety was most notable for a potentially serious issue called hemorrhagic encephalitis.  That’s where areas of the brain tissue undergo swelling and/or bleeding.  That combination is evidence of inflammation, the equivalent of a very sore arm after a Covid shot.  Among the 898 participants with AD who received active lecanemab over the 18 months of the trial, 13% had swelling, but for the 897 receiving placebo, the figure was 2% – a major difference.   For bleeding, the proportions were 17% for lecanemab and 9% for placebo – a minor difference.  Fortunately, none of those participants suffered important or permanent symptoms from the swelling or bleeding, which in most cases would not even have been suspected without the trial’s routine brain MRIs, and in all cases resolved in a few weeks.  However, one wonders how serious the problem could hypothetically be in a tiny percentage of people — too small a fraction to be detected in the 897 on lecanemab in this study.

The group on active lecanemab was a bit more likely than the placebo group to report a variety of serious side effects unrelated to brain swelling or bleeding: 14% vs 11%; and the lecanemab patients were more likely to drop out of the study because of other, assorted side effects: 7% vs 3%.

Now the FDA and Medicare/Medicaid have to decide if they’ll approve this treatment or if the cost (whatever that might turn out to be) and side effects outweigh the benefit. Or, they may require another large trial first.

So, the takeaway for those with PSP is that it’s possible to modestly slow the rate progression of a neurodegenerative disease with a monoclonal antibody treatment with probably only mild risk. The numbers about the hemorrhagic encephalitis are not to be ignored.  But I think that if a hypothetical treatment for PSP gave similar risk and benefit, and the out-of-pocket cost is affordable, I think the majority of people with PSP would ask where to sign up.