Tag Archives: ALS

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.)

No panacea

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In case you missed the front-page story three days ago (3/8/24) in The New York Times, the drug Relyvrio has failed to show benefit in a large (664 participants), Phase 3 trial in amyotrophic lateral sclerosis.  The drug did appear to show benefit in a much smaller (137 participants) Phase 2 ALS trial in 2020 and was provisionally approved for sale by the FDA on the strength of that result.  Now, the drug company, Amylyx, may have to discontinue marketing the drug for ALS. 

Why is this relevant to PSP?  Because four months ago Amylyx initiated a 600-participant Phase 3 trial of Relyvrio for PSP.  It’s called “ORION.” So far, recruitment has begun at only a handful of sites, all in the US, with plans to expand into Europe and Japan over the coming months.  The FDA’s permission to start ORION without a Phase 1 or 2 in PSP was based in part on the success of the drug in the Phase 2 ALS trial.  See my post of February 29 for details. 

Amylyx is also testing Relyvrio in people with Alzheimer’s disease, where a Phase 2 trial has demonstrated adequate safety and tolerability. I have no information on a Phase 3 in AD.

The question now is whether the ORION trial in PSP will continue.  So far, there’s been only one business day since the ALS news, and I’m not sure if the top brass at Amylyx — or the company’s sources of financing — have yet decided.  But the Times article reported that the FDA approved Relyvrio for ALS only after Amylyx agreed to withdraw the drug if the Phase 3 trial showed no benefit.  Furthermore, right after the ALS trial news hit, the stock price of Amylyx dropped from $19 to $3 and stayed about there.  Stock markets usually know how this sort of news is likely to play out.  Relyvrio is Amylyx’s only marketed product but they do have other drugs in the development pipeline.

The mechanism of action of Relyvrio addresses issues important to both disorders, which suggests that if it failed in one, it could well fail in the other.  But we don’t really understand the pathogenesis of either disease well enough to know if PSP might respond when ALS did not.

Meanwhile, if you were planning to try to enroll in the ORION trial, I’d advise you not to change your plans.  The ALS trial showed no important toxicity, at least in people with ALS, and you wouldn’t want to lose your potential spot at the study site because you delayed enrolling until definite information on the future of the ORION trial became available.  When other trials in PSP start enrolling, that advice could change, of course.

(I’ll repeat the disclosure I made in my 3/8/24 post: I’m a paid consultant for Amylyx, advising them on design of the ORION trial and training the participating neurologists on proper administration of the PSP Rating Scale.  But I have no stock in the company nor other financial interest in the drug’s success.)

Squares and jerks

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The fourth of the five PSP-related research papers to land in PubMed on a single day this week is from Ulm, Germany.   It compared PSP with ALS with regard “small involuntary fixation saccades” or SIFSs.  Here’s what that means and why it’s important: (Red alert: serious, nerdy neuroscience is coming.)

When we stare at a small visual target, we all have small, fast, irregular, eye movements away from the target.  Each is rapidly corrected by an equal and opposite movement and their size ranges from 0.01 degrees to 2 degrees.  (The normal full range of voluntary eye movement in each of the four directions is about 50 degrees.)  In PSP, these SIFSs become larger and more frequent in the horizontal plane (i.e., left and right), ranging up to 3 degrees and occurring up to twice per second.  The largest of these are called “square wave jerks.” They are so common in PSP, even in the earliest stages, that a neurologist finding signs of PSP but no square wave jerks must strongly consider some other diagnosis.  As you’d imagine, SWJs degrade vision by making it difficult to aim the most sensitive, central part of the retina at a target.

Square wave jerks and milder forms of SIFSs also occur in amyotrophic lateral sclerosis (ALS or Lou Gehrig disease).  ALS and PSP both include frontal cognitive loss and affect overall body movement, especially speech and swallowing, have frontal cognitive loss and have a similarly rapid course, but are otherwise not at all similar.  In ALS, the average age of onset is 10 years younger; the cognitive loss is a late occurrence; it affects the spinal cord worst; and the protein aggregating in the cells is TDP-43 rather than tau.  As eye movement are controlled, in part by the frontal lobes, it seems reasonable that the frontal damage is the source of SWJs in both diseases. 

Now, Drs. Wolfgang Becker, Anna Behler, Olga Vintonyak and Jan Kassubek have compared people with PSP and ALS with regard to the details of their SIFSs, including their square wave jerks.  In addition to making some new observations about SIFSs in general, they found that in ALS, the size and frequency of SIFSs are correlated, while such a relationship is absent in PSP. 

The researchers explain this result by suggesting that the basal ganglia, where the substantia nigra, globus pallidus and subthalamic nucleus are the first three nuclei affected in PSP, are the most likely source of SWJs in that disease, while in ALS, the SWJs probably arise from damage to the frontal cortex.  They suggest that in PSP, the amplitude and frequency of the SWJs are regulated by different sites in the basal ganglia, explaining their observed lack of correlation.  More work will be needed to confirm that suspicion, but some support comes from the observation in this paper that the severity of vertical eye movement loss, the cardinal feature of PSP, correlates closely with the amplitude of the (horizontal!) square wave jerks.

Why should anyone care?  First of all, a general point: One never knows when a “basic science” observation may lead to broader insights that could allow treatments to be developed.  More specifically, finding that a feature of PSP arises from multiple parts of the basal ganglia reduces the appeal of targeting just one allegedly critical or rate-limiting area of basal ganglia damage with a preventative or restorative treatment.  Such approaches have been proposed using injection of viral vectors to deliver gene therapy or growth factors.  Non-invasive targeting of the basal ganglia has been proposed using focused ultrasound.  This new paper suggests that a more general approach reaching the whole brain, or at least all the basal ganglia, might work better.