Tag Archives: ASO

We tauopathies have to stick together

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A post from two months ago explained why some positive results from a trial of an antisense oligonucleotide (ASO) drug for amyotrophic lateral sclerosis (ALS) is good news for PSP. Now, there’s similar but even better news about an ASO drug for Alzheimer’s disease called “diranersen.” Why better? Because unlike ALS, Alzheimer’s disease is a tau-based disorder, like PSP.

Quickie review: ASO drugs interfere with the action of messenger RNA, which is produced by a gene in the cell’s nucleus and carries it out to the ribosomes, where it’s translated into that gene’s specific protein. Trials of “neuroprotective” treatments hope to demonstrate a decline in the rate of worsening relative to placebo, affording the participant more time at each disease stage. Neuroprotective treatments like ASOs are not designed to produce improvement relative to the study’s baseline.

Yesterday (July 14, 2026) the results of a Phase 2 trial were released at the Alzheimer’s Association’s annual research conference in London. The double-blind design included 406 people with either “mild cognitive impairment” (MCI) or mild dementia caused by Alzheimer’s. (MCI does not include difficulties in performing daily activities and dementia does. For the purposes of the trial, MCI is defined as a score of 21-27 on the 30-point Mini-Mental Status Exam and dementia as 20 or less.) The participants were randomly assigned to one of three dosage levels or placebo for the 76 weeks of the double-blind period. The improvement was calculated as the difference between the first and last visit scores divided by the the first visit score.

The testing included five standard cognitive tests, tau levels in the spinal fluid, and positron emission tomography (PET) scans to image brain tau deposits. The drug, like all ASOs to date, is administered by injection into the spinal fluid space at the base of the spine, as for a spinal tap. Of those seven tests, the “primary outcome measure” was the Clinical Dementia Rating Sum of Boxes (CDR-SB), presumably because it’s the one with the most experience behind it.

Officially, the trial was negative because the CDR-SB failed to show a statistically significant slowing of the rate of worsening. But for two of the other four cognitive measures, there were statistically significant degrees of slowing of 50% in one and 42% in the other. The benefits shown by the PET and spinal fluid look equally impressive to my eyeballs, but their degree of statistical significance was not provided.

Transient pain in the head, limbs and/or back from the spinal taps were by far the most common side effects, occurring in about half of all participants, but no worse on diranersen than on placebo. The only side effect clearly worse on diranersen was a temporary confusional state (about 25% vs 5% on placbo). In all cases, it was gone within a week.

You can see and download the company’s detailed announcement here. Keep in mind that the drug company sponsor, Biogen, wrote it for public relations purposes. It is not sufficiently detailed for a research journal and has not been peer-reviewed, but Biogen has announced plans for an expensive Phase 3 trial, proving that they’re willing to put their money where their mouth is.

Biogen hasn’t parted with further details on the Phase 3, but if it starts in 2027 and is similar in design to the Phase 2 (but larger), one might expect results in 2030 and if all goes well, FDA approval shortly thereafter. Too long, I know, and besides, that’s Alzheimer’s — not PSP.

Of course, the elephant in the room is the trial of NIO-752, the ASO from Novartis, currently in a Phase 3 trial for PSP and stated for completion in mid-2029. The success to date of diranersen in Alzheimer’s, is excellent news for the prospects of a similar anti-tau ASO for PSP. As far as I know, there’s no clinically relevant difference between the two ASOs.

On behalf of the PSP community, I’ll thank Novartis for its efforts behind NIO-752 and encourage Biogen to extend its so-far-favorable Alzheimer’s program to PSP. Any other Pharma companies interested? The opportunity is ripe!

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Disclosure: In the past, I have consulted for both Novartis and Biogen, but have never had a financial interest in either company. The only possible exception is that Rutgers University, which owns the rights to the PSP Rating Scale because I was a professor there when I developed it, shares a fraction of its licensing fees with me.

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 – too 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.)