Tag Archives: NIO-752

We tauopathies have to stick together

Posted on by

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!

—–

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.

NIO-752 on the fast track

Posted on by

Some encouraging news from the AD/PD Conference held this past March in Copenhagen. NIO-752 is the anti-sense oligonucleotide drug being developed by Novartis for PSP and Alzheimer’s.  It reduces the ability of the messenger RNA encoded by the tau gene to be translated into tau protein.  The news is the results of a Phase I trial designed mainly to assess safety and tolerability of various dosage levels.  But the trial also included measures of efficacy, just in case something dramatic appeared despite the trial’s small size.  The PowerPoint slides from the presentation by Dr. Günter Höglinger of Munich can be downloaded here.

NIO-752 is a large molecule that can’t cross the blood-brain barrier, so it has to be injected directly into the spinal fluid via the same sort of needle insertion used in a diagnostic spinal tap.  In this trial, 80% of the 59 subjects (45 on active drug, 14 on placebo) received injections at baseline and at months 1, 2 and 3 at ascending dosage levels.  The other 20% received it at baseline and at months 3, 6 and 9. The final assessment for all subjects occurred at 12 months.  The trial ran from February 2021 to October 2024.

The drug caused very little by way of important side effects: confusion and or lethargy in two of the 25 patients on the two highest dosage levels and some brain inflammation in one patient on the highest level as evidenced by elevated white blood cells in the spinal fluid.  This is a very modest overall burden of adverse effects, and what’s more, the frequency of milder side effects was no different between the active drug (19 of 45) and placebo (7 of 14) groups. There’s lots more information at clinicaltrials.gov.   

An important goal of Phase I trials is to demonstrate “target engagement.”  That military-style term means the ability of a drug to accomplish its job in the body’s tissues regardless of whether it actually helps the person’s symptoms or long-term outcome.  NIO-752 did well on that score, reducing the spinal fluid tau levels, especially at the highest dose level.  (The level remained unchanged in the placebo subjects.)  It also prevented any rise in levels of neurofilament light chain (NfL), while the placebo group’s NfL rose by nearly 40%.  NfL is a sign of damage to axons (the long fibers emerging from brain cells) that is elevated in PSP and several other neurodegenerative diseases.

The question in your minds is, “But what about the rate of worsening of the symptoms and disabilities”?  That wasn’t reported because there weren’t enough patients to perform a proper statistical analysis.  If the worsening in the PSP Rating Scale had been less in the 45 participants on NIO-752 than in the 14 on placebo, that would be too few to exclude the possibility of confounders (a “Type I error” or false-positive) effect.  Similarly, if this small study failed to demonstrate a benefit, Novartis would not want anyone to draw negative conclusions about the drug without a properly powered trial.

Next step: Novartis will now skip directly to a Phase III trial and just yesterday they posted details on clinicaltrials.gov.  You can get a look here, but I’ll discuss that trial in a near-future blog post. The trial’s nickname is PRESERVE.

__

Full disclosure: I have consulted for Novartis on trial design in the past but not since 2023. I have no stock in the company nor any other financial interest in the success of NIO-752 or the company in general.

My bob-tail nag

Posted on by

One of this blog’s frequent commenters — OK, it’s my pal Jack Phillips, CurePSP’s Board Chair — prompted by my 3/8 26 post, has asked which of the three PSP Trial Platform drugs to bet on.  That’s a tough one, partly because unlike racehorses, each has a different mechanism of action, so it’s an apples/oranges/peaches comparison.  But as long as I don’t have to worry about peer review of my blog posts, here’s what I’m thinking at this point:

  • The AADvac anti-tau vaccine induces one’s immune system to make anti-tau antibodies, so one might expect it to do no better than the two failed passive (i.e., directly infused) monoclonal antibodies from a few years ago.  But the antibodies formed in response to AADvac recognize the middle part of the tau protein, while the monoclonals recognized the initial (i.e., N-terminal) end.  There’s good evidence now that the toxic part of abnormal tau is in AADvac’s middle-domain wheelhouse. So, the questions now are:
    • Has tau already done its dirty work before reaching the form or location susceptible to the antibody?
    • Most of the damage done by tau happens inside the brain cells, where antibodies can’t reach.  The hope is to pick off the abnormal tau in transition from one brain cell to another.  That works in mice with an abnormal version of the tau gene that causes a familial form of frontotemporal dementia with Parkinsonism.  But FTDP isn’t quite PSP and mice aren’t quite people.
  • LM11A-31 is very different.  It enhances the brain’s ability to repair existing damage.  It has shown benefit in a number of different animals models of different diseases with different aggregating proteins (or with none).  In humans with neurodegenerative diseases, the only published experience is in Alzheimer’s disease, where the benefit was modest, though the study was too small to assess efficacy in a valid way.  My concerns are that:
    • The drug’s modulation of the cells’ compensatory mechanisms might be too subtle to stand up to the onslaught of misfolded tau and other perturbations present in PSP.
    • Starting from an early stage of involvement in PSP, brain cells transmit misfolded tau to other cells.  It’s possible that this happens before the cells have lost much of their functional abilities, perhaps before the mechanisms that LM11A-31 modulates become relevant.
  • AZP-2006 improves lysosomal function, thereby helping the cells dispose of tau that’s overabundant, misfolded, aggregated or excessively phosphorylated. I personally favor that idea for three main reasons:
    • The high frequency of co-pathology (where the tauopathies have mild levels of other aggregating proteins) suggests that specific defects in a shared garbage disposal system affect specific combinations of proteins.  This in turn implies that if the predominantly affected protein is tau, then a tauopathy develops, with a few aggregates of other proteins such as α-synuclein, TDP-43 and others. I’d done research on the PSP cluster in a group of towns in northern France with severe ground contamination by multiple industrial metals. Lab experiments (performed in collaboration with a team under Drs. Aimee Kao and Carolina Alquezar at UCSF) have suggested that some of the metals in that environment can damage the disposal mechanism without affecting the production of tau itself.  That suggests that a treatment like AZP-2006 aimed at that mechanism could work.

So, my analysis gives AZP-2006 a slight edge among these three. But that’s based partly on results of my own research, so I have a sentimental bias.  Then there are other drugs in the pipeline, like:

  • NIO-752 (a tau-directed anti-sense oligonucleotide to reduce tau production)
  • FNP-223 (an inhibitor of an enzyme that allows phosphate group to attach to tau)
  • GV-1001 (mostly an anti-inflammatory to quell one important step in the disease process)
  • Bepranemab (passive, mid-domain antibody infusions)

Besides, much smarter people than I have been crashingly wrong in predicting clinical efficacy of drugs. But it’s a good mental exercise to think about it.