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. No, the company has not given the trial a cutesy name (yet). Any ideas, anyone?

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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.