Tag Archives: bepranemab

A good problem to have

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Now, this is progress.  Novartis just yesterday announced in clinicaltrials.gov that its Phase 3 trial of NIO752 is ready to accept volunteers for screening. The name of the trial is PRESERVE.  Good name.  No, it’s not an acronym for anything.

So far, the company has only announced three trial sites (Rochester, MN; Englewood, CO; and Ulm, Germany) but dozens more will follow, with a total recruitment goal of 300.  Here are some details of probable interest to potential volunteers:

  • The drug is an antisense oligonucleotide, which as you’ve learned from this blog, interferes with the brain cells’ ability to translate the RNA from a specific gene into its protein.  In this case, the protein is tau, which lies at the heart of PSP.
  • As a very large molecule, NIO752 cannot pass the blood-brain barrier, so it has to be injected directly into the cerebrospinal fluid in the lower spine, using the same procedure as a diagnostic spinal tap (lumbar puncture).  This will be given every three months, assuming it follows the plan of the Phase 1 study.
  • A trial of the drug for safety in 45 people with PSP showed no important or permanent adverse effects from the procedure – just harmless and transient headaches or back pain in some.  Some transient confusion or lethargy occurred in three of the 45 – an effect of the drug, not the injection procedure.
  • The trial will enroll 300 participants overall, of whom 100 will be randomly chosen to receive a placebo injection.  That treatment assignment will be double-blind — not revealed to participant or neurological staff until the whole trial is over.
  • The duration of the double-blind period will be 72 weeks – about a year and a half.  After that, all the patients will be offered the opportunity to continue receiving the drug at no cost, as long as it has not been found to be harmful, and as long as Novartis is still manufacturing it.  That “open-label extension” program may end if and when the drug works and is on the market (let us pray).

Your big question right now should be this: Should I volunteer for the PSP Trial Platform (PTP) or PRESERVE?  The scheduled start for PTP is next month (June 2026), and those sites will roll out gradually, just like the PRESERVE sites.  So, in theory, there’s no overall difference in the timing, though a site near you might open for one study well before the other, or there may be an accessible site for one and not the other.  All the PTP drugs and NIO752 are similarly and acceptably safe, in my view.

Right now, I’d say volunteer for PRESERVE, though by a slim margin.  Two reasons, each minor:

  • Like any large, complicated project requiring approvals from government, private companies and academic institutions, the PSP Trial Platform has been subject to unforeseen delays.  (All major drug trials require collaboration among these three, but the PTP is more complicated than most.) In fact, the company sponsoring one of the three drugs planned for the PTP has still not finalized the arrangements, according to clinicaltrials.org. If that can’t be accomplished soon, the trial will start with only two drugs.  So, a bird in the hand . . .
  • The PRESERVE trial will have an open-label extension (see the caveats above), while the PTP has not yet decided on that, and it may differ across the different drugs.  Without an open-label extension, someone completing the Phase 2 trial would have to wait until the Phase 3 is finished and the drug approved before gaining access to it.  On the other hand, the FDA has been known to approve drugs for general use after only a Phase 2 if the need is great, and for PSP, it surely is. The PTP double-blind trials are 12 months long and the PRESERVE double-blind is nearly 18 months, so assuming both offer open-label extensions, someone on placebo in PRESERVE would have to wait six months longer to receive their active drug than someone in the PTP.

Yes, there are other drugs whose sponsors are optimistic that trials will start within the next year or so.  Those include bepranemab (a monoclonal anti-tau antibody), GV1001 (an anti-inflammatory), ARV-102 (an enhancer of abnormal tau degradation) and TPN-101 (an inhibitor of a toxic protein called LINE-1).  But the timelines there are just too uncertain for someone with PSP to consider right now.

Maybe the most important consideration is which drug is mostly likely to work.  I honestly don’t know, and the Phase 1 data don’t answer that question.  So that simplifies things a bit.

A difficult choice, I know, but a good problem to have. 

My bob-tail nag

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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.