Tag Archives: PSP Trial Platform

A French Swiss Army knife

Posted on by

My last post was about AADvac1, one of the three neuroprotective drugs set to inaugurate the PSP Trial Platform (PTP) later this year. Today’s post is about the second drug, AZP-2006. The third drug has not yet been finalized, but at a conference in London last week, Dr. Adam Boxer, the leader of the PTP, said it will be revealed soon.


The PTP trials are all Phase 2a, meaning that they’re designed primarily to assess safety and tolerability. However, they do include enough patients, typically about 100 or 200, to detect drug benefit if any indeed exists. The benefit would be in the form of slowing of the rate of progression of PSP as measured by a newly abridged version of the PSP Rating Scale. The PTP will recruit one placebo group to serve as a comparator for all three active-drug groups.


An unpublished Phase 1 PSP trial in 36 people with no placebo group found a 31% slowing of the PSP Rating Scale progression relative to placebo groups in previous PSP drug trials. I hasten to add that comparing the results of active drug in an uncontrolled study to the placebo group in a completely different study is a minefield. So, let’s not jump to conclusions about the efficacy of this drug. All we can say is that the result justifies further investment and study.


That said, I’ll point out that in placebo-controlled Phase 2b and Phase 3 trials, a slowing of 20% or 25% relative to the placebo group is often considered adequate to consider the drug for approval.
AZP-2006 is administered as an oral liquid, which is more convenient than the intravenous, subcutaneous or intrathecal (into the spinal fluid) routes of some of the other current experimental PSP drugs. But of course, oral liquids can be a major issue for those with PSP, though it seemed not to cause any dropouts or serious adverse effects among the 36 patients in the Phase 1 trial. I don’t know if the AZP-2006 oral solution is compatible with the commonly used gelatin- or starch-based drink thickeners. The PTP trial will be confined to patients in early to moderates stages of disability, without the more pronounced swallowing difficulty of the later stages.


Nerd Alert: The main mechanism of action of AZP-2006 is at the lysosomes, one of the cell’s garbage disposal mechanisms, where it acts specifically at the lysosome’s prosaposin and progranulin pathways. Prosaposin is the metabolic precursor (a “parent molecule” cleaved by enzymes to produce the active molecule) of the saposins, a group of proteins required for the normal breakdown of various types of lipids that are worn out or over-produced or defective from the start. Progranulin is the precursor, as you’d guess, of granulin, which, like saposin, is involved in function of the lysosomes. But progranulin addresses disposal of proteins, not lipids. In mouse experiments, the drug also enhances the production of progranulin, mitigates the abnormal inflammatory activity in tauopathy, reduces tau aggregation, and stimulates the growth or maintenance brain cell connections. The company has not published or otherwise released details of the mouse work and if they know the details of these mechanisms of action, they’re keeping them secret for now.
One hereditary type of familial frontotemporal dementia where TDP-43 is the mis-aggregating protein is caused by mutations in the progranulin gene. However, progranulin mutations seem not to be related to PSP.


AZP-2006 was developed by Alzprotect, a company headquartered in Lille, France that was started in 2007 and has no approved drugs as yet. Here’s a page from the company’s website. It includes a nice video with an artist’s conception (or a PR consultant’s dream) of how the drug works.


AZP-2006 may be the most likely to succeed among the currently announced anti-PSP candidates in or nearing clinical trials. That’s because it addresses multiple important cellular abnormalities simultaneously (see the Nerd Alert above), something that many of the experts feel will be sine qua non for any successful PSP neuroprotective drug.

A PSP shot?

Posted on by

For years, I’ve looked at drug companies’ lists of tau-directed treatments in or nearing clinical trials for Alzheimer’s disease and wished that more of them would be tried for PSP. In both diseases, as most of you know, abnormalities in the tau protein are central to the brain cell damage. Of course, the prevalence of AD in the population is over 100 times that of PSP, with a correspondingly larger profit potential. But some big companies such as AbbVie, Biogen, Ferrer, GemVax & Kael, Novartis, TEVA, and UCB have given their AD drugs a shot against PSP. Even some smaller companies with lesser resources such as Allon, Amylyx, BioJiva, EmeraMed, Noscira, Sanofi, Transposon, and Woolsey have done so, and in some cases the failure of that PSP trial meant the bankruptcy of the company. Tough business.


Happily, two more companies have now taken the PSP plunge with drugs originally developed for AD. One is AADvac1, an active vaccine directed against the tau protein. An active vaccine is a component of the disease-causing protein, virus or bacterium. It stimulates the recipient’s immune system to make antibodies that then prevent, cure, or slow down the disease. You will recognize this as the mechanism for most disease-preventing vaccines like those for polio, measles and the flu. The other category of vaccines is passive, meaning that they are themselves antibodies against the relevant disease-causing molecule, virus or bacterium. Examples of passive vaccines are the rabies or tetanus shot given after an injury, and the anti-tau monoclonal antibodies from Biogen and AbbVie that have been tried unsuccessfully against PSP.


Early-phase clinical trials of AADvac1 for Alzheimer’s disease started in 2013. They were small, with only a few dozen participants, and although designed to assess safety, could have detected slowing of AD progression if it was dramatic.


The most recent such trial was published in late 2021. It showed no more side effects than placebo and excellent success in inducing anti-tau antibody formation. It was too small (117 subjects on AADvac1, 79 on placebo) to reveal less than a dramatic benefit and in fact there was no hint of benefit in its measures of dementia. However, a subsequent analysis of the trial published by a different research group in 2024 included only the 70% of the original group with high blood levels of p-tau217. That’s the most characteristic abnormal form of tau in AD, where the 217th amino acid in the protein carries a phosphate group. The re-analysis did show a strong trend toward benefit in several measures. The most dramatic effects, and the only ones reaching statistical significance, were the reduction and stabilization of blood levels of two proteins that rise in AD called neurofilament light chain and glial fibrillary acid protein. Less impressive but still favorable effects occurred in cognitive tests and imaging of brain atrophy. (Both the original and the re-analysis research groups did include important roles by employees of the drug company, Axon Neuroscience.)


I have no direct knowledge of whether the company is proceeding with a Phase 3 trial in AD based on this result, or if regulatory agencies would even allow them to do so. But I strongly suspect not, based on the absence to date of such a study from the company’s drug pipeline web page and from http://www.clinicaltrials.gov.

But PSP is another story! We now have a way for small companies like Axon Neuroscience to test a drug at relatively little expense. See my last post for some details on the PSP Trial Platform (PTP), headquartered at University of California San Francisco. Starting probably in late 2025, the PTP will perform a Phase 2 trial of AADvac1 in people with PSP in parallel with trials of the drug AZP-2006 and a third drug yet to be revealed. The three trials will share a single placebo group and coordination infrastructure, drastically reducing costs, and once things reach a steady state, reducing time delays as well.


In the Phase 2 AD trial, AADvac1 was administered as 11 subcutaneous injections, initially every four weeks and later, every three months. I suspect that the plan for the PSP trial will be very similar. The double-blind treatment period will be 12 months and the primary outcome measure will be a 15-item version of the original, 28-item PSP Rating Scale. I’ll pass along more details and contact information once these become available.


I’ll post something on the other drug planned for the PTP soon.


NERD ALERT: AADvac1 is a string of 12 amino acids from the microtubule-binding domain of tau. The full tau molecule has 352 to 441 amino acids, depending on which exons are spliced in by the cell. The two monoclonal antibodies that failed to help PSP are both directed at the N-terminal, conventionally shown as the left end (AbbVie’s tilavonemab against amino acids 25-30 and Biogen’s gosuranemab against 15-22). Subsequent research has shown that the disease-causing part of tau, however, is the middle region, which includes the microtubule-binding domain (amino acids 243 to 368). Another monoclonal antibody, bepranemab, which attacks a slightly different part of the middle region (amino acids 235-250), is currently being tested against AD and may enter a PSP trial in the next couple of years.

Two new drugs get a platform

Posted on by

This could be the best news ever in the history of clinical drug development for PSP.


Last week, I attended the Global Tau meeting in London as a representative of CurePSP. Plenty of excellent research was presented, but most of it was laboratory work that would be difficult to relate to the direct concerns of most of this blog’s readers. But there were some clinical advances, and here’s a big one.

Dr. Adam Boxer of the University of California, San Francisco is the project leader for the PSP Trial Platform (PTP). My Oct. 27, 2023 post briefly mentioned that the PTP had just been funded by the NIH. A trial platform is an organization, in this case about 50 study sites throughout North America, that invites multiple pharmaceutical companies to simultaneously allow it to test their trial-ready experimental drugs. The big news last week was Dr. Boxer’s announcement identifying the first two drugs and that enrollment should begin in late 2025.

One drug to be tested will be AZP-2006, from Alzprotect, based in Lille, France. It addresses tau accumulation and neuro-inflammation. The other is AADvac1, from Axon Neuroscience, based in Bratislava, Slovakia. It is an active vaccine directed against the tau protein. More on those drugs in a future post. Both will be Phase 2a trials, meaning that the emphasis will be on safety and tolerability, though efficacy will be detectable if it’s dramatic. The PTP has a candidate for a third company/drug in the wings awaiting final contract negotiations.


The double-blind phase for each drug would be 12 months, followed by an open-label phase, where the participants on placebo will be offered active drug. The primary efficacy outcome measure will be a version of the PSP Rating Scale abridged from its original 28 items to the 15 items best suited to daily disabilities.


Advantages of platform trials over traditional single-drug trials:
• Only one central coordination, technical and statistical staff is needed. This makes drug testing more economical in terms of both money and time, lowering the bar for smaller companies to test promising treatments.
• Only one placebo group is needed and more active-drug arms can be added in the future. So, if a traditional trial offers only a 50% chance of receiving active drug, a platform trial testing three drugs would offer a 75% chance of being assigned to active drug.
• Once the platform is up and running, there is no delay for test site recruitment, contracting and training. This further reduces the costs and allows a new drug to be smoothly slotted into a vacated spot.
• It’s possible to make the three drugs’ trial protocols relatively uniform, allowing the results to be compared with greater confidence than would be possible if each had been tested in separate projects.
• The availability of a completed control group facilitates an interim analysis (a peek at the incomplete data under strict confidentiality rules) to determine if continuing that drug’s trial would be futile. If the result is unfavorable, this saves time, money and most important, drug side effect risk for future participants. Such a drug could be withdrawn from the PTP and another drug could take its place.


The other Principal Investigators working with Dr. Boxer are Dr. Anne-Marie Wills at Massachusetts General Hospital, Dr. Irene Litvan at UC San Diego and Dr. Julio Rojas of UCSF. The NIH has committed $70 million over five years to this project and the participating drug companies would also contribute substantially (though much less than if they had mounted trials on their own). Dr. Boxer told me that as of last week, in late April 2025, the NIH funding had not been affected by the recent Federal research budget cuts, but we’re all holding our breath on that.