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.