When a patient or caregiver asks me if anything can be done for PSP aside from palliative measures, my ready answer is that there’s a lot of research now into specific treatments that might slow or halt disease progression. I never have time to get into details in the time available, so I’m not sure my assurance is credible. So, putting my keyboard where my mouth is, here is a pretty thorough list of treatments that are in human trials for PSP or will enter such trials this year:
Anti-tau antibodies: BMS-986168 (Phase 1), C2N-8E12 (Phase 1). Both are in early stages of recruitment at multiple North American sites. The rationale is to bind and destroy abnormal tau en route between brain cells. (Disclosure: I’m a consultant to Bristol-Myers Squibb and a site investigator .) Other drug companies and academic labs are also working on anti-tau antibodies, but at an earlier stage.
Tau anti-aggregants: Leucomethylthioninium (LMTX). This is a derivative of methylene blue in Phase III for Alzheimer’s and frontotemporal dementia; If successful, PSP could be next. But beware the hype that has accompanied methylene blue and its derivatives. The results from earlier-phase trials have not been published, which is curious.
Microtubule stabilizer: TPI-287 (Phase I). This is closely related to the taxane group of cancer drugs. In cancer, stabilizing microtubules helps prevent cells from dividing. In the brain, it compensates for the loss of tau, which normally stabilizes microtubules as the cells’ transport and skeletal system.
Tau acetylation inhibitor: Salsalate (Phase 1); This is being tested at UCSF, UCLA and UCSD in an open-label “futility” design. In other words, the study will determine not if the drug works, but if it deserves to be tested further. The same drug is being tested for multiple other disorders and has long been on the market as a non-steroidal anti-inflammatory drug.
Tau aggregation inhibitors: ASN-561, an O-GlcNAcase inhibitor. This will probably enter Phase I in 2016. It acts by promoting the attachment of a sugar molecule, N-acetyl glucosamine, to the tau protein, thereby inhibiting its aggregation. Such “OGA” inhibitors are also being tested for other conditions, including cancer.
Anti-sense oligonucleotides: These are RNA molecules designed to inhibit the production of 4-repeat tau, which is over-produced in PSP relative to 3-repeat tau. That imbalance could be contributing to tau aggregation. These have not reached human trials.
Anti-microglial agent: FK506 reduces the activity of microglia, inflammatory cells in the CNS. Evidence is increasing that such inflammation is a cause, rather than an effect, of cell loss in many of the neurodegenerative diseases. In fact, several immune-response-related genes were among the top 10 “hits” in the 2011 study of genetic risk factors in PSP.
Young plasma: Only in 10 patients, non-controlled and only at UCSF, this study will give plasma from healthy men younger than 30 to patients with PSP. The primary outcome issue is safety and tolerability, but efficacy measures will also be applied. Recruitment is under way. The theory is that some unknown blood-borne molecule in young people prevents them from developing PSP and could slow the process in someone with the disease.
Mitochondrial nutrient: Coenzyme Q-10 (Two small double-blind studies, one published and one unpublished) show similar modest improvement in PSP Rating Scale scores. This is a symptomatic treatment but the above items on this list are all potentially neuroprotective.
For more information on any of these, see http://www.clinicaltrials.gov.
4 thoughts on “PSP treatments in or near human trials”
How do we get access to medications granted Orphan status, such as the BMS drug? Thank you
Orphan status means that the drug has less of a testing hurdle to get approved and once approved, has a longer patent before it can go generic. It doesn’t mean that it’s available without a clinical trial.
Dear Dr Golbe – What do you think should be the best proof of concept endpoint(s) for PSP?
The PSP Rating Scale is nearly universally used these days as the primary outcome measure for PSP trials. Frequently used secondary outcomes are MRI morphometry, various cognitive tests and CSF measures of phospho-tau and neurofilament light chain. (Disclaimer: I authored the PSPRS.)