A welcome word from Australia

Here’s some nice news.  The Phase 2, double-blind trial of sodium selenate that I mentioned in my December 19 post as pending has just started recruiting patients.  That orally-administered drug may slow the progression of PSP and other tauopathies.  Unfortunately, at this point, it’s taking place only at six sites in Australia.

The trial is described in an article from late 2021 in the open-access journal BMJ Open. The first author is Lucy Vivash, a research fellow at Monash University in Melbourne.  Terence J. O’Brien, MD, the neurology chief at that prestigious institution, is the senior (i.e., last-named) author.  Australia does not require its trials to be listed in www.clinicaltrials.gov, and it isn’t.  But it is listed in an equivalent database for Australia and New Zealand trials.

The mechanism of action of sodium selenate against PSP is to activate an enzyme called protein phosphatase 2.  Like any phosphatase, it removes phosphate groups from the proteins to which they have become attached.  Our bodies normally use phosphates as a way to regulate the activity of enzymes, but under some disease conditions, phosphates are attached to excess or in the wrong spots.  In PSP, there is excellent evidence that inappropriate phosphorylation of tau encourages it to fold into a toxic form.  In the words of the researchers:

“Protein phosphatase 2 (PP2A) is the major tau phosphatase in the brain accounting for more than 70% of brain phosphatase activity, and thus stimulation of its activity presents a compelling strategy for reducing hyperphosphorylated tau. PP2A is colocalised [in the same locations within the same brain cells] with tau, and in many neurodegenerative diseases, reduced PP2A activity is observed alongside reductions in tau dephosphorylation.”

The year-long trial will include 70 patients with PSP-Richardson syndrome, half of whom will receive placebo.  This trial is unusual in that the primary outcome measure will not be a clinical evaluation of patients’ neurological performance and subject reports of symptoms such as the PSP Rating Scale (PSPRS).  Rather, the primary outcome will be a slowing of the rate of brain atrophy as measured by before-and-after MRI scans.  This has been shown to correlate better with the passage of time than the PSPRS or any other clinical measure of PSP progression.  However, it’s not clear if it actually correlates as well with daily functioning.  True, traditional measures are included as secondary outcome measures, but no drug developer wants to rest their case for drug approval on a secondary measure when the designated primary measure failed to show benefit.  

I suspect, but don’t know, that the MRI measure was chosen as the primary outcome measure because its greater sensitivity to change over time permitted enrolling only 70 patients (to be able to detect a 50% reduction in progression rate), as opposed to the 102 patients required by the next-most-sensitive measure, the PSPRS. Each additional patient increases the cost of the trial, and this one is financed by a grant from the Australian government rather than by any drug company. So financial constraints may have been more of an issue than usual in the study design.

So, let’s wish Dr. Vivash and her colleagues and patients every success in this trial and let’s hope that the pandemic allows it to proceed smoothly.