A bit of help with prognosis

A paper of mine just hit the streets today.  Actually, the idea and most of the work came from an old friend and colleague at the University of Chicago, Dr. Tao Xie.  (His last name is somewhere between “she” and “chee” and his first name is perfect for a PSP researcher.)  Here’s the story of that project, from the beginning.

From 1994 to my retirement from practice in 2020, I kept a careful record of the PSP Rating Scale (PSPRS) results in all 526 patients I saw with PSP.  The database includes each patient’s sex, birth year, month/year of PSP symptom onset, and death month/year (if deceased).  For each visit, I recorded the month/year and each of the 28 PSP Rating Scale item scores.  Back in 2020, some other colleagues and I published a paper on how to use the raw PSPRS scores to help predict prognosis in individual patients.

Tao asked if he could use my database, with my formal collaboration, to find a better way of predicting long-term survival.   He said he didn’t just want to look at raw scores – he wanted to look at their magnitude and rate of progression at one critical point: the time when the person first developed difficulty looking down.  That’s easily approximated by finding the date of the visit when the score on the PSPRS item for downgaze first exceeded zero.  He would then correlate those “input variables” with, as “output variable,” the patient’s overall survival.  The progression rate would be calculated as the raw item score divided by the number of years since PSP onset.  I said, “great idea.”  

Why choose the onset of downgaze palsy as the benchmark?  That’s when the insidious pathological process of PSP has first broken out of its three places of origin in the brain: the substantia nigra, the subthalamic nucleus and the globus pallidus.  Why it starts in those three places is a mystery, but from there the abnormally folded tau protein molecules travel along the axons to other places, and pretty much their first stop is the area where downgaze is controlled, in the dorsal midbrain.  (Perhaps relevantly, downgaze palsy is by far the most “specific” feature of PSP, meaning that of all of the disease’s features, that’s the one shared with fewest other diseases.)

So, Tao figured that once the process gets to the downgaze area, it has emerged from its birthplaces and is on its unfortunate way to other parts of the brain, probably at whatever speed is specified by the individual’s particular chemical and genetic makeup.  Because that rate of transmission varies among individuals with PSP, it makes sense to measure the progression rate of PSP as of that stage of the disease rather than at a one-point-fits-all stage such as a set number of years after symptom onset.

Here’s what we found:  The shorter survival is associated with older onset age and, as of the time of initial downgaze palsy, the PSPRS item scores for 1) difficulty swallowing liquids and 2) difficulty arising from a chair.

So, what does this mean?  For care of an individual patient, the neurologist’s recommendations might be shaded to an extent by the knowledge that the patient’s future course will be more – or less – favorable than the published averages for PSP.  In a large clinical trial, the statistician analyzing the data might want to achieve a more valid comparison of the active drug and placebo groups by weighting the progression data according to these factors. 

Yes, research proceeds in small steps, but proceed it does.

A rescue operation

It’s been 26 days since my last post.  Sorry.  I’ve been very busy with some consulting for drug companies and with co-authoring a research paper.  You’ll hear more about the fruits of those labors before too long.  But for now, I have some good news about a new drug:

Back in 2015, I reported to you on a conference presentation by the CEO of a tiny Swiss company called Asceneuron (“uh-SEH-nu-ron”).  They had a promising group of nearly identical drugs for PSP that were just entering the mouse testing stage.  Since that time, one drug has emerged from among its littermates as the leading candidate and has acquired the code name, “ASN90.”  Here’s that blog post’s maybe too-technical explanation of its mechanism of action:

All of the OGA inhibitors being developed are small molecules suitable for oral administration. . . . [These drugs reduce] tau aggregation by inhibiting OGA (O-GlcNAcase; pronounced “oh-GLY-na-kaze”). That enzyme removes the sugar N-acetyl-beta-D-glucosamine from either serine or threonine residues of proteins. The opposing reaction, catalyzed by O-GlcNAc transferase, like other post-translational modifications, is a common way for cells to regulate proteins. In the case of tau, having that sugar in place reduces aggregation.

In other words, ASN90 works via the ancient drug mechanism of inhibiting the action of an enzyme.

Since 2015, ASN90 has emerged from its littermates as Asceneuron’s favored OGA inhibitor.  It has passed its tests for efficacy in animals and for safety in three small trials in healthy humans and now it’s ready to be tested in people with PSP.  But Asceneuron has had trouble finding the multiple millions in funding for that, so for the past few years, poor ASN-90 has been languishing. 

But now, Asceneuron has announced that it has licensed ASN90 to a big Spanish drug company called Ferrer, which is ready to start a Phase II trial!  Cool!  That’s all I know so far, except that the drug also has potential in Alzheimer’s disease. I also know that Phase II trials in PSP typically need 6 months to organize, 6 months to fully recruit, 12 months as the double-blind treatment duration and another few months to organize the data’s loose ends and analyze the results. That’s about 2 to 2½ years — and then it takes a few months for the FDA has to scrutinize the results and issue its decision, and then it takes more time for the company to ramp up production and distribution.

Hope matters.

In case you don’t know, Phase II trials may be open-label or double-blind and serve mostly to test the safety and tolerability of the drug in people with the target disease, as opposed to healthy volunteers.  Such trials also help establish the optimal dosage needed to minimize side effects while keeping the dosage high enough to accomplish its job in the brain, based on previous lab and animal data.  Phase II trials often have a “multiple ascending dose” phase to establish the optimal dosage before proceeding with the main part of the trial using that dosage. When a Phase II trial is double-blind and sufficiently large, it can also serve as a test of efficacy.  In the past, the FDA has indicated that when it comes to PSP and other serious, rare diseases without existing treatment, a moderate-size (i.e., about 200-400 patients) Phase II trial with highly favorable safety and efficacy results would be enough for it to approve the drug. Ordinarily, for drugs targeting conditions that already have good treatments on the market, the FDA demands at least one larger Phase III trial, sometimes two.

I’ll report back the moment I know more, including the locations of study sites for Ferrer’s drug trial.