An experimental, orally-administered drug called ARV-102 will enter clinical trials for PSP very soon. 

Last month, a small, Connecticut-based biotech company called Arvinas announced favorable results of a Phase 1 safety/tolerability study in people with Parkinson’s disease and expects a Phase 1b trial in PSP to begin in the “second quarter” of 2006. 

(For most drug companies, the quarters conform to the regular calendar, but for others, it’s their fiscal year, and I don’t know which applies to Arvinas.  Phase 1b studies, like others in Phase 1, focus on safety rather than efficacy, but include patients with the target disease rather than healthy volunteers.)

ARV-102 is a member of a drug class called PROTACs, and here’s how they work, as described in my post from October 20, 2021 (yes, five years ago):

Another approach that sounds like science fiction is “proteolysis-targeting chimeras (PROTAC) molecules, first developed in 2001.  These are hybrids of two small molecules, one of which can bind to tau (in this case) and the other that is recognized by the brain cells’ internal garbage disposal called the ubiquitin-proteasome system.  Unlike antibodies, PROTACs can easily enter brain cells.  Their only human application so far has been in oncology, but experiments in mouse tauopathy models are proving successful.

The company has made an animated video showing how ARV-102, which you can find here (click the “watch video” button).  Arvinas has several other kinds of PROTAC under development, most of which are for forms of cancer.

As the video states, PROTAC drugs attach to the target protein like antibodies, but unlike antibodies, are not consumed by destroying a single molecule.  Rather, they are like enzymes in that they facilitate chemical reactions hundreds of times until they wear out. 

My explanation in italics above mentions tau as a potential PROTAC target, but ARV-102 targets a different protein called leucine-rich repeat kinase-2, or LRRK2 (pronounced, “lark-two”).  Like all other kinases, it attaches phosphate groups to proteins as a way to regulate their function. The proteins regulated by LRRK2 are involved in a few dozen important processes in brain cells, the most important of which for PSP is probably an enzyme called Rab GTP kinase.  Rab is a “master regulator” of the cell’s ability to direct tiny packets of compounds, called vesicles, from where they’re made to where they need to be.  That’s called “vesicular trafficking.”

Three of the leading reasons to suspect that LRRK2 is misbehaving in PSP are:

1. One of the gene variants most consistently associated with the risk of developing PSP is called STX6.  After Rab (see above paragraph) guides vesicles to their destinations, they are fused in place by the protein encoded by STX6.  
2. One variant of LRRK2 has been found to be strongly associated not with the risk of developing PSP, but with shorter survival of those with PSP.
3. Another LRRK2 variant called G2019S, which by itself causes a form of hereditary Parkinson’s disease, can in rare cases cause the signs and symptoms of PD during life but actually has the microscopical pathology of PSP.

The scientists among you are now thinking that this evidence for a LRRK2-PSP link is sort of indirect, as opposed to the direct evidence linking LRRK2 with Parkinson’s.  But the people at Arvinas may feel that PSP is also worth a try because the need there is so great and that success in PSP could open up potential for other tauopathies like Alzheimer’s.  

Let’s be glad that Arvinas has joined the list of companies with innovative drugs going to bat for PSP.  (Disclosure: No, I don’t consult for them nor hold their stock nor any of that other stuff that could explain my optimism.)