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.

10 thoughts on “A rescue operation

  1. Hi dr. Golbe

    I still referring to your former list
    How we distiguish between psp and vescular psp?
    The medical literature devoted to vescular psp is poor
    Vascular psp: what is it?
    Symptoms, diagnosis, causes and risk factors
    What is the specific treatment?

    • I’m working on a list of diagnostic tips and specific treatments for the PSP mimics. But to answer this question: vascular PSP isn’t really PSP in that it doesn’t have abnormal tau protein or any of the other microscopical abnormalities of PSP. Instead, the brain has evidence of many tiny strokes — areas of brain tissue that have died from lack of blood supply or from tiny hemorrhages, and turned into tiny scars. It’s caused by the same risk factors that cause larger strokes and heart attacks — poorly controlled high blood pressure, diabetes, and genetic flaws in the metabolism of fats. Of course, only a tiny fraction of the population with those risk factors gets vascular PSP, and we don’t know why they’re especially vulnerable. Diagnosing vascular PSP can be done by an MRI, which is very sensitive to small strokes. Also, vascular PSP tends not to progress smoothly like regular PSP, but to worsen quickly, remain stable for months or years and then progress again in a jump. Alzheimer’s and Parkinson’s also have their vascular equivalents, and, depending on the location of the strokes, those can blend with vascular PSP in their array of symptoms.

      • Vascular PSP is treated as regular PSP is, with therapies aimed at the individual symptoms as they appear. There’s no known way to heal the existing damage, unfortunately, but controlling the risk factors like blood pressure, lipids and diabetes can reduce the chance of future tiny (and large) strokes.

  2. This is very interesting news and does instill some degree of hope. If ASN90 reduces (completely inhibits?) tau aggregation via the mechanism you described, what would become of the already-aggregated tau proteins which would be already causing symptoms. Would these be affected as well or would ASN90 only prevent future aggregation?

    • Great question. In PSP and the other tauopathies, there’s probably a one-way process going from normal tau TO misfolded tau TO small aggregates of 20-100 tau molecules (called oligomers) that are still water-soluble TO large aggregates (the neurofibrillary tangles) that are not water-soluble. The toxic players are the misfolded tau and the small aggregates. If ASN90 succeeds in preventing the conversion of normal tau to misfolded tau, it would reduce the new production of both misfolded tau and the oligomers without affecting their existing concentrations. But the cells’ normal garbage disposal system may be able to dispose of those, now that it’s not being overwhelmed by the new production of misfolded and oligomeric tau.

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