Monthly Archives: August 2026

Censavudine hints at real neuroprotection

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Back in May 2024 I posted news about an experimental drug for PSP called TPN-101 with the generic name “censavudine.” 

The sponsoring company had just announced the results of a very small, double-blind trial showing that the drug slowed, or maybe stopped, the progressive increase of a protein in the spinal fluid that correlates with the progression of PSP.  (NfL levels are normal in Parkinson’s disease itself and in Alzheimer’s disease.)  That announcement came as a press release and a poster at a conference. Now, a peer-reviewed paper with far more detail has been published in the respected journal Movement Disorders.  The authors are mostly staff at the drug company, Transposon Therapeutics, headquartered in San Diego.

The graphs above show the change in spinal fluid NfL at the study’s baseline and at weeks 24 (left panel) and 48 (right panel, which also includes the week 0-24 data).  For the first 24 weeks, 10 patients received placebo and the 32 others were divided among three censavudine dosage levels.  The vertical axis represents the initial NfL level as 0 for all patients.  You can see that the average NfL level (in picograms per milliliter) among the placebo group (black line) increased to about 400 by week 24, the expected result.  But those on censavudine either remained unchanged (blue and yellow) or improved by about 200 (green).

Then, after it was clear that the drug was causing no important harm, all 42 patients received the top dosage level for weeks 24 to 48.  The average NfL level in the group initially on placebo improved almost back to the 0 level.  The group that had been on the high dosage level maintained that excellent result, with the NfL level still virtually unchanged from baseline.  The NfL levels in the participants on the two lower dosage levels worsened, as if those dosages lost whatever benefit they might have had after 24 weeks.

The paper explains that none of these effects reached statistical significance because of the small numbers of participants and the wide variance within each dosage group.  Still, this is very encouraging news, especially because spinal fluid levels of IL-6, a marker of inflammation, improved in similar fashion. (Failing to reach statistical significance means that the chance of this being a random fluke is more than 5%, which is the standard for medical research.) 

Unfortunately, the drug made no difference in the rate of progression in the PSP Rating Scale, which uses interview and “hands-on” examination to assess everyday things like gait, balance, speech, swallowing, eye movement, sleep, behavior and cognition. But Transposon is, and should be, encouraged to take censavudine to a Level 3 trial, where larger numbers of subjects might provide the ability to detect useful improvements in these measures. For the PSP Rating Scale to demonstrate that a trial drug slows progression by 50% relative to placebo would require 32 patients on the drug and another 32 on placebo. To demonstrate a 20% improvement would require 192 in each group.

The authors point out that other than that pesky statistical significance problem, this is the first time a treatment has been shown to slow the natural increase in NfL in PSP. NfL in the blood also increases over time in people with PSP, but more slowly than in spinal fluid (18% per year in blood, 36% in spinal fluid), which makes it more difficult to distinguish an effective treatment from placebo using blood levels. Ongoing research is working on turning NfL into a blood test usable for research or clinical care.

Censavudine works by reducing inflammation in the brain in a unique and complicated way. For a technical explanation that might make your hair hurt, see this post from November 2023.

An ALS/PSP alliance?

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A development in amyotrophic lateral sclerosis (ALS; Lou Gehrig disease) may have welcome implications for PSP.

A tiny drug company based in Blue Bell, PA called Mitochon Pharmaceuticals just announced having won a $1 million grant from the ALS Association to mount a Phase II, double-blind trial of their drug in ALS.  The company expects the trial to kick off in early 2027, with a six-month double-blind period.  That means that the result should be available in late 2028 (my own optimistic estimate). 

The drug, known as MP-101 or 2,4-dinitrophenol, is given as an oral capsule and exerts multiple actions in the brain.  Chief among these is to correct leaks in the membrane enclosing the mitochondria, the cells’ power plants where sugar and oxygen come together to produce energy.  PSP has a similar problem with its own mitochondria.  While it’s not as important in PSP as in ALS, it’s possible that neutralizing one important such issue could have a calming effect on the whole self-reinforcing cycle of damage. That’s why Mitochon is interested in testing MP-101 in PSP as well. But so far, they have been unable to raise financing for a PSP trial and have no other drugs on the market to provide that capital.

What probably swayed the ALS Association in deciding to support the Phase II trial was spinal fluid results from Mitochon’s much smaller (10 patients) and shorter (2 weeks) ALS trial, where MP-101 reduced levels of neurofilament light chain (NfL).  That’s a protein released into the spinal fluid and blood in multiple conditions involving rapid loss of axons connecting brain cells, including those in PSP.  While the NfL level, therefore, is a diagnostic marker and not part of the problem itself, it holds promise as a sensitive way to detect benefit from an experimental drug.  Demonstrating such an effect would require far fewer patients and/or dollars than relying on any imaging procedure or neuro exam result. 

There are other biological similarities between ALS and PSP despite the fact that ALS is mostly a disease of the spinal cord and PSP is mostly a disease of the basal ganglia and brainstem:

  • Aggregates of the protein TDP-43, the equivalent of the tau aggregates of PSP, occur in the spinal cord in nearly half of all people with PSP, often in the same set of cells as in ALS.
  • Both diseases include important defects in the brain cells “garbage disposal” systems.
  • Both have problems coordinating the transport of vesicles around the cell.  Those are tiny bubbles of membrane with chemicals that are made in one part of the cell but needed elsewhere.
  • Inflammation is important in both, and in both ALS and PSP it involves the microglia, which are the “white blood cells” of the brain and spinal cord.
  • The first and most important genetic risk factor in PSP, called the tau H1 haplotype, is also associated with ALS despite the fact that the latter is not a tau-based disorder.  (The same is true for Parkinson’s disease.)
  • Both diseases can involve the frontal cortex, producing “executive dysfunction” as a cognitive symptom.

Here’s what I hope: 

  • I hope that MP-101 will be spectacularly successful in slowing the progression of ALS, which is just as disabling as PSP but starts 20 years younger, on average, and is fatal after an average of only three years.
  • I hope that funders with pockets as deep as those of the ALS Association will take a cue from that fine organization and fund a trial of MP-101 in PSP. 

For the scientists among you, here’s Mitochon’s brief but technical explanation of the mechanism of action of MP-101, lightly edited by me:

MP101 is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP), a weak acid with a dissociable proton. The pharmacology of MP101 is unique in that it involves a transfer of proton (H+) into the pH-basic mitochondrial matrix, a non-genomic event. This event involves: 1) lowering damage by reducing ROS production and calcium overload, while 2) promoting repair with the induction of cAMP production, activation of CREB and production of BDNF.

For a far more detailed review by John Geisler, PhD, co-founder and chief scientific officer of Mitochon, see this link. As you’ll read, Dr. Geisler has more ambitions for the drug than just ALS and PSP.

Disclosure: I have consulted for Mitochon in the past but have never had, and do not have, a financial interest in the success of the company.