Some not-so-good news, I’m afraid: ORION trial has been discontinued for lack of benefit.
A combination of two oral drugs collectively called AMX0035 has been in a double-blind trial since late 2023. One component, sodium phenylbutyrate (brand name Buphenyl), helps brain cells get rid of misfolded, worn out or defective proteins, including tau. The other, taurursodeoxycholic acid (brain name TUDCA), stabilizes dysfunctional mitochondria. Both drugs are known to be safe in non-PSP populations, as they have long been approved and marketed for other conditions.
A few days ago, with about half of the ORION subjects having completed their 12-month double-blind observation, the sponsoring company performed an interim analysis. Their statisticians, under strict secrecy rules, “peeked” at the active drug vs. placebo assignments, comparing the groups on their degree of worsening on the PSP Rating Scale since the first visit. They found no difference, which means that allowing the remaining patients to complete their double-blind observation could never show a statistically significant improvement for the trial as a whole. Nor was there any slowing of progression on any of the secondary efficacy measures such as brain atrophy on MRI. Fortunately for the study participants, the frequency and severity of adverse effects were very low in both the active drug and placebo groups.
Where does PSP go from here, trial-wise? Lots of places:
- The trial of FNP-223, an oral drug that reduces abnormal phosphorylation and misfolding of tau, is nearly complete.
- A trial of NIO-752, an anti-sense oligonucleotide injected into the spinal fluid that reduces the manufacture of tau, will start in a few months.
- The PSP Platform Trial, which has teed up two two drugs and expects a third soon, should start later this year if changes in its NIH funding don’t stand in the way. Those are an active anti-tau vaccine called AADvac1 and AZP-2006, an oral drug that reduces inflammation and helps brain cells dispose of garbage. They will be tested separately, but using a common control group.
- The trial of GV-1001, a subcutaneous injection that works at the RNA level to reduce brain inflammation, will probably start in 2026 or late 2025 if all goes well.
Two drugs a bit further behind in the pipeline, based on my reading of the tea leaves, are:
- bepranemab, an anti-tau monoclonal antibody for intravenous infusion and
- an oral reverse transcriptase inhibitor called censavudine, where the results of the Phase I trial are sparsely reported to date.
That makes five new drugs to start trials within the next year or so — plus another one or two slightly later.
I liked the ORION trial’s idea to give two drugs simultaneously to address two different parts of PSP’s pathogenesis. Many PSP experts feel that at least that many drugs will be needed to do much to slow the progression of this complex disease. That’s what has proven necessary for things like AIDS, severe hypertension and many kinds of cancer. Those are only a few examples of multi-pronged attacks turning life-threatening, progressive diseases into chronic, manageable, non-disabling conditions.
I’m bullish on the same kind of thing happening to PSP.
PSP Blog 
Thanks for the update on candidate drugs and trials, Dr Golbe.
Are you aware of any activity in evaluating Lithium Orotate supplementation for PSP, given the recent Nature article https://www.pbs.org/newshour/science/4-things-to-know-about-a-new-study-on-lithium-and-alzheimers-disease reporting on what sounded to me like potentially revolutionary treatment for neurodegenerative diseases? The article focussed on Alzheimer’s disease but it claimed reversal of tau accumulation (not just Aβ), and reversal of symptoms in AD mice models.
Thank you for all your efforts and interest in finding a treatment or cure for PSP.
George Peponides, PhD
Dr. Peponides:
Thanks for pointing out that editorial and the Nature paper to which it refers. The mechanism of lithium’s benefit in the Alzheimer mice is thought to be at least partly its ability to inhibit GSK3-beta, an enzyme that attaches phosphate to tau. This property of lithium has been known for decades and the NINDS Intramural Branch organized a clinical neuroprotection trial of lithium for PSP about 20 years ago. Unfortunately, the trial was discontinued after the first few patients proved unable to tolerate lithium because of nausea, dizziness and somnolence. Two other GSK3-beta inhibitors – tideglusib and valproic acid – have also been tested as neuroprotection against PSP. They were both well tolerated but the trials failed to show benefit. The only slight ray of hope is that tideglusib did appear to slow the rate of progression of brain atrophy as shown by MRI scans.
My other reservation about overinterpreting the importance of the recent lithium results in the AD mice is that the tau effect may simply have been a result of a beta-amyloid effect. (It’s known, or strongly suspected, that in AD, the tau pathology is caused by the beta-amyloid pathology.) In that case, lithium would not help a “pure” tauopathy like PSP.
But there’s still ample hope that the effect of lithium in the AD mice could help pure tauopathies and that a formulation of lithium tolerable to people with PSP might be found.
I’ll keep an eye on developments, and if you see any new evidence to clear up this picture, please pass it along.
Yours,
Dr. Golbe
Thank you for the detailed and informative response, Dr Golbe.
I found the clinical study NCT00703677 that investigated Lithium for PSP and CBD and I suspect this is the one you are referring to in your reply. If so, I have the following comments:
This study used Lithium Carbonate, the standard Lithium compound used in bipolar depression. In contrast, the Harvard study in Nature used Lithium Orotate as a replacement therapy in AD mice models, and the study claims that Lithium Orotate (LO) is much more bioavailable than other Li salts and hence can be used at much lower dosages.
In the NINDS trial they used Li concentrations in the 0.4-1.2 mEq/L range, whereas in the Harvard study with LO they used Li concentrations of 4.3 μEq, which is 100 to 300 times smaller and is much closer to the physiological concentration range of Li in brain and serum (0–2 µEq L−1), according to the Nature article.
Thank you again for all your interest and active efforts regarding PSP and CBD, and for keeping the community informed and engaged.
George Peponides, PhD
Thanks for that information, Dr. Peponides, and for the kind word.
LG
Thank you for the update. My mom was part of the NIO 752 Phase 1 trial. It really seemed to stabilize, and perhaps improve, her condition. Where did you see that Novartis is moving on to Phase 2?
Dear Marko:
I’m very glad to hear that your mother seemed to stabilize on NIO-752. My sources for the info that Novartis is proceeding to the next phase for PSP include my contacts at the company itself.
Dr. Golbe