Tag Archives: clinical trials

Currently recruiting trial update

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In response to a reader’s question, here’s the most current list I can create of current or imminent clinical pharmacological neuroprotective treatment trials in PSP.  Maybe soon I’ll list the trials not covered by that list of adjectives, but you can do that yourself at www.clinicaltrials.gov.

For more information, including a phone number or email address, go to www.clinicaltrials.gov and search on the National Clinical Trials number shown or on the disease and drug names.  For the trial in Australia/New Zealand, use the link given.

  • Relyvrio (AMX-0035): A orally-administered combination of two existing medications to help brain cells resist the PSP process.  Will recruit 600 patients in the US, Canada, Europe and Japan. NCT06122662
  • NIO-752: An antisense oligonucleotide given by spinal injection once a month.  Still recruiting only in Germany and the UK.  A small, 3-month trial primarily designed to assess safety and tolerability. NCT04539041
  • GV-1001: a subcutaneously protein fragment administered daily by subcutaneous injection. A small trial primarily designed to assess safety and tolerability.  South Korea only.  NCT05819658

  • Set to start in a few months is the study of FNP-223.  This year-long trial will take place at dozens of sites in the US, Europe and Japan.  It’s an oral pill taken 3 times a day that reduces the abnormal phosphorylation and misfolding of tau.  It’s not yet on www.clinicaltrials.gov. 

You may be interested in joining an observational trial, where there’s no treatment – only testing and examinations, typically with the goal of developing new diagnostic tests and gathering other information of potential future use in developing new treatments.  If so, visit www.clinicaltrials.gov and search on PSP and, in the “focus” column, on “observational studies.”  One that I’d recommend highly is the ALLFTD study.  It’s centered around frontotemporal dementia but also includes PSP.  I know the people running it, and it’s a first-rate study that has already recruited several hundred people with PSP.  NCT04363684

Disclosures: I am, or have been, a paid consultant for the companies that make Relyvrio, NIO-752 and FNP-223. But I have no stock in the companies or other financial interest in the success of these drugs.

Make your opinion heard

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I need your opinion on a new way to design clinical trials for PSP.  New except that it was invented back in the 1980s.  It’s called “combined assessment of function and survival” or CAFS.

When a drug is tested for its neuroprotective property, traditional trial designs have measured only the slowing of the rate of worsening of function (i.e., symptoms and disabilities).  Most of the neuroprotective studies of PSP are 12 months long.  The progression rate of PSP being what it is, about 15% of people with PSP will die each year.  Trial participants who die during a trial are  dropped from the analysis and the data they generated are wasted. 

For PSP and most other chronic, progressive diseases, one hopes that the experimental drug wouldn’t just slow decline of function, but that it would prolong survival as well.  So why not somehow integrate measures of both outcomes into one combined outcome measure?  That could reduce the size of the trials needed to answer the question, which means less expense for the drug company.  That’s important to you and me because it lower the bar for a small, start-up company with a promising drug to mount a clinical trial.  Could the CAFS method work for PSP? 


Combining survival and slowing of progression into one statistical measure would work as follows:  Patients are evenly assigned to receive active drug or placebo.  At the end of the observation period, each patient is compared with each of the other patients, generating either -1 or +1 points for each patient for each comparison.  A patient receives a point if they have survived the observation period but the comparator patient has not.  A patient receives a negative point for the reverse.  If both have died, the patient receives a point if they survived longer than the comparator.  If both have survived (probably the plurality), whoever has progressed more slowly on the standard disability measure over the observation period receives a point.  So, in a study with 50 patients on active drug and 50 on placebo, the best possible score for each patient would be 99, and the worst, -99.  Then, the average points for the patients on active drug is compared with the average for those on placebo.

Sounds great so far, but here’s the rub:  For PSP, the statistics on the progression and survival dictate that this study design assign 50% of the patients to placebo, which is more than the 33% or 25% placebo proportion for most traditional PSP trials.  Furthermore, the observation period would have to be 2 years long, as opposed to the one year of most PSP trials . By that time, your PSP is likely to be too far advanced to qualify for another trial.

That raises some difficult questions for a prospective study subject: What if the drug works but I’m on placebo for the 2 years?  Would converting to the active drug at that later stage of PSP help me?  What if instead I have the opportunity to enroll in a traditionally designed trial  with only a 33% chance of receiving placebo and an observation period of only one year, but with some unattractive features such as greater risk or discomfort or distant and frequent study visits?

So, here are my questions for you. 

Question 1: Suppose that you’re offered a spot in a trial of an experimental drug – let’s call it “PSP1.”  It’s the only trial available to you for the next 6 months, but after that, there may be other trials.  The PSP1 trial uses the novel CAFS design I’ve just described, with a 50% chance of being assigned to placebo and a 2-year duration.  Assume that the science behind the drug suggests that it might slow the rate of PSP progression by 40%, which is quite a large benefit.  Assume that the mode of administration of the drug, the frequency and distance of the study visits and the likelihood of adverse effects are all quite acceptable for you. Would you want to participate despite the possibility that you might receive placebo and that by the end of the 2-year trial you’d be unlikely to benefit much from any neuroprotective drug?

Question 2: Now suppose that 2 drug trials are available to you and, of course, you can join only one.  The first is the PSP1 trial described just above.  The other, for drug “PSP2,” has only the standard 33% chance of placebo and only the standard 12-month duration.  That shorter duration means that you’re likely to still qualify for another drug trial afterwards. Assume the same 40% potential disease-slowing benefit as PSP1.  But the PSP2 trial has some problems such as a greater likelihood of adverse effects, a difficult administration method, or a greater distance or frequency for the study visits. How bad are those problems?  Assume that if the placebo likelihood and the duration were the same as for PSP1, the problems would make PSP2 half as attractive for you as PSP1.

Here’s a convenient summary of all that for you:

 Trial
 PSP1PSP2
DesignCombined assessment of function and survival (CAFS)Assessment of function only
Duration2 years1 year
Placebo likelihood50%33%
Chance of substantial benefit40%40%
Practical issues (mode of administration, chance of adverse effects, distance to travel, visit frequency)Very acceptableMore difficult, making PSP2 half as attractive as PSP1 if all other things were equal.
Likelihood that you could participate in another trial after thisLowHigh

OK – time to vote.  Using the Comments feature or ligolbe@gmail.com, please answer these 2 questions:

Question 1:  Would you enroll in the PSP1 trial?  YES or NO

Question 2:  Would you choose the PSP1 trial or the PSP2 trial?

Feel free to include any comments or explanation.

clinicaltrials.now

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My last two posts summarized the portions of the PSP Study Group’s October 4 meeting on imaging, markers and longitudinal observational studies.  This one’s on the current state of neuroprotective clinical trials.  The information is from presentations by Adam Boxer and Günter Höglinger and from informal contributions by other attendees.

First, some background

“Neuroprotective” means slowing or maybe halting the progression of the underlying disease process without improving the current symptoms or disability.  It is to be distinguished from “symptomatic” treatment, which only helps the symptoms or disability, typically transiently, while the underlying process continues. 

The four most recent failed neuroprotective treatments have been davunetide, a neurotrophic (i.e., neuron growth-promoting and repair) agent; tideglusib, a kinase inhibitor (that works by preventing abnormal attachment of phosphate groups to tau), tilavonemab and gosuranemab (both monoclonal antibodies directed against the “first,” or N-terminal, end of the tau molecule). None of these four slowed PSP progression as measured by the PSP Rating Scale or any other bedside test, although there’s controversial evidence that tideglusib slowed the progression of atrophy in relevant brain areas on MRI.  

Other hopeful PSP neuroprotective agents that have failed to work in double-blind trials in recent years.  These, in no particular order, are salsalate, an approved non-steroidal anti-inflammatory drug that reduces tau phosphorylation; TPI-287, an anti-cancer drug that improves microtubule function; coenzyme Q-10, a nutraceutical that enhances mitochondrial energy production; Juvenon, an antioxidant; pyruvate, creatine and niacinamide, other antioxidants; riluzole, a drug with multiple mechanisms that is approved for neuroprotection in ALS, where its benefit is minimal; rasagiline, an inhibitor of monoamine oxidase-B, an enzyme that produces toxic free radicals from dopamine; lithium, an approved drug in psychiatry that reduces tau phosphorylation; valproate, an approved drug in psychiatry and for epilepsy that does the same; and methylene blue, an approved drug for multiple medical problems that inhibits tau aggregation.

Monoclonal antibodies

We don’t know why the antibodies have failed to date.  Maybe tau’s the N-terminal isn’t consistently present or accessible to antibodies in whatever form of tau is relevant to the spread of PSP through the brain.  Maybe the trials started too late in the course of the disease.  Maybe not enough of the antibody was able to cross the blood brain barrier, even though the tau content of the spinal fluid as measured in the lumbar space (not near the brain) was dramatically reduced.  Maybe tau is protected from antibodies as it moves between neurons by some sort of bubble-like or bridge-like membrane structure.  Maybe the cell-to-cell transmission of tau isn’t the most critical or rate-limiting step in the pathogenesis of PSP. 

A promising bit of support for N-terminal antibody treatment comes from three patients who participated in the gosuranemab trial’s site at the University of Pennsylvania who later died and were autopsied.  Their brains showed changes in the glial cells suggesting that the antibodies had incited a clear anti-tau reaction that was absent in untreated patients with PSP.  Although the neurofibrillary tangles and other visible, insoluble tau deposits were unchanged by the antibody, the authors of the paper (and I) conclude that maybe all that’s required for clinical efficacy is some tweaking to the antibody, to its dosage, to its ability to cross the blood-brain barrier, or to the stage in the course of PSP when it’s given.               

Despite the failure of the two antibodies so far and our shortage of explanations, drug companies have continued to develop monoclonal antibodies against tau.  These are being tested (almost) exclusively in Alzheimer’s for the near future.  Zagotenemab (LY3303560, from Lilly) and semorinemab (RO7105705, from Roche) are both directed against tau’s N-terminal.  BIIB076 (from Biogen) and JNJ-63733657 (from Johnson & Johnson) are directed against tau phosphorylated at position 217.  Bepranemab (UCB0107 from UCB) and E2814 (from Eisai) target the mid-portion of tau.  Lu AF87908 (from Lundbeck) targets phosphorylated amino acid 396, near the C-terminal.  The lone PSP trial of any of these is a Phase 1b (i.e., double-blind but designed to test safety, not efficacy) trial of beprenamab at one center in Germany.  Even if the drug does well in that trial, further efforts are planned only for Alzheimer’s for the time being.

Anti-sense oligonucleotides

A Phase 1, double-blind trial of NIO752, an ASO from Novartis, is in progress at 7 sites in the US, 2 in the UK, 2 in Canada and 5 in Germany.  The 48 patients on active drug will be divided into three groups, each with a different dosage level, and 12 patients will receive placebo.  The lowest dosage level will start first and the next will start only if there is no immediate safety issue with the first. The drug must be given by intrathecal injection, which means directly into the spinal fluid by injection into the thecal sac at the base of the spine.  The procedure is identical to a diagnostic “spinal tap” except that that’s a fluid removal for diagnosis and this is a fluid administration for treatment.  This will be performed 4 times at 1-month intervals followed by another 3 months of observation.  More info is here.

ASOs are short strands of RNA with multiple mechanisms of action, each at a different step in the process of translating information from the MAPT (microtubule-associated protein tau) gene into the tau protein.  Many experts feel that this approach, being far “upstream” in the pathogenetic process, is the most promising of the current neuroprotective ideas for the tauopathies.  Obviously, the issues of safety and convenience of monthly spinal taps are potential obstacles.  ASO neuroprotection against Huntington’s disease, where the aggregating protein is “huntingtin,” was reported in June 2021 to have failed, but so little is known of the mechanisms of ASOs that this is not necessarily bad news for the tauopathies.

OGA inhibitors

To self-plagiarize from a 2015 post, a class of experimental drugs for the tauopathies “reduce tau aggregation by inhibiting OGA (O-GlcNAcase; pronounced “oh-GLIK-na-kaze”). That enzyme removes the sugar N-acetyl-beta-D-glucosamine from either serine or threonine residues [amino acids] 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.”  Got all that? A major plus for the OGA inhibitors is that they, like most enzyme-inhibiting drugs, are small molecules, which means they can be taken orally.

Trials of OGA inhibitors for PSP have not yet begun and there’s no clue in the grapevine as to when that might happen.  But a first-in-human study of ASN-51 (from Asceneuron) in 40 patients with Alzheimer’s is under way in Australia. 

My sources tell me that Merck has another OGA inhibitor that has not yet started clinical testing.  It’s not even listed as a pre-clinical candidate in the latest revision of Merck’s publicly available, on-line pipeline info, which was last updated on July 27, 2021.

Although salsalate failed to slow PSP progression, another approved non-steroidal anti-inflammatory called tolfenamic acid reduces tau production. A single-center, Phase 2a trial had planned to start enrolling 24 patients with PSP at the Cleveland Clinic in Las Vegas in early 2021, but the trial start is delayed indefinitely.  The drug is available by prescription for migraine in the UK and some other countries but not in the US. 

Finally, AZP2006 (from AlzProtect) activates secretion of progranulin in the brain, reducing inflammation, and also has an independent action as a tau anti-aggregant.  It is given as an oral solution.  A Phase 1 trial in progress at three centers in France and a Phase 2 trial at the same three sites is planned.

For more technical details on neuroprotection (and symptomatic treatment) in PSP, see the excellent recent review by Lawren VandeVrede and colleagues from UCSF.

Our CurePSP Centers of Care review is mostly on symptomatic PSP treatment but includes a section on neuroprotection.

PSP treatments in or near human trials

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When a patient or caregiver asks me if anything can be done for PSP aside from palliative measures, my ready answer is that there’s a lot of research now into specific treatments that might slow or halt disease progression. I never have time to get into details in the time available, so I’m not sure my assurance is credible. So, putting my keyboard where my mouth is, here is a pretty thorough list of treatments that are in human trials for PSP or will enter such trials this year:

Anti-tau antibodies: BMS-986168 (Phase 1), C2N-8E12 (Phase 1). Both are in early stages of recruitment at multiple North American sites. The rationale is to bind and destroy abnormal tau en route between brain cells. (Disclosure: I’m a consultant to Bristol-Myers Squibb and a site investigator .) Other drug companies and academic labs are also working on anti-tau antibodies, but at an earlier stage.

Tau anti-aggregants: Leucomethylthioninium (LMTX). This is a derivative of methylene blue in Phase III for Alzheimer’s and frontotemporal dementia; If successful, PSP could be next. But beware the hype that has accompanied methylene blue and its derivatives.  The results from earlier-phase trials have not been published, which is curious.

Microtubule stabilizer: TPI-287 (Phase I). This is closely related to the taxane group of cancer drugs. In cancer, stabilizing microtubules helps prevent cells from dividing. In the brain, it compensates for the loss of tau, which normally stabilizes microtubules as the cells’ transport and skeletal system.

Tau acetylation inhibitor: Salsalate (Phase 1); This is being tested at UCSF, UCLA and UCSD in an open-label “futility” design. In other words, the study will determine not if the drug works, but if it deserves to be tested further. The same drug is being tested for multiple other disorders and has long been on the market as a non-steroidal anti-inflammatory drug.

Tau aggregation inhibitors: ASN-561, an O-GlcNAcase inhibitor. This will probably enter Phase I in 2016. It acts by promoting the attachment of a sugar molecule, N-acetyl glucosamine, to the tau protein, thereby inhibiting its aggregation. Such “OGA” inhibitors are also being tested for other conditions, including cancer.

Anti-sense oligonucleotides: These are RNA molecules designed to inhibit the production of 4-repeat tau, which is over-produced in PSP relative to 3-repeat tau. That imbalance could be contributing to tau aggregation. These have not reached human trials.

Anti-microglial agent: FK506 reduces the activity of microglia, inflammatory cells in the CNS. Evidence is increasing that such inflammation is a cause, rather than an effect, of cell loss in many of the neurodegenerative diseases. In fact, several immune-response-related genes were among the top 10 “hits” in the 2011 study of genetic risk factors in PSP.

Young plasma: Only in 10 patients, non-controlled and only at UCSF, this study will give plasma from healthy men younger than 30 to patients with PSP. The primary outcome issue is safety and tolerability, but efficacy measures will also be applied. Recruitment is under way. The theory is that some unknown blood-borne molecule in young people prevents them from developing PSP and could slow the process in someone with the disease.

Mitochondrial nutrient: Coenzyme Q-10 (Two small double-blind studies, one published and one unpublished) show similar modest improvement in PSP Rating Scale scores. This is a symptomatic treatment but the above items on this list are all potentially neuroprotective.

For more information on any of these, see http://www.clinicaltrials.gov.