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.