He said he was just going out to buy cigarettes . . .

Yeah, yeah.  I know I haven’t posted anything in the past two years other than responses to questions.  No, I don’t know why.  But those who stray can be redeemed, I’m told.  So here’s the first installment of a quick and dirty summary of most of the important news in the world of PSP from 2018 and 2019:

I’ve mentioned with breathless hope the two large trials of monoclonal antibodies directed against the tau protein, one sponsored by Biogen, the other by AbbVie.  Both were designed to detect slowing of the progressive decline in function as measured by the PSP Rating Scale.  Bad news.  Back in July 2019, AbbVie ended its study prematurely after an interim analysis showed no benefit and that continuing the study would be futile.  Biogen completed its study in October and announced in early December that its results were no better than AbbVie’s.  In each case, there were no important adverse effects.  But each company is continuing development of its respective antibody for Alzheimer’s disease.  Those results won’t be available for a few years.

But there’s still hope for anti-tau antibodies in PSP.  Both the Biogen and the AbbVie antibodies were designed to recognize the “N terminal,” so-called because of its unattached amino group, which is based on nitrogen.  (The other end is called the “C terminal” because of its unattached acid group, which is based on carbon.)  But other drug companies are developing antibodies targeting other parts of the tau molecule, and they haven’t announced any intention to abandon those programs.  Next out of the gate will be the big Belgian company UCB, whose antibody targets the “microtubule-binding domain” of the tau molecule, which is much closer to the C terminal.  Its Phase 1 trial has started at selected centers in Europe and in the works is a larger, Phase 3 trial that will include sites in the US.  Still other anti-tau antibodies are being tested in Alzheimer’s by Lilly, Roche/Genentech and Johnson & Johnson, and there’s no reason to think that those antibodies couldn’t work just as well against PSP.

Other treatment ideas are approaching clinical trials as well.  The closest are the “OGA inhibitors,” which I described in a 2017 post.  Three companies are working on those: Asceneuron, Merck, and Lilly, though the last is just targeting Alzheimer’s so far.  I hope that Asceneuron’s trials will start in 2020, though my PSP treatment hopes have been dashed before. Also on deck are the “anti-sense oligonucleotides,” or ASOs, which prevent the tau molecule from being manufactured in the first place.  Such drugs are already on the market for Duchenne muscular dystrophy, spinal muscular atrophy and hereditary transthyretin amyloidosis, each of which affects the muscles or nerves rather than the brain and are not tau disorders.

You’ll recall that a new set of diagnostic criteria for PSP was published in 2017.  It’s called the MDS-PSP Criteria after the Movement Disorder Society (now renamed the “International Parkinson and Movement Disorder Society” for obscure reasons), which sponsored the project.  New criteria were necessary to recognize early stages of PSP, when enrollment in treatment trials (and later, in treatment) would be most advantageous, and also to recognize the recently-described PSP subtypes.  In the past two years, a few studies have validated the criteria to some extent by comparing autopsy results with how closely patients satisfied the criteria during life.  Just last month, researchers in the UK found that applying the new criteria allowed them to expand their population with PSP by 74%.  The new patients were those with the “atypical” forms of PSP that went unacknowledged by the older criteria published in 1996.  The thing is, most of the “atypical” PSP patients will evolve to also satisfy the criteria for typical PSP, which we call PSP-Richardson syndrome, or PSP-RS.  So they would eventually have been recognized as PSP, but usually after years of erroneous diagnoses, unnecessary tests and futile, expensive and inconvenient treatments.

Quite enough for now.  I’ll continue these updates more faithfully, only next time it will get more technical.  Careful what you wish for.

A welcome formality

I see my patients with PSP on special clinic days when I have arranged for specialized professional help and have allotted extra time for the visits. The downside is that that it can be a dispiriting few hours, with little to offer anyone that day beyond symptomatic treatment, information and a pep talk. So I use this blog to accentuate the positive.

In that vein, I’m happy to report the drug/biotech industry’s efforts to develop a therapeutic antibody are proceeding apace. The latest tidbit is that the FDA has granted orphan drug status to the anti-tau antibody designated C2N-8E12 being developed by a joint venture of C2N Diagnostics and Abbvie. A 32-patient Phase I trial headed by Adam Boxer at UCSF will begin sometime soon. Achieving orphan status allows the company certain financial advantages and a longer patent life. Both are critically important for any new treatment for a rare disease, as the potential profits wouldn’t otherwise justify the development cost and risk.
Several other companies are working on anti-tau therapeutic antibodies, many of them aiming initially at PSP. Their ultimate Holy Grail is a treatment for Alzheimer’s, but it’s easier to conduct a clinical trial in PSP, as its progression is more readily predicted and measured. Furthermore, tau is the only protein known to aggregate in PSP, which makes that disease a simpler “model system” than AD, where both tau and beta-amyloid aggregate. The company furthest along this road is Bristol-Myers Squibb, whose tau antibody trial seeks 48 patients with PSP at 12 centers across the US and will start enrolling in a few weeks.
So I’m hoping for sunnier PSP clinic days soon!

Two pieces of good news: antibodies and TPI-287

To help that last, depressing post on CSF diagnostic tests go down, here are two spoonfuls of sugar.

The first is that the tiny biotech startup iPierian, Inc. has been bought by the giant Bristol-Myers Squibb.   iPierian, like at least a half-dozen other companies and several academic labs, is developing an antibody against tau.  Their first disease target is PSP.  The mere fact that BMS is interested indicates that some smart people think this idea has legs, and the R&D resources that big pharma can bring to bear are a great shot in the arm for the tauopathies.  Of course, the Holy Grail from the commercial standpoint is an Alzheimer’s treatment, but if a PSP treatment is spun off as a preliminary or corollary product, excellent.

Antibodies can’t gain access to the intracellular space in the brain.  The scientific idea underlying the antibody development is that misfolded, aggregated tau molecules are vulnerable to antibody attack during their foray through the intercellular space en route from neuron A to neuron B.  It’s like the cute green sea turtle hatchlings getting picked off by gulls during their awkward sprint across the beach.   The notion of tau secretion by neurons is critical to the new templating hypothesis of spread of misfolded and aggregated proteins in neurodegenerative disease.  (The idea has also been called “prion-like” but I’m with those who feel that this creates misplaced fear that all neurodegenerative diseases are transmissible and their sufferers are to be shunned.)

Now, let’s just hope that the stuff is tolerated, both by patients and by BMS’s business strategy.

Another purveyor of anti-tau antibodies, C2N, is in a more advanced stage of the pipeline with its own product.  A Phase I trial is due to start within a year.  More on that in coming weeks.

The other nice piece of news is that a trial of a microtubule-stabilizing drug in PSP and CBD has received IRB approval and will begin soon.  Designated TPI-287, the intravenously infused compound is a member of the taxane family that has been successful as antineoplastic agents.  It’s only in Phase Ib at this point and confined to a handful of centers, mostly in California.  Details should be up on clinicaltrials.gov soon, but here they are now:
Study director: Adam Boxer, MD, PhD
Sponsor: UCSF (Funder: CBD Solutions, Tau Consortium)
Recruiting?: Yes
Official study title: A Phase I, Randomized, Double-Blind, Placebo-Controlled, Sequential Cohort, Dose-Ranging Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TPI-287 in Patients with Primary Four Repeat Tauopathies: Corticobasal Syndrome or Progressive Supranuclear Palsy
ClinicalTrials.gov identifier: not yet available
Conditions studied: Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP)
Intervention Drugs: TPI-287 or placebo control is administered as an intravenous infusion, once every 3 weeks for 9 weeks during the double-blind dose-finding phase (for a total of 4 infusions). There are 3 infusions in the optional open-label phase; total of 7 infusions in both phases.
Phase: Phase Ib
Purpose: Tau is a microtubule-associated protein, and abnormal tau function has been proposed to play a role in the development and progression of primary four repeat tauopathies, CBS and PSP. TPI-287 is a stabilizer of microtubule dynamics, and the stabilization of microtubules is hypothesized to compensate for the loss of tau function in primary four repeat tauopathies. The purpose of this study is to determine the safety and tolerability of intravenous (IV) infusions of TPI-287 in patients with four repeat tauopathies (4RT), CBS or PSP.
Duration of participation: Approximately 4 months, 7 months with open label extension
Inclusion criteria: Subjects must be between 50 and 85 years of age (inclusive) and be able to walk 5 steps with minimal assistance (stabilization of one arm or use of cane/walker). Subjects must also have a Mini Mental State Examination (MMSE) score of 14 through 30 at the screening visit. Subjects must be willing and able to have brain MRIs as well as two lumbar punctures performed. Subjects must have a reliable caregiver who has at least 5 hours of contact with them per week and is willing to accompany the subject to study visits.
Exclusion criteria: Subjects must not have any medical condition other than CBS or PSP that could account for cognitive deficits (such as Alzheimer’s disease, active seizure disorder, stroke or vascular dementia). Subjects must not have a prominent and sustained response to levodopa therapy. Subjects must not have a history of significant cardiovascular, hematologic, renal, or hepatic disease, significant peripheral neuropathy, major psychiatric illness or untreated depression. Subjects must not have previous exposure to microtubule inhibitors, must not have participated in another interventional clinical trial within 3 months of screening, and must not have been treated with another investigational drug within 30 days of screening.