Is PSP a Disease?

The neurodegenerative diseases are starting to merge. The most obvious level of commonality lies at the cellular level of pathogenesis, where each disease is now hypothesized to include protein misfolding, templating, intercellular spread and damage by oligomers. Within the tauopathies, there is major overlap among “diseases,” as shown in this superb diagram from David Williams and Andrew Lees (Lancet 2009).

The blue, green and purple areas are pathological syndromes and the reddish ones are clinical syndromes. Note that all of the patients with Richardson’s syndrome and PSP-parkinsonism have classic PSP pathology, but the reverse is not true. Corticobasal syndrome is only about half explained by corticobasal degeneration pathology (though the diagram suggests about 85%), most of the rest being PSP and frontotemporal dementia pathology. Similar shortfalls in clinicopathological correlation underlying our traditional definition of a “disease” plague the rest of the tauopathy diagram. A similar diagram can be made for the α-synucleinopathies.

How to explain this to our patients? Our students? Ourselves? I like to think of neurodegenerative diseases as a set of spectrums. As there are only a limited number of neural systems available to damage, inevitably some parts of some of the spectrums will overlap in their anatomical, therefore clinical, phenotypes. This idea may seem unsatisfying to our traditional, neat system of clinicopathological pigeonholes. It’s not as easy to digest as, for example, the “autism spectrum,” where we don’t yet have the messy variable of pathological correlates to contend with. But this state of neo-nosologic confusion is only temporary. Before too long, we will have a long list of genomic, epigenetic, toxic, proteomic variants along with just plain stochastic events that in combination produce neurodegenerative disease. We will then have an understanding of such diseases that is more sophisticated and rational than the current combination of microscopical, biochemical and clinical abnormalities. These insights will render our present concept of “a disease” obsolete and make it much easier to devise prevention for most of these conditions.

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 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 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.