Tag Archives: anti-sense oligonucleotides

What’s good for the goose . . . ?

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Biogen is currently testing an anti-sense oligonucleotide drug called BIIB-080 in patients with mild cognitive impairment and very mild Alzheimer’s disease. The goal would be to slow or prevent their conversion to full-blown Alzheimer’s disease. Today someone posted a comment asking if I thought this could work for PSP. I thought this could make a good, brief post:


Biogen has an early-phase trial of BIIB080 in Alzheimer’s, and there’s no reason to think it wouldn’t work as well in PSP.

Actually, the Alzheimer’s trial is mostly for people with “mild cognitive impairment” and the measure of success would be preventing progression (“conversion,” as it’s called) to full-blown Alzheimer’s. They are also enrolling some patients with mild AD, hoping to prevent progression to moderate stages. If the people at Biogen feel that BIIB080 should first be tested in such an early disease phase, that could be why they chose Alzheimer’s over PSP: there is no known equivalent of mild cognitive impairment for PSP.

Another reason Biogen might be starting with AD is the ready availability of a test for beta-amyloid in the brain in the pattern specific for that disease. It’s called an Amyvid scan, and participants in the BIIB080 trial have to show an AD pattern on the scan to qualify. There is no equivalent, road-tested, sensitive and specific diagnostic test for PSP, which means that a much larger trial would be necessary to overcome the “statistical noise” caused by people with a false-positive diagnosis of PSP.


The diagnostic criteria for PSP do define a state called “suggestive of PSP,” but there are still no data on what fraction of those individuals eventually progresses to probable or definite PSP, or how long it takes. On the other hand, there are excellent such data on the conversion of MCI to Alzheimer’s.


A couple of examples of symptoms that would result in a diagnosis of “suggestive of PSP” are repeated falls and slow downward eye movements. As you can tell, such symptoms in isolation are not very specific for PSP, so a trial enrolling such patients would have to have many hundreds of particicpants for a statistically useful fraction of them to convert to possible, probable of definite PSP, especially over only a 12-month period. Furthermore, the size of the trial would have to be large enough for the conversion rate among the recipients of the active drug to be validly compared to the rate among those on placebo.


So, my guess is that if BIIB080 works in mild cognitive impairment and very mild AD, Biogen will test it in PSP. But if a good pre-clinical marker for PSP becomes available, then it would much more practical to try such treatments in pre-clinical PSP.

But there are other drug companies with other anti-tau ASOs. One, from Novartis, is already enrolling patients. Others are approaching clinical trials.

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

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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.