Tag Archives: AbbVie

Zoë’s extraordinary statistical analysis

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A new paper has analyzed data from 863 people with PSP from the failed Biogen and AbbVie monoclonal antibody trials from the late 2010s.  The purpose was not to re-sift the data for signs of benefit, but to characterize the participants’ cognitive deficits in detail and to measure their rate of cognitive worsening over the 12 months of the trials. 

This sort of thing has been done before, but not with as many patient or using those trials’ main cognitive measure, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a 12-component test that has become the standard cognitive test in drug trials of PSP and other diseases.  It includes tests of:

  • Immediate memory
  • Delayed memory
  • Visuospatial/constructional ability
  • Language
  • Attention. 

The present analysis also included four timed tests that other work has shown to be affected early in PSP and to be sensitive to its progression:

  • Phonemic and semantic fluency (saying as many words as possible in one minute meeting a condition such as things starting with the letter T or things found in a supermarket)
  • Wechsler Letter-Number sequencing test (connecting randomly arranged letters and digits in order: A-1-B-2, etc.)
  • Color Trails Test 1 (connecting small, randomly arranged circles in order of their enclosed numbers, ignoring their two background colors)
  • Color Trails Test 2 (similar, but alternating the background colors)  

Other features of this analysis worth noting:

  • A lot of other data about the participants’ PSP was gathered in standardized fashion, per the two trials’ protocols.  As you’d imagine, a test requiring writing and drawing could be affected by PSP’s motor and ocular deficits.  So, the statistical analysis adjusted each participant’s cognitive performance by their scores on the eye movement and/or limb movement PSP Rating Scale sections.
  • These participants were in the early-to-middle stages of PSP, at a mean of 3.3 years since symptom onset, with a standard deviation of only 1.4 years. So, one cannot assume that the conclusions of this study apply to people in earlier or later stages.  The same applies to their average age of 68.7 (sd 6.9) years.
  • The analysis combined the placebo and active-drug groups; it did not compare them to each other.  The authors felt that this would be fine because the original study’s comparison between the two groups’ responses to the drugs showed no differences, unfortunately.

The results showed that all scores worsened to a statistically significant degree over the 12 months except for story memory (immediately after the story), story recall (after a delay), list recall (immediate recitation of a word list) and list recognition (after a delay, indicating which words on a second list were also on the first).

The most rapidly progressing tasks were complex figure copying (with the original visible) and coding. (That’s where nine geometric symbols are presented beside the digits 1 to 9. The person is allowed to refer to the “code” on the same page while drawing the symbols corresponding to a list of random digits.)

The take-home for patients and families is that memory is relatively preserved in PSP, at least through the first four or five years.  This despite the habit of many laypersons of referring to any cognitive deficit as a “memory problem.”  So, cognitive activities relying on memory such as listening to music, comedy or stories may remain a source of entertainment and satisfaction for those with PSP well into the disease journey.  On the other hand, puzzles, crafts, drawing and strategy games are likely to prove frustrating.

Another use of these results is in the design of future clinical treatment trials.  The RBANS is a time-consuming, fatiguing test for both patient and clinician, requiring 45-60 minutes for those with PSP.  If the RBANS can be reduced to its most rapidly progressing, most informative components, the same (or better) information on the subject’s progression might be obtainable in a fraction of that time, without the fatigue.  This could improve the quality of the data not only on the cognitive test, but on the study’s other tests as well.  An excellent start at this was made a few years ago by scientists at Biogen.

The new paper’s first author was Zoë Cappella Cooper, a Harvard undergraduate headed for a stellar career.  (I know this because I’ve worked with her on other projects.)  The senior author was her mentor, Anne-Marie Wills, MD, a long-time colleague of mine at Harvard Medical School and Massachusetts General Hospital.

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.