Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!
Before I lose my train of thought…the title should have been; “at 3,285 patients even the dead can walk…”. Another of my gross exaggerations.
The intrepid Aducanumab adds another $X billion to $BIIB market cap. New analysis claims that there is a glimmer of hope for the drug. I am not a statistician or did I see the study. All I can do is to look for differences in measurements and trials between Blarcamesine and Aducanmab, and there are some great differences. FDA’s clinicaltrials.gov lists both Biogen studies as almost identical and terminated upon futility study on 1,748 patients. Yet once the data on the full the set of 3,285 patients has been gathered a new life has been blown into Aducanumab’s claim of efficacy. Let’s look at some aspects of it Aducanumab’s trials and results.
Selection of Subjects
Both studies recruited patients between MMSE scores 24 and 30 but with positive amyloid Positron Emission Tomography, ergo the guy or gal can be normal but have deposits of amyloid plaque. If you have read my posts in the pasts you probably remember that I had learned that about 30% of deceased Alzheimer’s sick don’t have plaque and that some people have plaque but are perfectly normal. These people have either MCI or mild AD but at MMSE 30 they can fall into the category of “healthy + plaque”.
The other aspect is that APOE genotyping has been conducted which means that the carriers of e4 can be excluded but this has not been asserted when they talked about a subgroup of responders. Though the science on APOE e4 is not conclusive it is taken to be true that the single carriers have 20% probability of developing AD and much earlier, the progress of the diseaes is also much faster than for none e4 carriers. See my post on APOE genotyping Anavex2-73 Phase2a. https://wordpress.com/post/piotrpeterblog.com/460 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118550/
It has been reported that some subset of patients has responded positively to treatment with Aducanumab. Are carriers of APOE e4 excluded? What is the average MMSE score of those responders? One is certain that the drug has caused removal of plaque, which is deemed to have synergy in causing further deterioration in patients, so removal can be expected in some way to help the patients, theoretically. It could not have been found in 1,748 patients but was somehow conjured at 3,285.
It is very hard to compare Blarcamesine data and Aducanumab as the starting MMSE scores are different and the onset on Alzheimer’s is not linear which is explained in this reference. https://jamanetwork.com/journals/jamaneurology/fullarticle/775209 The data from this reference has been presented graphically beneath.
CDR-SB is not the same measure as used in $AVXL PDD Phase2 trial. This is just a very subjective questionaire with just 4 different outcomes. See it for yourself https://sites.cscc.unc.edu/aric/sites/default/files/public/forms/CDS%20Clinical%20Dementia%20Rating%20-%20Summary%20and%20QxQ.pdf
CDR-AC, which was used in the PDD trial, is a computerazied assesment for cognition and motor skills to be used in both Alzheimer’s and Parkinson’s diseases where some of the reuslts are measured in milliseconds. These are not the same measures. One is very objective and quantitative and the other is much more subjective and qualitative.
The reported 23% increase in the scores of CDR-SB is basically lowering the score by 25% in most subjects. This can be significant but the next measure that is MMSE scores paints rather different picture. The data on MMSE scores was supposed to be better than the placebo by 15%. MMSE is not perfect but it is a better measure as it it less prone to subjectivity.
Extrapolating from this graph MMSE scores in the initial period of the disease after 18 month should be lower on average by 3.38 MMSE points. Average MMSE score is let’s say (assumed) 27 points, including drop it is 27-3.38 points=23.62 points so after 18 months and 15% improvement (115% of placebo score) this is MMSE 27.16 points therefore improvement can be seen as illusory as that subset of early patients could have not deteriorated yet. These are the paients who postpon their slide into dementia for just a year or two. The power of the study is at p=.06 which means that 6% patients in the select group could be counted in the dispersion about placebo mean. See the plot and read that at 78 weeks there is still some 10% of patients who did not deteriorated at all in the background of other 90% who did, some even significantly. I present here a models of deterioration from other post as there always is a group with delayed deterioration which over years dwindles with accelerated rate as years progresses.
This depicts deterioration for patients on average at MMSE 20 points, that is on 60% percent of the scale (healthy). MMSE of 24 is 80% percent of scale and MMSE 30 is 100% of scale. Also these patients had been already followed for one year prior. The disease can have very nonlinear progression with large number of patients detriorating quicker than other and some lingering for quite some time. The above illistration drives the point in easy to see manner.
See this paper for source data https://jamanetwork.com/journals/jamaneurology/fullarticle/775209
By contrast the MMSE scores of the Super Responders in ANVEX2-73 AD Phase2a can be seen on this graph
If we talking selected groups the 4 assending patients have imporoment of MMSE 4 points which over placebo give improvent of 170% over placebo in span of 78 weeks, the same as the $BIIB trials.
If we try to compare oranges to oranges and apples to apples which anyway can not be perfect in he field of Alzheimer’s but at least semblence of such comparison is called for here then the improvement by Blarcamesine in MMSE scores over Aducnumab is almost ~5 times greater for selected groups
Biogen claims efficacy by separating th patients into selcted groups, subsets, the question is how valid is such division? Can it be justified on some bio marker grounds? Or is it just another case for crafting the trial to the drug vs. the drug to the trial?
I read following article https://www.statnews.com/2020/11/04/fda-scientists-appear-to-offer-major-endorsement-of-biogens-controversial-alzheimers-treatment/ . I would like to highlight following quotes. One of the authors here is no other than Adam Feuerstein https://twitter.com/adamfeuerstein
- $BIIB is picking and choosing studies and group of patients, and with the exclusion the fast and furious down the 6 feet down slide and at 3,285 patients much can be claimed.
- If the claim that the blinding of the study has been compromised and the fact that on qualitative and subjecive measures Aducanumab improved most the we can stipulate that the CDR-SB was affected by this.
- The improvement in MMSE scores puts in doubt the scenario of significant efficacy as applying the same criteria to Blarcamesine trial Phase2a gives 5 fold advantage over Aducanumab to Blarcamesine.
- The above point was made in face of assumed average initial MMSE score for Aducanumab of 27 point versus that of 22.5 for the Super Responders of Blarcamesine. Relatively healthy vs. Already diseased and rescued.
- Starting with almost healty subjects (MMSE scores 24 to 30) might distort the trial as the fast deteriorating patients are excluded and the duration is only 18 months. See illusration above.
- The incidence of ARIA still present vs. almost none on Blarcamesine side.
- Just another attempt to rescue the amyloid hypothesis for Alzhiemer’s on closer examination doesn’t hold water.
- The simplest expalaination of Aducanumab strategy is to remove the worst offenders and still compare to placebo arm containing those worst offenders but your claim rests on the fact that relatively healthy rest of the dosed arm do not start to deteriorate untill much later.
I beg for money here but I have the impression that had I stood on the corner I would get more money. Just drop a fiver!
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