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I have listen to the webinar from Elli Lilly $LLY on 15th of March, 2021 about the phase 2 Donanemab results. The biotech business is fraught with failure, and spinning the results so that investors won’t lose hope and leave. In just couple of years, we have witnessed triple failures of monoclonal antybodies aimed at the amyloid and tau plaque. I have to confess, I was unable to concentrate the whole time so I would rather go over the presentation slides.
The most interesting slide in the presentation, we saw at the very beginning of the show. I shall call the slide number 4 the Illumination on the Reasons for the Reluctance to Let Go of the Amyloid/Tau plaque.
Words in purple – Cure By The Other Name …..
The other name are the biomarkers named the Amyloid and Tau. This is the case of mistaken identity. The obstinacy is amazing. The Giants complain that FDA or rather all of us pay too much attention to symptoms. Haven’t they cured the disease already by removing the plaque? This indeed is the case of making the results for the drug not the drug for the sick.
Words in blue – The Statiscally Insignificant Blues
In a trial you have two populations, placebo and dosed. Each of these are defined by the mean and most of all by the distribution around the mean. The phrase “statistically significant” references to the possibility that distribution of those dosed can’t be part of the placebo cohort distribution, when the two overlap too much hypothesis that the drug has efficacy is in question. This might be the case when the efficacy is low and patients are widly scatered.
So $LLY decided to select its own patients, ITT (Intent To Treat (population)) became large enough to justify the drug financially but lowered the dispersion of the population. However $LLY selected intermediate tau deposits patient, and it threw out all those who decline rapidly. This significantly lowers the dispersion in the subjects. Hey, they almost made it! See those p-values! Hypothesis is not null! FDA did not let $AVXL to select patients based on biomarkers. There is tendency to set the bar even lower, since researchers have realized that there is a threshold at which a patients can not be turned back or helped. The example is $AVXL Blarcamesine phase 2b/3 trial with patients between 20-28 points on MMSE scale and with proven amyloid plaque deposits, but that is because many patients above 20 points can be actually rescued form the disease by the drug. Following this thinking $LLY went for average 23.6 ppoint MMSE.
The placebo performance can affect the statistical significance but it can not make the drug perform better. I wonder how far they got with negotaiting this with FDA on Trailblazer-ALZ 2 study. Let’s see!
Seems like FDA wants those rapidly declinning in, to add to the mix. $LLY got the traditional for plaque trials thousands. Oh! Things might not be going well! Whenever I see thousands I think watch out below.
Words in green – Green Light for Profit
Let’s start with the green stuff first. In 2018 the global market for oncology drugs has been about $77 billion, half of it is the US. Since 1970’s we made some progress against cancer but very significant only in few cases, the worst ones. So 5 years survival rate for liver and interahepatic bile duct cancer is now 19% which is 6 times more than it was in 1970’s. Similarly with pancreatic cancer, the worst offender, it is now 9% or 3 times what it was in 1970’s. Most kinds of cancer the improvement has been between 1.8 and 1.3 times. The best survival is with prostate cancer 99%, used to be 66%.
The cost per death is quite high, $65,000. There is about 600,000 deaths per year due to cancer in the US. But this is not the real toll of cancer. Some doctors once having cancer decide to forgo the slash and burn therapies which destroys the quality of life of people desperately fighting for few more years of life. We, the public, only hear the stories of the happy survivors, not those who were afflicted and lost threasure, life and final quality of life in the struggle.
This is a dream scenario for drug companies, drugs for terminal diseases with efficacy slowly rising so that higher prices can be justified, but also not quickly enough to lower the deaths significantly. This summarizes the oncology analogy.
FDA is a part of government bureaucracy and is relactant to open another pandor box of tens of billions of dollars to be paid out by Medicare in new field reminiscent of oncology, but even worse, since Donanemab can only make the disease more costly and still keep it not survivable. The rest of the words are just window dressing.
In the final calculation, would Donanemab hold its own with the placebo it would only delay the disease by theoretical 6 months, but at what cost? Few thousands a month, $30,000 a year? That would double the cost of Alzheimer’s care with almost no benefit. Is this accidental lack of ideas or something programed?
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