The 10% Edison Conjecture I'm not going to make argument against the Edison coverage of Bioasis. They're being conservative and given their need to be right about things, they will always err on the side of caution.
The question of a 10% chance of getting enough xB3-001 into the brain to be efficacious, however, is something, like digitel, I feel the need to discuss.
Bioasis has always discussed the possibility that xB3-001 could become standard of care for HER2+ brain tumours. As I have posted in the past, any discussion of xB3-001 as standard of care requires a discussion of actual doses that can reach the brain.
My contention has always been that a
standard dose of, say, 8 mg/kg of xB3-001 to a patient may severely overdose the brain. Don't be alarmed, it's a good problem to have. Getting too much into the brain could mean that you might have to lower the dose to the body. Seems like a simple enough solution. But, clearly, the notion runs completely counter to Edison's conjecture that there's a 10% chance we can get enough into the brain, or put another way, there's a 90% chance that we won't.
Here's why I think that xB3 can overdose the brain, which would be the exact opposite of Edison's conjecture. These thoughts are based on all of Bioasis's studies that indicate we can get 4% to 6% of a dose of any drug drug tested across the BBB and into the brain of any animal tested. I understand that we haven't tested it in monkeys or humans, but xB3 is, after all, based on the human form of melanotransferrin and the payload, Herceptin, has been put into human bodies for over 20 years.
The brain represents about
2% of the body's mass. If a standard initial dose of 8 mg/kg (8 mg of drug for each kilogram of body weight) is administered to a patient, then because at least 4% of the dose is getting into 2% of the body's mass, the brain, then that 2% of the body is being dosed at double the rate it should be. That means the dose that the brain just received is 16 mg/kg. If we can get 6% of a dose across the BBB then the brain is being dosed at 24 mg/kg, three times what it should be dosed.
I did a spreadsheet 2 or 3 years ago to calculate what the brain doses and residual drug would be. The spreadsheet makes simple calculations of residual drug in the body and brain with 3 weeks between doses and a 14-day half life of the drug.
Here are the numbers in mg/kg for each week, first in the body and at the same time in the brain. These numbers do not include the effects that the body has on the drug (pharmacokinetics), how the drug affects the body (pharmacodynamics) or how these and other processes such as target (tumour) engagement might cause xB3-001 attrition.
These numbers are for body dose of 8 mg/kg with 4% drug delivery to the brain. The numbers are expressed in mg/kg. This represents a logarithmic scale so the odd weeks end up having interpolated values. (My laziness.) These numbers are for the beginning of each week.
Week 0: 8.0 in the body - 16.0 in the brain (dose #1)
Week 1: 5.7 in the body - 11.4 in the brain
Week 2: 4.0 in the body - 8.0 in the brain
Week 3: 10.8 in the body - 21.6 in the brain (dose #2)
Week 4: 7.7 in the body - 15.4 in the brain
Week 5: 5.4 in the body - 10.9 in the brain
Week 6: 11.8 in the body - 23.6 in the brain (dose #3)
Week 7: 8.4 in the body - 16.8 in the brain
Week 8: 5.9 in the body - 11.9 in the brain
Week 9: 11.8 in the body - 23.6 in the brain (dose #4)
If xB3 can transport 6% of the dose then the brain residuals calculate out to be 50% higher than they are with a 4% delivery. The top brain residual works out at 23.6 mg/kg at 4% delivery and 35.4 mg/kg at 6% delivery.
Whether you followed all that or not, the point is that at standard body doses, xB3 may deliver double or triple doses to the brain, probably not something that oncologists would allow to be done.
The way around it, if we're treating brain tumours alone, may be to simply cut the normal dose to the body by half at 4% delivery and by two thirds at 6% delivery. If the requirement is to treat tumours in both the periphery and the brain then perhaps the dose of 8 mg/kg to the body would consist of one half xB3-001 at 4% delivery and one half straight Herceptin. With 6% delivery the ratio becomes one third xB3-001 and two thirds Herceptin. I do not know if clinical trials would be required for these mixtures.
And it may turn out that over-dosing the brain isn't a problem, or that natural attrition of xB3-001 in the brain shifts the numbers one way or the other, resulting in different numbers, but still with excess drug in the brain.
But for me, the problem isn't about having only a 10% chance of getting Herceptin into the brain. We might actually have the opposite problem of getting too much into the brain, and that's one helluva good problem to have. Nobody has ever had the problem of getting too much of any antibody into the brain.
There are some other things about the Edison report that could use some discussion, not so much contradiction, but maybe some gentle explanations.
My take on it. Not much worried about the 10% Edison Conjecture.
jdstox