RE:RE:Denali updateI really don't want to be here but the DNL747/DNL788 discussion is a little off track.
The Denali study with DLN747 was stopped because Sanofi/Denali needed to increase its clinical dose to achieve better efficacy, but a monkey study showed toxicity at the doses Sanofi/Denali needed. They simply couldn't put higher doses of DLN747 in humans so they stopped the clinical trial.
DLN747 does not need a transporter such as xB3 or Denali's Transport Vehicle (TV) to get across the BBB and into the brain. DLN747 is a small molecule that is small enough to cross the BBB. It is lipid soluble (lipophilic) meaning that it is soluble in fats. It is, therefore, hydrophobic and is not soluble in water.
Small molecules that are water soluble (hydrophilic) generally do not cross the BBB.
DNL747 is being replaced in the Sanofi/Denali pipeline and clinical trials with DNL788, which is also a small molecule with a slightly different molecular structure than DNL747 has. Both drugs attempt to mediate
necroptosis, a type of cell death process that occurs with various diseases like MS, ALS and Alzheimer's. You can read more about this and other cell-death processes in this
scientific paper from NIH.
Long-term readers, if they look at this NIH paper, will note reference to TNF, tumour necrosis factor. I and a couple of others discussed TNF back in 2014/15. At the time there was speculation that TNF was the subject of studies that MedImmune was doing with Bioasis, the speculation being that MedImmune had an antibody that needed delivery across the BBB for dealing with MS, ALS, Alzheimer's or something else related to TNF. We quickly dropped that discussion when it seemed evident that TNF-related treatments being developed may be small molecules and not antibodies. I also learned at that time that MedImmune was using xB3 (MTfp) to deliver an antibody that dealt with pain, but I couldn't discuss that until a little later when it became public knowledge.
So, that's my take on DNL747 story.
On another note, obviously SH hasn't yet shut down "jdstox" as I requested. Responses of this type will occur on my own site as soon as I can make that happen.
I also want to thank everybody for the incredible outreach to me over the past few days. I will attempt to deliver on a level consistent with your faith in me. Thank you so much.
jdstox