biOasis Technologies Ord Shs V.BTI.H

RE:RE:RE:RE:New Video about Scarpa

[BearDownAZ]

Sir Holler you are out of your comfort zone analyzing scientific data. Please let me step in.

We should all ask is how old were the mice when the 6 week treatment period began? Most likely, they were at least 3 weeks old. Mice have a 3 week gestation period and then are typically with their moms for 3 weeks following birth for lactation prior to being weaned. Weaning is the earliest that they probably started treatment. However, it might have been longer. Mice typically reach adult body size at 6-8 weeks of age. My guess is that the mice were in this 6-8 week range. So prior to any treatment being given, the mice had already had 6-8 weeks of growth after birth in which the IDS knockout mice were deficient in the I2S enzyme. As you can imagine, A LOT of brain growth occurs during this time. They treated for 6 weeks and were able to completely normalize the GAG levels in the corpus callosum (which was elevated in the untreated IDS knockout control group by the way), and achieve ~50% normalization in the cortex and thalamus. Amazingly exciting results for 6 week enzyme replacement therapy. My follow up questions would be did they achielve the 50% reduction primarily due to halting the progression of the GAG accumulation or by causing regression of the already established LSD that was present at the time treatment started. In humans, they would likely start treating very early on after birth if the disease had already been genetically diagnosed in order to prevent GAG accumualtion as the brain grows. If these mice could have been treated at an earlier age, the results may have been even more impressive.

Second big quesiton concerns method of dosing. They were doing 2 doses of drug per week: one was intravenous (i.v.), the other was i.p., which I interpret as intrapeitoneal, which is essentiallally an injection into the abdominal cavity. They opted for one i.v. and one i.p to avoid the stress of two i.v. injections per week in a mouse. I've done mouse i.v. and i.p.  injection before and take my word it is no fun doing i.v. injections in a mouse! For human studies, they will most likely ALWAYS do intravenous. So did the intraperitoneal (i.p.) have similar pharmacokinetics as the intravenous (i.v.) route? I don't know if any of us are privy to that information. So without that info, we must assume the likely possibility that in human trials, that it would be the more efficacious intravenous route for ALL dosing. Perhaps Scarpa's comment on optimal dosing wasn't so much about the concentration (they used 6 milligrams per kilogram body weight), but moreso on the route of delivery (i.v. vs. i.p.) or the frequency (# of injections per week?). Perhaps a method of continuous slow infusion would work even better.

Lastly a minor point. In the beginning of the video RH says 6 week study. This is consistent with treatment timeline listed in the press release for the Sandhoff LSD study, but I don't think that a treatmet timeline was ever stated in the Scarpa Hunter LSD press release. Toward the end of the video (~11:40) RH starts contrasting this Hunter LSD study to the MedImmune study and talks about 14 day study. It wasn't clear but I think he was bringing this up to indicate that just like MedImmune that BTI has shown that the MTfp works just as well as full lngth MTf in both the 2 week MedImmune study as well as the 6 week Hunter syndrome study.

Best,

BDAZ