Rick:
Keep in mind that all I know is little bit of neuro-chemistry. All other is *above my head*. I do tried to logically combine things in my rezoning.
Peter:
Thanks for visual interpretation of the PD and AD problems. It is not my field and I am learning.
Sibi's NAChR program is at least one third of their R&D. They invested a loot in this projects and investor expect that they capitalize on it, PD or AD no difference.
I do not put much value on what company said, write in IR materials, news. What account is scientific journal manuscripts, clinical data, patents.
SIB-1058Y:
1. All what is available on SIB-1058Y is articles on SIB-1765F, which describe preclinical study on rats.
2. Majority of the NAChR are stereospecific (preferentially binding of one enantiomer) and preferentional structure for sub-type which are we discussion are S(-)--substructure configuration.
3. (-)-Nicotine at lower level stimulate DA release, but at higher dose it inhibit DA reuptake-luck of motor activity: ncbi.nlm.nih.gov
4. In many case each enantiomer bind preferentially to different sub-type of the some receptor classes:
ncbi.nlm.nih.gov
5. In some case one (non active) enantiomer can directly reduce potency, mask potency, or its activity can neutralize positive effects of the active enantiomer.
I will assume that in monkey they are testing enantiomer: SIB-1058Y. If they have prolonged increase in ACh level, possibility is that (-)nicotine is also elevated and inhibition of the DA reuptake is undesired side effects. This will be negative for clinical outcome.
What are the reason for difference in rats compared to monkey? In first they tested racemate and in second they are testing enantiomer. There can be a loot difference, positive and negative.
I do not have any data from monkey study. Also, I can't speculate on study outcome.
53 SERIES:
I will assume that this are analogue of the some class of NAChR agonist which do not show DR They have (-)S-configuration and potent are at nM conc. Abbott also is developing this class NAChR agonist.
1. This agonist do not show effect on amyloid processing.
2. At the some time mAChR agonists show some characteristic in AD with effects on amyloid processing.
ncbi.nlm.nih.gov
ncbi.nlm.nih.gov
ncbi.nlm.nih.gov (your post)
WL's Milameline shown in vitro to alter amyloid precursor protein processing:
ncbi.nlm.nih.gov
3. Anti-inflamatory therapy: Sabeluzole, abenzothazide derivative shows neurotrophic activities and anti-inflammatory substances like indomethacin.
4. Diferent approach to AD therapy:
ncbi.nlm.nih.gov
ncbi.nlm.nih.gov
Sumary: Two approved and four at late stage neuro selective AChEsterase inhibitors, Milameline as mAChR agonist with several company working on class development, anti-inflammatory drugs, Amyloid processing drugs, neuroprotective drugs (grow factors), and other therapy.
How will (if and when approved) SIB-53 series compete with this drugs? At this point I am giving advantage to esterase inhibitors (inhibition of the depletion of the total released ACh, not only from nAChR), m1 and m4 mAChR agonist (difficult to develop selective inhibitor), grow factors, and primarily to Amyloid processing.
If Sibia do not prove that their compounds have effects on amyloid procesing with ACh level increase, the possibility that drug will be *second class* is significant.
Based on this rezoning, venture investing is OK for me if I figure out that science have good chance to be transformed in to drugs, SIB-1058Y has more value to SIBI than you have estimated, IMO.
Because entire NAChR project are not covered with partner, it is important that SIBI continue with 1058Y development. If possible, partner will be good confirmation for projects.
Definitely, I like much more their approach to amyloid procesing (protease inhibitor, BM). I didn't investigate in depth pre-synptic NMDA antagonist projects (Novartis).
IMO, failure of the 1058Y will effect stock price. As Peter said, cholinergic approach to PD has good chance if one can develop sub-type specific agonist to stimulate DA release. Without data from monkey study, I am not convicted that 1058Y is right molecule.
Everyone have a great Labor Day.
mz |
