Tom3 schreef op 13 december 2020 16:30:
De laatste bijdrage van BBS op Yahoo is als zo vaak de moeite van het lezen waard. Heel veel analisten zijn zeer sceptisch over de pogingen van ARWR om buiten de lever om haar missie te volbrengen. BBS heeft goede gronden om hier optimistisch over te zijn. Het is denk ik een reuze stap voorwaarts als het gaat lukken:
Since some colleagues brought the issue of HIF2 and ENaC effectiveness up, I was asked to share a snippet from my 52 page report dated August 14, 2019, as it's probably more relevant today than it was over a year ago. The links to the poster presentations at the bottom are well over a year old, but are finally coming into play in human trials. Let me know if yo have any comments.
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Reasons for Effectiveness – the Targeting Ligand.
? While the sequence used in the trigger is important, its effectiveness is greatly enhanced when used with the right targeting ligand. Arrowhead openly discloses that its TRiM™ platform includes “a high affinity targeting ligand.”12 Arrowhead’s hepatic drugs use a conjugated GalNAc as its targeting ligand, as the GalNAc is able to bind to receptors that are specific to the liver. Many analysts are skeptical that RNAi technology is ready to advance beyond the liver, which is why Arrowhead may be seeing depressed valuations and low analyst coverage. Some quotes from notable biotech analysts include:
- “It only works best in the liver.”
- “I’ll believe it when I see it, and then I won’t believe it until it actually gets approved.”
- “RNAi is at least another 10 years away from extrahepatic delivery.”
- “Arrowhead doesn’t have the scientists or the capabilities to make such significant advancements.”
- “There is no way to get effective knockdown in the lung using RNAi, the science just doesn’t allow it.”
- “Targeting a cancer tumor with RNAi will not work because the cancer is able to quickly adapt and change, thereby making the trigger ineffective.”
? While analysts have been quick to criticize, Arrowhead has been busy with its R&D efforts in the lab. Focusing on extrahepatic delivery, Arrowhead presented an abstract on its ARO-HIF2 drug (currently at a pre-IND stage) that targets cancerous tumors at the AACR Annual Meeting on April 3, 2019.13 The abstract explains how Arrowhead selected an extrahepatic Tumor Targeting Ligand (TTL) that selectively binds to integrin receptors avß3 and avß5 with high affinity, giving it the ability to target cancerous tumors that carry these receptors. The TTLs have been shown to facilitate the uptake of the HIF2a RNAi trigger into cancerous tumors, a percentage of which can identify as clear cell renal cell carcinoma (ccRCC). Arrowhead came to the conclusion that the TTLs improved gene silencing. As seen in Figure 3, taken from Arrowhead’s abstract, the TTLs coupled with pharmacokinetic enhancers have a 67% to 90% improvement over the trigger alone. The identification and reduction to practice of these specific targeting ligands that allow RNAi to be used extrahepatically to target tumors should be considered a significant scientific advancement. This is an indication of the research and development capabilities that Arrowhead possesses, and to the advanced experience of its scientific team.
? Regarding another extrahepatic target, Arrowhead gave a poster presentation on its ARO-ENaC drug (currently at a pre-IND stage) that targets cystic fibrosis at the North American Cystic Fibrosis Conference on October 18, 2018.14 The poster presentation shows how Arrowhead selected an extrahepatic Epithelial targeting avß6 ligand (EpL) that facilitates uptake of an aENaC RNAi trigger by human bronchial epithelial cells in vitro. Arrowhead came to the conclusion that the EpLs increased trigger potency 10x and improves uniformity of aENaC mRNA silencing in the lung. As seen in accompanying Figure 4 from Arrowhead’s poster presentation, EpLs conjugated to the aENaC RNAi trigger was shown to be more effective than the trigger alone. Yet again, the identification and reduction to practice of this specific targeting ligand that allows RNAi to be used extrahepatically within the lung should be considered another significant scientific advancement. It appears that Arrowhead’s scientists have the knowledge, know-how, and ability to identify critical tissue receptors so as to allow RNAi triggers to be delivered extrahepatically.
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