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Biotech / Medical : Ionis Pharmaceuticals (IONS) -- Ignore unavailable to you. Want to Upgrade?

To: tommysdad who wrote (1942)	4/22/1998 2:57:00 PM
From: Joe Wesley	Read Replies (1) \| Respond to of 4676

Hi td: This article was in the Feb. 9 BioCentury don't know if it helps. As always a subscription to BC can help. Sense from antisense Acceptance of antisense oligonucleotides as therapies has been slow in coming, with skeptics doubting the method's true mechanism of action as well as awaiting a proof-of-principle from the clinic. Isis Pharmaceuticals Inc. last week presented data from its previously disclosed Phase III trial of fomivirsen in cytomegalovirus (CMV) retinitis in AIDS (see BioCentury, Jan. 26), which it said adds to its collection of clinical and preclinical data validating both the antisense mechanism and the overall approach. The theory behind antisense is simple: the oligonucleotides block the synthesis of a target protein or RNA molecule by mirroring the RNA's nucleotide sequence. The mirror pairs with the RNA and prevents translation to a protein. Skeptics however, have doubted whether the sequences are actually playing this spoiling role. "No one can show proof of a mechanism in the clinic. Instead you show data consistent with the mechanism," said Stan Crooke, chairman and CEO. In fact, he said, ISIP has shown consistent data in its clinical trials of ISIS 2302 in Crohn's disease and ISIS 3521 and 5132 in solid tumors. In all three cases, he said, the company demonstrated that pa-tients given the molecules experienced a decrease in the levels of the protein targeted by its product. Showing an antisense mechanism of action has been more complex with fomivirsen, because the compound does have both an antisense and non-antisense mechanism of action outside the eye. When free virus particles come in contact with the molecule, fomivirsen binds to viral coat proteins instead of acting on a piece of the virus's IE2 gene. But, Crooke said, fomivirsen should be acting by the antisense mechanism in the eye, where "CMV spreads directly from cell to cell. There is no free virus for fomivirsen to interact with." The clinical results, he said, support in vitro experiments in which the company provided evi-dence for the action of the antisense molecule. For example, ISIP (Carlsbad, Calif.) has used specificity and potency studies to show that antisense se-quences block synthesis of their target proteins and nothing else in cells. ISIP has shown that levels of RNA and proteins from the same protein family as the target - and thus with sequences closely related to the target sequence - are not reduced by the antisense compound. Finally, Crooke said, the company has related sequence specificity to potency by adding single nucleotide mutations to the sequence one at a time and showing that the molecule's potency declines with increasing mismatches. The in vitro evidence combined with the clinical data in cancer, inflam-matory disease and viral disease, Crooke said, validate the antisense approach across a variety of indications. - Isis said Phase III data of its fomivirsen antisense compound to treat CMV retinitis in AIDS adds to its evidence validating both the applicability and the mechanism of action for antisense technology. Amateur P.S.: The reason Isis has been able to become the antisense leader is in a large part because they saw cells in culture are radically different than living cells and made the decision to move beyond the cultures to show consistent results while others stayed in the infinite loop of trying to get the cell cultures to work.

To: tommysdad who wrote (1942)	4/22/1998 9:55:00 PM
From: Cody Goebel	Read Replies (2) \| Respond to of 4676

Interesting how a major biotech analyst (Sturza) puts out a short ISIP recommendation and suddenly "its all a big lie" posts appear under anonymous authorship. I'm not accusing Mr. Sturza of anything but those shorting a stock, whether or not they are doing so on the basis of his advice or others, would certainly benefit from such data getting play. I leave it to the medically apt members of this thread to discuss the merits of the anonymous post, but I thought I'd comment on the timing at least.