Sensible Antisense RNA Modifications
Jun23

Sensible Antisense RNA Modifications

This is the first Haystack post from C&EN Intern Aaron Rowe. You may recognize Aaron from Twitter (@soychemist) or from his contributions to WIRED and its science blog. Isis Pharmaceuticals showed off its latest strategy for improving the potency and pharmacokinetics of antisense oligonucleotides at its annual shareholder meeting, held last week. Their structure, called cET (structure at bottom right), should bring the size of a dose down to 5-40 mg per week and allow oral delivery of antisense molecules for some diseases. In its drugs, Isis uses a mix of several different modifications. They call these molecules gapmers. For instance, its cholesterol-lowering phase 3 compound, mipomersen (molecular model at top), has 2’-methoxyethyl modifications on each end (see structure at bottom left) and central DNA region, and it also has a phosphorothioate backbone. The newer cEt modification will be featured in a cancer drug that targets STAT3, a transcription factor that is overactive in many different malignancies. Here's more on the cET...

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Isis Outlines Cancer Drug Strategy
May19

Isis Outlines Cancer Drug Strategy

Isis Pharmaceuticals is returning to its roots. The company held an investor call today to highlight its cancer pipeline, which has taken second fiddle in recent years to its cardiovascular pipeline, in particular the cholesterol drug mipomersen. Isis’ CEO Stanley Crooke appears confident that the technology has progressed enough and its clinical strategy has evolved to ensure a better path forward for antisense in cancer. Cancer has been a tricky target for antisense technology, which targets the RNA controlling the production of proteins. If you’ll recall, Isis and Eli Lilly & Company had a major disappointment in 2003 when Affinitak, one of the first antisense drugs to reach late-stage development, failed to improve survival in a Phase III trial in lung cancer. The next year, FDA rejected Genta’s skin cancer drug Genasense, and despite subsequent attempts to prove its worth, the drug has yet to make it to market. But Isis’ CEO pointed out the many lessons learned from those failures. “These are different times and we have different tools and there are different opportunities,” he said. First, the technology during the days of Affinitak and Genasense was nascent: both drugs were based on first-generation antisense technology that used a phosphorothioate backbone, an approach that was clearly too weak and not well tolerated. Second-generation antisense, which is both DNA-like and RNA-like due to a modification to the ribose ring of the individual nucleotides, has proven in the clinic to be far more potent. And the clinical strategy has been overhauled. “We need to do more definitive phase II clinical trials to be confident we have a signal we believe in before we mount very large phase III trials,” Crooke said. Further, those trials need to focus as much as possible on treating cancer patients early on in their disease. “We are not going to base a Phase III decision either on positive or negative news in patients who are too sick to really be evaluated,” he added. Isis now appears recommitted to cancer, and the company outlined upcoming milestones for its oncology pipeline: --ONX-011: Phase III studies of this clusterin inhibitor are expected to start “any day now.” Isis’ partner OncoGenex licensed ONX-011 to Teva in December. Isis got $10 million when Teva signed the deal for the drug, will collect 30% of all milestones and up to 7% of royalties on sales of the drug. --LY2181318: Phase II program of this survivin inhibitor, run by Isis’ partner Lilly, is expected to be completed late this year or early next year. --ISIS-E1F4E: Phase II program expected to start in the second half of this year. --ISIS-CRP: Phase II program...

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