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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Where Graphene Meets Antisense
Apr05

Where Graphene Meets Antisense

In today's issue we covered a new way to deliver short stretches of DNA into cells- with graphene, the nanoscale material that's made from sheets of carbon just one atom thick. There's been an explosion of papers on this versatile stuff, since it has potential applications in computing, digital displays and more. This is very early-stage work, but we at the Haystack were intrigued by the material's talent for ferrying a single-stranded piece of DNA into a cell. That's largely because we've been following the story of antisense technology, an approach that targets the RNA that controls production of disease-causing proteins. Most antisense drugs are single-stranded oligonucleotides, unlike RNA interference (RNAi) technology, which uses double-stranded oligos. As we've written, antisense drugs have been on something of a roller-coaster ride, being highly touted in the 90's and then later falling out of favor. It's not clear to me what would need to be fixed to stem more late-stage failures of antisense drugs, but maybe new techniques for delivery could be part of a solution. None of the potential applications are lost on the authors, led by Huang-Hao Yang at Fuzhou University in China. They say they're looking into delivery of both antisense DNA and siRNA. We'll have to see what...

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GSK and Isis in Antisense Deal
Mar31

GSK and Isis in Antisense Deal

Is antisense making a comeback? Isis Pharmaceuticals this morning announced a deal with GlaxoSmithKline worth up to $1.5 billion to develop drugs to treat rare and infectious diseases. Here’s how the math breaks down: Isis gets $35 million upfront, and on average $20 million for every program it brings into Phase II trials. At that point, GSK can exercise an option to license the compound and take on all the further development costs. If GSK opts in on and commercializes  all six drugs covered by the deal, Isis ends up with $1.5 billion, and also gets the usual double-digit royalties on sales. Technically, a range of technologies fall under the umbrella of “antisense,” which describes technology that targets the RNA controlling the production of proteins. That broad term encompasses RNAi, microRNA, and Isis uses oligonucleotides, or a string of nucleic acids, to intercept messenger RNA. But while RNAi-based drugs have been the darling of investors in recent years, antisense has had a bit more of a rollercoaster ride. The colossal failure of Genta's antisense drug Genasense (not to mention all the money Aventis spent on it) did not help the technology's cause. Isis has stuck with it, though, and for good reason: the biotech has a lock on the intellectual property around antisense, and now owns a piece of pretty much any antisense drug in development. Further, by tweaking the chemistry of its oligonucleotides, Isis managed to significantly improved delivery of the genetic bits, a problem siRNA has yet to overcome. Still, safety questions linger. Isis and Genzyme, which signed a major deal with Isis in 2008 to co-develop the cholesterol drug mipomersen, have seen investor hopes for a multi-billion dollar drug fade as the drug caused liver enzyme levels to be raised. Perhaps the deal with GSK suggests some confidence that the off-target effects of antisense can be tackled. Update: Needham & Co's Mark Monane was upbeat on the deal.  "We believe this collaboration represents another example of the value of Isis’ core technology for the potential treatment of hard-to-treat illnesses." he said this morning ina note to investors. "Furthermore, the agreement allows Isis to utilize its skills in early stage development, and GSK to use its skills in later stage...

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