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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Haystack 2010 Year-In-Review

This Friday, we’re looking back at 2010’s big news in pharma and biotech, both the good and the bad. Check out our picks and be sure to weigh in on what you think we missed. 1. Provenge Approved In April, Dendreon’s Provenge became the first approved cancer immunotherapy. Dendreon CEO Mitch Gold called it “the dawn of an entirely new era in medicine.” And while prostate cancer patients are excited for a new treatment option, the approval is perhaps most exciting for its potential to reignite interest in cancer immunotherapy research. There’s a lot of room for improving the approach—Provenge is, after all, expensive and highly individualized. Now that immunotherapy have been proven to work, there’s hope that the lessons learned in both its discovery and clinical development will aid scientists in inventing even better cancer vaccines. 2. Obesity Field Slims The obesity drug race played out in dramatic fashion in 2010, with three biotech companies-Vivus, Arena, and Orexigen, each making their case for its weight-loss medication before FDA. As of this writing, Orexigen’s drug Contrave seems to be on the surest footing to approval, but longtime obesity-drug watchers know that caution seems to rule the day at FDA, so nothing is a sure bet. Orexigen’s Contrave and Vivus’s Qnexa are both combinations of already-approved drugs, whereas Arena’s Lorqess is a completely new molecule. When C&EN covered the obesity race in 2009, it seemed that Lorqess (then going by the non-brand-name lorcaserin) had the cleanest safety profile, but Qnexa was best at helping patients lose weight. But FDA’s panels didn’t always play out the way folks expected. There were safety surprises- notably the worries about tumors that cropped up in rats on high doses of Lorqess, and the extensive questioning about birth defect risks from one of the ingredients in Vivus’ Qnexa. The fact that FDA’s panel voted favorably for Orexigen’s Contrave, a drug that’s thought to have some cardiovascular risks, generated discussion because FDA pulled Abbott’s Meridia, a diet drug with cardiovascular risks, from the market in October. The dust still hasn’t fully settled. Arena and Vivus received Complete Response Letters from FDA for Lorqess and Qnexa. Vivus has submitted additional documentation and a followup FDA meeting on Qnexa is happening in January. Also to come in January is the agency’s formal decision on Contrave. And if you’re interested in learning about the next wave of obesity drugs coming up in clinical trials, read this story in Nature News. 3. Sanofi & Genzyme: The Neverending Story Speaking of drama, Sanofi’s pursuit of Genzyme has been in the headlines for months now, and promises to stretch well into 2011. The...

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Roche Cuts Back RNAi Research

As part of sweeping job cuts announced this morning, Roche said it would close down RNAi research at three sites: Kulmbach, Germany; Madison, Wis.; and Nutley, NJ. It seemed worth taking a look at how much money Roche has sunk into RNAi research so far, and where it means for the overall RNAi landscape. Let’s start with the Kulmbach site. Back in 2007, Roche paid Alnylam $331 million in cash and equity for the site, as part of a broad pact covering RNAi drugs for oncology, respiratory diseases, metabolic diseases, and certain liver diseases. The 40 Alnylam employees working at Kulmbach were transferred over to Roche as it made the site its “center of excellence” for RNAi. According to Alnylam’s financial statements, Roche was its largest research collaborator, contributing $14 million last quarter. In 2009, Alnylam recorded $57 million in research revenues from Roche. In a statement this morning, Alnylam said that Roche’s RNAi overhaul “does not fundamentally impact Alnylalm’s financial position nor current or future plans in building its pipeline and advancing RNAi therapeutics as a whole new class of medicines.” Now onto the Madison, Wis., site. In 2008, Roche agreed to pay $125 million for Mirus Bio, which brought the Madison site along with 20 employees. As we described in an earlier article, Mirus had devised an siRNA delivery system called dynamic polyconjugate technology. Which brings us to 2009, when Roche said it would fork over $18.4 million upfront to use Tekmira’s lipid nanoparticle deliver technology to put its RNAi products into the clinic. Mirus’ technology was not quite ready for prime time, and Roche wanted to look at another delivery strategy to accelerate product development. When Roche signed that deal, it said the goal was to put its first RNAi-based product into human trials by the end of 2010. In a statement today, Tekmira noted that most of its revenues comes from a manufacturing deal with Alnylam, and it still has broad partnerships with Pfizer, Takeda, and Bristol-Myers. The tally? Upfront payments and the Mirus acquisition bring Roche’s investment in RNAi to nearly half a billion dollars in the last three years. That’s not taking into account whatever it was spending on development in Nutley, along with research support to Alnylam and, more modestly, to...

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RNAi Roundup #4

While everyone was focused on Avandia & Qnexa, a spate of RNAi-related news slipped past us: —Tekmira Pharmaceuticals scored a major contract through the U.S. Department of Defense’s Transformational Medical Technologies program. The biotech will use its lipid nanoparticle technology to deliver siRNA tailored to treat the Ebola virua. Tekmira could snag up to $34.7 million over the next three years to help bring the Ebola virus candidate through an investigational new drug filing and a Phase I clinical trial. If the government decides to extend the contract beyond Phase I, Tekmira is eligible for up to $140 million in funding. The contract comes a few months after Tekmira and the U.S. Army Medical Research Institute of Infectious Diseases published an article in The Lancet showing its lipid nanoparticle could protect non-human primates against the Ebola virus. —Nitto Denko of Japan and Fremont, Calif.-based Quark Pharmaceuticals will jointly develop RNAi-based drugs to treat fibrotic diseases. The companies will use Quark’s RNAi technology and patent fortress, and Nitto Denko’s drug delivery technology. Terms weren’t disclosed, but the companies say they “have an initial budget of double-digit million US dollars” with the goal of filing their first investigational new drug application with FDA by early 2012. Nitto, which has expertise in polymeric formulations, says it picked Quark because of the chemical modification it had made to the siRNA that have eliminated worries over an immune response from the therapeutic. —AstraZeneca has extended its siRNA research pact with Silence Therapeutics by one year. The companies have worked together since 2007 on finding five novel siRNA therapeutic molecules for oncology and respiratory diseases. The duo forged a separate pact around siRNA delivery in April. –The NIH has awarded RXi Pharmaceuticals a small business innovation research grant (SBIR) worth $600,000 to support the pre-clinical development of RNAi-based therapeutics. NIH has seen a surge in applications for SBIR grants amid a tougher financing climate for biotechs. RXi is eligible for an additional $1 million per year for up to three years during the second phase of the SBIR’s program. —Alnylam Pharmaceuticals has dosed its first patient in a Phase I clinical trial of ALN-TTR01, a systemically-delivered RNAi therapeutic for the treatment of transthyretin (TTR)-mediated amyloidosis, a rare, inherited disease in which a mutation in the TTR gene causes the build up of the toxic protein in the several tissues in the body. This study is designed to test the safety of the drug and show whether the drug is impacting TTR levels in the...

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RNAi Roundup #3

It’s time for another RNAi Roundup, this one featuring a few new faces and some oldies but goodies: –Regulus Therapeutics, the microRNA company backed by Isis Pharmaceuticals and Alnylam, has signed a major partnership with Sanofi-Aventis. The French pharma firm will pay $25 million upfront, make a $10 million equity investment down the road, and provide three years of research support to gain access to Regulus’ fibrosis research program. The companies will collaborate on up to four microRNA targets, including Regulus’ most advanced efforts around microRNA-21. Regulus could score more than $750 million throughout the lifetime of the pact. The deal marks Sanofi’s second move in the RNAi space this year. In March, Sanofi signed up to use San Diego-based Traversa’s siRNA delivery technology. –Santaris Pharma of Denmark and miRagen will jointly develop microRNA-targeted therapeutics for the treatment of cardiovascular disease. Boulder, Colo.-based miRagen will use Santaris’ locked nucleic acid drug platform to develop single-stranded LNA-based drug candidates. Santaris gets a minority stake in miRagen in exchange for use of its technology, and could see milestones and other payments as part of the pact. –Cequent Pharmaceuticals has been granted patent protection in Europe for its TransKingdom RNAi technology, which uses non-pathogenic bacteria, such as modified E. coli, to deliver siRNA against certain genes. In April, Cequent was bought by Bothell, Wash.-based MDRNA in an all-stock deal worth $46 million. The purchase gives MDRNA two distinct siRNA delivery platforms. –Mirna Therapeutics has won a $10.3 million “commercialization” award through the Cancer Prevention and Research Institute of Texas, a state-run investment program meant to spur innovation in cancer research. The money will be used to advance Austin, Tex.-based Mirna’s microRNA mimic discovery platform. –Arrowhead Research, the parent corporation of Calando Pharmaceuticals, has raised $8.65 million in a direct stock offering. The money will be used to support Calando and Arrowhead’s other subsidiary, Unidym, a carbon nanotube technology firm. Calando recently showed in a Phase I study that its targeted nanoparticle technology could be used to deliver siRNA into cells. –Alnylam came out with more data on the use of novel delivery lipids that carry siRNA into cell lines to improve the yield of biopharmaceutical manufacturing. Many biologics are produced by Chinese hamster ovary cells, but scientists have historically had few ways to control the output of those tiny drug factories. Alnylam’s goal is to turn off the activity of proteins that contribute to cell death, hopefully upping the yields of an otherwise expensive manufacturing...

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Exploding Microbubbles, RNAi, and RXi

The Haystack saw a press release yesterday out of Worcester, Mass.-based RNAi therapeutic firm RXi Pharmaceuticals that was intriguing. The company has signed a pact with Royal Philips Electronics to explore “image-guided therapy concepts based on RNAi.” What the heck does that mean? We were curious so we reached out to RXi for a primer, which turned into a bit of an update on where the company has come in the last year. Before we get into translating the mouthful of techno-speak from Philips and RXi, a few words to explain RXi’s delivery approach. Most folks in the RNAi therapeutics world are focused on encapsulating the siRNA in a lipid nanoparticle or polymer-based system: the formulation (in theory) guides the drug to its target cell and, once inside, releases its therapeutic payload. Check out our article on siRNA delivery for more details on the challenges and current limitations of that strategy. RXi is working on “self delivery” technology, which it bought from Boulder, Co.-based Advirna. As the company’s CSO (and Advirna co-founder) Anastasia Khvorova told me yesterday, the company is combining oligonucleotides, short single-stranded strings of nucleic acids, with small bits of double-stranded siRNA. RXi makes hydrophobic modifications to that hybrid molecule that stabilize the structure and allow it to be taken up by the cell of interest. They wind up with a large complex that has been tricked out to behave like a small molecule. So what does Philips bring to the table? RXi hopes to improve the potency of its self-delivery RNAi molecules using Philips’ formulation technology, which traps drugs inside “microbubbles” that are sensitive to ultrasound pulses. After a drug is dosed, it travels to the tissue of interest and an ultrasound pulse is applied, causing the bubbles to explode and the drug to be released. It all sounds rather futuristic, but RXi thinks it could significantly improve the potency of its molecules by one-to-two orders of magnitude. “Our RNAi molecules are very good at getting into cells once they’re kind of in the proximity, whereas their technology helps us get into the right organs,” RXi’s CEO Noah Beerman says. It’s cool stuff, but will it work? It remains to be seen, but it’s nice that some outside-the-box thinking is getting play in the RNAi arena. As mentioned, many companies continue to beat the lipid nanoparticle drum, but that technology has yet to work across a wide range of diseases. The need for chemistry and engineering to step in and come up with some innovative approaches to RNAi delivery is great. It’s worth noting that all this shiny new technology is a bit of a departure...

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