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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 story.

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 story goes something like this: Genzyme had a tumultuous year, as it struggled to correct the manufacturing issues that created product shortages and eventually led to a consent decree with FDA. In walked Sanofi, who offered—in a friendly way—to buy the company for $18.5 billion. Genzyme refused to consider what it viewed as a lowball offer. Weeks passed, they remained far apart on price with no signs of anyone budging, until Sanofi finally went hostile. Genzyme suggested it would be open to an option-based deal, which would provide more money later on if its multiple sclerosis drug candidate alemtuzumab reached certain milestones. Sanofi stuck to its $18.5 billion guns and is now trying to extend the time period to convince shareholders to consider its offer.

4. Final Stretch in HCV Race

This year, the industry finally got a peek at late-stage data for what are likely be the first drugs approved for Hepatitis C in more than two decades. Based on Phase III data, analysts think Vertex’s telaprevir will have an edge over Merck’s boceprevir once the drugs hit the market. Meanwhile, the next generation of HCV drugs had a bumpier year, with several setbacks in the clinic. Still, the flood of development in HCV has everyone hoping that eventually people with HCV can take a cocktail of pills, rather than the current harsh combination of interferon and ribavirin.

5. Pharma Covets Rare Diseases

Historically, research in rare diseases has been relegated to the labs of small biotechs and universities. But in 2010, big pharma firms suddenly noticed that if taken in aggregate, a pretty sizable chunk of the public—on the order of 6%–suffer from rare diseases. They also noticed that when there’s a clear genetic culprit, drug discovery is a bit more straightforward. Further, rare disease can sometimes be a gateway to approval in larger indications, making them all the more appealing. With that, Pfizer and GlaxoSmithKline both launched rare diseases units and made a series of acquisitions and licensing deals (Pfizer/FoldRx, GSK/Amicus, GSK/Isis, etc) to accelerate their move into the space. Meanwhile, Sanofi is trying to jump in with both feet through its proposed acquisition of Genzyme.

6. MS Pill Approved

Novartis gained approval in September for Gilenya, the first treatment for multiple sclerosis that is a pill rather than an injection. In even better news for people with MS, there more pills are rounding the corner towards FDA approval: Sanofi’s teriflunomide, Teva’s laquinimod, and Biogen’s BG-12. All of these drugs come with safety caveats, but the idea of new treatment options after years depending on interferons has gotten everyone in the MS field pretty excited.

7. Antibody-Drug Conjugates Prove Their Mettle

The concept of linking a powerful chemo drug to a targeted antibody, thereby creating something of a heat-seeking missile to blast tumor cells, isn’t new. But antibody-drug conjugate technology has finally matured to a point where it seems to be, well, working. Seattle Genetics presented very positive results from mid-stage studies of SGN-35 in two kinds of lymphoma. And ImmunoGen provided clear data showing its drug T-DM1 could significantly minimize side effects while taking down breast cancer.

8. Pharma Forges Further into Academia

With nearly every pharma firm paring back internal research, the focus on external partnerships has never been greater. Broad deals with universities are becoming more common, and Pfizer has arguably gone the furthest to evolve the model for working with academic partners. In May, Pfizer announced a pact with Washington University under which the academic scientists will look for new uses for Pfizer drug candidates. As part of the deal, they gain unprecedented access to detailed information on Pfizer’s compound library. And last month, Pfizer unveiled the Center of Therapeutic Innovation, a network of academic partnerships intended to bridge the “valley of death,” between early discovery work and clinical trials. The first partner is University of California, San Francisco, which scores $85 million in funding over five years, and the network will eventually be comprised of seven or eight partners, worldwide. Most notable is that Pfizer is planting a lab with a few dozen researchers adjacent to the UCSF campus to facilitate the scientific exchange.

9. Finally, New Blood Thinners

This year saw the FDA approval of a viable alternative to coumadin (aka warfarin), a 50-plus-year-old workhorse blood thinner that interacts with many foods and herbal supplements.

Boehringer’s Pradaxa (dabigatran) got a unanimous thumbs-up from an FDA panel for preventing stroke in patients with a common abnormal heart rhythm called atrial fibrillation. FDA approved the drug in October. The next new warfarin alternative to be approved could be Xarelto (rivaroxaban), which has had favorable results in recent Phase III clinical trials, as David Kroll over at Terra Sig explained. Both Xarelto and Pradaxa had already been approved for short term use outside the US.

Rivaroxaban and dabigatran work at different stages of the biochemical cascade that leads to clotting, as we illustrated here. Another drug candidate in the warfarin-alternative pipeline is BMS’s and Pfizer’s apixaban. Check out coverage of apixaban trials here and at Terra Sig. And in a separate blood-thinner class, FDA today rejected Brilinta, a possible competitor to mega-blockbuster Plavix.

10. Alzheimer’s Progress & Setbacks

Alzheimer’s disease has been a tough nut to crack, and news in 2010 has done little to dispel this reputation. This year Medivation’s Dimebon, which started life as a Russian antihistamine and showed some promise against Alzheimer’s, tanked in its first late-stage clinical trial. Later in the year, Eli Lilly halted development of semagacestat after the compound actually worsened cognition in Alzheimer’s patients. Semagacestat targeted the enzyme gamma-secretase, and the New York Times and other outlets reported the news as shaking confidence into a major hypothesis about what causes Alzheimer’s and how to treat it– the amyloid hypothesis.

But not everyone agreed with that assertion. Take Nobel Laureate Paul Greengard, who told C&EN this year (subscription link) that semagacestat’s troubles may have been due to the drug’s incomplete selectivity for gamma-secretase.

This year Greengard’s team discovered a potential way to sidestep the selectivity issue, by targeting a protein that switches on gamma-secretase and steers it away from activities that can lead to side effects. Greengard thinks the amyloid hypothesis is very much alive. But the final word on the amyloid hypothesis will come from trial results in next year and beyond, for drugs such as BMS-708163, Bristol Myers Squibb’s gamma-secretase inhibitor.

11. Avandia (Barely) Hangs On

Avandia was once the top selling diabetes medication in the world, but in 2010 long-running rumblings about the drug’s cardiovascular risks reached fever pitch. By the fall, Avandia was withdrawn from the European Union market and heavily restricted in the US.

Avandia (rosiglitazone) helps diabetics control their blood sugar levels by making cells more responsive to insulin. Widespread scrutiny of Avandia dates back to 2007, when a study led by Vioxx-whistleblower and Cleveland Clinic cardiologist Steve Nissen suggested Avandia increased the risk of heart attacks. In February 2010, a leaked government report that recommended Avandia be pulled from the market made headlines. In July, an FDA advisory panel voted on what to do about Avandia, and the results were a mixed bag, with most panel members voting either to pull the drug entirely or add severe restrictions. In the end, FDA sided with the “restrict” panelists- Avandia is still on the market, but it can only be prescribed to patients who can’t control their blood sugar with a first-line medication.

Clearly, researchers still have a lot to learn about how the drugs in Avandia’s class work. But we enjoyed reading Derek Lowe’s self-characterized rant about just how much effort has been put in so far. Among several other drugs in Avandia’s class, Rezulin (troglitazone) was pulled from the market many years ago because of adverse effects on the liver, but Actos (pioglitazone) remains on the market and appears to be safe.

12. Executive Musical Chairs

The year after a trio of mega-mergers and at a time when patent losses are piling up, drug companies shook up their management. The most notable changes came at Pfizer: First, the company abandoned its two-headed approach to R&D leadership and picked Michael Dolsten, former head of R&D at Wyeth, to lead research. Martin Mackay, Pfizer’s head of R&D, meanwhile jumped ship to lead R&D at AstraZeneca. Then, in a move that took everyone by surprise, Pfizer’s CEO Jeff Kindler suddenly stepped down and Ian Reade took over. At, Merck, president Kenneth Frazier will take over as CEO in January;  Richard T. Clark will stay on as chairman of Merck’s board. And just this week, Sanofi-Aventis saidformer NIH director Elias Zerhouni would replace Marc Cluzel as head of R&D, while Merck KGaA appointed Stefan Oschmann as head of pharmaceuticals. Oschmann comes on from Merck & Co., where he was president of emerging markets.

In the biotech world, the most notable shift came in June, when George Scangos moved over from leading Exelixis totake the top job at Biogen Idec.

13. RNAi Rollercoaster

The year has been a tumultuous one for RNAi technology. Leaders in siRNA technology are experiencing growing pains as they try to turn promising science into commercialized products. Alnylam, arguably the best-known and biggest player in the RNAi arena, laid off 25% of its staff after Novartis decided not to extend its pact with Alnylam. Things only got worse when Roche announced it was exiting RNAi research, a move that hit its development partners Alnylam and Tekmira. Roche seemed to be primarily worried about delivery, an issue that is holding the field back from putting more RNAi-based therapeutics into the clinic.

But it’s not all bad news: the year brought a spate of big-ticket deals for companies developing other kinds of RNAi technology. GSK signed on to use Isis Pharmaceuticals’ antisense technology, which uses single-stranded rather than double-stranded oligonucleotides. And Sanofi entered into a pact with Regulus, the microRNA joint venture between Isis and Alnylam, worth $740 million. Further, Isis and Genzyme made some progress with mipomersen, the cholesterol drug developed using Isis’ antisense technology.

14. Revival of Interest in Cancer Metabolism

In cancer research, the old was new again in 2010, with a flurry of publications about depriving cancer cells of their energy source by taking advantage of quirks in their metabolism. That idea has been around since the 1920′s- when German biochemist Otto Warburg noticed differences in how cancer cells and normal cells deal with glucose. This year, Celgene handed over $130 million upfront for access to any cancer drugs that come out of Massachusetts biotech Agios Pharmaceuticals’ labs. One target in Agios’s crosshairs is an enzyme involved in glucose metabolism- pyruvate kinase M2. In addition to the Celgene/Agios deal, we noted that AstraZeneca and Cancer Research UK are in a three-year pact related to cancer metabolism, and the technology behind GlaxoSmithKline’s much-talked-about $720 million purchase of Sirtris has to do with depriving cells of energy.

15. More Job Cuts

Not to end this list on a sour note, but it wouldn’t be complete without acknowledging the ongoing narrative of layoffs and retooling at drug companies. This year brought brutal cuts at AstraZeneca, GSK, Bristol-Myers Squibb, and Abbott, along with the widespread and ongoing layoffs at Pfizer and Merck. Several features in C&EN looked at the impact the cuts are having on chemists:

How some laid-off pharma chemists migrate to new careers

How academic programs are adapting

And the views from the ground in New England and California, two hotbeds of pharma/biotech (hint- it ain’t pretty).

For more jobs insight, join the discussions happening with Chemjobber and Leigh aka Electron Pusher, and check out their chemistry jobs blog roundtable, which just wrapped today.

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 Tekmira.

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 blood.

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 process.

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 from what RXi was focused on just a year ago. Before bringing in the Advirna technology, the company was touting its glucan-encapsulated particle delivery technology.

Now that it has settled into its self-delivery approach, look for the company to provide details about its overall strategy during its presentation next Thursday at the Jefferies Global Life Sciences Conference. “One of the things we’ve been working on very hard here is defining the core therapeutic areas to focus on,” Beerman says. “We’re now turning that page and focusing in on a handful of areas that will roll out next week at the Jefferies conference.”

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 with this cardiovascular risk factor protein blocker is expected to start in multiple myeloma later this year.

–ONX-427: Phase II program for this HSP27 blocker, being developed by partner OncoGenex, should start this year, with more data on this drug to be unveiled next month at ASCO.

–ISIS-FXI: Phase II study of the ability of this Factor XI inhibitor to reduce blood clots in cancer patients and prevent cancer vasculature growth should begin later this year or early next year.

–Expect to see one other trial started up this year with a yet-to-be disclosed target. Possible targets? The company called the transcription factor STAT3 “a particularly attractive target, but also made mention to the anti-apoptosis protein Mcl1, the glial promoting factor Glide2, and STAT5. The call included a lot of hype around the company’s efforts to use antisense to tackle non-coding RNA, or RNA that aren’t used to make proteins, but play an important role in regulating cell behavior. Apparently encouraging preclinical data has been generated around non-coding RNA targets.

Crooke also said its “generation 2.5” antisense chemistry will be unveiled later this year. He expects the improved molecules to be 10 times more potent than its current drugs, making oral dosing a viable proposition. Stay tuned!

Beyond siRNA: Alnylam’s Other Biotherapeutics Ambitions

Alnylam gave a first peek today inside its new biotherapeutics manufacturing business, launched in November. So far, it looks kind of intriguing. Though best known for as a leader in the race to turn siRNA into viable therapeutics, the company has embarked on a bit of a side project: using siRNA to improve the yield of biologics manufacturing process.

As you’ve probably read, therapeutic proteins such as monoclonal antibodies ain’t cheap. And though it’s safe to assume the mark-up on biologic drugs like Genentech’s Avastin is high, they also are quite expensive to produce. One major issue has been the low yield of those infamous Chinese hamster ovary cells churning out some of our antibody therapeutics—they don’t live long and not everyone in the pot likes to make drugs.

Alnylam is hoping to fix that yield problem. As Stuart Pollard, Alnylam’s vice president of scientific and business strategy explained in a chat today, the goal is to move beyond the crude modifications to temperature, pH, and nutrient content that companies make to improve biologics manufacturing yields. Alnylam’s idea was that siRNAs could be used to silence some of the proteins that contribute to cell death.

Today’s data is an early look at how effective siRNA might be at improving yields. The company looked at two metabolic pathways that impact the viability of cells, and, though it was done at a small scale, did show that its siRNA was able to nearly double the number of cells that were active. “We see almost doubling of the viable integral cell tanks over that period of 15 days where we’re applying siRNAs,” Pollard said.

Yes, you might say, but many others are looking at how to improve yield through new technologies. Merck didn’t pay $400 million for GlycoFi in 2006 for nothing: the biotech’s engineered yeast that can make consistent, complex proteins laid the groundwork for Merck’s biosimilars strategy. So why would using siRNA in manufacturing be an interesting proposition? Aside from improving yield, siRNA could be simply added to existing master cell lines. In other words, this is a process improvement that could be applied to drugs already on the market, those in development, and anything on the horizon.

Still, these results were only at the one-liter scale, and Alnylam has yet to come out with data showing it has successful made a protein out of the process. Pollard says scale-up is underway, and more data will be forthcoming. But Pollard seems confident of its potential: “When will this application be used commercially? We think it could be pretty near term.”

Any route that can make manufacturing of biotherapeutics more affordable will surely be in demand, particularly as big pharma pushes into making generic biologics (or, if you prefer, “biosimilars”). Just today, the WSJ reported that Pfizer had revealed its first three biologics that aim to outdo existing drugs, two improving upon Genentech/Biogen Idec’s Rituxan and another improving the potency of Amgen’s Embrel.