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ficer of Cambridge, Mass.-based biotech company RXi Pharmaceuticals, about the field’s heyday. “Certainly, in the last year or so, the pendulum has swung in the other direction.” Roche’s decision late last year to abandon research in RNAi only added to investor unease. The company had sunk more than $500 million into the field with its 2007 pact with Alnylam; the 2008 purchase of Mirus Bio, a Madison, Wis.-based biotech with an siRNA delivery system; and a deal with Tekmira, a Canadian firm with expertise in delivering RNAi using lipid nanoparticles. Alnylam was particularly affected by Roche’s withdrawal from RNAi. The Cambridge, Mass.-based company had been receiving substantial research funding—$57 million in 2009 and $54 million in 2008— as part of its research pact. But Alnylam CEO John Maraganore insists Roche’s decision is having limited impact on his company. The Swiss firm’s exit “had nothing to do with RNAi whatsoever,” Maraganore says. Rather, he says, it was simply a case of a big drug company deciding to cut costs. “As part of their cost-cutting decisions, RNAi, which is an earlier-stage discovery for them, fell prone to the ax.” Still, Roche’s exit did cast a pall over the field. RXi’s Beerman recalls being at the Lazard Capital Markets Healthcare conference on the day the Roche news broke and immediately getting questions from investors about the state of the industry. “Our view,” he says, “is that this is part of the standard ebbs and flows that go on in biotech.” PUSHING FORWARD
Alnylam scientists are making strides in siRNA delivery.
RNAi GROWING PAINS Roche’s exit CAST A PALL, but others claim progress in developing RNAi-based drugs LISA M. JARVIS, C&EN NORTHEAST NEWS BUREAU
WHEN ROCHE announced in November
2010 that it would jettison research in the field of RNA interference, industry observers were stunned. After all, it had been among the few big pharma companies putting significant cash into what many considered the most promising new pharmaceutical technology in recent years. But Roche’s exit was only one sign of problems for companies developing RNAibased drugs. Several biotech firms failed to meet their goal of signing a partnership by the end of 2010. And some companies are running out of cash, creating the kind of desperate situation that gives prospective partners an upper hand in negotiations. Given the stream of negative news, the question arises: Was RNAi just a fad? Companies developing RNAi-based drugs say that real innovation requires patience. They point to progress over the past year in overcoming some of the technical hurdles to creating workable therapies. RNAi refers to a range of technologies aimed at turning off a problematic gene. In the past five years, much of the attention
has been on creating and delivering drugs made from small interfering RNA (siRNA), a double-stranded molecule that plays a key role in silencing genes. In the mid-2000s, the promise of a means of shutting down the manufacture of disease-causing proteins spurred investors and big pharma to sink billions of dollars into companies developing RNAibased drugs. In 2007, Merck & Co. paid $1.1 billion for Sirna, one of the biggest players in the siRNA field. Alnylam, meanwhile, cut lucrative alliances with Roche and Novartis. But delivering siRNA to targets inside human cells has proven complex. The move from good idea to drug candidate has been slower than some investors have the stomach for. “The pendulum swung in one direction,” says Noah D. Beerman, chief executive of-
INVESTORS WERE AWARE of other set-
backs as well. Just weeks earlier, Novartis declined to continue working with Alnylam at the end of their five-year research pact. The decision cost Alnylam a $100 million payment, and the biotech firm subsequently laid off more than 25% of its employees. And several smaller companies including RXi, Calando Pharmaceuticals, and Marina Biotech were unable to forge new partnerships in 2010 after promising inves-
In the timeline of a technology, RNAi “is still in kindergarten or grade school.” WWW.CEN-ONLINE.ORG
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tors that deals were imminent. the past year, Maraganore says. “People are playing a little bit By tweaking the composition PIPELINE PROGRESS more of ‘show me the data as of its lipid particle delivery Several companies have RNAi drugs that are opposed to the promise,’ ” system, the firm has improved undergoing human testing Beerman acknowledges. the potency of its RNAi-based COMPANY STATUS The partnering challenge is drugs 100-fold. In the past, dosAlnylam Initiating Phase I trial of ALN-TTR01 in third-quarter not entirely due to research or es of 0.5 mg/kg were required 2011 investment setbacks, Marina to shut down 50% of gene exAlnylam Initiating Phase I trial of ALN-PCS in second-half 2011 CEO J. Michael French says. pression; today, Alnylam can Alnylam Filing INDA for two drug candidates by end of 2011 When Merck bought Sirna and achieve the same results by Calando Completing Phase I trial of CALAA-01 and selecting indication for Phase II trial Alnylam sealed its big-ticket administering 5 µg/kg. Marina Biotech Continuing enrollment of Phase I trial of CEQ508 deals, there were fewer compaFurthermore, “the vistas of RXi Filing INDA for RXI109 in second-half 2011 nies and delivery technologies delivery have expanded signifiSilence Completing Phase I trial of Atu-027 in second-half 2011 to choose from. Today, the field cantly,” Maraganore says. Just Therapeutics has more competitors, all looka year ago, he says, “virtually Tekmira Reporting data from Phase I trial of TKM-PLK1 in ing for partnerships. all the data were for liver gene second-half 2011 And the science itself has silencing.” Today, Alnylam says INDA = Investigational New Drug Application. SOURCE: Companies advanced to more-difficult it can turn off target genes in challenges. “We are all in this immune cells, epithelial cells, space a lot smarter than we were six years polymer-based delivery system. In a Naand tumors outside of the liver. ago,” French says. In 2005, demonstrating ture paper, the firm showed that its lead knockdown of a gene in a mouse was a macompound, CALAA-01, accumulated inADVANCES IN lipid nanoparticle delivery jor advance, he points out: “That was a Naside tumor cells in a dose-dependent way, “are great news for the field,” says Alan ture paper.” Today, the field needs to show an accomplishment that had eluded sysSachs, head of Merck’s exploratory and that gene silencing can work in humans. temically delivered siRNA (DOI: 10.1038/ translational sciences organization. For its Some of those data are emerging. Last nature08956). part, Merck is “very aggressively” working year, Calando made progress with its And Alnylam has made major strides in on three delivery platforms: lipid nanopar-
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ticles, polymers, and a conjugate-based platform it calls “single chemical entities.” Alnylam’s delivery advances are prompting it to shift strategy. It is making the transition from focusing on research alliances to developing its own products. This month, the firm unveiled its “5x15” program, which sets the goal of having five proprietary drug candidates in clinical studies by 2015. By the end of this year, two of them will be in Phase I studies. The candidates in the 5x15 program have been on Alnylam’s radar for some time. But getting nearer to commercialization is important, analysts say. In the timeline of a technology, says Simos Simeonidis, a stock analyst with Rodman & Renshaw, RNAi “is still in kindergarten or grade school.” Putting five compounds in the clinic by 2015 would be significant progress, he argues. “This is not just an attempt to spin things,” Simeonidis says. “They are trying to get the message out that ‘we are a drugbased company.’ ” The next two years will be important for generating clinical data. In addition to starting Phase I trials for two drug candi-
The move from good idea to drug candidate has been slower than some investors have the stomach for. dates, ALN-TTR01 and ALN-PCS, Alnylam will ask for regulatory approval to start human studies of two more candidates by the end of the year. Even further ahead, Marina Biotech is enrolling patients in a Phase Ib/IIa trial of CEQ508, an RNAi-based therapy for the treatment of a rare genetic disease called familial adenomatous polyposis. Marina’s French believes the rareness of the disease will enable the company to move from a small, 12-patient study to a Phase II trial in 2012, giving it “a reasonable chance of launch” by 2014. RXi has also chosen its first clinical candidate, RXI109, which targets a gene involved in fibrosis. It expects to file an Investigational New Drug Application (INDA) with the Food & Drug Administration in the second half of the year.
PUBLIC AUCTION OF OF THE ASSETS PUBLIC AUCTION THE ASSETSOF OFANLYTICS, ANLYTICS, INC., CHEMIR ANALYTICAL SERVICES, INC., CHEMIR ANALYTICAL SERVICES, LLC, LLC, CAS-MI LLC, AND CAS-MI LABORATORIES, LABORATORIES, LLC, AND AZOPHARMA CONTRACT PHARMACEUTICAL AZOPHARMA CONTRACT PHARMACEUTICAL SERVICES, LLC SERVICES, LLC
LEGAL NOTICE: Pursuant to the authority of the Amended and Restated Receivership Order dated May 3, 2010 and as required by 28 U.S.C. §§ 2001-2004, on February 15, 2011 at 10:00 a.m. (Central), Morris-Anderson & Associates, Ltd. in its capacity as the Receiver for the assets of Analytics, Inc., Chemir Analytical Services, LLC, CAS-MI Laboratories, LLC and certain assets of Azopharma Contract Pharmaceutical Services, LLC (the “Receiver”) shall conduct an auction at Thompson Coburn LLP, One US Bank Plaza, Suite 3500, St. Louis, Missouri for the purpose of selling all the transferable assets owned by defendants Analytics, Inc., Chemir Analytical Services, LLC, CAS-MI Laboratories, LLC, and Azopharma Contract Pharmaceutical Services, LLC and held by the Receiver. SUCH SALE BY THE RECEIVER IS SUBJECT TO APPROVAL BY THE UNITED STATES DISTRICT COURT FOR THE EASTERN DISTRICT OF MISSOURI (the “DISTRICT COURT”). All parties wishing to be eligible to participate in the auction must submit bids to the Receiver at the address set forth below on or before 5:00 p.m. (Central) on February 9, 2011 Morris-Anderson, Receiver c/o Terry J. Bartz 55 W. Monroe, Suite 2500 Chicago, Illinois 60603 Phone: 612-865-2123 All bids (such bids are referred to as “Qualifying Bids”) must satisfy the criteria set forth in the Order Approving Sale and Bid Procedures by Receiver, Approving Form and Content of Notice, and Setting Sale Hearing entered by the District Court on January 5, 2011 which can be obtained at www.analytics-receiver.com. A hearing to consider the results of the auction will be held on February 22, 2011 9:30 a.m. (Central) at the United States District Court for the Eastern District of Missouri, 111 S. Tenth Street, Courtroom 10-South, St. Louis, MO. Additional information about the sale may be found at www.analytics-receiver.com.
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As for larger drug companies, the focus will continue to be on letting the technology percolate. “I don’t believe any of them are ready to go into the clinic in 2011,” says Alan Carr, a stock analyst at Needham & Co. The earliest the industry could see one of big pharma’s siRNA-based drugs entering clinical trials will be 2012, he adds. Merck is taking a cautious approach, Sachs concedes. The company has yet to publicly comment on its plans for pushing an RNAi-based drug into the clinic, deciding to wait until it’s more confident in the efficacy of delivery systems. In the meantime, it will focus on using the technology as a research tool for other drugs in its pipeline. “Some companies are claiming INDAs for particles that are very safe, because they are, but they may not have any efficacy,” Sachs says. “Other companies are trying to
work with particles that are very potent but aren’t particularly safe.” For many smaller firms, forging alliances is a critical, renewed goal for 2011. Marina Biotech continues to look for a partner that can test its delivery systems and tease out indications for its compounds, French says. Alnylam is looking to add new alliances that either provide broad access to its technology or are focused on specific drug targets. Dicerna, a Cambridge, Mass.-based biotechnology company, was able to secure lucrative deals with Kyowa Hakko Kirin and Ipsen Pharmaceuticals last year, and it expects to sign similar pacts this year. “The deal we have with Kyowa Hakko is a template for partnerships going forward,” Dicerna CEO Douglas M. Fambrough says. MEANWHILE, Roche is working to sell off its RNAi assets. “Ideally, by creating a new entity, Roche would then consider the possibility of reentering the field as clinicalstage compounds emerge,” the company tells C&EN. Gordon Beck, from Roche Pharma Partnering, is spearheading the divestiture with the support of Louis M. Renzetti, the firm’s vice president of RNA therapeutics. The goal is to complete the transaction by the end of 2011. Roche had previously set a goal of asking for regulatory approval to test its first RNAibased therapeutic in humans by the end of 2010; the Swiss company says that the program will be transferred to the new entity. Whether Beck and Renzetti will find buyers for the business remains to be seen. “My understanding is it’s already been shopped around to everybody,” Needham’s Carr says. “Before we have some moreextensive clinical proof of concept, it’s going to be hard to find investors that want to commit to it.” That same investor wariness could sink new companies that might have transformative delivery technologies. “I really do worry about the short term,” Merck’s Sachs says. “It is difficult for a small company in an area that doesn’t have major revenues associated with it to be launching a discovery platform for delivery.” However, Sachs is much more optimistic about the long-term outlook for RNAi. He compares the maturation of RNAi to that of monoclonal antibodies or peptides. All it will take is one commercial success and the field will bounce back, he predicts: “That feeds back into more investor confidence and innovation.” ■
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