RNAi momentum fizzles as pharma shifts priorities
RNAi momentum fizzles as pharma shifts priorities
复制标题
随着制药公司转移优先事项，RNAi 势头逐渐减弱
DOI：
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发表时间：
2011
影响因子：
46.9
通讯作者：
Charles Schmidt
中科院分区：
文献类型：
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作者：
Charles Schmidt
Shock waves continue to reverberate around the RNA interference (RNAi) commercial sector following announcements last year from Baselbased drug giants Novartis and Roche that they were curtailing their programs in this technology. In September, Novartis terminated its partnership with Cambridge, Massachusetts–based RNAi flagship Alnylam; in mid-November, Roche also killed its entire RNAi program after ploughing $500 million into the area over three years. Although it wasn’t all bad news for the field—RNAi company Dicerna of Watertown, Massachusetts, signed a $1.4 billion agreement with Japanese firm Kyowa Hakko Kirin— concerns linger over the ability of RNAi technology to deliver new drugs to the clinic in the next few years, even in niche indications. “Investors and pharmaceutical companies are looking for a clinical payoff,” says Alan Carr, a senior analyst with Needham & Company, in New York. But that payoff isn’t coming fast enough, according to Arthur Krieg, director of Pfizer’s oligonucleotide therapeutics unit, in Cambridge, Massachusetts. Exploiting the technology as a drug is plagued by delivery challenges and mechanistic uncertainties. “Loss of enthusiasm for the field might be [because] this is taking a lot longer than people had initially hoped,” he says. “RNAi is now seen as a longterm therapeutic prospect at best.” Novartis sees its 5-year collaboration with Alnylam as a capability-building exercise, which came to its “natural, contractual conclusion,” the company said in an e-mail. They now plan to move forward independently working on the 31 therapeutic targets from this collaboration. Roche, however, is giving up on RNAi as a drug mechanism altogether. The Swiss company has also discontinued RNAi work with Tekmira of Burnaby, British Columbia. Though dramatic, RNAi’s fall from grace is not definitive. For instance, Pfizer announced in 2008 that it would take an RNAi drug to the clinic by 2011, and has now amended that goal, Krieg says. Instead, the company plans to broaden its oligonucleotide drug development efforts to include competing RNA-targeted technologies. Indeed, in January, Pfizer of New York, and Santaris of Horsholm, Denmark, announced a $14 million alliance to develop RNA-targeted drugs using the biotech’s drug platform of locked nucleic acids (LNAs)— antisense DNA phosphorothioate oligonucleotides flanked at each end by 2–4 oligos modified with an extra methylene bridge that fixes the ribose moiety in the C3′-endo sugar conformation (leading to a higher melting temperature). Santaris is eligible to receive milestone payments of up to $600 million as well as royalties on products developed for up to ten new RNA targets selected by Pfizer. This new alliance expands on an original collaboration with Wyeth, later acquired by Pfizer, and has already reached several early milestones for the biotech. The LNA-based drug projects are targeted to undisclosed indications. Krieg says Pfizer plans to submit an oligonucleotide investigational new drug application this year, which may be an LNA-based compound. Other bonanza deals in the RNAi field have also yielded little in terms of products. In 2006, Merck of Whitehouse Station, New Jersey, paid $1.1 billion to buy Sirna Therapeutics, of San Francisco, a company with one of the broadest RNAi patent estates in existence. As yet, Merck has brought no RNAi drugs into clinical development. At the time of the acquisition, Sirna had several drugs in its pipeline, including a treatment for hepatitis C virus infection. Sirna had developed structural modifications to its RNAi compounds (naked, double-stranded, short-interfering RNA (siRNA) molecules), designed to increase their stability and halflives in blood. Yet those modifications ultimately weren’t successful; the compounds were degraded by nucleases, resulting in unpredictable pharmacokinetics. But Merck still uses the knowledge acquired through Sirna in its R&D, specifically to support drug development of traditional compounds, such as small molecules and antibodies, according to Alan Sachs, Merck’s vice president for exploratory and translational science. Asked if those uses justify Sirna’s price tag, Sachs replied, “Decisions based on RNAi technology can save our company a considerable amount of money—clinical trials are enormously expensive and if we can avoid one by running smaller RNAi-based studies, we can quickly realize the value of that acquisition.” RNAi drugs, though, remain a formidable challenge—a challenge that, in Carr’s opinion, major drug companies are now leaving to the biotech sector. Delivery remains the main obstacle, particularly by systemic routes to distant sites in the body. Even heavily modified, naked siRNA molecules might not survive long enough in blood to reach target tissues. So RNAi must rely on carrier vehicles engineered to protect siRNA compounds in blood and to facilitate their absorption by target cells. According to Pfizer’s Krieg and others contacted by Nature Biotechnology, Tekmira Pharmaceuticals has made the most impressive gains in this area. Tekmira encapsulates its RNAi compounds in lipid nanoparticles (LNPs; ionizable aminolipids such as 1,2-dioleoyl-3-dimethylammonium propane) that the company claims resist endonucleases in blood and accumulate where vascular leakage occurs, such as tumors or sites of infection or inflammation. LNPs traverse cell walls that nucleic acids like siRNAs don’t easily pass, according to Tekmira’s chief executive officer, Mark Murray. But carriers have their own set of problems. For example, they’re much more expensive to develop and manufacture than the RNAi Santaris Pharma (Danish headquarters pictured above) recently received $14 million from Pfizer to extend a locked nucleic acid technology collaboration for RNAi targeting initiated by Wyeth. sa nt ar is NEWS
