Replies to post #109440 on Biotech Values

[DewDiligence]

Although Alnylam shed about 50 of its 225 employees when its partnership with Novartis ended, chief executive John Maraganore is optimistic. "There's going to be a steady drumbeat of increasing frequency that really validates RNAi as a whole new drug class," he says. "We're feeling pretty damn good about where things are right now."

John Maraganore has done a pretty good job for ALNY with the cards he was dealt. If there’s a way to pull the company out of its funk, he will probably find it.

[DewDiligence]

Big Pharma’s Fever for RNAi Has Cooled

http://www.nytimes.com/2011/02/08/science/08rna.html

›February 7, 2011
By ANDREW POLLACK

When RNA interference first electrified biologists several years ago, pharmaceutical companies rushed to harness what looked like a swift and surefire way to develop new drugs.

Billions of dollars later, however, some of those same companies are now losing their enthusiasm for RNAi, as it is called. And that is raising doubts about how quickly, if at all, the Nobel Prize-winning technique for turning off specific genes will yield the promised bounty of innovative medicines.

The biggest bombshell was dropped in November, when the Swiss pharmaceutical giant Roche said it would end its efforts to develop drugs using RNAi, after it had invested half a billion dollars in the field over four years [#msg-56863582].

Just last week, as part of a broader research cutback, Pfizer decided to shut down its 100-person unit working on RNAi and related technologies. Abbott Laboratories has also quietly shelved its RNAi drug development work.

“In 2005 and 2006, there was a very sudden buildup of expectation that RNAi was going to cure many diseases in a very short time frame,” said Dr. Johannes Fruehauf, vice president for research at Aura Biosciences, a small company pursuing the field. “Some of the hype, I believe, is going away and a more realistic view is setting in.”

The issue is that while drugs working through the RNAi mechanism can indeed shut off genes, it has been difficult to deliver such drugs to the cells where they are needed. At a time when hard-pressed pharmaceutical companies are already scaling back research expenditures, RNAi is losing out to alternatives that seem closer to producing marketable drugs.

“I have no doubt that at a certain point in time RNAi will make it to the market,” said Klaus Stein, head of therapeutic modalities for Roche. But he added, “When we looked into this, we came to the conclusion that we have opportunities that have higher priorities.”

The loss of appetite at the big companies is hurting smaller companies that specialize in RNAi. Alnylam Pharmaceuticals, widely considered the leader among these companies, cut a quarter of its work force late last year after Novartis did not extend a partnership. And several small companies failed to fulfill promises to investors that they would forge alliances with big pharmaceutical companies in 2010.

Still, many executives and scientists say progress is being made. Just last week, two midsize European drug companies signed small deals to explore development of RNAi drugs. While there has not yet been definitive proof that a drug using RNAi can effectively treat a human disease, there are now about a dozen RNAi drugs in clinical trials, more than ever before.

It is not unusual, the executives and scientists say, for the initial enthusiasm for a new technology to wane, even as the technology slowly is perfected. It took more than 20 years for the discovery of monoclonal antibodies in the mid 1970s to translate into huge-selling drugs like Avastin for cancer and Humira for rheumatoid arthritis.

“A lot of the excitement for RNAi was irrationally high to begin with, and now is irrationally low,” said David Corey, a professor of pharmacology at the University of Texas Southwestern Medical Center in Dallas.

RNA is a chemical cousin of the DNA in genes. Both are strings of chemicals called bases that spell out the genetic code and are usually represented by the letters A, C and G, plus T for DNA and U for RNA.

While it was once thought that RNA was merely a messenger, scientists now recognize that RNA plays a powerful role in turning genes on or off. The discoverers of RNAi, Andrew Z. Fire and Craig C. Mello, won the Nobel Prize in 2006, a mere eight years after publishing their seminal paper.

RNA interference is a natural phenomenon. When a cell senses a double strand of RNA, it acts to silence any genes with the corresponding sequence of bases. It is thought this is a defense against viruses because RNA is usually found as a single strand except in viruses.

The implications for drug companies were obvious. Virtually any disease-related gene could, in theory, be silenced by synthesizing a short snippet of double-stranded RNA — called a small interfering RNA, or siRNA — with the proper sequence of bases. Imagine disabling a gene that contributes to high cholesterol, or one that a pathogen needs to survive.

By 2005, three drugs were ready for clinical trials, a rapid turnaround by pharmaceutical industry standards.

But two of them — both aimed at treating the eye disease called age-related macular degeneration — have already been dropped after not working well enough. The third, aimed at treating a respiratory infection, has shown some signs of effectiveness, but conclusive trials are only now under way.

One obstacle is that the double-stranded RNA snippets, perhaps because they do resemble viruses, can wake up certain immune system sentinels and set off an immune response.

Such responses can be an unwelcome side effect in some cases. In other cases, like in treating cancer or infections, an immune response might be welcomed — but might also obscure whether the gene silencing itself is working.

Dr. Arthur M. Krieg, who runs RNAi research at Pfizer, said he looked at 35 studies in which RNAi drugs were reported to have shrunk tumors in animals. Only two of the studies used controls that could rule out the possibility that the tumor shrinkage was caused by an immune response, rather than a silencing of specific genes.

But the biggest challenge has been delivery. RNA is quickly broken down in the bloodstream. And even if it gets to the cells in the body where it is needed, it has trouble entering the cells.

Still, scientists have learned to chemically modify RNA to make it survive in the bloodstream and to avoid eliciting immune responses. And various mechanisms are being worked on to help deliver the RNA.

Last year scientists led by Mark Davis at the California Institute of Technology, who is a founder of Calando Pharmaceuticals, published a paper in Nature demonstrating the first proof of RNAi delivered through the bloodstream working in humans.

By using various molecular tests performed on tumor biopsies, the scientists demonstrated that an siRNA drug had entered tumors and inhibited the activity of its target gene. It is still too soon to tell whether the drug will actually help patients with cancer, however.

The leading approach to delivery now is to package the short RNA snippets in tiny lipid particles, like those developed by a company called Tekmira Pharmaceuticals. These particles naturally accumulate in the liver, so many of the RNAi drugs in clinical trials now aim at liver-related problems, like liver cancer and high cholesterol. But these particles can have side effects of their own.

To deliver elsewhere in the body, scientists are experimenting with attaching something to the RNA to guide it to particular organs or cells.

In a paper published recently in Science Translational Medicine, John J. Rossi of the City of Hope medical center in Duarte, Calif., and colleagues used an aptamer, a piece of RNA that twists into a particular shape. Dr. Rossi’s aptamer was designed to bind to immune cells infected by H.I.V. While the siRNA by itself did not lower levels of the virus in mice, the siRNA attached to the aptamer did — a sign of successful delivery.

Still, many problems remain. Dr. Alan Sachs, the global head of exploratory and translational science at Merck, said the company had looked at more than 300 ideas for delivery of RNAi drugs but had not found anything that was safe and effective enough and available for licensing.

Merck was one of the drug companies that plunged most heavily into RNAi, paying $1.1 billion in 2006 to acquire Sirna Therapeutics, a pioneer in the field. While Dr. Sachs said Merck is happy with its investment [uh huh], the company does not yet have an RNAi drug in clinical trials and is using the technique more for basic biological studies.

One factor diminishing the appeal of RNAi is the rise of alternatives. Most drugs work by blocking the action of a protein in the body. But some proteins, by dint of their location or structure, cannot easily be inhibited and are said to be “undruggable.”

The promise of RNAi is that it can inactivate the gene and thereby prevent a troublesome protein from being produced in the first place. Suddenly, all proteins would become druggable.

But other techniques are improving. Dr. Stein of Roche said his company thought it would use RNAi to block production of a protein called Mdm2, which binds to a tumor-fighting protein called P53 and renders it inactive. But the company now believes it can develop a conventional drug that will prevent Mdm2 from binding to P53, he said.

Another example is a protein called PCSK9. People who have certain genetic mutations that render this protein inactive have very low cholesterol and a decreased risk of heart attacks. So drug companies are eager to design drugs to block the action of PCSK9.

While it once looked as if only RNAi could shut down PCSK9, Pfizer, Amgen and Regeneron Pharmaceuticals have all raced into clinical trials with monoclonal antibodies, a more conventional technique. Alnylam, meanwhile, will not start its RNAi trial until later this year.

Additional competition to RNAi might come from antisense, another technique for silencing genes that uses RNA . It has been worked on for more than 20 years without much success. But in the last two years, big pharmaceutical companies have licensed as many or more drugs using stodgy antisense technology than the hotter and more powerful RNAi.

But that is also a sign of hope for RNAi. If antisense is finally about to be successful, it might be only a matter of time for RNA interference.

“A lot of people think it’s winter out there for RNAi,” said John Maraganore, the chief executive of Alnylam. “But I think it’s springtime.”‹

[DewDiligence]

MRK throws in the towel on RNAi-based therapeutics:

http://www.xconomy.com/san-francisco/2011/07/29/merck-shuts-down-rnai-research-center-in-sf-cutting-50-jobs/

Merck has decided to close down the RNA interference research facility it obtained through its $1.1 billion acquisition five years ago of San Francisco-based Sirna Therapeutics (#msg-14401261), the company said late today. About 50 jobs are being eliminated, while about 10 people are being offered transfers to other Merck facilities on the East Coast and in Palo Alto, CA, says company spokesman Ian McConnell. The company still plans to utilize the RNAi technology it got via the Sirna acquisition throughout its global R&D operation, he says. [Translation: RNAi will be used by MRK as a lab tool only.]

…Merck’s acquisition of Sirna raised eyebrows across the industry from the beginning, because of the high price tag, and the early-stage nature of RNAi technology. This technology has electrified scientists for several years, because it offers the potential of hitting biological targets of disease that are currently inaccessible by conventional small-molecules or larger biotech drugs. Merck paid what many considered to be the lavish sum of $1.1 billion to acquire Sirna, one of the first movers in RNAi.

Since then, Merck hasn’t pointed to any RNAi-based drugs that have emerged in its pipeline, and it has publicly emphasized the challenge it has faced finding ways to effectively deliver these drugs in the body. Merck’s decision comes just a few months after fellow pharma giant Roche pulled out of a high-profile RNAi collaboration with Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY). There are no such RNAi-based drugs approved yet by the FDA for sale in the U.S.

Still, McConnell said Merck plans to continue to use the RNAi technology to help screen drug candidates...

With a price tag of $1.1B, this ranks as a pretty expensive mistake, even for a company of MRK’s size. Thanks to ‘tuck’ on SI for the above find.