Two Nobel Prize winners, each working with his own biomedical company in the Boston area, are racing to turn a 10-year-old genetic discovery into novel therapies that may help drug development at Merck & Co. and Novartis AG.
Phillip Sharp’s Alnylam Pharmaceuticals Inc. and Craig Mello’s RXi Pharmaceuticals are seeking to be the first to use a new technology called RNA interference (RNAi), that blocks the action of genes. RNAi’s potential against almost any disease may lead to drugs with sales “in the billions,” says Ding Ding, a Maxim Group Llc. analyst.
Sharp, 62, who won the Nobel in 1993, has seen shares of his Alnylam Pharmaceuticals triple since 2004 on research indicating that technology may lead to therapies against infectious diseases, cancer and arthritis. Licensing deals with Merck, Novartis and 23 drug makers have the potential of providing the company $1 billion (Rs4,100 crore). Pfizer Inc., the world’s largest drug maker, is also investing in the new approach.
“This is really something revolutionary, and nothing has blown it out of the water yet,” said Judy Lieberman, a biochemist at Harvard Medical School in Boston. “It provides the chance to target all the so-called non-druggable targets, it opens up a universe of molecules you can intervene with.”
As scientists gain more knowledge of the role of genes in disease, the RNAi’s promise has grown. Viruses, for example, are composed almost entirely of genetic material and cancer is principally a disease of flawed DNA. By turning off certain genes, the process of RNAi, scientists are attempting to squelch the biological machinery that drives illnesses as varied as bird flu and AIDS. “Over time, we see the potential for treating or curing some of the most horrendous diseases known to man,” said Steven Kriegsman, chief executive officer of RXi’s parent, Los Angeles-based CytRx Corp. “The sky’s the limit.”
There have been other DNA-based treatments that have fallen short when tested in humans. Gene therapy, after much promise, proved to be a failure for treating diseases. Side effects, which may still crop up in tests, and particularly the problem of getting the molecules into cells may similarly delay RNAi drugs from reaching the market, Maxim’s Ding said.
“We still have so little experience with RNAi,” she said. “I think we will get there. The question is, whether it will be 10 years before we have significant products, or more like 20 or 30 years.”
Mello and Sharp are betting the time span will be shorter.
Sharp, a biochemist at the Massachusetts Institute of Technology (MIT) in Cambridge, won his Nobel for discovering how cells splice together genes to make the protein chemicals carrying out the functions of life. While, Mello did the initial work on RNAi in animal studies in 1998. He was awarded his Nobel prize for the advance last year and helped found RXi this year.
Like two captains in a pick-up basketball game, Sharp and Mello have drafted top scientists from a relatively small field of experts, many of whom they worked with in the past. Prized qualities are scientific acumen, patents and an idea of how to get RNAi drugs into tumours, the liver, lungs, eyes or other tissues where they can do the most good.
Sharp, for instance, recruited Tom Tuschl, a former student, into Alnylam, bringing along exclusive rights to a patent called Tuschl 2. That gives the firm control over use of so-called small interfering RNAs (siRNAs), strands of genetic material researchers say may form the basis for drugs.
RXi added Greg Hannon, adding his expertise in so-called “short hairpin RNAs” that have the same gene-cancelling effect as the siRNAs.
Mello with his long, brown hair swept back, a lantern jaw and the look of an athlete, “doesn’t look like us nerdy scientists,” said RXi CEO and former classmate Tod Woolf. “He was the only cool graduate student.” Yet, he said, Mello’s “a very clear thinker, and interested in all of the basic, fundamental things about genes.”
Sharp is a classic bench scientist, colleagues say. Balding and bearded, with a ready smile and friendly manner, Sharp trained at the elbow of James Watson, the 1953 co-discoverer of DNA. The five-year head start over Mello is just one of Sharp’s advantages, analysts say.
Alnylam’s licensing deals with drug makers such as Whitehouse, Merck and Novartis are providing critical research funds. RXi has no such licences. Alnylam is located near MIT and Harvard, and has about 120 employees, many from the two universities. RXi, some 65km away, has fewer than 20 in its employ.
Sharp founded Alnylam in 2002, three years after reading a paper written by a former student of his, named Andrew Fire, who shared the 2006 Nobel with Mello. In that paper, Fire showed how feeding RNAi molecules to nematode worms blocked their genes from producing proteins.
Sharp says he was stunned by the implications. “I understood that this was really a very general biological phenomenon,” Sharp recalled. “It was ancient and broad and deep and powerful, and no one had ever recognized it. It had to?be a fundamental principle.”
Even algae use RNAi to turn off genes when they need to stop making certain proteins or turn off a biological process, researchers at the John Innes Centre in Norwich (UK) said. That suggests RNAi evolved as part of a molecular on-off switch millions of years sooner than multicelled plants and animals themselves, they said in a 30 May study in the journal Nature.
Sharp also has a leg up in business experience. He was a co-founder in 1978 of Cambridge-based Biogen, now Biogen Idec Inc., and made “gobs of mistakes” he was determined not to make a second time through.
RNAi drugs may be relatively safe, cheap and easy to make, Sharp says, and the impact on organisms was bulletproof. The only thing standing in the way of making RNAi into drugs was finding a way to put the molecules into the right cells.
When Sharp founded Alnylam, he named it for a star in the constellation?Orion 250,000 times brighter than the sun. His plan was to gain rights to all the important patents governing RNAi. While Fire, now a professor at Stanford University, and Mello had taken out a patent on their ground-breaking work with RNAi, Alnylam was able to get non-exclusive rights to it from the University of Massachusetts.
Mello says his team is undaunted by the challenge. CytRx separated the subsidiary from its main business after Merck’s announcement in October that it would pay more than the $1.1 billion to acquire eye-drug developer Sirna Therapeutics Inc., which is also exploiting the technology.
“We announced we were going to create a pure-play RNAi company to go head-to-head with the only remaining pure-play in Alnylam,” said CytRx’s Kriegsman. “We want to make Worcester a dominant player in the space to go head-to-head with Cambridge.”
The unit is owned 85% by CytRx and 15% by Mello and three other researchers, said Kriegsman. CytRx’s ownership will fall to less than 49% through dividends or distributions to shareholders, he said.
Big drug makers see the possibilities too. After paying $1.1 billion for Sirna in January, Merck said it plans to spend $1 billion more to develop RNAi drugs over the next five to 10 years. “It’s a game changer for Merck,” said Alan Sachs, vice-president of RNA therapeutics. “It’s a big-investment, big-win type of scenario.”
Pfizer has a two-year agreement to work with closely held Mirus Bio Corp., based in Madison, Wisconsin, to research RNAi in animal models. It plans to become involved in drug development. “At Pfizer, we are determined to be a major player and a significant component of the RNAi community,” said Tom Turi, director of translational biomarkers and mechanistic biology for the firm. The firm may license technology, acquire a drug developer, or develop its own drugs, he said.
It’s a good move, Sharp says. RNAi is “the next great product platform for the development of new therapeutics,” he said.
“It’s the revolution of the decade.”