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RNAi Field Looks to Late-Stage Clinical Data, Approvals to Regain Pharma Interest


Though the RNAi field was shaken in late 2010 and early 2011 by the decisions of two major pharmaceutical players to drop their in-house development of oligonucleotide medicines, industry insiders saw a modest renewal of big pharma's interest in the gene-silencing technology in 2012.

However, concerns that RNAi won't live up to its potential remain, making solid clinical demonstrations of its therapeutic utility and even regulatory approvals a must before it will be embraced as warmly as it had in previous years, they said.

“Within pharmas, there are ongoing discussions between the people who see the remaining issues with oligonucleotides and the people who don't want to get left out of the future growth of this field … because of their excessive caution with a new technology platform,” Art Krieg, CEO of Rana Therapeutics and former head of Pfizer's oligonucleotide therapeutics unit, told Gene Silencing News.

Still, what big pharma decision-makers want to see are commercialized products, he said. “The phase I human clinical trials and the animal data ... just don't convince them that these [drugs] are not going to cause some other significant side effects that are going to limit their use.”

After bursting onto the scene in 2002 when Science named small RNAs as the breakthrough of the year, and with a 2006 Nobel Prize going to its discoverers Andrew Fire and Craig Mello, RNAi was heralded as having the potential to treat those diseases unamenable to small molecule intervention.

The pharmaceutical industry took notice and made major investments in the technology. Most notably, Merck shelled out $1.1 billion to acquire RNAi drug developer Sirna Therapeutics in 2007, marking the industry's biggest deal to date (GSN 1/4/2007).

Also in 2007, Roche paid Alnylam Pharmaceuticals over $330 million in upfront fees and equity investments to gain non-exclusive access to its intellectual property and technological know-how, as well as control of its German subsidiary (GSN 7/12/2007). The next year, Roche paid $125 million to acquire Mirus Bio and its proprietary conjugate delivery technology (GSN 7/24/2008).

All the while, companies including Pfizer and Novartis, which had forged an alliance with Alnylam in 2005 (GSN 9/9/2005), steadily built up their own internal RNAi research and development programs.

But within a few years, RNAi began to lose its gleam, and in late 2010 Roche announced that it was shuttering its in-house RNA drug efforts as part of a broader restructuring in response to "increasing hurdles for the approval and pricing of new medicines” (GSN 11/18/2010). Just months later, Pfizer followed suit, closing down its oligo drugs unit (GSN 2/3/2011).

Also in 2010, Novartis opted not to exercise a $100 million option to pick up broad non-exclusive access to Alnylam's IP and technology, instead sticking with the 31 targets it already had access to (GSN 9/30/2010).

These developments were perceived by the wider biopharmaceutical community as indications that RNAi was not as robust a therapeutic modality as previously thought, despite the fact that Novartis and Merck continue to work with the technology in earnest. As a result, companies developing RNAi drugs found themselves in a difficult position when looking for the partnerships and investments that once seemed so forthcoming.

Yet over the past year, significant advances have been made, with an increasing number of drug candidates entering clinical trials, some yielding extremely positive data such as Alnylam's phase I TTR-mediated amyloidosis treatment ALN-TTR02 (GSN 7/9/2012), and steady improvements to delivery technologies.

But according to Krieg, there is a “lack of awareness” among many in the pharmaceutical field about the significant progress that has been made, not only with RNAi but all oligo drugs, in recent years.

“As people become more aware of that progress, it will help," he said. “But ultimately, we just have to get products approved.”

To University of Texas Southwestern Medical Center researcher David Corey, “it's been frustrating to watch an industry in which large companies have bought up [RNAi] companies or started their own RNAi efforts, and then after two or three years close them down because they weren't making rapid enough progress.

“That's a waste of money and a waste of people's talents, especially when you have these really great teams of researchers that are making progress and are then disbanded,” he said. “We lose that progress as an entire field when that happens.

“I'd hope that [industry would] take the lessons that we've learned over the years that there are not going to be miracles happening overnight,” Corey added. “This is inventing a new kind of pharmaceutical science — there are going to be some challenges and it's going to take a while.”

But with the work already done and clinical studies underway, 2013 may become the year when the broader pharmaceutical industry once again finds value in RNAi, especially if its sees this kind of recognition from one of its own.

“People really want to see Merck do something,” Dicerna Pharmaceuticals CEO Doug Fambrough said. “That would change the perspective of the field a lot.”

The broader drug-development community tends not to place too much importance on a clinical trial initiated by a pure-play RNAi therapeutics firm because doing so represents its only chance at success, he said. “It's do or die, so even if [a drug candidate is] kind of crappy, they're going to do it.

But if a company like Merck starts clinical testing, “it will be taken very seriously,” he said, noting that pharmas routinely write off investments that don't pan out.

Merck has said publicly that it intends to move an RNAi drug into clinical testing before the end of 2014.