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New Research Could (Finally) Remove RNAi’s Commercial Limitations

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out there two or three years ago,” he says. “But there’s now a resurgence of interest” in pharmaceuticals based on nucleic acids. “Everyone understands they can become drugs—and safe drugs—if they’re delivered to the right tissues.”

He says recent work with nucleic acid therapies—of which RNAi-based drugs are a subset—has eased safety concerns. But there is still plenty of discussion about toxicity, and any new construct, like Solstice is building, will bear close observation.

As noted earlier, Merck didn’t believe enough in the resurgence to continue its program, but there have been other signs of rekindled belief. At the same time it bought Merck’s old Sirna assets, Alnylam also deepened its partnership with Sanofi’s Genzyme division, trading commercial rights to its lead drug, patisiran, outside North America and Western Europe for a $700 million purchase of Alnylam stock—12 percent of the company.

And in one of the most surprising biotech IPOs of 2014—or any recent year—public investors went nuts in January for shares of Dicerna Therapeutics, an RNAi company that at the time had nothing in the clinic. (Even in this historic two-year IPO window, in which biotech has outshone all other industry sectors, drug companies have almost always needed some clinical data to go public.)

The $15-a-share issue shot up to $46 the first day out. Preclinical RNAi mania wore off, however, and shares have deflated to below $10 each. Dicerna did start a Phase 1 trial in April, with an early focus on liver cancer.

All of this means very little until Solstice itself shows the outside world it has taken concrete steps to “pharmaceuticalize” what Dowdy and his UCSD lab mates have done, as Bradshaw puts it. There are already significant differences from what’s in Dowdy’s paper, says Bradshaw, who speaks of “manipulating the backbone” of RNNs while maintaining the compounds’ activity but doesn’t get into more details.

All the while, there have been significant distractions, too, as I reported in June. Bradshaw is being sued over the bankruptcy of Traversa Therapeutics, a previous company that Dowdy cofounded and where Bradshaw was also CSO. [A previous version of this story mistakenly said Bradshaw “ran” Traversa.] More significantly, Dowdy was shot last year by his Traversa co-founder, Hans Petersen. The same night, Petersen also shot his estranged wife’s brother, Ronald Fletcher, and Fletcher also survived. (When I spoke to Petersen’s lawyer in June, he did not dispute that Petersen was the shooter and said the case would hinge upon Petersen’s mental state at the time.)

Those will remain distractions. The lawsuit continues; the next hearing is scheduled for mid-December. And Hans Petersen’s trial for the two shootings will start next year.

At the end of our conversation, Dowdy without prompting asked me not to mention either the lawsuit or the shooting. He’s healthy and ready to move on and says he ultimately doesn’t want to be remembered as the biotech guy who got shot, and oh yeah, by the way, he helped cure cancer.

I can’t rewrite history or sweep it under the rug, so I politely declined his request. But I assured him that if his work leads to treatments for previously stubborn diseases—let alone cure cancer—all the weird stuff will be pushed much farther down the page.


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One response to “New Research Could (Finally) Remove RNAi’s Commercial Limitations”

  1. cvrichard says:

    Tissue targeting is the holy grail of drug delivery very few have achieved. Most targeting companies ended up ‘targeting’ liver (including Dowdy’s latest paper) because that’s where most of these (larger) molecules end up anyway.

    siRNN availability inside the cell is another big issue. In his paper, Dowdy claims his “siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses.” Yet, Solstice’s molecule would get stuck in endosome, inaccessible to thioesterase. These conflicting observations indicate two different cell entry pathways. In my opinion, the Solstice/Dowdy team has a loooong way to go before they sort out the exact nature of their molecules.

    The path to targeted drug delivery and intra-cellular delivery of large molecule is littered with the skeleton of failed companies. I wish these guys the best of luck.