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

Xconomy National — 

[Corrected 11/17/14, 12:30pm. See below.] If nothing else, the acronym RNAi, which stands for ribonucleic acid interference, should be familiar to biotech observers as something that won two researchers the Nobel Prize in 2006, and that a few companies have tried to turn into drugs. Alnylam Pharmaceuticals (NASDAQ: ALNY) is the most well-known. But in treating human disease, its promise has outpaced its utility.

In Nature Biotechnology today, University of California, San Diego researcher Steve Dowdy and colleagues have published a paper that Dowdy says could be the foundation that drug developers use to overcome the biggest obstacle keeping them from delivering upon RNAi’s promise.

Or perhaps it’s better to say: the foundation that one drug developer uses. That’s because Dowdy’s work is the exclusive property of San Diego-based Solstice Biologics, a two-year-old, venture backed firm that Dowdy cofounded. I’ve written about Solstice and its dramatic history before, most recently in June when it hired Lou Tartaglia away from Third Rock Ventures to become CEO.

Dowdy, Tartaglia, and others involved in Solstice believe they’ve cracked a very important code—how to get RNAi drugs into all manner of cell types. They have voiced that belief for some time now, and some of the specifics of Dowdy’s work are well known. But the paper published today provides a more intricate look under the hood, and supplemented with conversations with Dowdy, Tartaglia, and Solstice chief scientific officer Curt Bradshaw, also gives a clearer idea of what Solstice still needs to do to turn its ambition into breakthrough RNAi medicines.

Turning the fascinating mechanism of RNAi into a widely deployed weapon against cancer, infectious disease, and more would indeed be a breakthrough. To date, Alnylam and a few others have only advanced drugs to treat liver and eye disease, the only tissue types relatively amenable to RNAi delivery. (Nothing yet has been approved; Alnylam’s most advanced program, aimed at a genetic disease called TTR amyloidosis, is in Phase 3.)

In fact, those delivery problems bedeviled other early enthusiasts, often with much deeper pockets: Roche and Novartis ((NYSE: NVS), two of Alnylam’s first development partners, dropped their programs after a few years; and Merck & Co. ((NYSE: MRK), which bought Alnylam’s rival Sirna Therapeutics for $1 billion in 2005, ended up selling those assets in 2014 for $175 million (of which only $25 million was cash)—to Alnylam, no less.

It’s easy to see why so many companies spent so much money within a few years of RNAi’s emergence. The overarching concept is simple and elegant. The DNA code of life must be transcribed, transported out of the nucleus, and ferried to the main part of the cell, the cytoplasm, where ribosomes await to turn the code into proteins.

The bridge between DNA and protein is RNA, or, because of the nature of its job, messenger RNA (mRNA). You’ve heard people say “Don’t shoot the messenger”? Substitute “hijack and slice up” for “shoot,” and there you have RNAi: If the mRNA is hijacked and destroyed on its way to the ribosome, the protein in question never gets produced. (A common description of RNA interference is “gene silencing.”)

How that happens inside a cell is complex and includes more than one form of RNA and enzymes that do the slicing and dicing.

It’s a mechanism that helps cells defend against intruders like viruses, whose genomes are encoded in RNA, not DNA. And the therapeutic implications are obvious: Use the mechanism to prevent the production of disease-causing proteins, like the ones tumor cells make to survive; or the ones that cause rare diseases; or the ones viruses use to infect cell after cell (which I suppose you could call hijacking the hijackers).

As Dowdy describes RNAi, “it’s like a gift from God or whoever’s upstairs.”

As with anything in biology, however, the complications pile up quickly—the “dirty little tricks,” Dowdy says, that have kept that gift mainly beyond our reach. Many of them stem from this fact: RNA—or the RNA-like strands that companies have engineered to do therapeutic work—aren’t meant to be outside a cell, which makes getting them into the body and to the right spot a very frustrating exercise.

RNA molecules are fragile. Floating around in the bloodstream, they’re like foreign invaders, but not particularly tough ones. The body’s defenses recognize and chew them up easily. (Eye and liver cells are less problematic to reach and penetrate, which is why those areas have seen some clinical success.) Even if they evade detection, RNA have the same negative electric charge as cell membranes. Similar charges repel each other, as anyone knows after playing with magnets. It’s really hard to get RNA into a cell.

The big takeaway from Dowdy’s work is that he and colleagues have created RNA-like strands that hide from the body’s defenses and slip into cells more easily. They have a neutral charge, so the researchers have dubbed them RNNs, or ribonucleic neutrals. And they build upon a concept used by a lot of other pharmaceutical research programs: conjugation. Most notably, Seattle Genetics (NASDAQ: SGEN) and Immunogen (NASDAQ: IMGN)—and their larger partners Genentech, now part of Roche, and Takeda Pharmaceutical—have brought to market antibody-drug conjugates: cell-killing drugs chemically bonded to antibodies, which serve as homing devices that deliver the drugs into tumor cells.

Solstice wants to conjugate RNNs to similar homing devices—“targeting agents” is the term of art—that not only get them to the right cell, but hide them from the body’s defenses on the long journey. Once they’re in the cell, enzymes cut the targeting agent away from the RNN—the oligonucleotide is now active and can do its interference work.

One of Alnylam’s earliest employees who asked not to be named called Dowdy’s paper “a great advance” but cautioned that there’s much work to do to hone the principle into therapeutics.

Solstice’s executives would undoubtedly agree, and, although generally circumspect, they outlined several areas in which they have been building on top of the Dowdy work.

For example, if RNNs getting into cells will leave behind a lot of snipped-off waste, is there a safety risk? “You have to account for the potential toxicity of that entity,” says Tartaglia, and so far in preclinical tests, he says there have been no worrisome signals.

And what about those targeting agents that get the RNN into the cell? “We can place ‘handles’ anywhere we want on the structure and then conjugate whatever we want,” says Dowdy, and lists the various attributes of antibodies, ligands, synthetic molecules, and peptides. “All four are readily ‘conjugatable’ to the RNN backbone,” he says.

Solstice chief scientific officer Curt Bradshaw says, “We’re interested in all those, but we think we can also write some new rules when it comes to oligonucleotide delivery.”

There will be several factors to understand and fine-tune: size, ability to mask the payload as it travels to the target, and interaction with the target itself. Another big problem Dowdy continues to work on, and Bradshaw says Solstice is pursuing independently, is what happens after the molecules get past the cell membrane. At that point, an RNN is about as scot-free as the jewel thief who picks the front door lock, walks inside, and finds himself in a foyer full of trip-wire alarms. The cell has another layer, the endosome, from which very little escapes. “Getting out of the endosome is important for increasing efficiency,” says Tartaglia. “We’re in the early stages in trying to consider what our own proprietary methods would be in that space.”

It’s important not just for a more effective drug, but to lower the amount injected into a patient. The less drug that a patient needs, the better the safety potential—and the lighter the cost of goods to produce.

Solstice’s RNN backbone needs not only to hold onto a targeting agent but also an “endosomolytic agent”—something that can punch a hole through the endosome. This is not a new concept, and plenty of labs in academia and industry are working on the “endosome escape” problem.

Arrowhead Research (NASDAQ: ARWR), for example, calls its construct a “dynamic polyconjugate” and uses a synthetic polymer to crack open the endosome. (Arrowhead released disappointing interim Phase 2 results in October for its lead candidate, for Hepatitis B, and the stock has yet to recover.)

Dowdy more than once has touted RNNs as a way to go after diseases driven by rapid mutations, such as cancer or infectious viruses. That’s because nucleic acids are relatively easy to program to match to a disease-causing genetic code, then quickly synthesize. “Pull any sequence out of a hat,” says Dowdy, and within five days his lab team will “hand you those oligos”—meaning the backbone of the RNN.

When I ask Tartaglia how that rapid-response approach fits into Solstice’s plans, he taps on the brakes. “How regulatory agencies will handle drug approvals for mutating tumors or viruses when you have to introduce new sequences, and hence a new drug, rapidly is not clear,” he says. “Regulatory agencies will continue to weigh the benefits and risks as this technology becomes more available. It is safe to say our earliest therapeutic programs will not be based on this.”

Tartaglia declines to discuss the targets and tissue types Solstice is considering, although he reels off a long list of cell types—B cells, T cells, macrophages, lung, muscle, and more—that potential partners said they’d like to see targeted.

Since signing on as CEO in June, Tartalglia has been on what might be described as a listening tour to hear what those drug firms have in mind. It’s important to note that Solstice’s main backer is venBio, a fairly young venture firm based in San Francisco whose modus operandi is to build companies around assets that customers want. And the customers are drug companies with pipelines to fill, so Tartaglia and colleagues are paying close attention.

VenBio and Swiss investor Aeris Capital were behind Solstice’s $18 million Series A; the final $6.5 million slice of that cash flowed to Solstice last month after it hit undisclosed milestones, which means the need to raise more cash is not imminent, says Tartaglia.

I asked Tartaglia if the negative experiences of so many Big Pharma—Roche, Merck, Novartis—with RNAi programs in the past decade colored the reaction he got as he explained the RNN concept this summer. “We would have gotten cold shoulders, so to speak, if we were 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.