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Oligo Drugs Advance in the Clinic in 2012 as Delivery Hurdles are Addressed

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Though not defined by any one major breakthrough as in years past, the RNAi therapeutics field made steady progress in 2012, particularly in terms of product and technology development, according to industry insiders.

“2012 was really a year where the field built on the success of 2011 in keying up additional opportunities for clinical applications, and some novel delivery systems” that reflect the growing awareness of the issue of endosomal escape, Jeremy Caldwell, vice president of RNA Therapeutics at Merck, told Gene Silencing News.

To Art Krieg, CEO of Rana Therapeutics and former head of Pfizer's oligo therapeutics unit, “it's been a year of advancing product portfolios,” not just within RNAi, but for the entire oligonucleotide drug field. “I would go out on a limb to say that oligonucleotides are increasingly being viewed as a platform that is on the verge of becoming the third major platform for drug development.”

In the Clinic

In terms of RNAi, it was the phase I data from Alnylam Pharmaceuticals' investigational TTR-mediated amyloidosis treatment ALN-TTR02 that generated the most buzz, with the company reporting that a single dose of the drug was able to reduce levels of its target protein — transthyretin — by up to 94 percent (GSN 7/19/2012). Additionally, the effects were rapid, dose-dependent, and durable, and Alnylam has said it will move ALN-TTR02 into phase III testing pending the outcome of an ongoing phase II trial.

Douglas Fambrough, CEO of Dicerna Pharmaceutics, noted that the ALN-TTR02 data were particularly compelling because, even though they were from a study in healthy volunteers, transthyretin levels are so tightly linked to the disease's etiology that they “carried a lot of weight.”

The data, Krieg added, did a lot to “help convince people that RNAi can be developed as a drug.”

Meanwhile, Isis Pharmaceuticals scored a victory this year when its cholesterol-lowering antisense agent mipomersen, now branded as Kynamro, received a nod from the US Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee.

The achievement was marred, however, by the panel's split 9-to-6 vote, which resulted from data suggesting liver toxicity and, possibly, a cancer risk associated with the drug. Investors reacted negatively to news, sending shares of Isis tumbling at the time.

“A lot of people were quite disappointed and surprised with what happened with ... the FDA advisory committee,” Krieg said. “But I don't think we should lose sight of the fact that it was a positive vote at the … meeting.

“As more data come out, I think people will see that the safety concerns that had investors nervous are not really grounded on anything real, actually,” he added. “I think it was a huge overreaction to the questions from the agency.”

The nascent miRNA field saw its own clinical success in 2012 when Santaris Pharma reported positive phase II data on its miR-122-targeting hepatitis C drug miravirsen (GSN 4/26/2012).

In a five-week phase IIa trial, treatment-naive patients with HCV genotype 1 received once-weekly subcutaneous doses of the drug at 3, 5, or 7 mg/kg. The mean of the maximum decline from baseline in HCV RNA for the 5 mg/kg group was 2.9, and was 1.2 for those receiving the lowest dose. Four out of nine patients in the highest dose cohort also became HCV RNA undetectable after treatment.

Delivery, Delivery, Delivery

The past 12 months have also seen significant advances with technologies addressing the RNAi drug field's biggest hurdle: delivery.

Lipid nanoparticle-enabled drugs, such as ALN-TTR02 and Tekmira Pharmaceuticals' phase I cancer drug TKM-PLK1, have continued to move through the clinic with positive results, but in 2012 it was the rise of conjugates that garnered the most attention.

“Other than solid tumors and the normal liver, lipid nanoparticles look pretty restricted where you can go with them,” Fambrough explained. “If you're trying to get more broadly to a wide variety of tissues,” conjugates appear to be the way to go.

Conjugates “are theoretically simpler [than lipid nanoparticles], and have the potential to be administered subcutaneously” with wider safety margins, Caldwell added.

Alnylam has made conjugates the centerpiece of its delivery efforts going forward, with its CEO John Maraganore calling them the “future for delivery of small interfering RNAs” in 2011.

Since that time, the company has focused heavily on its GalNAc conjugates, which facilitate liver delivery by uptake through asialoglycoprotein receptors, which are abundantly expressed on the surface of hepatocytes. Alnylam has stated that it intends to use the GalNAc technology to enable a subcutaneous version of its TTR amyloidosis drug, as well as with other drug candidates including the preclinical hemophilia treatment ALN-AT3.

Fambrough noted that GalNAc conjugates are not new to the oligonucleotide drug field, and had been tested by antisense drug developers in years past. However, they were generally ineffective because their payloads would mostly remain trapped in endosomes. But during 2012, they've proven to work “quite well” with siRNAs, taking advantage of the RNAi molecules' increased potency.

“The fact that you get enough [siRNAs escaping the endosome] with GalNAc is probably the biggest point that has emerged” in 2012, he said.

Similarly, Arrowhead Research made waves in 2012 with its dynamic polyconjugates, or DPCs, which it acquired from Roche in late 2011 (GSN 1/27/2011). In their original form, DPCs were composed of an endosomolytic polymer linked to an siRNA, which was then modified with carboxy dimethylmaleic anhydride derivatives containing polyethylene glycol and a tissue-specific targeting ligand.

Roche researchers, now with Arrowhead, discovered that DPCs and siRNAs didn't need to be joined as long as they were targeted to the same cell type, which allowed them to create next-generation versions of the delivery agent using a different endosomolytic polymer with improved pharmacokinetics.

Arrowhead late last year published data on the use of DPCs with cholesterol-conjugated siRNAs, and plans to use the approach in with its hepatitis B therapy ARC-520 (GSN 11/29/2012).

“I'm very intrigued by ... the way [Arrowhead scientists have] changed DPCs in a manner that provides a very good chemical strategy for endosomal escape, [one] that may be refined to work in the conjugate field,” Fambrough said. “That's pretty impressive data.”

Overall, the increased recognition of endosomal escape as “the major barrier to potency,” both within the liver and outside of it, was a key development in 2012, Caldwell said. But recognizing a problem and solving it are two different things, he cautioned.

“There have been a lot of presentations of unpublished data demonstrating advances in understanding the trafficking by which siRNAs traverse the cell from the membrane into endosomes, and then ultimately out of endosomes,” he said. Such discoveries “could lead to advances in paving the path for increased escape from the endosomal compartment, but we're at the stage where it's largely descriptive. The next step is turning those descriptions into more profound mechanistic understandings that lead to tools to improve on endosomal escape.”

While this might not be necessarily required for using RNAi to treat liver-based diseases, “certainly any of the extra-hepatic applications are likely going to require significant improvements in endosomal escape,” Caldwell said. “We're at the beginning of that new frontier, which is very exciting.”

He added that successfully using RNAi to target tissues outside of the liver represents, to him, the next major milestone for the field. “While that has been done to some extent in oncology settings, we really need to push the boundaries … into chronic diseases,” he said.

According to Caldwell, “another milestone would be showing the siRNA technology to be competitive in a disease area where there is a large unmet medical need,” which often means orphan diseases.

For its part, Alnylam “has smartly tapped into that,” Fambrough noted, pointing to the company's decision to focus on genetically defined diseases where there are few, if any, treatment options. “It's a great way to build a company with a wholly owned asset … [and] it makes especially good sense for a company that wants to ... bring a drug to market on their own.”

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