Delivering RNA

WHEN EXECUTIVES from Calando Pharmaceuticals met with the management team of Agilent Technologies' nucleic acid solutions division, the chemistry was obvious, says John Petrovich, Calando's chief executive officer.

The drug company was in the market for a custom supplier of the active molecule in its lead anticancer therapy candidate: a system called CALAA01, which is based on short interfering RNA (siRNA) and incorporates a deliberate cancer-cell-targeting delivery mechanism. Calando was impressed by the RNA drug development experience of staff at Agilent. As it turned out, Agilent could offer more than just RNA production. It is also putting its expertise at PEGylation—the practice of linking molecules to polyethylene glycol to improve stability and regulate size—to work on a component of the drug delivery system.

Calando, formed in 2005 with funding from Arrowhead Research to develop siRNA drugs, also saw a size fit. Agilent had been custom manufacturing siRNA and other oligonucleotide-type molecules for less than a year. It was still operating on a small scale that, according to Petrovich, matched Calando's preclinical needs better than larger suppliers in the RNA market did.

And once Agilent started producing the siRNA, Calando learned of the firm's experience with PEGylation. This skill would be useful in producing the cyclodextrin-based drug delivery system that Calando hopes will get its siRNA molecule inside tumor cells.

James Powell, general manager of Agilent's nucleic acids division, says Calando's drug delivery system will be key to the success of CALAA01. "It's a novel system that will encapsulate the siRNA and deliver it to the target of interest rather than let it float around the body," Powell says. "This has been the Achilles' heel of all oligonucleotides to date. Delivery is the challenge."

Powell is familiar with the difficulties in bringing RNA drugs to market; he's been working in the field since 2002, when he started a custom oligonucleotide manufacturing unit at Transgenomic, a biotech automation firm. Transgenomic subsequently sold the Boulder, Colo., business to Eyetech Pharmaceuticals, the manufacturer of Macugen, a macular degeneration treatment that is one of the few oligonucleotide-based drugs on the market. When Eyetech determined in 2005 that it did not need the facility, Powell bought it and formed SynPro. Agilent, the life sciences measurement and equipment company, purchased SynPro last April.

Agilent, which manufactures microarrays for nucleic acid chemistry, aspires to a top-three position in custom manufacturing of oligonucleotides, a frustrating field that has attracted plenty of interest but has so far yielded few drugs on the market. Merck paid $1.1 billion in November to acquire the RNA drug firm Sirna Therapeutics, an indication that big pharma sees potential in such drugs. On the other hand, the custom manufacturer Dowpharma revealed earlier this year that it is no longer pursuing new business with firms developing RNA therapies due to the long wait for a payday on drugs in development.

Petrovich says Agilent's commitment to the business gave it an edge in competing for the project. The firm is "new and aggressive in pursuing business," he says. "It has dynamic leadership and impressive science and project management."

Powell attests to that commitment. "RNA is what we specialize in," he says. "We have people and experience to effectively make RNA with high yields. It is not a trivial piece of chemistry. We have good protocols and excellent trade secrets." He notes that Boulder is a hotbed of RNA research. Much of the science was pioneered by Marvin H. Caruthers at the University of Colorado, Boulder, and nearby companies such as Ribozyme Pharmaceuticals, Sirna, and Dharmacon manufacture RNA for research purposes. Many of the scientists at Agilent have worked at these places, Powell says.

He claims Agilent can afford to be choosy in forming partnerships with drug companies. "In a market with a lot of customers and limited capacity, we will take on customers whose technology provides them a pipeline of drugs," he says. "One of the reasons we like Calando as a partner is that it isn't trying just to throw RNA into somebody and hope it gets into the cell."

Calando is employing a drug delivery system, licensed from Insert Therapeutics, which is also funded by Arrowhead Research, that consists of three parts: a cyclodextrin-containing polycation, a PEGylated adamantane, and a PEG bound to adamantane on one end and to a transferrin targeting ligand on the other. When these are formulated with siRNA, the cyclodextrin-containing polycation causes siRNA molecules, which are anionic, to condense into nanoparticles small enough for efficient transport through the body and into tumors. "They are suitable for cellular uptake, and they protect the siRNA from degradation in blood," says Jeremy D. Heidel, Calando's chief science officer.

The PEGylated adamantanes keep the siRNA nanoparticles from aggregating in the blood. The adamantane-PEG-transferrin component brings the nanoparticles to transferrin receptors, which are known to be expressed more in many types of cancer cells than in normal cells; Agilent is working with Calando to optimize the manufacture of this last component.

Petrovich describes the agreement with Agilent as an open-ended "master supply" agreement, under which specific volumes are contracted for as development progresses. So far, Agilent has worked on process development and produced preliminary volumes for toxicology assessment. Petrovich says Calando can contract with other siRNA suppliers as the drug proceeds through clinical trials and larger quantities are needed.

BUT AGILENT is scaling up production. It recently completed a $5 million, 10-fold expansion to its three manufacturing trains in Boulder. According to Powell, the facility can now handle up to 15 projects per year. And he says the firm is providing more than just bulk siRNA. He characterizes Calando as a typical small biopharmaceutical company that requires a broad range of services in drug development and manufacturing, and he sees Agilent going "into the clinic and beyond" with CALAA01.

Nor is supplying siRNA a commodity service, Powell notes. Although the relevant chemistry is in the public domain, "the trick is making it work really well," he says, noting that the company has worked to innovate automated solid-phase synthesis manufacturing. Agilent wants to provide a "one-stop shop," encompassing process design and regulatory support from toxicology testing to commercialization, Powell adds.

As with most RNA drugs in development, CALAA01 is moving toward the clinic in hopes of a breakthrough. "We were sort of a latecomer, but we thought there was room for another start-up RNA interference company that has this delivery technology as its ace in the hole," Petrovich says. He says the company hopes to begin Phase I clinical trials later this year.

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