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Systemic RNAi Delivery Gets Traction as Four Shops Prep for Phase I; Others Report Delays

Although it has been two and a half years since the first siRNA-based therapeutic entered clinical trials, that and other candidates that have reached human testing have all been directly delivered.
That is set to change this summer. After a bumpy start, Nucleonics now expects to start a phase I study of its systemically delivered hepatitis B treatment NucB 1000.
At least three other systemically administered RNAi drugs are expected to reach human trials later this year, including two for cancer and a combination therapy for AIDS-related lymphoma.
Meantime, at least two companies, Silence Therapeutics (formerly Atugen) and Intradigm, have found the road to the clinic a little rocky and have pushed back their clinical development timelines from 2007 into 2008.
Two Steps Forward
According to Nucleonics, NucB 1000 is plasmid DNA encoding four short hairpin RNA molecules, each under the control of an RNA polymerase III promoter, that target a different portion of the hepatitis B genome.
Though Nucleonics had at one time predicted that this expressed RNAi therapy would enter the clinic in early 2005 (see RNAi News, 4/16/2005), optimization of the drug’s formulation for intravenous delivery proved more challenging than expected.  
By late 2006, the company had worked out these kinks but hit another roadblock when the National Institutes of Health’s Recombinant DNA Advisory Committee expressed concerns over the design of its proposed phase I trial for NucB 1000 (see RNAi News, 12/21/2006).
Among the committee’s top concerns were the doses Nucleonics proposes to test in the study, which the committee believed could potentially overwhelm patients’ natural RNAi processes, as well as the company’s decision to evaluate NucB 1000 only in mouse models in its preclinical research.
At the time, Nucleonics argued that its dosing schedule begins very low and that its protocols include numerous safety reviews, and that there are few good animal models for hepatitis B since chimpanzees are no longer available due to animal protection rules.
In the end, the US Food and Drug Administration sided with Nucleonics and cleared the proposed phase I study, which is set to enroll 15 patients in the US and Europe.
Nucleonics has said it expects the trial to begin in June.
Next in line to bring a systemic RNAi drug into human trials is Calando Pharmaceuticals, a firm founded in early 2005 to develop and commercialize its cyclodextrin-containing polymer delivery technology for RNAi therapeutic applications (see RNAi News, 2/25/2005).
Since that time, the company has aggressively developed its lead drug candidate, CALAA-01, which comprises an siRNA targeting the M2 subunit of ribonucleotide reductase. RRM2, an established cancer target, is an enzyme that catalyzes the formation of the deoxyribonucleotide precursors required for DNA synthesis.
In March, the company published data in the Proceedings of the National Academy of Sciences demonstrating that the drug can be systemically administered to non-human primates with no adverse events (see RNAi News, 3/22/2007).
Earlier this month, the company announced that it would meet its previously stated goal of moving CALAA-01 into phase I testing this year in collaboration with the City of Hope and the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (see RNAi News, 5/17/2007).
Also poised to advance a systemically delivered RNAi-based cancer treatment into phase I testing this year is Israel’s Quark Biotech, which recently filed to float its shares on the Nasdaq exchange through an initial public offering.
Quark is developing a number of siRNA-based therapies, including AKIi-5 for acute renal failure. The drug is designed to temporarily inhibit the expression of the transcription factor human p53, which is associated with DNA repair and apoptosis.
In acute kidney injury, the temporary inhibition of p53 at the time of injury delays the induction of cell death, allowing natural repair mechanisms to restore normal DNA and cellular integrity, according to Quark.
Finally, this year Australia’s Benitec plans to move into a human study an AIDS-related lymphoma therapy that incorporates its expressed RNAi technology.
The therapy involves using granulocyte colony stimulating factor to mobilize stem cells in AIDS-related lymphoma patients. Once the stem cells begin circulating peripherally, they can be collected, isolated, and genetically modified with a lentiviral vector containing three therapeutic genes: DNA that encodes for shRNAs targeting the tat-rev exon, a ribozyme that cleaves the mRNA for CCR5, and a nucleolar-localizing TAR decoy.
The patients undergo full chemoablation, which kills both the regenerative cells of the bone marrow and lymphoma cells, and then the stem cells are infused back into their bloodstreams so that they can migrate to, and engraft in, the marrow.

“Drug development is not easy, otherwise everyone would do it.”

While Benitec last summer shut down its US operations (see RNAi News, 6/29/2007) and has been struggling to raise desperately needed cash (see RNAi News, 4/5/2007), the AIDS program has moved forward since it is being funded by partner City of Hope.
One Step Back
As often is the case in drug development, things do not always go as planned. As such, two RNAi drug companies have pushed back their development timelines.
The first, Silence Therapeutics, is developing the siRNA-based drug Atu-027 for gastrointestinal cancers. The candidate combines Silence’s proprietary blunt-ended siRNA molecules with its so-called lipoplex delivery technology, which comprises a mixture of cationic and fusogenic lipids.
In February, the company announced that it had completed preclinical toxicology work on the drug, setting the stage for a mid-year phase I trial (see RNAi News, 2/1/2007).
However, this month Silence said that it would not meet this deadline, citing the need to “optimize the risk/benefit ratio in acutely ill patients” (see RNAi News, 5/3/2007). Instead, Silence said Atu-027 would move into phase I trials in 2008.
As recently as this April, Silence had also been expecting to bring a non-small cell lung cancer therapy into the clinic in 2007 (see RNAi News, 4/5/2007). However, according to the company’s website, this drug, called Atu-093, also won’t enter human studies until 2008.
The other RNAi drug firm that has readjusted its development timeline is Intradigm, which recently underwent a corporate reorganization that included relocating the firm’s headquarters to Palo Alto, Calif., from Rockville, Md., and naming a new president and CEO (see RNAi News, 11/22/2006).
Intradigm’s lead drug candidate, called ICS-283, targets the VEGF pathway, although the specific gene or genes it is designed to inhibit have not been disclosed, and is delivered using a proprietary nanoparticle technology that involves coating an RNAi payload with polyethylene glycol.
The company had at one time been expecting to begin phase I studies of ICS-283 in mid-2006, but missed that goal amid financial constraints. When the company secured $16 million in funding late last year, President and CEO Mohammad Azab said that the company was on track to begin clinical testing of the drug before the end of this year.
That timeline has now been pushed back to 2008, Azab told RNAi News this week, as Intradigm addresses manufacturing scheduling issues and finishes toxicology studies required for an investigational new drug application.
“There are no major changes to the program … [but] drug development is not easy, otherwise everyone would do it,” he noted.

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