By Doug Macron
After its novel RNAi-based hepatitis C treatment generated positive data in rodents, SomaGenics now aims to advance the drug into the clinic next year, skipping a previously planned non-human primate study, a company official told Gene Silencing News last week.
However, with would-be partner Roche broadly losing interest in the gene-silencing technology, the privately held company has begun looking elsewhere to fund its phase I goal. CEO Brian Johnston noted sources for this cash could be either investors or a bigger company interested in co-developing the drug.
SomaGenics is focused on proprietary oligos it calls short shRNAs, or sshRNAs. According to Johnston, they are hairpin molecules shorter than standard shRNAs, which means they function independently of Dicer.
“We hit upon this structure by doing fairly extensive structure-activity analyses of synthetic hairpins of all different shapes and sizes, and we noticed that when you make the stem 19 base pairs or shorter, and the loop small — typically we use a two-nucleotide loop … we get the maximum efficacy,” he explained. “In many cases, this is potency in the low picomolar IC50 range.”
Additional experimentation by the company revealed a series of chemical modifications that could boost the sshRNAs stability in serum while eliminating immunostimulatory effects, he said, adding that SomaGenics is preparing a paper that will describe the molecules' mechanism of action.
Though the company was initially interested in a variety of disease areas, it narrowed its focus onto liver indications based on the success it was having delivering sshRNAs into that organ with a lipid nanoparticle technology developed by collaborator Tekmira Pharmaceuticals.
That success also attracted the interest of Roche, which in recent years had made significant investments in RNAi including a broad technology-licensing deal with Alnylam Pharmaceuticals that included an upfront payment of $274 million in 2007 (GSN 7/12/2007) and the $125 million acquisition of Mirus Bio the following year (GSN 7/24/2008).
Roche arranged for a company with expertise using an HCV mouse model to test SomaGenics' sshRNA constructs, which had been formulated with Tekmira's nanoparticles, in vivo, Johnston said.
Once stable HCV infection had been established in the mice, they received standard, low-pressure intravenous injections of various versions of the drug. Some mice received treatment that targeted one of two different sites on the HCV genome, while others received a cocktail therapy containing sshRNAs against both sites.
The mice were followed over 28 days, during which time their blood was analyzed for viral load, human albumin, and levels of liver enzymes, Johnston said. They were also evaluated for weight changes and other health markers.
“The results were better than we'd hoped,” he said last week. “We saw a prompt viral knockdown of two logs in the circulating HCV” after a single dose, with a 2.5 log reduction in total viral load with the cocktail therapy. There were no apparent toxicities.
“In all cases, these administrations have a long-lasting effect,” he added. "For example, by the end of 28 days, which was three weeks after the second dose, we still had 90 percent knockdown on average.”
Notably, mice that had a lower viral load prior to treatment fared better with treatment than those with a higher viral load. This suggested that the sshRNA treatment might be even more effective in humans “because in this model, the viral load is much higher than a typical [human patient] is infected with,” Johnston said.
“At the level of viremia that would be seen in a typical HCV patient, it looks like we might have quite an effective treatment” even without the addition of existing treatments, he said.
Pass the Monkey
Based on these data, SomaGenics plans to pass on a planned study of the drug in chimpanzees and move directly into a phase I trial as soon as possible with a cocktail that adds a third sshRNA to the therapy.
“Because we saw such a clear advantage of adding a second sshRNA, even if it wasn't that potent, we decided to follow this one more step and are refining a third component of the cocktail,” Johnston said. “As soon as we are comfortable with that [oligo] and the mixture in replicon models … we plan to out together our [investigational new drug application]-enabling toxicology package and apply for a phase I trial” with US regulators.
“In talking to a lot of experts in this field … we realized that doing a chimpanzee study was probably unnecessary in view of the success of this [mouse] experiment,” he said. “So we've opted to put our resources into moving more quickly toward human trials.”
He noted that the company is negotiating with Tekmira about licensing its nanoparticle technology to deliver the drug.
SomaGenics hopes to move the HCV program into phase I next year, but doing so will depend on obtaining undisclosed additional funding, Johnston cautioned. Roche at one time had been the likely source of that capital, but late last year the Swiss giant announced it was halting all in-house RNAi-related activities as part of a sweeping reorganization (GSN 11/18/2010).
Although the company had been interested in SomaGenetics' sshRNA technology and was “very happy with the results” of the mouse study, “events sort of overcame us in terms of [Roche's] broader decision" to move away from RNAi.
“We would be pleased if they wanted to continue, but so far it looks as though they are moving all their programs away from RNAi,” Johnston said. As such, “we're looking for another co-development partner for HCV.”
Officials from Roche were not available for comment in time for this publication.
However, SomaGenics is considering a backup plan. According to Johnston, it is exploring the possibility of going into phase I on its own with funding from the investment community.
Should it do so and succeed with its HCV treatment, the company aims to advance its other programs, including those in hepatitis B and liver cancer.
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