| |
Santaris Study Shows HCV Drug Inhibits miRNA Target in Chimps
|
| |
| |
December 03, 2009
http://www.genomeweb.com
By Doug Macron
Researchers from Santaris Pharma this week published data in Science showing that intravenous administration of its phase I hepatitis C therapy SPC3649 could silence its target microRNA in chimpanzees infected with the virus without triggering resistance or adverse effects.
Separately, an official from Santaris confirmed that GlaxoSmithKline's option to license the drug has expired, and that deal negotiations are underway with other companies.
"The current standard anti-HCV treatment, which combines pegylated interferon-alpha with ribavirin, is effective in only about 50 percent of patients and is often associated with severe side effects," Robert Lanford, a researcher at the Southwest Foundation for Biomedical Research and study co-author, said in a statement. "Because of the unique mechanism of action of SPC3649 and its tolerability profile, this new therapy could have the potential to replace interferon to treat disease progression or be combined with current treatments."
SPC3649 targets miR-122, the most abundantly expressed miRNA in the liver and one linked to cholesterol regulation and lipid metabolism, and is based on Santaris' locked nucleic acid technology. LNAs are essentially nucleic acid analogs in which the ribose ring is locked by a methylene bridge connecting the 2'-O atom with the 4'-O atom.
Previously, the company reported data showing that the drug significantly decreased total plasma cholesterol levels in African green monkeys when administered as an IV bolus at doses ranging from 3 mg/kg to 10 mg/kg. Given to the animals on days 1, 3, and 5, the drug also maintained its dose-dependent, cholesterol-lowering effect out to 90 days, according to Santaris.
By comparison, the Science study "investigated the potential of miR-122 antagonism by SPC3649 as a new anti-HCV therapy in chronically infected chimpanzees," according to the paper.
After obtaining baseline measurements from four chimps, the animals were evenly divided into low- and high-dose groups of 1 mg/kg and 5 mg/kg, respectively, and were treated with the drug once a week for 12 weeks. This was followed by a 17-week period of no treatment.
"The two animals that received the 5 mg/kg dose had a significant decline in viral levels in the blood and liver of approximately 2.5 orders of magnitude, or approximately 350 fold," the company said.
"One low-dose animal achieved a viral decline of 1.3 orders of magnitude, while the other experienced fluctuations in HCV RNA levels during dosing that made evaluation of the degree of suppression difficult," the investigators noted in the paper.
The Santaris team then examined the in vivo antagonism of miR-122 in chimp liver biopsies. Mature miR-122 was found in the baseline samples of all the animals, and SPC3649 was detected in RNA samples obtained during the treatment period and up to eight weeks after the last dose in the high-dose animals.
RT-PCR analysis revealed a greater than 300-fold drop in free miR-122 levels among chimps in the high-dose cohort, according to the paper. Northern blotting revealed that "free SPC3649 was markedly reduced in the liver at week 25 in the high-dose animals, accompanied with detection of free miR-122 alongside the miR-122/SPC3649 heteroduplex band.
"These findings demonstrate efficient delivery of SPC3649 to the chimpanzee liver resulting in potent and sustained antagonism of miR-122," the team wrote. However, they added that the "reason for the reduced response in the low-dose group was not apparent from the Northern data since no miR-122 was detected at the end of dosing."
The researchers also found no evidence of rebound in viremia during the study's 12-week dosing period, with HCV RNA levels remaining ten-fold below baseline 16 weeks after dosing. Additionally, deep sequencing of the HCV 5' non-coding region from the two high-dose chimps showed no enrichment of adaptive mutations in the miR-122 seed sites.
Taken together, these observations "imply that no viral resistance to therapy occurred during treatment," according to the paper.
"To assess the safety of miR-122 antagonism after prolonged treatment with SPC3649, an extensive set of clinical chemistries were monitored and correlated with plasma levels of the compound," but no side effects were observed in the treated animals, the investigators wrote. Further analyses revealed down-regulation of interferon-regulated genes and improvement of HCV-induced liver pathology.
"Our results show that antagonism of miR-122 by É SPC3649 leads to marked suppression of viremia in chronically HCV-infected chimpanzees, implying that miR-122 is essential for accumulation of HCV RNA in vivo," they concluded. "The good [pharmacokinetic] properties, safety profile, and high stability of SPC3649 in vivo, combined with the prolonged suppression of viremia beyond treatment, suggest that less frequent dosing could be employed after viral suppression is attained."
Treatment with SPC3649 "provided a high barrier to resistance, as demonstrated by the lack of rebound in viremia during the 12-week treatment and the lack of adaptive mutations in the two miR-122 seed sites of HCV 5Õ NCR," they wrote. Also, conservation of both miR-122 seed sites in all HCV genotypes and subtypes "suggest that such therapy will be genotype independent."
Earlier this year, Santaris completed a phase I trial examining a single dose of SPC3649 in healthy volunteers and said that data was expected to be reported before year-end. Meanwhile, in September, the company began a second phase I study, this time evaluating multiple doses of the drug in healthy volunteers.
That study is expected to enroll up to 30 participants and wrap up in August 2010.
Glaxo Passes
Despite the progress of the drug, GlaxoSmithKline has decided against taking over its development.
In late 2007, the companies signed a deal to develop and commercialize antiviral drugs based on Santaris' LNA technology (see RNAi News, 12/20/2007). As part of that arrangement, GlaxoSmithKline had the option to in-license SPC3649.
According to Santaris CSO Henrik Orum, GlaxoSmithKline has let the option expire. Still, "there is great interest in SPC3649, and we are in discussions with multiple potential partners," he told RNAi News in an e-mail.
Officials from GlaxoSmithKline were not available for comment by press time.
The British drugs giant was one of the first big pharmas to play in the miRNA space with a 2008 strategic alliance with Regulus Therapeutics to discover, develop, and market microRNA-based therapeutics for inflammatory diseases (see RNAi News, 4/172008).
Regulus, a joint venture between Alnylam Pharmaceuticals and Isis Pharmaceuticals, announced earlier this year that it met a milestone in the partnership with GlaxoSmithKline, successfully delivering miRNA inhibitors into mice and identifying changes in target gene expression in their immune cells (see RNAi News, 5/14/2009).
Notably, Regulus is also developing its own miR-122 antagonist as a treatment for HCV in collaboration with Rosetta Genomics, which had originally been focused on miRNA drugs but has increasingly been shifting its focus onto diagnostics based on the small, non-coding RNAs.
A Santaris official also confirmed that an option giving GlaxoSmithKline an option to license the drug has expired, and that deals with other companies are underway.
About Locked Nucleic Acid (LNA) Drug Platform
The Locked Nucleic Acid (LNA) Drug Platform developed by Santaris Pharma A/S creates synthetically modified chemical versions of the normal nucleic acid building blocks of ribonucleic acids (RNA). These modified chemical versions called LNAs improve the drug-like qualities of resulting therapeutics (oligonucleotides) by improving affinity to their target RNA, boosting resistance to metabolism and improving tissue uptake. Upon systemic administration of these "naked" molecules, LNA-based therapeutics are delivered to many different tissues where they show potencies many-fold better than other oligonucleotide therapeutics.
About Santaris Pharma A/S
Santaris Pharma A/S is a clinical-stage biopharmaceutical company focused on the discovery and development of RNA-targeted therapies. The Company's proprietary Locked Nucleic Acid (LNA) Drug Platform, in combination with its highly specialized and targeted drug development capabilities, offers potential partners pre-screened drug candidates for commercial consideration across a multitude of disease states. Santaris Pharma A/S research and development activities focus on infectious diseases and metabolic disorders while partnerships with major pharmaceutical companies include a range of therapeutic areas including cancer, rare genetic disorders and inflammatory diseases. Santaris Pharma A/S, founded in 2003, is privately-held and headquartered in Denmark with operations in the US. As part of its broad patent estate, the Company holds exclusive worldwide rights to all therapeutic uses of LNAs. The Company has strategic partnerships with Enzon Pharmaceuticals, GlaxoSmithKline, Wyeth Pharmaceuticals (now part of Pfizer) and Shire plc. Please visit http://www.santaris.com for more information.
|
|
| |
| |
|
|
|
