Liver on their plates

Regulus, GSK to develop HCV therapies

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CARLSBAD, Calif.—Drugmaker Regulus Therapeutics LLC announced recently it is expanding a partnership with GlaxoSmithKline plc (GSK) to develop drugs with hepatitis C (HCV) infection as the lead indication for the effort.

Regulus said it could get more than $150 million from the new collaboration, along with royalty payments of up to 10 percent on sales of any drugs developed under the agreement.

Additional terms were not disclosed.

Regulus is a joint venture between Alnylam Pharmaceuticals and Isis Pharmaceuticals. It develops drugs that use microRNA technology, which can turn parts of genes on or off to treat diseases.

"This new collaboration with GSK demonstrates the clear scientific leadership that Regulus has established in advancing a whole new frontier of pharmaceutical research. MicroRNA therapeutics target the pathways of human diseases, not just single disease targets, and hold considerable promise as novel therapies across a broad range of unmet medical needs," says Dr. Kleanthis G. Xanthopoulos, president and CEO of Regulus.

GlaxoSmithKline and Regulus began collaborating in 2008 to develop four treatments for inflammatory diseases like rheumatoid arthritis. All told, Regulus could get more than $600 million from that deal, along with royalty payments on sales.

According to Xanthopoulos, GSX has been a perfect fit for the collaboration, keeping with Regulus' business strategy to establish a limited number of significant and credible partnerships.  

"With the maturation of our technology, we are seeking partners with specific expertise to help drive the development of microRNA therapeutic programs," he says. "Regulus has been working closely with GSK on the first ever microRNA-focused strategic alliance to discover, develop and commercialize novel microRNA-targeted therapeutics to treat inflammatory diseases."

Additionally, Xanthopoulos points out that the partners are extremely motivated to develop high-impact medicines to treat patients infected with HCV.

The collaboration provides GSK with access to Regulus' comprehensive and robust intellectual property estate. Regulus exclusively controls patent rights covering miR-122 antagonists and their use as HCV therapeutics in the United States, Europe and Japan.
A liver-expressed microRNA, miR-122 has been shown to be a critical endogenous "host factor" for the replication of HCV, and anti-miRs targeting miR-122 have been shown to block HCV infection. In earlier work, scientists at Alnylam and Isis demonstrated the ability to antagonize miR-122 in vivo using chemically modified single-stranded anti-miR oligonucleotides.

Further, work by Regulus scientists and collaborators showed that inhibiting miR-122 results in significant inhibition of HCV replication in human liver cells, suggesting that antagonism of miR-122 may comprise a novel "host factor" therapeutic strategy. Regulus scientists have shown in multiple preclinical studies a robust HCV antiviral effect following inhibition of miR-122.  

Xanthopoulos adds that Regulus plans to identify a clinical development candidate in the second half of 2010 and file an investigational new drug (IND) application in 2011.
For its part, Regulus is also responsible for the continued research and development of the microRNA antagonists targeting microRNA-122.

"GSK has the option to license the anti-122 drug developed by Regulus for further development and commercialization on a worldwide basis at any time prior to clinical proof-of-concept," notes Xanthopoulos. "Payments will be made to Regulus by GSK for achievement of preclinical, clinical and commercial milestones. If GSK decide not take a license, the program is returned to Regulus at no charge and Regulus will fully own the program."

There will be no shortage of patients seeking newly developed treatments. HCV infection is a disease with an estimated prevalence of 170 million patients worldwide, with more than 3 million patients in the United States.

"HCV shows significant genetic variation in worldwide populations due to its frequent rates of mutation and rapid evolution," Xanthopoulos says. "There are six genotypes of HCV, with several subtypes within each genotype, which vary in prevalence across the different regions of the world."

Xanthopoulos notes that the response to treatment varies from individual to individual, underscoring the inadequacy of existing therapies and highlighting the need for combination therapies that not only target the virus but endogenous "host factors" as well.

"Strategies that include the Regulus miR-122 antagonist as part of emerging combination therapies to shorten duration of treatment and interferon use, improve the safety profile and sustained virologic response (SVR), increase the barrier to drug resistance and address difficult-to-treat genotypes hold significant potential to expand the limited therapies available to physicians treating HCV patients," he says.

The discovery of microRNA in humans is one of the most exciting scientific breakthroughs in the last decade. Xanthopoulos notes that microRNAs are small RNA molecules, typically 20 to 25 nucleotides in length, that do not encode proteins but instead regulate gene expression.
"Nearly 700 microRNAs have been identified in the human genome, and more than one-third of all human genes are believed to be regulated by microRNAs," he says. "As a single microRNA can regulate entire networks of genes, these new molecules are considered the master regulators of the genome. MicroRNAs have been shown to play an integral role in numerous biological processes including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation and human development.
Xanthopoulos also notes that many microRNAs are conserved across multiple species indicating the evolutionary importance of these molecules as modulators of critical biological pathways.

"Indeed, microRNA expression or function has been shown to be significantly altered in many disease states, including cancer, heart failure and viral infections," he adds.

"Targeting microRNAs opens the possibility of a novel class of therapeutics and a unique approach to treating disease by modulating entire biological pathways."

With a single microRNA controlling the expression of multiple genes, there are myriad advantages to target microRNAs. Xanthopoulos notes that microRNAs have been evolutionary selected to regulate gene networks or pathways.

"Modulating microRNAs with Regulus' therapeutics leads to subtle changes in many genes within a network," he says. "The additive effect of subtle changes produces an overall multiplicity that results in dramatic phenotypic changes."

Over the course of the last two years, Xanthopoulos notes that the Regulus-GSK collaboration has proven to be very successful, as demonstrated by achievement of the first scientific milestone and payment made within a year and the selection of targets on time per the original research plan.
"Having a second, new alliance in less than two years clearly exemplifies the strong bond between the companies and provides affirmation that both parties are pleased with the progress," he concludes.

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