GlaxoSmithKline (LONDON, UK) and Regulus Therapeutics LLC (CARLSBAD, CA), a biopharmaceutical company founded in late 2007 as a joint venture between Alnylam Pharmaceuticals, a leader in RNAi therapeutics, and Isis Pharmaceuticals, a leader in antisense technologies and therapeutics, announced a worldwide strategic alliance to discover, develop, and market novel microRNA(miRNA)-targeted therapeutics to treat inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD).

The alliance leverages Regulus’ unique expertise and intellectual property position in the discovery and development of miRNA-targeted therapeutics and provides GSK with an option to license product candidates directed at four different miRNA targets with relevance in inflammatory disease. Regulus will be responsible for the discovery and development of the miRNA antagonists through completion of clinical proof-of-concept, unless GSK chooses to exercise its option earlier. After exercise of the option, GSK will have an exclusive license to drugs developed under each program by Regulus for the relevant miRNA target for further development and commercialization on a worldwide basis. Regulus will have the right to further develop and commercialize any miRNA therapeutics that GSK chooses not to develop or commercialize.

Regulus will receive $20 million in upfront payments from GSK, including a $15 million option fee and a $5 million note (guaranteed by Isis and Alnylam) that will convert into Regulus common stock in the future under certain specified circumstances. Regulus could also be eligible to receive up to $144.5 million in development, regulatory and sales milestone payments for each of the four miRNA-targeted therapeutics discovered and developed as part of the alliance. In addition to the potential of nearly $600 million Regulus could receive in option, license, and milestone payments, Regulus would also receive tiered royalties up to double digits on worldwide sales of products resulting from the alliance.

A recently discovered class of genetically encoded small RNAs, miRNAs are approximately 20 nucleotides in length and are believed to regulate the expression of a large number of human genes. Like messenger RNAs, miRNAs are also transcribed from genes. However, miRNAs do not encode proteins but have been found to regulate the expression of other genes. There are approximately 500 miRNAs that have been identified in the human genome, and these are believed to regulate the expression of up to 30% of all human genes by preventing translation of messenger RNAs into proteins. The inappropriate absence or presence of specific miRNAs in various cells has been shown to be associated with specific human diseases including cancer, viral infection, and metabolic disorders.  

Isis and Alnylam scientists and collaborators were the first to discover miRNA antagonist strategies that work in animal models. Isis and Alnylam have also created and consolidated key intellectual property for the development and commercialization of miRNA therapeutics.

In preclinical research conducted by Alnylam and collaborators, a specific miRNA, miR-181a, was shown to play an important role in controlling T-cell responsiveness to antigens by regulating the T-cell receptor signaling pathway. In the current study, increasing expression of miR-181a was found to increase T-cell sensitivity to antigens, whereas inhibiting miR-181a was found to decrease the immune response. miR-181a was found to regulate the responsiveness of the T-cell receptor to antigens by the coordinated down-regulation of a set of phosphatase genes. Inhibiting miR-181a function with a selective antagomir (a member of a novel class of oligonucleotide-based inhibitors of specific miRNAs), antagomir-181a, resulted in efficient reduction in T-cell receptor sensitivity to antigens. Since abnormal T-cell activity toward “self” antigens underscores the pathology in many autoimmune disorders, antagomirs selective for miR-181a could represent a future therapeutic strategy for the treatment of these diseases.