AZ, ISIS expand partnership to develop novel delivery methods for antisense oligonucleotides
Initial project areas for the collaboration will be in oncology and cardiovascular and metabolic diseases (CVMD). The agreement builds on an existing collaboration between AstraZeneca and Isis Pharmaceuticals, which offers Ligand Conjugation Antisense (LICA) technology. The first example of this technology was with Isis' GalNac-conjugated antisense oligonucleotides targeting liver hepatocytes, which lowers the therapeutic dose needed for liver targets nearly 10-fold.
Under the terms of the agreement, each party will fund its own contribution and commit investigators to the collaboration. The companies will also share the rights to the results of the research. An Isis spokeswoman declined to offer further comment on the nature of the partnership.
"If successful, we'll have a way to selectivity modulate therapeutic targets in specific cell types that are intractable to small molecules and antibodies. This could lead to a number of ground breaking drugs for both oncology and cardiovascular and metabolic diseases," Susan Galbraith, Head of the Oncology Innovative Medicines Unit at AstraZeneca, said in a statement.
Past Success
The expanded partnership builds on a deal forged in 2012 that was centered on the development of new cancer drugs. In June 2013, Isis earned a $6m (€4.8m) payment from AstraZeneca as part of the initial deal. In total Isis has now earned $41m (€33m) in upfront and milestone payments from AstraZeneca and is eligible to earn up to $170m (€136m) in additional payments as the collaboration progresses and royalties result.
In addition to the research collaboration, which includes three cancer targets, Isis and AstraZeneca are developing two antisense drugs, ISIS-ARRx, which is now in a Phase I study, and ISIS-STAT3Rx, which is being developed as an immunomodulatory agent in combination with EDI4736, AstraZeneca's investigational anti-PD-L1 immune checkpoint inhibitor.
Last week, Isis said it earned a $7.5m milestone payment, the first of two milestone payments totaling $15m, fromAstraZeneca for the advancement of ISIS-STAT3Rx.
Antisense oligonucleotides
Antisense oligonucleotides are short, single strands of DNA or RNA molecules. Rather than modulating the activity of already-formed proteins, antisense oligonucleotides act before proteins are produced at the level of messenger RNA in the cell, thus opening up new opportunities for therapeutic intervention. The new delivery methods will aim to enhance the access of antisense oligonucleotides into specific organs and cells.
To improve cellular uptake and oligonucleotide spatial and temporal activity, a range of techniques and transporters have been developed, according to the American Association for Cancer Research’s journal Molecular Cancer Therapeutics.
The first generation of vectors developed were liposomes, which are vesicular colloid vesicles generally composed of bilayers of phospholipids and cholesterol, though the use of cationic polymers, including poly-L-lysine, PAMAM dendrimers, polyalkylcyanoacrylate nanoparticles, and polyethyleneimine, have been also developed for drug delivery.
