By Doug Macron
Though they remain relatively unproven, antisense technologies are poised to join small molecules and biologics as a key drug-discovery and -development platform, with next-generation chemistries helping to improve their therapeutic profiles, an Isis Pharmaceuticals executive said this week.
But to realize that potential, drugs that work through antisense mechanisms, including the RNAi and microRNA pathways, need to be pushed forward into later-stage clinical testing and expand their delivery to tissues outside of the liver, according to Frank Bennett, Isis co-founder and senior vice president of research.
Compared with small molecules, which have been in existence for around 150 years, and biologics, which become a therapeutic modality in the 1920s with the first administration of insulin to man, “we're still in the infancy of antisense technology,” Bennett said during a keynote address at the Drug Information Association/FDA Oligonucleotide-Based Therapeutics 2012 conference in Washington, DC.
“There is still a lot to learn,” he said of the different technologies he places under the antisense umbrella, including ones that act on RNase H and ones that modulate splicing. Yet it is apparent that antisense represents “the most efficient” approach out there for identifying drug candidates.
Part of the reason is because of the existence of multiple antisense mechanisms, all of which are viable, he said.
“Another important thing to keep in mind … is that over the last ten years, the number of targets for the technology has really exploded,” Bennett said. “You not only have messenger RNA as targets, but there is a whole series of non-coding RNAs that is present in cells that will be interesting therapeutic targets,” miRNAs being just one example.
“There is an RNA revolution, which puts this technology in the sweet spot,” he said.
This hasn't always been the case, Bennett noted, with most first-generation antisense drugs falling by the wayside, often before even reaching the clinic, due to potency and tolerability issues. The result was what he referred to as the “dark age” of antisense during the mid-to-late 1990s, when the technology was being questioned both scientifically and commercially.
Things began to improve for the field with the recognition of the “limitations” of first-generation chemistries and efforts to develop new chemical modifications, he said.
An additional boost came with an improved understanding of which tissues were the most amenable to antisense agents, so that drug developers could “ask the technology to do what it could do, and not what it couldn't do,” Bennett said.
“The discovery of RNA interference was [also] an important contribution to the field in that it brought a lot of renewed interest back ... at a time many companies were exiting, and the interest in pharma and the investment community was exiting,” he added.
RNAi “brought a lot of high-quality science back into the field,” Bennett said.
But despite the progress that has been made — Isis' cholesterol-lowering antisense drug mipomersen was recently submitted to US regulators for approval; a number of siRNA therapeutics are in human testing; and Santaris Pharma's miRNA-targeting hepatitic C treatment miravirsen is under phase II development — more work remains.
“We have numerous examples documenting that we can target the transcript of interest in man,” and that the antisense approach is safe and well tolerated, he said. But such proofs of concept, while exciting, are “a long way from showing that we produce a therapeutic benefit.”
“As a field, it is important for us to focus on moving drugs further into [clinical] development and being able to show the technology really is a platform technology,” he added. “We're doing well today … but we're at the very beginning of the technology, and there are still opportunities to further improve that.”
One such opportunity lies in expanding delivery of antisense drugs beyond the liver, Bennett said. Another key opportunity lies in making oral delivery of these agents “commercially feasible.”
He also said that the antisense field will benefit from a better understanding of the basic science behind the technologies, pointing to the lack of knowledge about the proteins that interact with oligonucleotides. To highlight this point, Bennett cited a paper published this week by Isis researchers showing that some chemically modified antisense oligos can modulate alternative splicing of target transcripts by recruiting certain proteins.
Lastly, Bennett said that although rare diseases are promising opportunities for antisense intervention, the field needs to identify how to develop drugs for such indications in an economically viable way.
“I think we have a technology that is quite amenable to targeting such diseases,” he said, but “it's hard to go after a patient population [of a few hundred worldwide] and justify doing that commercially."
Indeed, a number of companies in the RNAi space alone have taken aim at orphan indications, including Marina Biotech with its phase I familial adenomatous polyposis drug, TransDerm with a phase I therapy for pachyonychia congenita, and Quark Pharmaceuticals with its phase II delayed graft function agent QPI-1002.
“We need to figure out how to [address these indications] in an economic and efficient way,” he said.
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