Two properties of antisense technology that have proven to be a bit difficult for observers to fully understand are first, that within a given chemical class of antisense oligonucleotides (ASOs), the behavior of individual ASOs is reasonably consistent. This derives from the fact that within a given chemical class, physico-chemical properties are quite similar as the ASOs differ only in the nucleotide sequence selected to bind to their complimentary binding sites in their targeted RNAs. Some observers have sometimes lumped all ASOs together, regardless of what chemistry is used. This is, of course, unreasonable. Alternatively, others have treated each ASO as a unique drug as is the case for small molecules. This is equally unreasonable. Rather, within well-defined chemical classes, basic chemical, pharmacokinetic, pharmacodynamic and toxic properties (other than those directly related to the target) are shared. This is an important advantage because it makes it possible to predict how one ASO will behave based on the behavior of other members of a chemical class, which greatly facilitates development of ASO drugs.
A second attribute that has been difficult for some observers to digest is that, in contrast to other drug discovery platforms that are static, antisense technology continues to advance. Antisense researchers continue to discover more about the technology, applying new advances to antisense drugs being developed and enhancing their performance. A recently published paper exemplifies both these attributes (see below).
Because of the shared properties of ASOs within a chemical class, for each chemical class we are developing at Ionis, we have constructed databases that integrate observations from studies in non-human primates and all randomized double blind clinical trials. Findings from these studies have been published in several papers that describe the properties of 2’MOE phosphorothioate (PS) ASOs, the most extensively studied ASO chemical class. The recently published Crooke et. al. manuscript summarizes the properties observed in initial clinical trials of 10 2’MOE PS ASO that are conjugated with an N-acetylgalactosamine moiety (GalNAc). The purpose of GalNAc is to enhance productive delivery of PS ASOs to hepatocytes, resulting in lower doses for antisense drugs developed for hepatocyte targets, thereby reducing exposure to non-hepatocyte cell types. In this paper the consistent pharmacodynamic performance of PS 2’MOE ASOs designed to reduce hepatocyte produced mRNAs and their protein products are compared to the performance of their GalNAc analogs. 2’MOE PS ASOs are potent with the average dose required to reduce a hepatocyte target by 50% (ID 50) of about 150-200 mg/week. In matched Phase 1 clinical studies, the GalNAc conjugated PS ASOs displayed a consistent 30-fold increase in potency with an ID 50 of 4-5 mg /week. This increase in potency was achieved without major alterations in pharmacokinetic behavior in NHPs or humans. The increase in potency, due to enhanced delivery to hepatocytes, resulted in lower doses being required which resulted in excellent safety and tolerability. Thus, for targets expressed in hepatocytes, GalNAc conjugation represents a significant advance.
Today, Ionis has 13 GalNAc conjugated ASOs in development with several in advanced clinical trials. In long term studies in patients, once again consistent potency, excellent safety, tolerability and compliance are being observed. The results from the ongoing studies will be reported independently as well as contributing to future integrated analyses of performance of this chemical class of PS ASOs.
Read more here.