New DMPK and Toxicology Data Presented at Drug Information Association (DIA) Conference

New DMPK and Toxicology Data Presented at Drug Information Association (DIA) Conference

We presented data on DMPK and safety of GalNAc-siRNA conjugates at the DIA/FDA Oligonucleotide-Based Therapeutic Conference, held September 9 – 11, 2015, in Washington, D.C.




A Platform-based View of Drug Metabolism and Pharmacokinetic (DMPK) Properties of GalNac-siRNA Conjugates

One presentation discussed the DMPK properties of a range of GalNAc-siRNA conjugates targeting the hepatic asialoglycoprotein receptor (ASGPR) for liver delivery.  The subcutaneous route was superior to intravenous administration for focused liver delivery, with >95% of the dose administered reaching the liver (site of ASGPR and target mRNA expression) and kidney (organ of elimination). At a molecular level,  first generation standard template chemistry (STC) conjugates were more susceptible than second generation enhanced stabilization chemistry (ESC) conjugates to metabolism by exo- and endo-nucleases, leading to significantly greater in vivo hepatic exposures for the latter.  In terms of pre-clinical PK properties, supra-pharmacologic doses up to ~30 mg/kg demonstrated excellent dose-proportionality, with liver concentrations increasing progressively whilst maintaining much lower kidney exposures.  Overall, these DMPK properties were shown to translate consistently from rodents, to nonhuman primates and humans.  Most importantly the consistency included hepatic target knockdown where in recent Phase 1/2 studies of second generation ESC-GalNAc-siRNA conjugates, doses below 1 mg/kg resulted in up to ~90% liver target knockdown, with durability suggesting once monthly or once quarterly dosing.  The profound duration of knockdown from single doses could be explained by RISC immunoprecipitation assays revealing stable retention and activity of the siRNA antisense effector strand, weeks after a single dose, in the face of decay in overall liver drug concentration. In conclusion, the findings provide a scientific basis for the reproducible and modular nature of RNAi therapeutics.


Toxicity, Pathology & Safety Profiles of GalNAc- siRNA Conjugates

In a separate presentation, Alnylam scientists reviewed preclinical toxicology findings for the platform, including both first- (STC) and second-generation (ESC) GalNAc-siRNA conjugates.  At supra-pharmacologic doses up to 30 mg/kg, neither the rat nor the nonhuman primate (NHP) demonstrated any significant toxicities.  At doses significantly greater than 30 mg/kg, and often greater than 100 mg/kg, toxicologically the liver was the predominant target organ (associated with minor reversible LFT changes), with fewer findings in the kidney and lymph nodes.  The latter organs appeared to reversibly accumulate excess drug through passive mechanisms (neither uniformly expresses ASGPR) at these high exposures.  There were no functional changes associated with any of the renal or lymphoid microscopic findings and none of these histologic changes were seen at pharmacologic doses.   Typically, the rat is more sensitive than the NHP, with the characteristic hepatic finding being reversible vacuolation, leading to no-adverse-event-levels (NOAEL) of ≥ 30 mg/kg.  For some conjugates, the NOAEL could not be established with all dose levels resulting in little to no findings.  As compared to short-term 4- or 13-week GLP toxicology studies, no additional or cumulative findings were found, including a lack of antidrug antibodies, when conjugates were evaluated in chronic GLP toxicology studies of up to 9 months. Conjugates were found to be non-genotoxic via three different ICH-approved assays (Ames test, and mammalian chromosomal aberration and micronucleus assays).  Preliminary findings for GalNAc-siRNA conjugates confirmed that they do not appear to cross the placenta and are negative on reprotoxicity assays. These findings again support the concept that RNAi therapeutics constitute a true platform with reliable and reproducible pre-clinical characteristics from compound to compound, all of which appear to show a wide therapeutic index.


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