Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

Abstract

Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25-10 mg/kg in the single and 2.5-10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5-10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p < 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

“…Specific target engagement in patients has been demonstrated for oligonucleotide therapeutics in cardiovascular diseases (54), viral infection (55), rare genetic diseases (56) and cancer (57). For the latter, safe and efficient tumor-selective drug delivery technology remains a key limitation.…”

Stable and efficient generation of poly(β-amino ester)s for RNAi delivery

“…In particular, the most clinically advanced formulations are Dynamic PolyConjugates (DPCs) and triantennary N-acetylgalactosamine (GalNAc), which are commonly used to target hepatocytes. 16,17 However, targeting organs other than the liver using conjugate-based delivery systems is still challenging.…”

Diverse lipid conjugates for functional extra-hepatic siRNA deliveryin vivo

“…Therapeutic oligonucleotides-i.e., antisense oligonucleotides, small interfering RNA (siRNA), and aptamers-are emerging as a new class of drugs in addition to small molecules and biologics 1 . Their advantages over conventional drugs include: (i) ease of design, rationally achieved based on sequence information and straightforward screening, leading to drug candidates within short periods of time; (ii) ability to target disease genes previously considered "undruggable"; and (iii) unprecedented potency and duration of effect 2,3 . Clinical success is dependent on their efficient delivery to disease tissues.…”