Oligonucleotides: Chemistry & Therapeutics Symposium

Comparison of clinical oligonucleotides against HBV - what are crucial PK/PD features?

Ben-Fillippo Krippendorff

1. Hoffmann-LaRoche AG, Innovation Center Basel [e-mail]

PK/PD processes of ASOs and siRNAs

Targeting hepatocytes via GalNAc

SC Dose

Plasma exposure

Nonspecific uptake + GalNAc targeting

Liver exposure

Hepatocyte exposure

GalNAc targeting

Internalization

Endosomal escape

Cytosol*

Nucleus*

Binding to targeted mRNA

	Bind to Dicer, TRBP and			RNAse H1 recruitment
	Argonaute to form mature
	RISC
			Binding to targeted mRNA
						Reduction in mRNA levels

Reduction in protein levels

Chan et al., Poster, Alnylam
Pharmaceuticals, Inc.,
Cambridge, MA, USA	* siRNAs and ASOs with different cellular location have also been described

PK/PD of oligonucleotides vs small and large molecules

PK/PD	Small Molecule	Large Molecule	Oligonucleotide
Exposure	Relevant exposure is	Relevant exposure is	Relevant exposure is
	typically plasma PK	typically plasma PK	intact drug in tissue
Tissue penetration	good tissue penetration	Fair/low tissue penetration	High tissue penetration
			(when targeted)
PK T1/2	hours-days	days-weeks	weeks-months
Scaling methods	Scaling from in-vitro to	Scaling from in-vivo to	Scaling on anticipated
	human established	human established (if no	tissue concentrations
		TMDD)

• Oligonucleotides create new PK/PD challenges mostly due to their delivery and long effects.
• Mechanistic frameworks that could guide species translation and dose finding are often lacking so far.

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PK in relevant tissue is often not measurable in the clinic

What can be done?

1. Relationship between tissue PK/ knock down/ biomarker kinetics established in preclinical species or in-vitro
2. Modeling often crucial to identify relevant PK/PD parameters
3. Species scaling based on anticipated tissue concentrations, turnover models
4. Biomarkers in the clinic used to infer crucial PK/PD parameters in relevant tissues

ASOs

siRNAs

Inferring Half-Lives at the Effect Site of Oligonucleotide Drugs 10.1089/nat.2018.0739

Rasmus Jansson-Löfmark and

Peter Gennemark, AZ

Oligonucleotides for blocking HBV protein synthesis

Multiple molecules now in the clinic that target viral RNA

RNAse H1

Naked (non-GalNAC)

• ISIS505358/GSK836

GalNAC conjugated

• RO7062931
• GSK3389404

cccDNA

				Viral RNA			siRNA,
									ASOs
NUCs
	DNA			Proteins

HBsAgHBsAg

Virions and SVPs

Ratio 1:10,000

All clinical trials for these molecules have HBsAg response as an endpoint, which creates unique opportunity to compare ASOs and siRNAs

RISC

GalNAC conjugated

AB-729

ARO-B/JNJ-3989

DCR-HBVS/RG-6346

ALN HBV02/VIR-2218

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