PK and PD Properties of Antisense Oligonucleotides: Bridging Nonclinical to Clinical
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1 PK and PD Properties of Antisense ligonucleotides: Bridging Nonclinical to Clinical Rosie Z. Yu, Ph.D. Pharmacokinetics & Clinical Pharmacology Isis Pharmaceuticals, Inc. Carlsbad, CA USA
2 2 Antisense Mechanism of Action RNase H ligonucleotides
3 Structure of Representative 2 nd Generation Antisense ligonucleotide (AS) 3 Gapmer design (to activate RNase H) Phosphorothioate throughout ME modification at ends ( wings ) Unmodified in middle ( gap ) 5 -wing gap 3 -wing G C C T C A G T C T G C T T C G C A C C H B B B S P CH 3 B CH 3 S S P P CH 3 B B H CH 3 ME DNA ME Molecular model of AS Phosphorothioate linkage ME side chain
4 Traits of ligonucleotides in Comparison with Small Molecules and Biologics 4 Ref: Lee S.. In Advanced Delivery and Therapeutic Applications of RNAi, First Edition. Edited by Kun Cheng and Ram I. Mahato
5 Predictions of Human PK from Preclinical Species
6 Allometric Scaling: Similar Plasma (Distribution Phase) PK Across Sequences and Between Species (except mouse) ISIS-TNF Rx 00 0 Dog Monkey Man ISIS-PTP1B Rx ISIS-APB Rx 10 Mouse Rat Slope of 1 indicates CL increases directly proportional to BW Body Weight (kg) Refs: Yu et al. Drug Metab Dispos, (3): Geary et al. Drug Metab Dispos, (11):
7 Mean ISIS Conc. in Plasma (µg/ml) Comparison of Plasma Concentration-Time Profiles Across Species (mg/kg dosing) 7 Distribution Phase Post-Distribution Phase AS Concentrations in Plasma ( g/ml) Time (hr) Mouse, 3 mg/kg Monkey, 3 mg/kg Human, 200 mg (2.8 mg/kg) Human, 200 mg (~2.7 mg/kg), s.c. (n= 8) Monkey, 4 mg/kg, 1-hr I.v. (n= 2) Time (hr) Ref: Yu et al. Drug Metab Dispos, (3):
8 Plasma Distribution PK Scales Approx. by Body Weight from Monkeys to Humans 8 Compound Dose* (mg/kg/week) Route Monkey C max AUC (µg/ml) (µg h/ml) Human C max AUC (µg/ml) (µg h/ml) ISIS-APB Rx 3 SC ISIS-FXI Rx 3 SC ISIS-APCIII Rx 3 SC ISIS-TTR Rx 3 SC *3 mg/kg/week = 200 mg/week dose in humans (~70 kg) Some monkey data are dose-normalized. Ref: Data on file (Isis Pharmaceuticals).
9 Monkey-to-Human Scaling (TBW vs. BSA Dose Normalization Comparison) 9 RMR = Dose Ratio AUC Ratio Dashed line shows acceptable relative exposure multiple ratio range of 0.5 to 2.0. o TBW normalization: 23 of 26 cases (88%) acceptable RMR values. RMR(mg/m 2 ) = 0.32 ± 0.13 RMR(mg/kg) = 0.98 ± 0.41
10 Mouse-to-Human Scaling (TBW vs. BSA Dose Normalization Comparison) 10 Single Dose Multiple Dose Dose by mg/kg Dose by mg/m 2 Dose by mg/kg Dose by mg/m 2 Relative Multiple Ratio 10 1 Relative Multiple Ratio Case No. Case No. RMR = Dose Ratio AUC Ratio Dashed line shows acceptable relative exposure multiple ratio range of 0.5 to 2.0. o Single dose BSA normalization has acceptable RMR values. RMR(mg/m 2 ) = 0.82 ± 0.35 RMR(mg/kg) = 10.1 ± 4.3 o Multiple dose neither BSA nor TBW normalization has acceptable RMR values. RMR(mg/m 2 ) = 0.48 ± 0.22 RMR(mg/kg) = 5.87 ± 2.75
11 ASs Rapidly/Extensively Distribute to Tissues after Dosing (similar between species; monkey shown) 11 LIGNUCLETIDE CNC. IN TISSUE (µg/g) 0 4 mg/kg, IV Infusion (6 doses over 1 month) Mesenteric LN Bone Marrow Brain Heart Kidney Cortex Kidney Medulla Liver Lung varies Spleen Testes Parent 20mer Total ligo Uterus
12 ISIS AS A Conc. (µg/ml or µg/g) ISIS AS B Conc. (µg/ml or µg/g) Post-Distribution Plasma Concentrations in Equilibrium with Tissue Concentrations in Monkeys 12 AS A AS B 0 Plasma Liver 0 Plasma Liver Mean Ratio = Mean Ratio = Time (hr) Time (hr) Treatment: 3 mg/kg, 1 hr IV, q3d x 3 Treatment: 4 mg/kg, 1 hr IV, q2d x 4
13 Consistent Liver to Plasma (Post-Distribution) Conc. Ratio Across Species and Between Different ASs 13 Species AS 2 -ME Motif Liver : Plasma Conc. Ratio Mouse ISIS-APB Rx ISIS-FAS ISIS-CD49d Rx Monkey ISIS-APB Rx ISIS-TNF Rx ISIS-PTP1B Rx ISIS-FXI Rx ISIS-CRP Rx Refs: Yu et al. Biochem Pharmacol 77 (2009) Data on file (Isis Pharmaceuticals)
14 Plasma Post-Distribution PK Scales Approx. by Body Weight from Monkeys to Humans 14 Compound Dose (mg/kg/week*) ISIS-PTP1B Rx 3 Route IV (monkey) SC (human) Plasma C trough Range (ng/ml) Monkey Human ~ ISIS-APB Rx 3 SC ISIS-FXI Rx 3 SC ISIS-APCIII Rx 3 SC ISIS-TTR Rx 3 SC *3 mg/kg/week = 200 mg/week dose in humans (~70 kg) Ref: Data on file (Isis Pharmaceuticals). Some monkey data are dose-normalized.
15 Tissue Elimination t ½ in Monkeys is Consistent with Plasma Elimination t ½ in Humans 15 AS Monkey Liver t ½ (days) Monkey Kidney Human Plasma ISIS-TNF Rx ISIS-PTP1B Rx ISIS-APB Rx ISIS-FXI Rx ISIS-APCIII Rx Refs: Yu et al. DMD 35(3) 2007: ; Data on file (Isis Pharmaceuticals)
16 Predictions of Human PD from Preclinical Species
17 ISIS Conc. In Liver (µg/g) In Vivo (Murine) apob Inhibition by an AS: 6 Week Dosing Study Predicted Conc. bserved Conc. apob mrna Predicted mrna End of Treatment Liver apob mrna (%Control) Time (Days) Ref: Yu et al. Biochemical Pharmacology 77 (2009):
18 Target (Liver) Exposure-Response Relationship in Mouse Models 18 HF-Fed C57BL Mice Human ApoB Tg Mice 120 Liver EC 50 = 101 ± 32 µg/g 140 Liver EC 50 = 119 ± 15 µg/g bserved Predicted bserved Predicted Liver Conc. of ISIS Liver Conc. of ISIS (µg/g) *Best Fit Inhibitory Effect E max Model of liver ApoB mrna Levels vs. liver AS conc. Ref: Yu et al. Biochemical Pharmacology 77 (2009):
19 Similar Plasma Exposure-Response Relationship in Human ApoB Tg Mouse and Human 19 Tg Mice Tg Mice Vs. Human 140 Plasma EC 50 = 18 ± 4 ng/ml 140 Plasma EC 50 = 14 ± 21 ng/ml bserved Predicted Human, bserved Human, Predicted Mouse, bserved Mouse, Predicted ISIS Conc. in Plasma (ng/ml) ISIS Conc. in Plasma (ng/ml) *Best Fit Inhibitory Effect E max Model of liver ApoB mrna Levels vs. liver AS conc. Ref: Yu et al. Biochemical Pharmacology 77 (2009):
20 Less Sensitive Exposure-Response Relationship in Monkeys 20 Liver apob mrna Serum apob bserved Predicted bserved Predicted Liver Conc. of ISIS (µg/g) Liver Conc. of ISIS (µg/g) Ref: Yu et al. Biochem Pharmacol 77 (2009)
21 ED 50 (EC 50 ) in Target Tissue across Species 21 AS Target Mouse Human ApoB in Liver (Mipomersen) ApoC-III in Liver (Isis) TTR in Liver (GSK/Isis) Survivin in Lung/Colon Tumor (Lilly/Isis) Clusterin in Prostate Tumor (ncogenix) STAT3rx (Gen 2.5) in Tumor (AstraZeneca/Isis) 25 mg/kg/wk (85 µg/g) 12.5 mg/kg/wk (55 µg/g) 12.5 mg/kg/wk (50 µg/g) 50 mg/kg/wk (20 µg/g ED50) 62.5 mg/kg/wk (5 µg/g) 15 mg/kg/wk (5 µg/g) *Predicted based on measured trough plasma levels of drug in man a Talbot, Ranson and Davies et al., Clin Cancer Res, November 2010 b Chi, Eisenhauer and Gleave et al., JNCI, Vol 97, mg/kg/wk (110 µg/g*) 2 mg/kg/wk (150 mg/wk) (65 µg/g*) 2 mg/kg/wk (150 mg/wk) (65 µg/g*) 7 mg/kg (500 mg/wk) (est. based on PK modeling 20 µg/g) a 6 mg/kg (320 mg/wk) (3 µg/g measured median) b 2 mg/kg (140 mg/wk) (est. based on PK modeling 1-3 µg/g)
22 Cross-Species PK/PD Model Predictions vs. Actual Clinical bservations for an AS 22 PK-PD Model Diagram Predicted vs. bserved Clinical Response CL CL m SC Dose K a Plasma [drug] Q Tissue C 1 IC p 50 I max C p K in Target Protein (or biomarker) K out Treatment: 200 mg/week for 13 weeks.
23 Conclusions 23 Plasma PK in monkeys well extrapolates to humans Monkey plasma AUC directly extrapolates to human by mg/kg dosing At post-distribution phase, plasma levels are in equilibrium with tissue and thus provide surrogate measure of tissue concentrations Plasma elimination t 1/2 is similar to tissue t 1/2 and similar across species (typically 2 4 weeks) PD relationship from mice well extrapolates to humans Pharmacologic effects of ASs directly are related to drug concentrations in target organ. Similar EC 50 (based on plasma trough levels, or expected tissue levels) Challenges: Altered plasma post-distribution to target tissue concentration relationship due to immunogenicity with chronic AS administration AS may be less well distributed to certain target tissue/cell type Distribution to productive vs. non-productive pathways
24 Acknowledgements 24 John Grundy Richard Geary Jennifer Burkey Dan Norris Scott Henry Yanfeng Wang
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