Arrowhead Pharmaceuticals, Inc. · NASDAQ:ARWR
Arrowhead Pharmaceuticals — Complement Based Drug Development Summit 2024
20 slides from Arrowhead Pharmaceuticals's conference presentation, Dec 11, 2024
Slide 1: Targeting Complement Factor B with siRNA: Concept to Clinic
Targeting Complement Factor B with siRNA: Concept to Clinic Complement Based Drug Development Summit Boston, MA December 11, 2024
Slide 2: Conflicts
Conflicts • Arrowhead employee and shareholder Complement Based Drug Development Summit 2
Slide 3: TRiM Platform: Targeted RNAi Molecule
TRiM Platform: Targeted RNAi Molecule • Rules and algorithms to inform siRNA sequence selection and trigger design • Library of linkers and targeting ligands facilitate delivery to new cell types • CMC, Tox well characterized, enabling rapid progression to Phase 1 Complement Based Drug Development S
Slide 4: Arrowhead Clinical Pipeline
Arrowhead Clinical Pipeline Therapeutic Area Pre-clinical Phase 1 Phase 2 Phase 3 Product Rights Plozasiran FCS/SHTG/ASCVD Zodasiran Dyslipidemia Olpasiran ASCVD Cardiometabolic GSK4532990 MASH ARO-PNPLA3 MASH ARO-INHBE Obesity ARO-RAGE Inflammatory Lung Diseases Pulmonary ARO-MMP7 Idiopathic Pulmon
Slide 5: ARO-CFB designed to target and silence CFB mRNA expression by the liver
ARO-CFB specifically designed target and silence CFB mRNA expression by the liver, reducing plasma complement levels ARO-CFB • RNAi GalNAc conjugates designed to target and silence hepatic CFB mRNA which inhibit production of complement factor B • Conjugates are composed of synthetic, double-strande
Slide 6: Targeting the alternative pathway and Complement Factor B
Targeting the alternative pathway and Complement Factor B • CFB primarily expressed by hepatocyte • Depletion of FB reduces tick over, ARO-CFB amplification, and activity of the AP without directly inhibiting the classical or lectin pathways. • Pharmacodynamics can be readily measured via blood biom
Slide 7: Therapeutic Landscape for Complement-targeted siRNA
Therapeutic Landscape for Complement-targeted siRNA Frontiers in Immunology, 13.https://doi.org/10.3389/fimmu.2022.860689 Complement Based Drug Development Summit 7
Slide 8: Preclinical Development of ARO-CFB
Preclinical Development of ARO-CFB
Slide 9: ARO-CFB reduces CFB and Bb protein by >98% in cynomolgus monkeys
ARO-CFB reduces CFB and Bb protein by >98% in cynomolgus monkeys Serum Serum CFB CFB Serum Serum Bb Bb Normalized to D1 predose levels Normalized to D1 predose levels 120 120 0.5 mpk 0.5 mpk 100 100 100% 1.5 mpk 1.5 mpk 100% 80 4.5 mpk 80 4.5 mpk 60 60 40 40 20 10% 20 5% 0 0 0 2 4 6 8 10 12 14 0 2 4
Slide 10: Silencing CFB selectively decreases alternative pathway activity in monkeys
Silencing CFB selectively decreases alternative pathway activity while leaving total complement activity intact in monkeys AH50 AH50 CH50 Relative level to each animal's D1 CH50 Percentage of D1 pre-dosing levels 120 0.5 mpk 120 100% 0.5 mpk 100 1.5 mpk 100 1.5 mpk 80 4.5 mpk 80 4.5 mpk 60 60 39.0%
Slide 11: Silencing CFB selectively decreases membrane attack complex formation
Silencing CFB selectively decreases the formation of membrane attach complex (MAC) mediated via alternative pathway Wieslab Wieslab assay, APAP ® Wieslab Wieslab ® CP assay CP Percentage of D1 pre-dosing levels Percentage of D1 pre-dosing levels 120 120 0.5 mpk 0.5 mpk 100 100% 1.5 mpk 100 1.5 mpk 8
Slide 12: Early Clinical Development of ARO-CFB AROCFB-1001 Study
Early Clinical Development of ARO-CFB AROCFB-1001 Study
Slide 13: Phase 1/2a Study of ARO-CFB Safety, Tolerability, PK and PD
Phase 1/2a Study to Evaluate the Safety, Tolerability and Pharmacokinetics and Pharmacodynamics of ARO-CFB in Adult Healthy Volunteers and Patients with Complement-Mediated Kidney Disease Part 1: Randomized, double-blind, placebo-controlled cohorts to evaluate single- and multiple-ascending doses of
Slide 14: Demographics and Baseline Complement Parameters
Demographics and Baseline Complement Parameters Pooled Placebo Pooled Active Parameter (SD) (N=16) (N=32) Age (years) 34.4 (8.6) 32.8(8.7) Sex (M/%) 4 (25.0%) 14(43.8%) BMI (kg/m2) 26.6 (4.6) 26.7(3.0) Reference Ranges CFB (mg/dL) 40.0(10.0) 38.5(8.9) 27 – 73 mg/dL AH50 (U/mL) 133.4 (31.1) 114.8 (21
Slide 15: ARO-CFB rapidly reduces mean circulating CFB protein by up to 90%
ARO-CFB rapidly reduces mean circulating CFB protein by up to 90% with >3 months duration after single dose Serum CFB - SAD Cohorts Serum CFB - MAD Cohorts SAD Cohorts MAD Cohorts Change (± SD) from Baseline Change (± SD) from Baseline 80 60 60 25 mg 40 40 50 mg 20 100 mg Mean Percent Mean Percent 2
Slide 16: Near complete inhibition of alternative pathway activity by Wieslab AP
Near complete inhibition of alternative pathway activity based on Wieslab AP after single and multiple doses of ARO-CFB Wieslab® AP – SAD Cohorts Wieslab® AP – MAD Cohorts Change (± SD) from Baseline Change (± SD) from Baseline 60 60 25 mg 40 40 100 mg 50 mg 20 Mean Percent 20 Mean Percent 0 200 mg
Slide 17: Near complete inhibition of alternative pathway hemolytic activity (AH50)
Near complete inhibition of alternative pathway hemolytic activity (measured by AH50) after single and multiple doses of ARO-CFB AH50 – SAD Cohorts AH50 – MAD Cohorts Change (± SD) from Baseline Change (± SD) from Baseline 60 40 100 mg 25 mg 40 20 200 mg 20 50 mg Mean Percent Mean Percent 0 400 mg 0
Slide 18: Safety data supportive of further clinical development
Safety data supportive of further clinical development Safety Summary TEAEs Reported in ≥10% Subjects Pooled Placebo, N=16 Pooled Active, N=32 • ARO-CFB was well-tolerated overall. Adverse Event n (%) n (%) Upper respiratory tract 4 (25.0) 9 (28.1) • Most TEAEs were mild in severity. infection Heada
Slide 19: Summary
Summary • Healthy volunteer enrollment complete • Safety profile supportive of continued development • ARO-CFB achieved mean serum CFB knockdown of 90% after a single 400 mg dose • ARO-CFB achieved near complete inhibition in hemolytic activity and functional activity of alternative pathway that sho
Slide 20: Questions? Answers.
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