Slide 1: ARO-C3 RNAi Therapeutic Targeting Complement C3 Reduces Proteinuria, Hematuria in IgAN
ARO-C3, an investigational RNAi Therapeutic Targeting Complement C3, Reduces Proteinuria, Hematuria, and Complement Activity in IgAN Patients Seungyeup Han1, Sug Kyun Shin2, Muh Geot Wong3, Seung Hyeok Han4, Adrian Liew5, Ashley Frazer-Abel6, James Hamilton7, Grigoriy Shekhtman7, Eric Garcia-Medel7,
Slide 2: Disclosures
Disclosures J. Barratt reports grants and/or honoraria from Alexion, Alnylam, Arrowhead Pharmaceuticals, Astellas, Argenx, BioCryst, Calliditas, Chinook, Dimerix, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, Vera Therapeutics, Visterra
Slide 3: Background
Background • Dysregulated activation of the complement cascade mediates tissue injury in complement-mediated kidney diseases such as IgA Nephropathy • The central role of complement component 3 (C3) in the cascade makes it a unique therapeutic target for complement inhibition • ARO-C3 is an siRNA de
Slide 4: ARO-C3 Designed to Target and Silence C3 mRNA Expression in the Liver
ARO-C3 is Designed to Target and Silence C3 mRNA Expression in the Liver, Reducing Serum C3 Protein Levels • ARO-C3 is a synthetic, double-stranded oligonucleotide • Chemical modifications enhance pharmacokinetics (PK) and pharmacodynamics (PD) • The GalNAc (N- Acetylgalactosamine) ligand facilitate
Slide 5: Complement Mediates Glomerular Injury in IgAN
Complement Mediates Glomerular Injury in IgAN Gd-IgA-containing Immune Complement Complexes Cascade Inflammation and Tissue Injury
Slide 6: ARO-C3 Reduces Serum C3 and Inhibits Complement Activation
ARO-C3 Reduces Serum C3 and Inhibits Complement Activation Gd-IgA-containing Immune Complement Complexes ARO-C3 Cascade Reduced Inflammation and Tissue Injury
Slide 7: AROC3-1001 Study Design, Part 1: Phase 1 SAD/MAD Study in Healthy Volunteers
AROC3-1001 Study Design, Part 1: Phase 1 Randomized, Placebo-Controlled SAD/MAD Study in Healthy Volunteers Single Ascending Dose Day 1 Baseline Day 29 Day 169 Dosing Follow-up every 2 months Cohort 1 (25 mg ARO-C3): n=4 active, n=2 placebo Day 15 Safety Evaluation Day 169 Cohort 2 (50 mg ARO-C3): n
Slide 8: AROC3-1001 Study Design, Part 2: Open-Label Phase 2a in IgAN Patients
AROC3-1001 Study Design, Part 2: Open-Label Phase 2a in Patients with IgA Nephropathy 400mg Dose Selected for Part 2 Repeat Dose based on Part 1 Day 1 Pharmacodynamic Baseline Day 29 Day 113 Day 169 and Safety Data Dosing Follow-up every 2 months Cohort 7 (C3G) (400 mg ARO-C3): n=up to 6 active Coho
Slide 9: Study Endpoints
Study Endpoints ▪ Primary: Incidence, frequency, and severity of treatment-emergent adverse events (TEAEs) ▪ Secondary: Plasma Pharmacokinetics (PK) of ARO-C3 ▪ Exploratory: ▪ Serum Complement Levels ▪ Complement Function: ▪ Total complement activity, hemolytic (CH50) ▪ Alternative pathway activity,
Slide 10: Recruitment at 26 Sites in 7 Countries
Recruitment at 26 sites in 7 Countries ❯ Australia ❯ Georgia ❯ Germany ❯ New Zealand ❯ South Korea ❯ Thailand ❯ UK
Slide 11: Part 1: Baseline Characteristics and Demographics
Part 1: Phase 1 Randomized, Placebo-Controlled SAD/MAD Study in Healthy Volunteers Baseline Characteristics and Demographics Healthy volunteers received vaccination against: • N. meningitidis (two weeks prior to Baseline Characteristics dosing with booster at Day 57) Pooled Placebo Pooled Active Par
Slide 12: ARO-C3 Reduces Serum C3 in Healthy Volunteers Up to 88%
ARO-C3 Reduces Serum C3 in Healthy Volunteers Up to 88% from Baseline after Two Doses SingleDose Single Dose Cohorts Cohorts Multiple Dose Multiple Dose Cohorts Cohorts 40 40 200 mg Change (± SD) from Baseline Change (± SD) from Baseline 20 25 mg 20 400 mg 50 mg 0 0 Placebo Mean Percent Mean Percent
Slide 13: Individual Reductions in Serum C3 of up to 93% After Two Doses
Individual Reductions in Serum C3 of up to 93% After Two Doses of ARO-C3 Multiple Multiple Dose Cohorts(Individuals) Dose Cohorts - Individuals MultipleDose Multiple Dose Cohorts Cohorts - Individuals (Individuals) 40 Placebo 40 Placebo 20 200 mg 20 400 mg† Percent Change 0 Percent Change 0 from Bas
Slide 14: Reductions in Alternative and Classical Pathway Activity in Healthy Volunteers
Reductions of >90% in Alternative Pathway and >60% in Classical Pathway Activity after Two Doses of ARO- C3 in Healthy Volunteers AH50 Wieslab® AP CH50 40 60 40 Change (± SD) from Baseline Change (± SD) from Baseline Change (± SD) from Baseline 20 40 20 0 20 0 Mean Percent Mean Percent Mean Percent
Slide 15: Favorable Safety Profile in Healthy Volunteers
ARO-C3 Demonstrates a Favorable Safety Profile in Healthy Volunteers • ARO-C3 was well-tolerated overall. Pooled Active Pooled Placebo Adverse Event N=28 N=14† – Most TEAEs were mild in severity. n (%) n (%) Headache 12 (43) 5 (36) – No TEAEs led to study or study drug discontinuation. COVID-19 8 (2
Slide 16: IgAN Study Population
IgAN Study Population Key Inclusion Criteria Key Exclusion Criteria ▪ Adults, 18 – 70 years old ▪ History of chronic or recurrent infection, including HIV, HBV, HCV ▪ Renal biopsy demonstrating IgAN with positive C3 deposition within 5 years ▪ Uncontrolled hypertension (BP ≥160 / 100 at Screening) ▪
Slide 17: Part 2: Baseline Characteristics and Demographics
Part 2: Open-Label Phase 2a in Patients with IgA Nephropathy Baseline Characteristics and Demographics Characteristic Cohort 8 (IgAN, n = 14†) ▪ All patients: Age, mean (SD) 40 (11) • Received protocol-required Sex, male, n (%) 5 (36) vaccinations within 2 years, or Race • Were vaccinated per-protoc
Slide 18: Biopsy Characteristics
Biopsy Characteristics Characteristic Cohort 8 (IgAN, n = 14†) Time Since Biopsy, mean (SD) 613 (543) days C3 Intensity, n (%) 1+ | 2+ | 3+ 6 (43) | 6 (43) | 2 (14) M (mesangial hypercellularity), n (%) M0 (<50%) | M1 (>50%) 9 (64) | 5 (36) E (endocapillary hypercellularity): E0 (none) 10 (71) E1 (p
Slide 19: ARO-C3 Reduces Serum C3 in IgAN Patients up to 94%
ARO-C3 Reduces Serum C3 in IgAN Patients up to 94% After Multiple 400mg Doses Mean Percent Change in Serum C3 Percent Change in Serum C3 40 40 Percent Change from Baseline Change (± SEM) from Baseline 20 20 0 0 Mean Percent -20 -20 -40 -40 -60 -60 -80 -80 -100 -100 0 2 4 6 8 10 12 14 16 18 20 22 24
Slide 20: Reductions in Alternative and Classical Pathway Activity in IgAN Patients
Maximum Reductions of >85% in Alternative Pathway and >60% in Classical Pathway Activity after Multiple Doses of ARO-C3 in IgAN Patients AH50 Wieslab® AP CH50 40 40 40 Change (± SEM) from Baseline Change (± SEM) from Baseline Change (± SEM) from Baseline 20 20 20 0 0 0 Mean Percent Mean Percent Mean
Slide 21: ARO-C3 Decreases Markers of AP Activation
ARO-C3 Decreases Markers of AP Activation Mean Percent Change in Serum Bb Mean Percent Change in Serum C3b 40 40 Change (± SEM) from Baseline Change (± SEM) from Baseline 20 20 0 0 Mean Percent Mean Percent -20 -20 -40 -40 -60 -60 -80 -80 -100 -100 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 1
Slide 22: Mean Proteinuria Reduction of 41.1% in Spot UPCR
Mean Proteinuria Reduction of 41.1% in Spot UPCR at Week 24 Percent Change in Spot UPCR Individual Percent Change in Spot UPCR 100 40 75 Day 85 Day 169 50 Change (± SEM) from Baseline 25 20 0 -25 0 -50 Mean Percent -75 -100 Patients (n=13†) -89% -20 Individual Percent Change in 24hr UPCR -40 100 75
Slide 23: Improvement in Hematuria and Stable eGFR
Improvement in Hematuria and Stable eGFR through Week 24 Hematuria Over Time eGFR Over Time 15 100 80.6 80.8 84.3 2 2 eGFR (mL/min/1.73 m2) 2 1 3+ (≥1.0 mg/dL) 80 10 2 2+ (0.20, 0.50 mg/dL) 3 Patients 6 1+ (0.06, 0.10 mg/dL) 60 7 Negative/Trace 1 40 5 1 2 9 7 20 4 4 0 0 Screening Day 1 Week 12 Week
Slide 24: Favorable Safety Profile in Patients with IgAN
ARO-C3 Demonstrates Favorable Safety Profile in Patients with IgAN ▪ ARO-C3 was well-tolerated overall. IgAN, N=14† • All TEAEs were mild or n (%) moderate in severity. Any TEAE 11 (78.6) • No TEAEs led to study or study Serious TEAEs 0 drug discontinuation. Severe TEAEs 0 ▪ No infections with encap
Slide 25: Conclusions
Conclusions • ARO-C3 was well-tolerated and had a favorable safety profile at all dose levels evaluated across SAD, MAD, and CMRD cohorts. • In patients with IgAN, administration of ARO-C3 400mg led to robust reductions in serum C3 and measures of alternative and classical complement activity. • Imp
Slide 26: Acknowledgements
Our heartfelt gratitude to the investigators, coordinators, staff, patients, and their families.