Aligos Therapeutics, Inc. · NASDAQ:ALGS
Aligos Therapeutics — Technical Presentation (February 2023)
20 slides from Aligos Therapeutics's technical presentation, Feb 1, 2023
Slide 1: Preclinical Profile of ALG-125755, a GalNAc-siRNA Targeting HBV
Preclinical Profile of ALG-125755, a GalNAc-siRNA Targeting HBV C Jin Hong, Ph.D. Aligos Therapeutics, Inc.
Slide 2: Disclosures
Disclosures This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and f
Slide 3: Therapeutic Approaches to CHB Functional Cure
Therapeutic Approaches to CHB Functional Cure Inhibit Viral Replication Lower Antigen Burden Boost Immune Response Aligos is developing CAM-E ALG-000184, siRNA ALG-125755 and liver targeting PD-L1 inhibitor 2
Slide 4: ALG-125755 Structure and Target Sequence
ALG-125755 Structure and Target Sequence 5’ 10 10 5’ ALG-125903: Aligos Stabilization Chemistry GalNAc4: Aligos GalNAc ALG-125755 Homology to >9700 HBV Clinical Isolates GalNac Gt A Gt B Gt C Gt D Gt E Gt F Gt G Gt H Gt I Gt J siRNA ALG- 100% 100% 100% 100% 100% 99% 100% 100% 100% 100% 125755 Homolo
Slide 5: ALG-125755 Target Site in cccDNA and Integrated HBV DNA
ALG-125755 Target Site in cccDNA and Integrated HBV DNA ALG-125755 ALG-125755 Mainly Integrated Adapted from Lamontagne et. al. Hepatoma Res 2016;2:163-186 Adapted from Wooddell et. al. Viruses 2021, 13, 581 ALG-125755 targets an essential region that is present in HBsAg mRNA produced from cccDNA an
Slide 6: The Antisense Strand of ALG-125755 Demonstrates Activity in an Ago-2 Biochemical Assay
The Antisense Strand of ALG-125755 Demonstrates Activity in an Ago-2 Biochemical Assay Antisense Strand of ALG-125755 Non-Target RNA Target RNA Target HBV RNA 5’ 5’ Antisense Strand of ALG-125755 Ago-2 with antisense strand of ALG-125755 cleaves complementary HBV RNA at expected location 5
Slide 7: In Vitro Activity of ALG-125903: The Unconjugated Form of ALG-125755
In Vitro Activity of ALG-125903: The Unconjugated Form of ALG-125755 HepG2.2.15 HBV Infected Primary Human Hepatocytes EC50 = 17.48 pM; CC50 >1000 pM EC50 = 5.58 pM; CC50 >1000 pM Unconjugated version of ALG-125755 showed pM EC50 values in HBV cell models 6
Slide 8: ALG-125755 Demonstrated Potent Antiviral Activities vs. HBV Clinical Isolates
ALG-125755 Demonstrated Potent Antiviral Activities vs. HBV Clinical Isolates Gt H, EC50 = 350 pM Gt H, EC50 = 390 pM Gt H, EC50 = 250 pM Gt H, EC50 = 200 pM Gt F, EC50 = 110 pM Gt F, EC50 = 150 pM Gt F, EC50 = 120 pM Gt F, EC50 = 170 pM Gt J, EC50 = 200 pM Gt E, EC50 = 130 pM Gt E, EC50 = 550 pM Gt
Slide 9: In Vivo Activity in the AAV-HBV Mouse Model
ALG-125755 In Vivo Activity in the AAV-HBV Mouse Model Change in Serum HBsAg Mean ± SEM 0 .5 Parental siRNA with off- 0 .0 the-shelf chemistries Log10 (IU/mL) -0 .5 -1 .0 ALG-125755 with proprietary -1 .5 stabilization chemistries -2 .0 0 5 10 15 21 28 Day of study G 01: Vehicle, SC, Day 0 Negative
Slide 10: ALG-125755: In Vivo MOA Analysis at the End of Study
ALG-125755: In Vivo MOA Analysis at the End of Study AAV HBV: 42 days post single dose of 5 mg/kg Liver HBV RNA by Northern Liver HBsAg by ELISA Serum HBsAg by ELISA AAV-HBV: Day 42 HBsAg in Serum 150000 Vehicle ALG-125755 HBsAg IU/mL 100000 1X5mg/kg 50000 0 Vehicle ALG-125755 1X5mg/kg ALG-125755 MO
Slide 11: ALG-125755: Repeat Dosing in the AAV-HBV Mouse Model vs. VIR-2218
ALG-125755: Repeat Dosing in the AAV-HBV Mouse Model vs. VIR-2218 VIR-2218* ALG-125755 Mean Log10 IU/mL HBsAg Reduction Relative to Day 0 Mean Log10 IU/mL HBsAg Reduction Relative to Day 0 ALG-125755 demonstrates a more sustained reduction in HBsAg vs. competitor siRNAs *Data from Anglero-Rodriguez
Slide 12: ALG-125755: PK-PD Correlation in Mouse
ALG-125755: PK-PD Correlation in Mouse • For siRNA, Cavg appears to be more relevant PK parameter for efficacious target • Only maximum HBsAg change from baseline was considered; sustained PD durability was not taken into consideration for the mouse PK/PD analysis EC99=6 µg/g EC99.9=17 µg/g • ALG-12
Slide 13: ALG-125755: Single SC Dose PK at 5 mg/kg in Rat and Monkey
ALG-125755: Single SC Dose PK at 5 mg/kg in Rat and Monkey Rat liver Cmax 64.8 µg/g and T1/2 6.8 days Monkey liver Cmax 38.4 µg/g and T1/2 26.4 days ALG-125755 single SC injection in rat and monkey: high liver exposure and long liver half life 12
Slide 14: ALG-125755 Activity in a Human PBMC Assay
ALG-125755 Activity in a Human PBMC Assay ALG-125755 showed no immune activation in cytokine release assays performed in PBMC from 8 donors 13
Slide 15: ALG-125755 In Vitro Off Target Profile
ALG-125755 In Vitro Off Target Profile • Experimentally investigated potential off targets identified by bioinformatics HepG2.2.15 HepG2.2.15 Gene Primer No. 25 pM 250 pM Human (96 hour) (96 hour) 0 MM 1 MM 2 MM 3 MM 4 MM mRNA Gene 1 1 0.53±0.015 1.41±1.10 2 0.66±0.292 1.34±0.73 ALG- 0 0 0 0 7 Gene
Slide 16: ALG-125755 FIH-enabling GLP Tox Studies
ALG-125755 FIH-enabling GLP Tox Studies • Negative in the in vitro Ames and MNT studies • Negative in rat MNT up to 2000 mg/kg • No apparent changes in hemodynamic, ECG or respiratory parameters in monkeys or neurobehavioral findings in rats or monkeys up to 100 mg/kg, the highest dose tested • Well
Slide 17: Further De-risked Preclinically in PXB Mice with Humanized Livers
ALG-125755: Further De-risked Preclinically in PXB Mice with Humanized Livers 800 Vehicle 600 50 mg/kg ALG-755 %Change hALT 48.3 mg/kg ALN-HBV 400 50 mg/kg VIR-2218 200 0 -200 11 15 18 22 25 29 32 36 39 43 46 50 1 4 8 Day 1) Confirmed ALN-HBV is hepatotoxic, VIR-2218 is not 2) ALG-125755 showed no e
Slide 18: Short Interfering Nucleic Acid ALG-125755: Discovery and Advancement of a Differentiated siRNA
Short Interfering Nucleic Acid ALG-125755 Discovery and Advancement of a Differentiated siRNA • siRNAs have demonstrated clinical validation in CHB infected patients • We have designed our siRNA sequences using our proprietary technology and liver targeting conjugation to maximize in vitro and in vi
Slide 19: Acknowledgements
Acknowledgements • Bioinformatics: Aneerban Bhattacharya, Antitsa Stoycheva • Oligo Chemistry: Saul Martinez Montero, Vivek Rajwanshi, Tilani De Costa, John Cortez, Dana Cho • Biology/Biochemistry: Hua Tan, Hyunsoon Kang, Vera Huang, Elen Rosler, Min Luo, Cheng Liu, David Cai • PK: Kusum Gupta, Kha
Slide 20: Aligos Therapeutics
ALIGOS THERAPEUTICS
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