Aligos Therapeutics to present Phase 1 data for ALG-010133

Aligos Therapeuticsannounced that a poster describing preliminary data in healthy volunteers from the ongoing Phase 1a/b multi-part umbrella clinical trial of Aligos' S-antigen Transport-inhibiting Oligonucleotide Polymers compound ALG-010133 will be presented at the European Association for the Study of the Liver Digital International Liver Congress 2021. ILC 2021 is being held virtually on June 23-26, 2021. The company will also present four other posters at the meeting, which are detailed below and highlight nonclinical data from multiple drug classes within Aligos' chronic hepatitis B portfolio: STOPS molecules, a novel capsid assembly modulator candidate, and the company's lead small interfering RNA and antisense oligonucleotide drug candidates. The posters are expected to be made available to conference registrants beginning June 23. Aligos' five ILC 2021 presentations, and their potential implications, are summarized below. ALG-010133: S-antigen Transport-inhibiting Oligonucleotide Polymer. Title: Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of ALG-010133, an S-antigen Transport-inhibiting Oligonucleotide Polymer for the Treatment of Chronic Hepatitis B. Summary: The poster details the initial safety and pharmacokinetics of single ascending doses (SAD) and multiple ascending doses of ALG-010133 in healthy volunteers. These SAD and MAD studies constitute two parts of a three-part, multicenter, double-blind, randomized, placebo-controlled study - ALG-010133-101. ALG-010133 was generally safe and well tolerated in HVs when given as single and multiple subcutaneous doses of up to 200 and 180 mg, respectively. No serious adverse events, adverse events leading to premature study drug discontinuation, nor concerning laboratory, ECG, vital sign or physical examination findings were reported. Injection site reactions were seen in 19% of ALG-010133-treated subjects. Based on the PK exposures achieved in HVs, we expect that weekly subcutaneous doses of 120 mg and higher will be evaluated in cohorts of CHB subjects in Part 3. These data formed the basis for the prior decision to initiate 12 weeks of ALG-010133 dosing in CHB subjects. To potentially mitigate any ISRs in CHB subjects, use of topical steroids has been implemented as a prophylactic measure. Title: Mechanism of Action of Hepatitis B Virus S-antigen Transport-inhibiting Oligonucleotide Polymers Molecule. Summary: In HepG2.2.15 cells transfected with the STOPS molecule ALG-10000, the molecule reduced both intracellular and extracellular S-antigen levels. As the molecule did not significantly co-localize with or bind to S-antigen, we believe it likely acts through other host cellular factors to reduce S-antigen levels. Five host proteins, all of which have roles in RNA processing, translation, or protein folding/degradation and are believed to function in viral replication and infection, were found to bind to ALG-10000: SRSF1, HNRNPA2B1, GRP78, RPLP1, and RPLP2. These data suggest that STOPS have a complex mechanism of action involving interactions with host factors which play a role in RNA processing, protein translation/folding, and transportation of the S-antigen protein. Title: Capsid Assembly Modulator ALG-000111 and its Prodrug ALG-000286 Display Excellent In Vitro and In Vivo Antiviral Activity. Summary: As part of a strategy to develop multiple structurally diverse CAM candidates to inhibit HBV viral replication in CHB, the authors characterized ALG-000111, a novel Class II CAM candidate. In vitro, ALG-000111 demonstrated sub-nanomolar potency, sustained antiviral activity and significant HBV DNA knockdown. The compound's prodrug form, ALG-000286, showed strong in vivo antiviral activity in an AAV-HBV mouse model as measured by declines in HBV DNA. Further development of this candidate is warranted as part of a diverse CHB portfolio. Title: ALG-125755, A Small Interfering RNA Against Hepatitis B Virus Effectively Inhibits Hepatitis B Surface Antigen Secretion in HBV Cell Models and the AAV-HBV Mouse Model. Summary: Aligos' lead siRNA candidate, ALG-125755, which targets the small open reading frame of the S-antigen transcript in HBV, was shown to knock down S-antigen by 1.5 log10 IU/mL 28 days after a single subcutaneous dose of 5 mg/kg in the AAV-HBV mouse model of HBV infection. This encouraging degree of S-antigen reduction in vivo is corroborated by its potency in vitro, where the candidate demonstrated 23.9 pM and 28.8 pM EC50 values in two different cell culture assays. The compound also demonstrated a favorable pharmacological profile in vitro in multiple other cell culture systems. Taken together, these data suggest that the compound is a potent agent with respect to S-antigen reduction and warrants further development as a potential therapeutic for chronic hepatitis B. Title: Combination Drug Interactions of Hepatitis B Virus Small Interfering RNA and Antisense Oligonucleotides In Vitro and In Vivo. Summary: As ASOs and siRNAs utilize independent pathways to potentially reduce S-antigen levels, unconjugated forms of Aligos' siRNA candidate ALG-125755 and of Aligos' ASO candidate ALG-020572 were evaluated for any additive or synergistic effects with respect to S-antigen knockdown, both in vitro and in vivo. In vitro, in dual combinations with each other as well as with other anti-HBV agents such as nucleos(t)ide analogs and capsid assembly modulators, the siRNA or ASO candidate each demonstrated a range of additive to significantly synergistic effects, depending on the specific combination used. With one another, the siRNA and ASO candidates exhibited synergy in vitro. These in vitro effects were confirmed in an AAV-HBV mouse model of HBV infection, where the ASO and siRNA exhibited additive effects with respect to S-antigen knockdown when combined. Based on the results of these interaction studies, further study is warranted to identify the most strategic combinations of siRNA and ASO candidates in CHB.