Benzinga | Jun 21, 2021 08:15AM EDT

Aligos Therapeutics To Present Phase 1 Safety, Pharmacokinetic Data for STOPS Molecule Drug Candidate ALG-010133 And Several Nonclinical Chronic Hepatitis B Programs At Digital International Liver Congress 2021

Aligos Therapeutics, Inc. (NASDAQ:ALGS), a clinical-stage biopharmaceutical company focused on developing novel therapeutics to address unmet medical needs in viral and liver diseases, today announced that a poster describing preliminary data in healthy volunteers (HVs) from the ongoing Phase 1a/b multi-part umbrella clinical trial of Aligos' S-antigen Transport-inhibiting Oligonucleotide Polymers (STOPSTM) compound ALG-010133 will be presented at the European Association for the Study of the Liver (EASL) Digital International Liver Congress(tm) 2021 (ILC 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 (CHB) portfolio: STOPS molecules, a novel capsid assembly modulator (CAM) candidate, and the company's lead small interfering RNA (siRNA) and antisense oligonucleotide (ASO) drug candidates. The posters are expected to be made available to conference registrants beginning June 23. Theposters will be available subsequently on the "Scientific Presentation and Publications" page in the "Presentations" section of Aligos' website at www.aligos.com.

"Our team continues to be highly productive in advancing our CHB portfolio," said Lawrence Blatt, Ph.D., MBA, Chairman and CEO of Aligos. "The determination of the STOPS mechanism of action and advancement of our STOPS lead candidate, ALG-010133, from healthy volunteers into chronic hepatitis B patients, along with our recent presentation of the safety, pharmacokinetic, and antiviral proof-of-concept data for our lead CAM candidate, ALG-000184, at the HBV-TAG 2021 conference, highlights our ability to identify and develop drugs with best-in-class potential. We plan to share additional emerging antiviral activity for our lead STOPS and CAM programs, each of which are currently being dosed in the second of up to 6 CHB cohorts, in the second half of this year. Additionally, these promising data that we presented at the HBV-TAG 2021 conference support our recent decision to accelerate advancement of our portfolio of drug candidates toward combination therapies in CHB. To this end, we plan to also initiate a clinical trial evaluating our lead antisense oligonucleotide ALG-020572 in the second half of this year followed by initiation of a clinical trial for our siRNA ALG-125755 in the first half of 2022. By suppressing viral replication with our CAM molecule ALG-000184 as well as utilizing several complementary mechanisms for suppressing the production of HBsAg (STOPS, ASO and siRNA), we hope to identify a regimen that can lead to higher rates of functional cure for patients living with CHB."

Leonid Beigelman, Ph.D., President at Aligos, noted, "We are excited to share the progress of our HBV portfolio at the EASL meeting. The mechanism of action data for our STOPS molecule highlighted the potent effects this drug class appears to have in suppressing the production of HBsAg by blocking host molecular pathways. Similarly, the data with our lead siRNA drug candidate showed how potently this compound suppresses production of HBsAg by catalyzing the destruction of HBsAg mRNA. We believe these complementary mechanisms, along with our ASO program, will work together, potentially synergistically, to reduce HBsAg levels in CHB patients.

Aligos' five ILC 2021 presentations, and their potential implications, are summarized below.

ALG-010133: S-antigen Transport-inhibiting Oligonucleotide Polymer (STOPS(tm))

Poster number: 1004

Title: Safety, Tolerability and Pharmacokinetics (PK) of Single and Multiple Doses of ALG-010133, an S-antigen Transport-inhibiting Oligonucleotide Polymer (STOPSTM) for the Treatment of Chronic Hepatitis B

Presenter: Ed Gane

Summary: The poster details the initial safety and pharmacokinetics of single ascending doses (SAD) and multiple ascending doses (MAD) of ALG-010133 in healthy volunteers (HVs). These SAD and MAD studies constitute two parts of a three-part, multicenter, double-blind, randomized, placebo-controlled study - ALG-010133-101 (NCT04485663).

ALG-010133 was generally safe and well tolerated in HVs when given as single and multiple (3 weekly) 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 (ISRs) 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 (Part 3). To potentially mitigate any ISRs in CHB subjects, use of topical steroids has been implemented as a prophylactic measure.

Poster number: 1305

Title: Mechanism of Action of Hepatitis B Virus S-antigen Transport-inhibiting Oligonucleotide Polymers (STOPS(tm)) Molecules

Presenter: Cheng Kao

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.

Capsid Assembly Modulators (CAMs)

Poster number: 1386

Title: Capsid Assembly Modulator ALG-000111 and its Prodrug ALG-000286 Display Excellent In Vitro and In Vivo Antiviral Activity

Presenter: Yannick Debing

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.

Small Interfering Ribonucleic Acids (siRNA)

Poster number: 1196

Title: ALG-125755, A Small Interfering RNA (siRNA) Against Hepatitis B Virus (HBV) Effectively Inhibits Hepatitis B Surface Antigen (HBsAg) Secretion in HBV Cell Models and the AAV-HBV Mouse Model

Presenter: Jin Hong

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.

Combination of Small Interfering RNA (siRNA) and Antisense Oligonucleotides (ASO)

Poster number: 1257

Title: Combination Drug Interactions of Hepatitis B Virus (HBV) Small Interfering RNA (siRNA) and Antisense Oligonucleotides (ASO) In Vitro and In Vivo

Presenter: Hua Tan

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 (NA) and capsid assembly modulators (CAM), 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.