Aligos Therapeutics (Aligos) is targeting multiple, clinically validated mechanisms of action (MOAs) as it seeks to identify curative therapies for hepatologic diseases and viral infections, including chronic hepatitis B (CHB), nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Aligos’ development program MOAs include:
- Capsid assembly modulators (CAMs)*: : Also known as hepatitis B virus (HBV) core inhibitors, CAMs are small molecule allosteric inhibitors that interfere with the formation of intact (i.e., infectious) HBV particles. In the presence of CAMs, non-infectious empty (Class II CAMs) or aberrantly shaped (Class I CAMs) viral particles are produced instead. In CHB clinical trials, treatment with Class II CAMs has resulted in significant reductions in HBV nucleic acids (deoxyribonucleic acids (DNA) and ribonucleic acids (RNA)) (1, 2). Aligos has identified multiple promising Class II and Class I CAMs, that are currently being optimized. Aligos’ most advanced CAM, ALG-000184, has best in class properties compared to other Class II CAMs currently in development and is due to enter the clinic in 2020.
- S-antigen Transport-inhibiting Oligonucleotide Polymers (STOPS)*: STOPS (closely related to nucleic acid Polymers (NAPs)) are oligonucleotides that work via an as yet undefined mechanism of action that results in profound inhibition of Hepatitis B surface antigen (HBsAg) formation in vitro and in CHB clinical trials (3). HBsAg is thought to have broad Immunosuppressive properties in CHB patients, preventing eradication of the virus (4). As a result, sustained HBsAg loss is considered an essential step to achieving functional cure of CHB (5). Aligos’ lead STOP candidate, ALG-010133, appears to have best in class properties compared to other STOPS currently in development and is due to enter the clinic in 2020.
- Antisense oligonucleotides (ASOs)*: ASOs are oligonucleotides that bind to complementary messenger RNAs (mRNAs) and trigger their degradation via the enzyme Ribonuclease H (RNAse H). ASOs can therefore be used to target viral mRNAs such as those encoding the HBsAg protein to lower HBsAg levels and enable reconstitution of the host immune system against the virus. Aligos has a number of ASOs in development that may offer best-in-class properties compared to other oligonucleotide approaches currently in the clinic.
- Thyroid hormone receptor beta (THR-β) agonists:Thyroid hormone receptors (THRs) are composed of two main sub-classes (alpha and beta) that are stimulated by the thyroid hormone, triiodothyronine (T3). Over stimulation of THR alpha results in tachycardia, bone loss, and muscle wasting, while THR beta stimulation primarily affects the liver and results in reductions in lipids, including cholesterol, triglycerides, and liver fats (steatosis). Therefore, selective stimulation of THR-β receptors has the potential to reduce a patient’s lipid burden, including the steatosis which underpins NASH, while avoiding unwanted THR alpha-mediated side effects. Indeed, several THR-β agonists are in the clinic and have demonstrated favorable effects on plasma lipid levels, liver fat burden, as well as liver histology (6, 7) in NASH patients. Aligos has THR-β agonists in development that may offer best-in-class properties compared to other compounds currently in the clinic.
- Aligos is currently optimizing and validating a number of compounds targeting undisclosed MOAs which are thought to be central to the pathogenesis of HCC.
*The Aligos strategy to achieving functional cure in CHB is to use a combination of multiple highly effective therapeutics with unique MOAs and additive/synergistic effects. This strategy has been highly effective in the treatment of other chronic viral diseases such as chronic hepatitis C and human immunodeficiency virus (HIV). Aligos has positioned itself to be able to potentially offer all components of the combination of STOPS, ASOs, and/or CAMs with or without standard of care CHB treatments (e.g., nucleos(t)ides, pegylated interferon alpha). We believe that these complimentary mechanisms directed at rapid and substantial reduction of HBsAg while fully suppressing HBV replication represent a paradigm shift that should lead to functional cure in a large percentage of CHB patents.
- Ma et al., Abstract LBO-06, EASL 2019
- Zoulim et al, Abstract LBO-004, EASL 2018
- Bazinet et al, Abstract FRI-210, EASL 2019
- Ortega-Prieto et al., Vaccines 2017; 5(3): 24
- Lok et al.Hepatology, 2017; 66(4):1296-1313
- Harrison et al., Oral Abstract 14, AASLD 2018
- Loomba et al., LBP-20, EASL 2019