Advances in Developing Therapies for Chronic Liver Diseases and Viral Infections
By: Ayesha Rashid, PhD
Interviewee: Lawrence Blatt, PhD, MBA, Chairman, President and CEO, Aligos Therapeutics
Advances in Developing Therapies for Chronic Liver Diseases and Viral Infections
By: Ayesha Rashid, PhD
Interviewee: Lawrence Blatt, PhD, MBA, Chairman, President, and CEO, Aligos Therapeutics
In the rapidly evolving field of drug development for chronic liver diseases and viral infections, innovative strategies and a deep understanding of molecular targets are crucial.
Xtalks spoke with Lawrence Blatt, PhD, MBA, Chairman and CEO of Aligos Therapeutics, a company developing targeted therapies for liver diseases like MASH (metabolic dysfunction-associated steatohepatitis), formerly known as NASH (non-alcoholic steatohepatitis), and viral diseases such as chronic hepatitis B (CHB) to address important unmet medical needs.
Dr. Blatt, a seasoned biotech entrepreneur, co-founded Aligos Therapeutics in 2018 after a significant career at Janssen Pharmaceutical Companies of Johnson & Johnson. His transition from a large pharmaceutical environment to a smaller, more agile biotech setting was driven by a desire to focus on novel therapies for liver diseases and viral infections with a dedicated team of scientists.
Dr. Blatt shares the broader strategy and approach to developing therapeutics in today’s drug development landscape, current unmet medical needs in chronic liver disease and the future of liver disease treatment.
Strategy and Approach in Drug Development
Aligos Therapeutics is committed to addressing the unmet needs in liver diseases like MASH and CHB. Dr. Blatt explains that both conditions, despite having differing origins, often lead to similar outcomes like liver fibrosis and cirrhosis, eventually progressing to end-stage liver disease or liver cancer.
Regarding the overall strategy and approach in developing therapeutics for chronic liver diseases and viral infections, Dr. Blatt emphasizes the importance of selecting the right molecular targets. “One of the biggest challenges in drug development is what we call target risk. You might create the perfect drug, but if it doesn’t address the correct target causing the disease, it will not be effective,” he explains.
Dr. Blatt elaborates on the company’s “fast follower” strategy, which involves targeting known pathways with clinical validation and then improving on existing drugs in terms of efficacy, safety and convenience. “Historically, the first drugs for an indication launch quickly but often have a short product lifecycle. We focus on developing best-in-class molecules that optimize these aspects.”
A Vision for Targeted Liver Disease Therapies
One of Aligos Therapeutics’ lead candidates is ALG-055009, a novel thyroid hormone receptor beta (THR-β) agonist, being developed for MASH. The compound is in the same class as Rezdiffra (resmetirom), the first approved treatment for MASH.
Aligos Therapeutics’ compound aims to provide a more effective treatment option by targeting the specific metabolic pathways disrupted in MASH. The goal is not just to reduce fat in the liver but to prevent the progression to severe liver disease and cancer.
ALG-055009 specifically targets liver fibrosis and inflammation by correcting a metabolic defect in the liver that leads to hypothyroidism-induced fibrosis and fatty-liver disease. “We are reversing this defect with our active beta thyroid hormone agonist, effectively putting out the fire that causes tissue damage and inflammation, which eventually leads to fibrosis,” explains Dr. Blatt.
Addressing the initial insult in liver diseases rather than just the resulting fibrosis is key, he explains, as many current approaches fail because they do not stop the root cause of the disease.
Compared to Rezdiffra, Aligos Therapeutics’ approach involves a more potent and precise beta agonist, which Dr. Blatt explains has a higher selectivity ratio for the THR beta isoform over the alpha isoform. This specificity is crucial to avoid systemic hyperthyroidism, which could lead to other health complications.
Dr. Blatt says there is significant room for improvement upon Rezdiffra’s efficacy due to suboptimal pharmacokinetics and potency. Aligos Therapeutics’ approach is to improve efficacy while maintaining safety, despite some signals of potential autoimmune issues observed in other Phase III trials. “We target known pathways, leveraging our strong chemistry and pharmacology teams to focus on potency and all pharmacological aspects,” Dr. Blatt says.
Aligos Therapeutics’ ongoing Phase IIa trial for ALG-0055009 is a randomized, placebo-controlled, blinded study with a wide range of doses.
Dr. Blatt notes the use of MRI-PDFF (magnetic resonance imaging proton density fat fraction) as a surrogate endpoint for beta thyroid agonists, validated by Phase III data. “This gives our Phase II study a strong predictive value for Phase III outcomes, which is a big value creator for the company.”
“One of the biggest challenges in drug development is what we call target risk. You might create the perfect drug, but if it doesn’t address the correct target causing the disease, it will not be effective.”
— Lawrence Blatt, PhD, MBA, Chairman, President, and CEO, Aligos Therapeutics
“One of the biggest challenges in drug development is what we call target risk. You might create the perfect drug, but if it doesn’t address the correct target causing the disease, it will not be effective."
— Lawrence Blatt, PhD, MBA, Chairman, President, and CEO, Aligos Therapeutics
Addressing Unmet Medical Needs
Dr. Blatt notes several areas with significant unmet medical needs. “Current therapies for MASH and hepatitis B virus (HBV) are inadequate. For coronaviruses, a broad-spectrum inhibitor is needed, not just one for SARS-CoV-2.”
Aligos Therapeutics is also making strides in the treatment of chronic hepatitis B, a disease that affects millions worldwide and is a leading cause of liver transplantation. The company’s novel capsid assembly modulator has shown promising results in clinical trials. The drug effectively blocks the assembly of the viral capsid, thereby preventing the replenishment of covalently closed circular DNA (cccDNA) in the nucleus and significantly reducing viral replication.
Dr. Blatt explains that current HBV therapies do not adequately suppress the virus or reduce the cccDNA reservoir, a crucial factor in the chronicity of the infection. Aligos Therapeutics’ therapy has demonstrated unprecedented efficacy in achieving full viral suppression in both hepatitis B e antigen positive and e negative HBV patients, showing potential as a first-in-class treatment for the condition.
Aligos Therapeutics is not limited to liver diseases. The company is also working on a pan-coronavirus protease inhibitor in collaboration with government agencies like the National Institutes of Health (NIH). The drug, designed to target all known strains of coronavirus, including SARS-CoV-2, SARS-CoV and MERS-CoV, aims to provide a comprehensive antiviral solution.
Unlike current treatments like Paxlovid, which require co-administration with drugs like ritonavir, Aligos Therapeutics’ protease inhibitor is formulated to avoid such complications, making it a more versatile and patient-friendly option.
Upcoming Milestones
Aligos Therapeutics is poised for several key milestones in the coming months. The company anticipates the readout of its Phase IIa trial for ALG-055009 later this year. This trial aims to provide data on the drug’s effectiveness in reducing liver fat, a critical marker for MASH. Additionally, Aligos Therapeutics is preparing to advance its HBV treatment into Phase II trials, with plans to further investigate the reduction of cccDNA and other viral markers.
The company is also exploring grant opportunities to support the development of its coronavirus protease inhibitor, positioning itself as a leader in both liver disease and antiviral therapies.
Dr. Blatt’s vision for Aligos Therapeutics is clear: to develop best-in-class and first-in-class therapies that address some of the most pressing medical needs.
Key Trends and the Future of Liver Disease Treatment
Reflecting on his extensive experience in the field, Dr. Blatt stresses the importance of target validation in the treatment of MASH.
“Early on, many targets were tested and failed. The advent of beta thyroid agonists proved that disease-modifying drugs are possible, leading to a renaissance in MASH treatment with fibroblast growth factor 21 (FGF21) molecules, fatty acid synthase inhibitors and glucagon-like peptide-1 (GLP-1) agonists.”
He also champions the need for patient-centric therapies. “What’s best for patients are oral, safe and convenient therapies, likely in combination. Injectables may not be viable for chronic conditions like MASH, where patients don’t feel sick until the late stages. Oral therapies are more practical and have better patient adherence,” he says.
Dr. Blatt’s insights underscore the critical role of innovative strategies, target validation and patient-centric approaches in advancing the treatment of chronic liver diseases and viral infections.
As the fields continue to evolve, these principles will guide the development of effective and convenient therapies, improving outcomes for patients.
ABOUT Lawrence M. Blatt
Lawrence M. Blatt, Ph.D., MBA, has served as Chief Executive Officer and a member of Aligos’ board of directors since February 2018. Prior to co-founding the Company, Dr. Blatt served as the Global Head of Infectious Diseases and Vaccines at Janssen Pharmaceutical Companies of Johnson & Johnson, a pharmaceutical company, from November 2014 to February 2018. Dr. Blatt co-founded Alios BioPharma, Inc., a biotechnology company, and served as its Chief Executive Officer, President and Director from January 2009 until its acquisition by Janssen Pharmaceutical Companies of Johnson & Johnson in November 2014. Prior to Alios, he served as Chief Scientific Officer at lnterMune, Inc., a biotechnology company, from 2002 to 2008. Dr. Blatt previously served on the board of directors of ReViral Ltd. and Alveo Technologies, Inc., which he co-founded in 2014, and Meissa Vaccines, Inc. Dr. Blatt received a B.S. in Microbiology from Indiana University Bloomington, an MBA from California State University, Northridge, and a Ph.D. in Public Health Administration from the University of La Verne.