Model Medicines, Icahn School of Medicine at Mount Sinai, and University of California, San Diego Researchers Publish Groundbreaking Preprint on MDL-001, A Broad-Spectrum Antiviral

Co-authors:

• Adolfo García-Sastre, PhD, Icahn School of Medicine at Mount Sinai in New York - Director, Global Health and Emerging Pathogens Institute. Director, Center for Research on Influenza Pathogenesis (CRIP), National Institute of Allergy and Infectious Diseases (NIAID) Center of Excellence for Influenza Research and Surveillance.
• Kris White, PhD, Icahn School of Medicine at Mount Sinai in New York - Co-Investigator, National Institute of Health (NIH) Antiviral Drug Discovery (AViDD), AI-driven Structure-enabled Antiviral Platform (ASAP) Center and Quantitative Biosciences Institute Coronavirus Research Group (QCRG).
• David "Davey" Smith, MD, MAS, FACP, FIDSA, University of California, San Diego, School of Medicine - Assistant Vice Chancellor of Clinical and Translational Research. Director, Altman Clinical and Translational Research Institute (ACTRI). Director, Pandemic Response to Emerging Pathogens, Antimicrobial Resistance and Equity (PREPARE) Institute. Protocol Co-Chair, ACTIV-2.

LA JOLLA, Calif., Jan. 21, 2025 /PRNewswire/ -- Model Medicines, a pioneering biotech company focused on developing first-in-class therapeutics addressing urgent global health challenges, today announced the release of its latest scientific pre-print, titled "MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases". This landmark study highlights the development of MDL-001, a first-in-class, oral, broad spectrum antiviral therapy with efficacy against multiple viral pathogens of pandemic potential. The company was recently named one of the "Ten Companies to Watch in AI Drug Discovery" by Genetic Engineering and Biotechnology News, where it was featured alongside Recursion Pharmaceuticals, Schrödinger, Relay Therapeutics, Insilico Medicine, and Generate Biomedicines.

Viral pathogens such as SARS-CoV-2, Influenza, Norovirus and Hepatitis C globally impact billions annually, leading to significant morbidity, mortality, and healthcare system strain. SARS-CoV-2 has caused over 7 million deaths globally, seasonal influenza infects up to 1 billion people each year, resulting in 290,000 to 650,000 deaths annually, and norovirus and hepatitis C account for 171,000 to 277,000 and 250,000 deaths annually, respectively. In response to this large unmet medical need, the National Institute of Allergy and Infectious Diseases (NIAID) has developed a target product profile (TPP) to guide the development of future antivirals, emphasizing the need for broad-spectrum activity against emergent viruses with pandemic potential and the importance of therapeutics with novel inhibitory mechanisms. MDL-001 may be the first single therapeutic to meet NIAID's stringent TPP, which has achieved preclinical proof of concept (PoC). 

Target Discovery and First-In-Class Chemistry Previously, Model Medicines' GALILEO™ platform identified the viral RNA-dependent RNA polymerases (RdRp) Thumb-1 subdomain as a promising structurally conserved, broad-spectrum druggable site across numerous RNA viruses. ChemPrint™, a customizable bioinformatics pipeline and geometric deep learning algorithm in the GALILEO™ platform was combined with a large chemical repositioning library to discover MDL-001, which was found to interact with the Thumb-1 subdomain of multiple single-stranded RNA viruses in-silico. These results were previously reported in the preprint, "Discovery of RdRp Thumb-1 as a novel broad-spectrum antiviral family of targets and MDL-001 as a potent broad-spectrum inhibitor thereof".

Broad Spectrum Antiviral Activity In the current manuscript, MDL-001 is reported to demonstrate robust activity against four viral families, seven distinct viruses, and 13 viral variants and strains, including potency that is orders of magnitude lower than the Cmax obtained in lung. Its effectiveness spans critical pathogens, including SARS-CoV-2 (multiple variants), Norovirus, Influenza and Hepatitis C underscoring its potential as a potent, versatile therapeutic against both existing and emerging viral threats.

Best-in-Class Preclinical Antiviral Activity In preclinical animal studies, results demonstrate that MDL-001 has in vivo antiviral efficacy comparable to that of remdesivir (Veklury). Moreover, the magnitude with which MDL-001 reduced viral accumulation in the lung (2.9 Log10) was significantly higher than that reported for nirmatrelvir (1.4 Log10 with 300 mg/kg and 1.9 log10 with 1000 mg/kg), the active ingredient in Paxlovid. These results position MDL-001 as a best-in-class antiviral candidate.

Oral Bioavailability and Dosing MDL-001's extended half-life supports potential once-daily oral administration, providing a significant advantage in ease of use and patient compliance compared to existing antiviral therapies.

Favorable Pharmacokinetic Profile MDL-001 was observed to be tolerable at concentrations as high as 1000 mg/kg, and accumulates in lung at levels 10-40 times higher than the EC50 values obtained in in vitro assays. The rapid and sustained accumulation of MDL-001 in the lung, provides for exceptional EC50/Cmax ratios and minimizes viral infection.

Safety and Tolerability MDL-001 has been extensively evaluated in preclinical and clinical studies. It was safe and well-tolerated in ~100 healthy subjects across two Phase 1 clinical trials, with doses of up to 200 mg/day for 28 days. These results validate MDL-001's safety profile, ensuring suitability for outpatient treatment settings.

A New Era of Antiviral Collaboration

This groundbreaking study was co-authored with leading virologists and infectious disease experts from the Icahn School of Medicine at Mount Sinai and the University of California, San Diego, School of Medicine.

"A broad spectrum, orally available antiviral therapeutic with an extended half-life and a well-documented safety and toxicity profile that can be administered on an outpatient basis is an extreme and urgent unmet medical need, which would be a game-changer," said Adolfo Garcia-Sastre, Ph.D., Director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai.

"This is an exciting next-generation oral SARS-CoV-2 and broad-spectrum antiviral therapeutic candidate," added Kris White, Ph.D., Assistant Professor, Icahn School of Medicine at Mount Sinai and Co-Investigator, National Institute of Health (NIH) Antiviral Drug Discovery (AViDD), AI-driven Structure-enabled Antiviral Platform (ASAP) Center and Quantitative Biosciences Institute Coronavirus Research Group (QCRG).

"The development of MDL-001 underscores our commitment to addressing urgent global health challenges," said Daniel Haders, Ph.D., CEO of Model Medicines. "By leveraging cutting-edge technology and collaborating with leading experts, we aim to deliver transformative therapies that can redefine pandemic preparedness and response."

"MDL-001 represents a significant potential step forward in pandemic preparedness. Its broad-spectrum efficacy and oral bioavailability position it as a key tool for rapid deployment during viral outbreaks. By addressing critical gaps in the antiviral landscape, MDL-001 is poised to become an integral part of future global health strategies," added David "Davey" Smith, MD, MAS, FACP, FIDSA, University of California, San Diego, School of Medicine Assistant Vice Chancellor of Clinical and Translational Research.

Model Medicines Endeavor (MEE) Program

In conjunction with the preprint, Model Medicines is launching the Model Medicines Endeavor (MME) program. Each MME is focused on a specific indication or disease area and represents a strategic approach to tackling urgent healthcare challenges by leveraging the company's advanced AI-driven drug discovery platform. The first of these, ViroMME, is dedicated to addressing infectious diseases and launches with a robust pipeline that includes MDL-001, a library of 12 novel chemical entities (NCEs), and the groundbreaking discovery of RdRp Thumb-1—a cryptic allosteric target that is highly conserved across multiple RNA viruses. The launch of ViroMME marks the beginning of Model Medicines' broader vision to create multiple Endeavors, each driving innovation in distinct areas of unmet medical need. Learn more at www.viromme.com

Preprints

MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases

Discovery of RdRp Thumb-1 as a novel broad-spectrum antiviral family of targets and MDL-001 as a potent broad-spectrum inhibitor thereof

ChemPrint: An AI-Driven Framework for Enhanced Drug Discovery

About Model Medicines

Model Medicines is an AI-driven, human health company using AI to model all of chemistry and human biology, to accelerate the creation of life-changing drugs.

The company was founded in 2019 to deliver on the promise of AI-Drug discovery. They have discovered 192 compounds and advanced 67 assets in cellular models of disease, or beyond, across 12 therapeutic targets for multiple areas of biology. Their data has been validated by preeminent researchers and scientists at premier academic and corporate laboratories. The company has developed a robust pipeline of patent-pending therapeutics for oncology, infectious diseases, gastric disorders, neurological disorders, and weight disorders. The company is based in La Jolla, CA.

To learn more, visit www.modelmedicines.com

SOURCE Model Medicines