Lead Asset
MDL-001
A Next-Generation Broad-Spectrum Antiviral
For decades, broad-spectrum non-nucleoside antivirals were considered biologically impossible. MDL-001 is the first to overcome this challenge by targeting a cryptic, conserved RdRp polymerase mechanism shared across six viral families, providing a unified oral therapeutic for respiratory and chronic liver disease.
MDL-001 is a Game Changer
It's time to move beyond the "one bug, one drug" paradigm
MDL-001’s broad-spectrum efficacy and oral bioavailability make it a potential key tool for rapid deployment in pandemic preparedness.
New Results
MDL-001: An Oral, Safe, and Well-Tolerated Broad-Spectrum Inhibitor of Viral Polymerases
Virgil Woods, Ph.D
Senior Scientist, Model Medicines
Overview of RdRp Thumb-1
MDL-001 is a first-in-category, oral, direct-acting, broad-spectrum antiviral targeting the RdRp Thumb-1 allosteric site of viral polymerases. It is the world's first conserved, broad-spectrum, non-nucleoside RdRp Thumb-1 inhibitor. The asset was discovered using the GALILEO™ platform, identifying the RdRp Thumb-1 pocket as a structurally conserved and targetable site across single-stranded RNA virus families.
MDL-001 has demonstrated nanomolar potency against six pathogenic viral families, including:
Respiratory Viruses
Influenza A and B, Respiratory Syncytial Virus (RSV), and SARS-CoV-2.
Hepatic Viruses
Hepatitis C (HCV), Hepatitis B (HBV), and Hepatitis D (HDV).
The program is being developed as a unified, oral therapeutic approach to address both the annual endemic respiratory tripledemic and chronic liver disease.
Standard of Care
MDL-001 establishes equivalence or superiority to every approved standard of care tested across four viral families. This comparative data set is considered unprecedented in the antiviral field.
Endpoint
MDL-001 Result
Comparator (standard of care)
Outcome
Lung viral titer
2.6 log₁₀ reduction
Oseltamivir (Tamiflu, Genentech/Roche), 5 mg/kg BID — 1.5 log₁₀
Superiority
Symptoms & mortality
No symptoms or mortality (5 d.p.i.)
Oseltamivir (Tamiflu), 5 mg/kg BID
Equivalency
Lung viral titer
2.9 log₁₀ reduction
Nirmatrelvir (Paxlovid, Pfizer), 1,000 mg/kg BID — 1.9 log₁₀
Superiority
Lung viral titer
2.9 log₁₀ reduction
Molnupiravir (Lagevrio, Merck), 20 mg/kg BID — 1.0 log₁₀
Superiority
Symptoms & mortality
Reduced symptoms; no mortality (head-to-head)
Remdesivir (Veklury, Gilead), 100 mg/kg BID s.c.
Equivalency
In vitro EC₅₀
79.4 nM
Ribavirin (Bausch Health) — 33,000 nM
Superiority (~416× improvement)
In vivo viremia (humanized-liver mice)
3.3 log₁₀ reduction over 28 days
Sofosbuvir (Gilead), 50 mg/kg — equivalent reduction by Day 21
Equivalency
Preclinical Proof of Concept in Respiratory
MDL-001 has established in vivo equivalency or superiority across all three respiratory viruses in the annual tripledemic:
Influenza
MDL-001 prevented body weight loss and mortality in a mouse-lethal H1N1 strain, demonstrating full symptomatic protection and equivalency to oseltamivir (Tamiflu). It also retains nanomolar in vitro activity against oseltamivir-resistant variants of H1N1 and H3N2, sitting outside that resistance pathway entirely.
SARS-CoV-2
It produced a greater reduction in lung viral burden than both nirmatrelvir (Paxlovid active) and molnupiravir (Lagevrio active). MDL-001 also demonstrated symptom reduction equivalent to subcutaneous remdesivir.
RSV
MDL-001 showed a 416-fold improvement in in vitro potency over the off-label standard of care, Ribavirin, with an EC50 under 80 nM.
Preclinical Proof of Concept in Liver
MDL-001 provides single-agent activity against chronic hepatic infections:
HCV
In a humanized mouse model, oral MDL-001 reduced plasma viremia by 3.3 log₁₀, achieving efficacy equivalent to the standard of care, sofosbuvir.
HBV
Oral MDL-001 reduced plasma HBV DNA by 1.8 log₁₀ at Day 28.
Coinfections
MDL-001 is active as a single agent against HCV/HBV and HBV/HDV coinfections in vitro. Its single-agent activity against both HCV and HBV potentially obviates the FDA black box warning for HBV reactivation that constrains every approved interferon-free HCV regimen.
Pharmacokinetics
Oral MDL-001 is rapidly absorbed and demonstrates favorable pharmacokinetics for outpatient dosing:
Tissue Partitioning
MDL-001 partitions extensively into target tissues, achieving concentrations far exceeding the in vitro EC₉₀ values.
Lung Cmax exceeded the respiratory geometric mean EC₉₀ by greater than 120x at the high dose, with Lung Kp ranging from 39x to 76x.
Liver Cmax exceeded the hepatic geometric mean EC₉₀ by greater than 200x at the high dose, with Liver Kp ranging from 65x to 104x.
Metabolism & Clearance
MDL-001 exhibits high metabolic stability in human hepatocytes and is classified as a low-clearance compound.
This data supports the potential for a once- or twice-daily oral outpatient dosing frequency.
Mechanism of Action
MDL-001 is a direct-acting, non-nucleoside polymerase inhibitor targeting the RdRp Thumb-1 allosteric pocket.
Targeting RdRp
The viral RNA-dependent RNA polymerase (RdRp) is essential for copying the viral genome.
Inhibition
The drug hijacks the viral initiation mechanism by competing with the Lambda-1 loop for the Thumb-1 pocket. When occupied by MDL-001, the polymerase cannot transition into its catalytically competent initiation state, blocking viral RNA synthesis.
Mechanism Validation
The Thumb-1 mechanism was confirmed via a resistance selection study where resistant colonies converged on a mutation at P495, the canonical resistance site for Thumb-1 inhibitors.
Host Sparing
The Thumb-1 pocket is specific to viral RdRp and has no equivalent in the host RNA Polymerase II, circumventing the host-polymerase liabilities of the nucleoside antiviral class.
Safety Data
The host-sparing mechanism is reflected in a clean preclinical safety package, which is compatible with chronic outpatient dosing.
Tolerability
The drug was well tolerated in over 400 animals across seventeen independent preclinical studies, even at doses up to 16x the minimum therapeutic dose, and at 6x the efficacious dose for 28 consecutive days. No treatment-related adverse events were reported
Genetic and Cardiac Safety
MDL-001 was negative in both the Ames and micronucleus genotoxicity assays. The hERG IC50 of 13 µM provides a high cardiac safety margin, exceeding the projected unbound human plasma Cmax at the minimally efficacious dose by greater than 5,000-fold.
Timeline for IND and Clinical Trials
The program is currently completing IND-enabling studies.
IND Submission Target
Late 2026.
Clinical Trials Start
Estimated to commence in early 2027.
Readiness
Pivotal efficacy studies are complete, and key IND-supporting studies, including AMES, hERG, MNT (micronucleus), and metabolism are finished.
Manufacturing
Chemistry, Manufacturing, and Controls (CMC) scale-up is initiated and aligned to support clinical entry.
