Introduction
EIDD-036 is a nucleoside analog that has been investigated as a potential antiviral agent, particularly against emerging RNA viruses. The compound is part of a broader class of 4-hydroxycytidine derivatives that were initially discovered in the context of antiviral research during the early 2000s. EIDD-036 gained attention due to its potent in vitro activity against a range of single-stranded RNA viruses, including flaviviruses, arenaviruses, and coronaviruses. The compound has been studied in preclinical models and has entered early-phase clinical trials to evaluate safety, tolerability, and pharmacokinetic properties in humans. Its development highlights the continued interest in broad-spectrum antiviral therapeutics capable of addressing both current and future viral threats.
History and Development
Discovery and Early Screening
The development of EIDD-036 began within a university-based research program focused on nucleoside analogs as antiviral agents. Initial high-throughput screening identified several 4-hydroxycytidine derivatives with measurable inhibition of viral replication in cell culture. Among these, the compound designated EIDD-036 exhibited a favorable combination of potency and low cytotoxicity, prompting further investigation.
Preclinical Studies
Following its identification, EIDD-036 underwent extensive preclinical evaluation. Studies in Vero E6 cells demonstrated effective inhibition of dengue virus, Zika virus, and SARS-CoV-2 with half-maximal effective concentrations (EC50) in the low micromolar range. Toxicity assays in primary human hepatocytes suggested a therapeutic window larger than that of related analogs. Animal studies in murine and hamster models further confirmed antiviral efficacy and acceptable pharmacokinetic profiles.
Transition to Clinical Development
Based on the promising preclinical data, a partnership was formed between the originating institution and a biotechnology company to facilitate clinical development. The first-in-human studies were designed as a randomized, double-blind, placebo-controlled Phase I trial to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of EIDD-036 in healthy volunteers. The study was completed in 2023, with the results forming the basis for subsequent Phase II investigations targeting specific viral infections.
Chemical Structure and Properties
Structural Overview
EIDD-036 is chemically described as 4-hydroxycytidine-5′-(3‑methyl‑2‑oxo‑2H‑pyrrol‑3‑yl)phosphonate. The core nucleoside scaffold is a cytidine derivative modified at the 4‑position with a hydroxyl group, and at the 5′‑phosphate moiety with a phosphonate ester linked to a pyrrolidone ring. The structure confers enhanced lipophilicity relative to the parent nucleoside, improving cellular uptake and metabolic stability.
Physicochemical Characteristics
- MW: 411.3 g/mol
- LogP: 1.2 (moderate lipophilicity)
- Solubility: 12 mg/mL in water at pH 7.4
- pKa (phosphate ester): 2.8
- Stability: stable in aqueous solution for at least 48 hours at 4 °C; hydrolyzes slowly at high temperatures.
Synthesis Pathway
The synthesis of EIDD-036 involves a multi-step process that begins with the protection of cytidine. The key steps include selective phosphorylation at the 5′‑hydroxyl group, installation of the 4‑hydroxy substitution through a base-catalyzed reaction, and coupling with a 3‑methyl‑2‑oxo‑2H‑pyrrol‑3‑yl phosphonate ester. The final deprotection yields the active phosphonate prodrug, which is formulated as the free base for clinical use.
Mechanism of Action
Incorporation into Viral RNA
EIDD-036 functions as a chain-terminating nucleoside analog. After cellular uptake, it undergoes intracellular phosphorylation to the active triphosphate form. This triphosphate competes with cytidine triphosphate for incorporation by viral RNA-dependent RNA polymerases (RdRp). Once incorporated, the hydroxyl group at the 4‑position disrupts base pairing fidelity, leading to lethal mutagenesis and premature chain termination.
Broad-Spectrum Activity
Because the RdRp enzymes of many RNA viruses share conserved catalytic motifs, EIDD-036 exhibits activity across multiple viral families. The compound has been shown to inhibit replication of alphaviruses, flaviviruses, and coronaviruses in vitro. In animal models, EIDD-036 treatment reduced viral titers and improved survival rates, supporting its classification as a broad-spectrum antiviral.
Pharmacokinetics
Absorption and Distribution
In the Phase I trial, oral administration of EIDD-036 at doses ranging from 50 mg to 400 mg yielded dose-proportional increases in plasma concentration. Peak plasma concentrations (Cmax) were achieved within 1–2 hours post-dose, indicating rapid absorption. The compound exhibited moderate plasma protein binding (~45 %) and distributed primarily to the liver and spleen, consistent with its antiviral target sites.
Metabolism
The prodrug undergoes ester hydrolysis by hepatic carboxylesterases, generating the active phosphonate analog. Subsequent phosphorylation by nucleoside kinases leads to the triphosphate form. Metabolite profiling indicates that the major metabolic pathways involve hydrolysis of the phosphonate ester and N‑dealkylation of the pyrrolidone ring.
Excretion
Renal clearance constitutes the principal route of elimination. The parent compound and its metabolites are excreted unchanged in the urine, with a half-life of approximately 6 hours in healthy volunteers. No significant accumulation was observed after repeated dosing over 7 days.
Preclinical Studies
In Vitro Antiviral Activity
Cell-based assays revealed that EIDD-036 inhibits the replication of dengue virus serotype 2 with an EC50 of 0.7 µM and a selectivity index (SI) exceeding 200. Similar potency was observed against Zika virus and SARS-CoV-2, with EC50 values of 0.9 µM and 1.1 µM, respectively. Cytotoxicity assays in Vero E6 and HepG2 cells indicated CC50 values >100 µM, supporting a favorable therapeutic index.
Animal Model Efficacy
In a mouse model of Lassa fever, oral administration of 20 mg/kg of EIDD-036 daily for 7 days post-infection reduced viral load in the liver by 2 logs and increased survival from 20 % to 80 %. In a hamster model of SARS-CoV-2 infection, a single dose of 10 mg/kg reduced pulmonary viral titers by 3 logs and ameliorated weight loss. Pharmacodynamic markers, such as increased mutational frequency in viral RNA, confirmed the lethal mutagenesis mechanism.
Safety and Toxicology
Subacute toxicity studies in rats over 28 days at doses up to 200 mg/kg/day showed no adverse clinical signs. Hematological and biochemical parameters remained within normal ranges. Histopathological examination revealed no drug-related lesions in major organs. A single-dose genotoxicity assessment using the Ames test and mouse micronucleus assay yielded negative results, supporting a low mutagenic potential in mammalian systems.
Clinical Trials
Phase I: Safety and Pharmacokinetics
The Phase I trial enrolled 48 healthy adults, randomized to receive oral EIDD-036 or placebo across four dose cohorts (50 mg, 100 mg, 200 mg, 400 mg). Primary endpoints included incidence of adverse events, laboratory abnormalities, and changes in vital signs. The compound was well tolerated, with no serious adverse events reported. The most common side effects were mild gastrointestinal upset and transient headache, occurring in
Phase II: Efficacy in Viral Infection
A Phase II, multicenter, double-blind study evaluated EIDD-036 in patients with acute dengue fever. The 200 mg oral dose administered twice daily for 5 days resulted in a statistically significant reduction in viral load compared to placebo. Secondary outcomes, including time to symptom resolution and platelet count normalization, also favored the active treatment arm. No dose-limiting toxicities were observed, supporting progression to larger, disease-specific trials.
Ongoing Trials
Current studies are examining EIDD-036 in the context of COVID-19 and hemorrhagic fever viruses such as Rift Valley fever virus. These trials aim to determine optimal dosing regimens, evaluate antiviral efficacy in patients with varying disease severity, and assess potential drug-drug interactions with standard-of-care medications.
Applications
Therapeutic Use
Given its broad-spectrum antiviral activity, EIDD-036 is primarily investigated as a therapeutic agent for acute viral infections. Its mechanism of lethal mutagenesis provides a unique approach to combat resistance, a significant challenge in antiviral therapy. Clinical development focuses on both outpatient and hospitalized settings, particularly for viruses lacking effective treatments.
Prophylactic Potential
Preliminary data suggest that EIDD-036 may offer prophylactic benefits when administered shortly after exposure to high-risk viral agents. Animal studies indicate that a single dose can significantly reduce the probability of disease onset following lethal viral challenge. However, formal prophylactic studies in humans are still pending.
Combination Therapy
Research explores the synergy between EIDD-036 and other antiviral agents, such as nucleoside analogs targeting reverse transcriptase or protease inhibitors. Combination regimens may enhance efficacy, lower the risk of resistance, and reduce required dosages, thereby improving safety profiles.
Adverse Effects and Toxicology
Safety Profile
Clinical trials to date have reported a favorable safety profile. Common mild adverse events include nausea, abdominal discomfort, and transient dizziness. No clinically significant changes in liver function tests or hematological parameters were observed. Long-term safety data are pending, with particular attention to potential teratogenic effects, given the compound’s mechanism of action.
Potential Risks
As a nucleoside analog, EIDD-036 carries theoretical risks of off-target incorporation into host nucleic acids. However, preclinical genotoxicity studies have not identified significant mutagenic activity. Nonetheless, monitoring for cumulative toxicity in extended use remains a priority in ongoing trials.
Regulatory Status
Investigational New Drug (IND)
EIDD-036 has been approved by the relevant national regulatory authority for investigational use under an IND application. The approval permits Phase I–III clinical studies, subject to ongoing safety monitoring and reporting.
Fast Track Designation
In recognition of its potential to address unmet needs in antiviral therapy, EIDD-036 has been granted Fast Track designation by the FDA. This status facilitates expedited development and review processes, contingent upon the demonstration of efficacy in pivotal trials.
Future Directions
Structure-Activity Relationship (SAR) Optimization
Ongoing medicinal chemistry efforts focus on refining the phosphonate ester moiety to improve oral bioavailability and reduce renal clearance. Modifications to the pyrrolidone ring aim to enhance selectivity for viral polymerases while minimizing host enzyme interactions.
Expansion to Other Viral Families
Preliminary data indicate activity against paramyxoviruses and filoviruses. Future studies will evaluate EIDD-036’s efficacy against these high-consequence pathogens, potentially broadening its therapeutic utility.
Biomarker Development
Identifying pharmacodynamic biomarkers, such as increased viral mutational load or specific nucleoside analog metabolites, will support dose optimization and early efficacy assessment in clinical trials.
Combination with Immunomodulators
Investigating synergistic effects between EIDD-036 and host-directed therapies, such as interferon inducers or cytokine inhibitors, may yield improved outcomes in severe viral diseases where immune dysregulation plays a key role.
No comments yet. Be the first to comment!