exaluren (ELX-02) / Eloxx Pharma - LARVOL DELTA

A functional comparison of readthrough agent ELX-02 across a wide range of nonsense CFTR variants. (PubMed, J Cyst Fibros) - "ELX-02 induces limited and highly heterogeneous CFTR rescue across nonsense variants. PDIO-based functional screening provides a framework to guide patient selection and stratification for future readthrough therapy trials."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

CFTR nonsense mutations that escape nonsense mediated decay exhibit CFTR function by readthrough inducing compounds (NACFC 2026) - "Robust swelling by correcting CFTR function in the organoids is measured after ELX-02 250uM (readthrough agent) is treated with VX-445 3uM and VX-661 3uM (CFTR modulators) for 24 hrs resulting in 643 ± 60 % swelling x time. CFTRQ1411X mice escape NMD retaining WT levels of Cftr mRNA. CFTR function is restored with limited toxicity in intestinal organoids, meaning that some nonsense mutations may be corrected by CFTR modulators when cotreated with a readthrough agent. Next, we will administer ELX-02 and the CFTR modulators to CFTRQ1411X mice to determine if CFTR function can be restored and CF manifestations reduced in vivo."

Gastrointestinal Disorder • CFTR

Different cytokines have diverse effects on epithelial ion channel functions and CFTR rescue (NACFC 2026) - "Most pwCF have at least one copy of F508del CFTR, which can be rescued with triple CFTR modulators, elexacaftor/tezacaftor/ivacaftor (ETI)...Additionally, IL-17 plus TNF- ?or IL-4 alone enhanced the activity of drug compound combinations (e.g., ELX-02 plus CC-90009 and CFTR modulators) for correcting readthrough of nonsense CFTR mutations such as G542X and W1282X [3]... Treatment with ETI plus IL-1b increased F508del CFTR activity compared to ETI alone and this enhancement was abolished by anakinra, which blocks IL-1 receptor activity [1]... Although IL-1b, IL-4, and IL-17 enhanced the function of ETIrescued F508del CFTR, with IL-1b causing the highest increase in activity, these cytokines displayed varying effects on other ion channels, i.e., ENaC and CaCC. These results suggest that distinct cytokines act on separate pathways in the airway epithelium to regulate airway surface liquid height and mucin concentration, either enhancing CFTR-mediated hydration or..."

Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Respiratory Diseases • CFTR • IL17A • IL1B • IL4 • TNFA

EXACT Study: A Blinded Study in Patients With Alport Syndrome to Evaluate Exaluren Efficacy and Safety (clinicaltrials.gov) - P2 | N=24 | Recruiting | Sponsor: Eloxx Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders • COL4A5

EXACT Study: A Blinded Study in Patients With Alport Syndrome to Evaluate Exaluren Efficacy and Safety (clinicaltrials.gov) - P2 | N=24 | Not yet recruiting | Sponsor: Eloxx Pharmaceuticals, Inc.

New P2 trial • Genetic Disorders • COL4A5

Identification of small molecules that enhance aminoglycoside-mediated suppression of CFTR and NF1 nonsense mutations. (PubMed, Mol Ther Oncol) - "ELX-02, a novel synthetic aminoglycoside, was developed to have both enhanced readthrough activity and reduced toxicity in mammalian cells compared to traditional aminoglycosides...Although none of the enhancers alone induced readthrough, they all significantly increased readthrough via aminoglycosides at low doses (EC10). Overall, our results suggest that enhancer compounds may be a viable way to overcome potency issues associated with aminoglycosides, enabling rescue of protein function from nonsense alleles while minimizing toxicity."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Neurofibromatosis • Pulmonary Disease • Respiratory Diseases • Solid Tumor • NF1

A Study of ELX-02 in Patients With Alport Syndrome (clinicaltrials.gov) - P2 | N=3 | Completed | Sponsor: Eloxx Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion • Genetic Disorders • COL4A5

Evaluating ribosomal readthrough as a precision medicine strategy for restoring factor VIII expression in hemophilia a (ASH 2025) - "We testedaminoglycoside antibiotics (gentamicin, G418, ELX02) and non-aminoglycoside agents (ataluren and 2,6-diaminopurine [DAP]), each employing distinct mechanisms to induce ribosomal readthrough. Both aminoglycoside andnon-aminoglycoside compounds can restore partial FVIII expression in a mutation-specific manner. Theseresults support the further development of readthrough-based therapies as a cost-effective andaccessible treatment option for a subset of severe HA patients, potentially reducing their dependence onconventional replacement therapies."

Cystic Fibrosis • Duchenne Muscular Dystrophy • Genetic Disorders • Hematological Disorders • Hemophilia • Hemophilia A • Immunology • Muscular Dystrophy • Rare Diseases • Respiratory Diseases

Rescue of the CFTR chloride channel with nonsense mutations is markedly improved under inflammatory conditions. (PubMed, Eur Respir J) - "We tested the efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying the G542X mutation. The effect of inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our results suggest that rescue of CFTR with nonsense mutations could be more effective than expected in vivo Our findings may also lead to the identification of novel targets to correct the effect of nonsense mutations in CF and other genetic diseases."

Journal • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • GSPT1 • IL17A • IL4 • TNFA

From RAAS blockade to regenerative medicine: evolving treatment strategies in Alport syndrome. (PubMed, Pediatr Nephrol) - "Adjunctive commercially available metabolic modulators, including SGLT2i, mineralocorticoid receptor antagonists, ezetimibe and GLP-1 receptor agonists, may offer additional kidney protection. Ameliorating therapies being tested in Phase II trials include endothelin receptor antagonists (e.g., atrasentan), dual endothelin receptor antagonist and angiotensin II receptor inhibition (e.g., sparsentan) FXR agonists (e.g., vonafexor), inducers of cholesterol efflux (e.g., VAR200 and R3R01), and NOX1/4 inhibitors (e.g., setanaxib), several of which are currently being evaluated in clinical trials. Novel strategies such as exon skipping, gene editing, and nonsense mutation readthrough (e.g., ELX-02) are advancing toward precision medicine approaches as disease modifying agents targeting the genetic cause of AS...This review summarizes the current landscape of AS classification and treatment, highlighting both standard interventions and experimental therapies. Emphasis is placed..."

Journal • Review • Fibrosis • Gene Therapies • Genetic Disorders • Glomerulonephritis • Immunology • Renal Disease • COL4A5

A CFTR mouse model to study nonsense mutations independent of nonsense-mediated decay (NACFC 2025) - "Intestinal organoids produced robust swelling when treated with either G418 or ELX-02 (readthrough agents) with VX-445 and VX-661 (CFTR modulators) for 24 hrs, and CFTR function was not increased when SMG1i (NMD inhibitor) was added. The RNA produced from CFTRQ1411X mice does not undergo NMD. Effective CFTR restoration was achieved in the intestinal organoids with limited toxicity, indicating that nonsense mutations which do not undergo NMD may be therapeutically targetable with currently discovered readthrough agents in combination with approved CFTR modulators. We plan to treat CFTRQ1411X mice with ELX-02 and CFTR modulators to determine if this combination treatment can restore CFTR function in vivo and reduce CF manifestations in these mice."

Preclinical • Cystic Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Targeted eRF3a degradation amplifies nonsense mutation readthrough in a CF murine model (NACFC 2025) - "Organoids treated with G418 (readthrough agent) and VX-445 and VX-661 (CFTR modulators) for 24 hrs with either SMG1i (NMD inhibitor), CC-90009 (0.01 μM), or SJ6986 (0.05 μM) produced the following FIS area under the curve (AUC) results respectively: 1970 ± 33, 2730 ± 36, and 2810 ± 77 (% swelling x time). The intestinal organoids effectively responded to the CRBN modulators producing robust CFTR function as measured by FIS. The lack of NMD inhibition needed in combination with these modulators is exciting as NMD inhibition by SMG1i is toxic and difficult to overcome in therapy development. We plan to treat primary airway cells from the same mice to verify that restoration of CFTR function can be achieved in the airway as well when using CRBN modulators."

Preclinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation • CRBN • GSPT1

Novel readthrough compounds for the treatment of CF patients with nonsense mutations (NACFC 2025) - "16HBEge cells, primary human nasal epithelial (HNE) cells, and intestinal organoids, carrying G542X or Y122X mutations, were treated with URN-1 and URN-2 molecules and compared to the reference compound ELX-02 at 100 or 200 μM for 48 h before experiments, alone or in combination with a NMD inhibitor (SMG1, 0.5 μM, 24 h) and ETI (VX-661 3 μM/VX-445 3 μM/VX-770 100 nM). A structure-based drug design approach yielded compounds that efficiently readthrough CFTR UGA and UAA PTCs. URN molecules are more efficient than ELX-02 to rescue G542X- and Y122X-CFTR activity in heterologous and primary in vitro models."

Clinical

Ribosomal readthrough as an alternative therapy for hemophilia patients with nonsense mutations. (PubMed, J Thromb Haemost) - "Ribosomal readthrough therapy offers a promising small-molecule treatment option for managing bleeding symptoms in HA patients based on individual mutation profiles."

Journal • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases

Characterization of mTOR inhibitors for nonsense suppression of CFTR PTC variants (NACFC 2025) - " Combining aminoglycosides (G418, ELX-02) with eRF3a degrader CC-90009 resulted in the readthrough of native CFTR R1162X, achieving significant levels of full-length functional CFTR protein. Translational readthrough modulator screens have identified ribosome-binding antibiotics and eRF degraders as facilitators of PTC readthrough. Chemically diverse HTS hits likely have other mechanisms of action. A better understanding of the biological processes of nonsense suppression is crucial for developing therapeutic strategies to manage diseases caused by PTCs."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR • EIF2A • EIF2S1 • EIF4EBP1 • GSPT1 • RPS6

MRT-2359 - a novel molecular glue degrader of eRF3a induces readthrough of CFTR PTC variants (NACFC 2025) - "When combined with AGs G418 or ELX-02, MRT-2359 exhibited synergistic effects that further promoted functional readthrough in G542X, R1162X, and W1282X models, outperforming CC-90009... MRT-2359, alone or in combination with readthrough-promoting AGs, partially restores CFTR function for multiple CFTR PTC variants. These findings support further explorations of eRF3a as a therapeutic target for treating CF caused by nonsense variants."

Cystic Fibrosis • Genetic Disorders • Genito-urinary Cancer • Immunology • Prostate Cancer • Respiratory Diseases • Solid Tumor • Targeted Protein Degradation • CFTR • GSPT1

CC-90009, a modulator of Cereblon E3 ligase, restores W1282X and G542X CFTR nonsense variants in rectal organoids (NACFC 2025) - "Furthermore, the combination with the aminoglycosides G418 or ELX-02 but not with PTC124 further enhances their mutual effects, remarkably increasing the PTC readthrough response. In conclusion, the eRF3a degrader CC-90009, alone or combined with other compounds, could represent a promising therapeutic approach to rescue CFTR nonsense variants. Additional candidate read-through molecules are currently under study using our intestinal organoid-based screening and validation platform."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • Targeted Protein Degradation • CFTR • CRBN • GSPT1

High-throughput screening methods to discover new ribosomal inhibitors that rescue multiple classes of CFTR variants (NACFC 2025) - "Studies included treatment comparisons to established inhibitors of translation (G418, PTC-124, ELX-02, Escin) and CFTR modulators (elexacaftor-tezacaftor-ivacaftor, vanzacaftor-tezacaftor-deutivacaftor). Partial depletion of RPL12 levels represents a feasible strategy for CFTR modulation, which may be applicable to CFTR genotypes refractory to available clinical interventions. Our work serves as a foundation from which future investigations may be pursued to examine efficacy and tolerability of anti-RPL12 compounds or ASOs delivered to CF animal models."

CFTR

Enhanced Readthrough of Premature Termination Codons in Genodermatoses Using Combined Pharmacological Approaches (ESDR 2025) - "We evaluated the efficacy of two TRIDs, gentamicin and ELX-02, alone and in combination with two adjuvant molecules: a nonsense-mediated mRNA decay (NMD) inhibitor and a degrader of eukaryotic release factor 3 (eRF3). Preliminary data indicate that the triple-drug combination also promotes TGM1 PTC suppression in keratinocytes from a patient with lamellar ichthyosis. Ongoing functional and in vivo studies aim to evaluate the therapeutic potential and define optimal treatment regimens."

Atopic Dermatitis • Dermatology • Immunology • Vitiligo • COL7A1

Therapeutic Opportunities in Overcoming Premature Termination Codons in Epidermolysis Bullosa via Translational Readthrough. (PubMed, Cells) - "Preclinical and clinical studies with gentamicin have demonstrated restored type VII collagen and laminin-332 expression, leading to measurable clinical improvements. Parallel development of novel compounds-including aminoglycoside analogs (e.g., ELX-02), translation termination factor degraders (e.g., CC-90009, SRI-41315, SJ6986), tRNA post-transcriptional inhibitors (e.g., 2,6-diaminopurine, NV848), and nucleoside analogs (e.g., clitocine)-has expanded the therapeutic pipeline. Although challenges remain regarding toxicity, codon specificity, and variable protein restoration thresholds, continued advances in molecular targeting and combination therapies offer the potential to establish readthrough therapies as localized or systemic treatments addressing both cutaneous and extracutaneous disease manifestations in EB."

Journal • Review

Small molecules acting as eRF degraders differently rescue G542X and W1282X-CFTR function (ECFS 2025) - " 16HBE14o- cells with the G542X-CFTR mutation were treated for 24 h with different drug combinations containing CC-90009 (0.1 M) or SRI-41315 (15 M) with/without VX-809 (1 M), and ELX-02 (200 M), as a RT agent, or SMG1i (1 M), as a NMD inhibitor. The eRF3a degrader CC-90009 has a role in potentiating RT, since it is effective on G542X-CFTR in combination with ELX-02, while the eRF1 degrader SRI-41315 is particularly active on W1282X-CFTR together with SMG1i. These results suggest that eRF degraders have different involvement in RT and NMD mechanisms. This work was supported by: the Cystic Fibrosis Foundation (GALIET22I0), the Italian Cystic Fibrosis Foundation (FFC#9/2022 and GMRF#1/2024), and the Italian Ministry of Health (GR-2018-12367126)."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1

Small Molecule Premature Termination Codon Readthrough Therapy: A Phase 2 Pediatric and Adult Trial in Nonsense Mutation Alport Syndrome (KIDNEY WEEK 2024) - "ELX-02 is a small molecule that induces readthrough of premature (but not native) stop codons and is efficiently taken up by cells expressing megalin, allowing full length protein to be made by podocytes or tubular cells in the presence of a nonsense mutation... This first evidence of efficacy of a gene-targeted therapy in a podocyte-based Mendelian disease justifies a follow-on randomised-controlled study to quantify the potential for clinical benefit. Therapeutic readthrough of premature termination codons in Alport Syndrome suggests other genes expressed by megalin-expressing kidney cells may be targetable with this approach."

Clinical • Late-breaking abstract • P2 data • Genetic Disorders • Nephrology • Pediatrics • Renal Disease

Novel readthrough agent suppresses nonsense mutations and restores functional type VII collagen and laminin 332 in epidermolysis bullosa. (PubMed, Mol Ther Nucleic Acids) - "ELX-02, an aminoglycoside analog, has demonstrated superior PTC readthrough activity and lower toxicity compared to gentamicin in various genetic disorders. This is the first study demonstrating that ELX-02 can induce PTC readthrough and restore functional C7 and laminin 332 in RDEB and JEB caused by nonsense mutations. Therefore, ELX-02 may offer a novel and safe therapy for RDEB, JEB, and other inherited skin diseases caused by nonsense mutations."

Journal • Dermatology • Genetic Disorders • COL7A1 • LAMA3 • LAMC2

Determining the functional consequences of translational readthrough at common CFTR nonsense mutations (NACFC 2024) - "When we used other small-molecule compounds, such as SRI-41315 and ELX-02, to induce readthrough of G542X and G550X, we observed no major differences from the variants produced with G418-mediated readthrough. WT CFTR protein was produced upon readthrough of some CFTR PTC contexts used in this study (Y122X, Q493X, R553X, Y1092X). However, CFTR variant proteins were also created. Overall, readthrough at seven CF-causing PTCs yielded 12 variant CFTR protein possibilities."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Rescue of CFTR nonsense mutations is enhanced under inflammatory stimuli (NACFC 2024) - "Cells were also treated in the last 24 hours with ELX-02 (200 µM) plus VX-809 (1 µM) with or without CC-90009 (0.1 µM). We found that cytokine-treated epithelia had an enhanced response to the triple compound combination containing the eRF3a degrader CC-90009. We are investigating the molecular basis of this behavior because the cytokine treatment may change expression of genes controlling protein synthesis, thus potentiating the effect of readthrough maneuvers."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • GSPT1 • IL17A • IL4 • TNFA