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

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

Development of a drug testing platform for CFTR premature termination codon variants based on rectal organoids (NACFC 2024) - "Incubation with the aminoglycoside G418, as expected from the literature, caused a significantly greater in FIS rate than control (vehicle) and ELX-02 or PTC124, with further improvement in combination with CFTR modulators (elexacaftor/tezacaftor/ivacaftor [ETI]). Our preliminary data indicate that the levels of swelling induced by G418+ETI reached reference AUC values of F508del/F508del organoids treated with VX809/ VX770 (mean 2,487.9 ± 504). Our data show that this platform may be able to evaluate the drug response that reflects variability in genotypes and individual response to pharmacological treatment to direct clinical research toward a rapid, reliable evaluation of the most promising compounds for CFTR PTC variants. Additional candidate readthrough molecules are being studied using this screening and validation platform."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Targeting elexacaftor/tezacaftor/ivacaftor-unresponsive CFTR mutations: novel drug combos in patient-derived organoids (NACFC 2024) - "We tested combinations of phosphodiesterase-4 (PDE4) inhibitors (roflumilast, apremilast) and the readthrough agent ELX-02 with a nonsense-mediated mRNA decay (NMD) inhibitor (SMG1i), alongside ETI. Testing combinations of modulators for mutations insufficiently responsive to or ineligible for ETI in PDROs can open novel therapeutic solutions for PwCF."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR

Screening for translational readthrough of CFTR R1162X leads to the identification of mammalian target of rapamycin inhibitors for nonsense suppression (NACFC 2024) - " Combining aminoglycosides (G418, ELX-02) with CC-90009 results in translational readthrough of native CFTR R1162X, achieving full-length CFTR protein levels equivalent to 20% of normal CFTR expression in parental 16HBE14o- cells. Screening a repurposing library is an attractive option to accelerate drug discovery for PwCF with CFTR nonsense variants. Further evaluation of the effect of mTOR inhibitors on the readthrough of CFTR nonsense variants may help reveal their therapeutic potential in nonsense suppression."

CFTR • GSPT1

A novel induced pluripotent stem cell-derived intestinal organoid protocol to assess CF therapies (NACFC 2024) - "Results by FIS indicate matched functional responses to ELX-02 in multiple PTC variants... This work represents the next generation of intestinal differentiation from iPSCs and focuses on advancing therapies for rare and nonsense CFTR variants. We generated and validated an isogenic panel of iPSC intestinal organoids with PTC-CFTR mutations and have begun exploring potential curative strategies including SuperExon approaches."

Clinical • Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases • CFTR • KRT20 • OLFM4

CFTR premature termination codon readthrough can be enhanced by a transcript-specific antisense oligonucleotide approach (NACFC 2024) - "We also investigated whether combining ASOs with PTC modulators such as aminoglycosides (G418, ELX-02) and eRF degraders (SRI-41315, CC-90009) enhances PTC readthrough. This study presents a new approach for enhancing specific PTC readthrough in CFTR using ASOs that target a sequence near PTCs. This approach has the potential to safely increase the efficacy of current PTC modulators without exacerbating transcriptome-wide undesired effects."

CFTR

Induced pluripotent stem cell-derived airway basal cell direct thaw protocol: A method to generate reproducible induced pluripotent stem cell-derived air-liquid-interface cultures (NACFC 2024) - "For example, representative AUC/min (mA/cm2) for a W1282X+/+ iBC line treated with ELX-02/CC-9009/VX445/VX661/VX770: Standard protocol = 2.67; iBC-direct thaw: 3.16. We have thoroughly analyzed the iBC-direct thaw protocol and shown its utility in CF research, specifically for genotypes with limited or no availability of primary cells. iBCs will be made available to the community upon request."

Cystic Fibrosis • Genetic Disorders • Immunology • Respiratory Diseases

Eloxx Pharmaceuticals Provides ELX-02 and ZKN-013 Program Updates (GlobeNewswire) - "Eloxx Pharmaceuticals, Inc...provided program updates for ELX-02 and ZKN-013, including Orphan Drug Designation (ODD) for ELX-02....Initiated Phase 1 Single Ascending Dose (SAD) study: Initiated Phase 1 SAD study in Australia with initial results expected in 2nd half of 2024."

Orphan drug • P1 data • Dermatology • Genetic Disorders • Muscular Dystrophy • Rare Diseases