ELD607 / Eldec Pharma - LARVOL DELTA

Neutrophil store-operated Ca2+ entry: A correctable biomarker of cystic fibrosis lung disease progression. (PubMed, J Cyst Fibros) - "Our findings highlight SOCE as a novel biomarker of CF lung disease. ELD607 can be used to reduce SOCE and subsequent degranulation in CF neutrophils. We therefore hypothesize that ELD607 may be of benefit in the management of inflammation in pwCF."

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

Is the SPLUNC1-Orai1 axis a critical determinant of lung health? (PubMed, Biochem Soc Trans) - "Here, we discuss how dysregulation of SPLUNC1-Orai1 interactions may contribute to hyperinflammation in multiple pulmonary diseases. We, and others, have also targeted Orai1 therapeutically, and we will also discuss how Orai1 inhibition may overcome SPLUNC1 deficiency and be beneficial for the treatment of chronic lung disease."

Journal • Review • Asthma • Bronchiectasis • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation

ELD607, an Orai1 antagonist, reverses goblet cell metaplasia in βENaC mice. (NACFC 2024) - "However, beyond ibuprofen, there are no currently approved anti-inflammatory drugs to treat PwCF...However, chronic ELD607 dosing had no effect on isoprenaline or amiloride-sensitive currents (markers of CFTR and ENaC activity, respectively) in WT or βENaC mice... Chronic ELD607 inhalation significantly reduced pulmonary inflammation, goblet cell metaplasia, mucus obstruction, and lung damage, which led to greater likelihood of survival. These data indicate that inhibition of Orai1-mediated inflammation can significantly reverse CF-like lung disease without affecting the primary defection (Na+ absorption). ELD607 is a novel, inhaled immunomodulator that may be suitable for treating CF lung disease."

Preclinical • Bronchiectasis • Cystic Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE

Inhibition of Orai1 with ELD607 is immunomodulatory and reduces chronic lung disease in CF ferrets (NACFC 2024) - "These experiments were performed in adult CF ferrets with established lung disease, Intratracheal ELD607 is a viable option to reduce CF lung inflammation and mucin levels. Our data also suggest that local inhibition of Orai1 with inhaled ELD607 may help repair the CF lung."

Immunomodulating • Cystic Fibrosis • Genetic Disorders • Immunology • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE • MUC5AC

Inhibition of Orai1 downregulates MUC5AC in human bronchial epithelial cultures (NACFC 2024) - "Similarly, ELD607 had no significant effect on baseline, amiloride-sensitive, forskolin-activated or UTP-activated Isc (n = 3 per group) or ASL height (n = 6 per group). Our data indicate that ELD607 directly reduced MUC5AC expression in inflamed airway epithelia and predicted that inhibition of Orai1 will not impair ion or fluid transport or ciliary beating, suggesting that ELD607 may reverse mucus hypersecretion without impairing mucus hydration. We propose that ELD607 inhalation may be a viable therapy to reduce goblet cell metaplasia in CF lungs, although the contributions of Orai1 vs other Ca2+ channels to airway epithelial function need further exploring."

Inflammation • MUC5AC • MUC5B

ELD607 specifically traffics Orai1 to the lysosome leading to inhibition of store operated calcium entry. (PubMed, Cell Calcium) - "Finally, ELD607 caused Orai1, but not Orai2, Orai3, or STIM1 to traffic to lysosomes. We conclude that ELD607 rapidly binds to Orai1 and works in an identical fashion as full length SPLUNC1 by internalizing Orai1 and sending it to lysosomes, leading to a decrease in SOCE."

Journal • Inflammation • Targeted Protein Degradation • NEDD4 • RAB5A • STIM1

The Orai1 Antagonist, ELD607, Reduces Chronic Neutrophilic Inflammation in βENaC Mice (ATS 2024) - "However, beyond ibuprofen, there are no currently approved anti-inflammatory drugs to treat CF patients. Chronic ELD607 inhalation significantly reduces pulmonary inflammation and lung damage, leading to increased survival. These data suggest ELD607 serves as a novel, inhaled immunomodulator that may be suitable for repeated use in CF patients and other individuals with chronic lung disease."

Preclinical • Bronchiectasis • Cystic Fibrosis • Fibrosis • Genetic Disorders • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE

The Orai1 Antagonist ELD607 Safely Reduces Lung Inflammation in G551D Cystic Fibrosis Ferrets (ATS 2024) - "Histology/proteomic studies in acute ferrets and chronic studieswith ELD607 in G551D ferrets are ongoing. However, these data support our over arching hypothesis that ELD607 acts as an immunomodulator that can normalize neutrophilic inflammation to reduce lung damage."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an ARDS Model. (PubMed, Am J Respir Crit Care Med) - "Indeed, when alveolar macrophages were depleted with inhaled clodronate, ELD607 was no longer able to resolve inflammation or clear bacteria. These data indicate that specific Orai1 inhibition by ELD607 may be a novel approach to reduce multi-organ inflammation and treat antibiotic-resistant bacteria."

Journal • Acute Lung Injury • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

ELD607, a Novel Orai1 Antagonist, Reduces Inflammation and Clears Burkholderia cepacia Complexand Multidrug-Resistant Pseudomonas aeruginosa from the Lungs. (NACFC 2023) - "To determine if macrophages underpinned the ELD607- induced increase in bacterial clearance and phagocytosis, mice were treated intratracheally with liposomes containing clodronate to deplete alveolar macrophages. ELD607 lowered neutrophilia and promoted macrophage-mediated resolution of inflammation regardless of pathogen. ELD607 reduced lung bacterial burden of Bcc and MDR-Pa. ELD607 may be a novel therapeutic to clear antibiotic-resistant bacteria from CF lungs."

Infectious Disease • Inflammation

Normal, but not cystic fibrosis, sputum inhibits pro-inflammatory Orai1 Ca2+ signaling (NACFC 2023) - "This work identifies a unique and surprising mechanism of Orai1 inhibition that involves STIM1-independent Orai1 puncta formation. Because we have demonstrated this puncta formation with SPLUNC1, as well as ELD607, we conclude that this is an endogenous mechanism that occurs in vivo. We also demonstrated that this inhibitory mechanism is lacking in CF sputum."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • ELANE • STIM1

Abnormal calcium signaling in cystic fibrosis neutrophils is inversely correlated with FEV1 and can be corrected with the Orai1 antagonist ELD607 (NACFC 2023) - "Thapsigargin (SECRA pump inhibitor, depletes endoplasmic reticulum of Ca2+)-induced SOCE was measured using the Ca2+-sensitive dye fluo4...Elexacaftor-tezacaftor-ivacaftor treatment did not normalize SOCE in the neutrophils of people with CF (n = 12, p = 0.003, t-test)... These data indicate that current CFTR modulator therapies fail to treat the excessive pro-inflammatory Ca2+ signaling observed in CF neutrophils and that SOCE in CF neutrophils may serve as a minimally invasive biomarker of disease progression. These data also suggest that additional immunomodulatory therapies will be required to reduce inflammation for optimal management of CF, highlight Orai1 as a potential target for immunomodulators, and demonstrate proof of concept for the use of ELD607 to modulate CF neutrophil function."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • STIM1

The Novel Orai1 Antagonist ELD607 Rescues the Hyperinflammatory Ca2+ Signaling Seen in CF Neutrophils (ATS 2023) - "Thapsigargin stimulated SOCE was measured using the Ca2+ sensitive fluorescent dye, fluo-4. Normalizing Ca2+ homeostasis in these cells improved defective apoptosis responses which may promote the resolution of inflammation. Future work will characterize further functional effects of ELD607 treatment."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • ANXA5 • RAI1

ELD607, a Novel Anti-Orai1 Peptide, Clears Methicillin-resistant Staphylococcus Aureus and Reduces Inflammation in the Lungs (ATS 2023) - "Here, we tested whether inhaled ELD607 could inhibit local Orai1 and reduce pulmonary MRSA infections in mice. To determine if ELD607 peptide inhibits Orai1, thapsigargin-induced Ca2+ release ± ELD607 was measured in HEK293T cells. ELD607 was well-tolerated in mice. Despite not being an antibiotic, ELD607 reduced neutrophilia and cleared MRSA from murine lungs. We hypothesis that local Orai1 inhibition leads to macrophage-dominated MRSA clearance from lungs."

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Infectious Disease • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

ELD607 inhibits excessive proinflammatory Ca2+ signaling in cystic fibrosis neutrophils (NACFC 2022) - "To measure Ca 2+Posters / Journal of Cystic Fibrosis 21S2 (2022) S1 –S378 S224 signaling, neutrophils were loaded with the Ca2+-sensitive fluorescent dye fluo-4, and fluorescence was measured in response to stimulation with1 mM thapsigargin using a Tecan plate reader.Neutrophils were collected from four people without CF and 12people with CF with a range of CF transmembrane conductance regulatormutations including F508del, L467P , 4209TGTT >A, G551D, and N1303K.Eleven of the12 were undergoing elexacaftor/tezacaftor/ivacaftor treat-ment at the time of collection. Collectively, these data indicate that CF neutrophils displayexaggerated Ca 2+signaling in response to thapsigargin that can beinhibited by ELD607. We predict that ELD607 treatment will benefitpeople with CF by rebalancing Ca 2+signaling in CF neutrophils and reducing inflammation."

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

Toxicology of ELD607, a novel immunomodulator of inflammatory responses in cystic fibrosis lungs (NACFC 2022) - "Background:Management of airway inflammation is a vital aspect of cysticfibrosis (CF) treatment, but beyond ibuprofen, there are no approved anti-inflammatory drugs to treat people with CF. ELD607 has no significant toxic effects in vitro or in vivo insmall animal models and may serve as a safe, novel therapeutic for anti-inflammatory effects in people with CF."

Allergy • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immune Modulation • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] ELD607 inhibits proinflammatory Ca2+ activity in cystic fibrosis patient neutrophils (NACFC-I 2021) - " Three-hour exposure to ELD607 dose-dependently inhibited thapsigargin-induced SOCE in HEK293T cells by approximately 50%, with an IC50 of 95nM. These data demonstrate that ELD607 is an effective novel Orai1 inhibitor that can provide localized immunomodulation in the airway lumen. We hypothesize that ED607 can promote resolution of neutrophilic inflammation in CF airways and reduce tissue damage."

Clinical • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immune Modulation • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • ELANE

[VIRTUAL] Toxicity profile of ELD607, a novel immunomodulator that reduces inflammation (NACFC-I 2021) - "We investigated the toxicity of ELD607 using a high-profile in vitro and in vivo panel of industry-validated assays. ELD607 was found to be safe and well tolerated in animals even at concentrations that were well above therapeutic dosing."

Immune Modulation • Immunology • Inflammation • Non‐Cystic Fibrosis Bronchiectasis • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Novel immunomodulator ELD607 reduces neutrophilic inflammation in βENaC and Pseudomonas aeruginosa–infected mice (NACFC-I 2021) - "ELD607 significantly reduces pulmonary inflammation and lung damage, suggesting that it may serve as a novel inhaled antiin flammatory immunomodulator."

Preclinical • Immune Modulation • Immunology • Infectious Disease • Inflammation • Non‐Cystic Fibrosis Bronchiectasis • Pneumonia • Pulmonary Disease • Respiratory Diseases • ELANE