Cerdelga (eliglustat tartrate) / Sanofi - LARVOL DELTA

Pharmacogenomics and rare diseases: optimizing drug development and personalized therapeutics. (PubMed, Pharmacogenomics) - "Case studies such as eliglustat for Gaucher disease and ivacaftor for cystic fibrosis demonstrate the efficacy of PGx-guided treatment strategies. Modernizing drug labeling with PGx information is critical to ensuring safe and effective druguse. Collectively, PGx offers transformative potential in RD therapeutics by facilitating personalized medicine approaches and addressing unmet medical needs."

Biomarker • Journal • Cystic Fibrosis • Gaucher Disease • Genetic Disorders • Immunology • Metabolic Disorders • Pulmonary Disease • Rare Diseases • Respiratory Diseases

Eliglustat and cardiac comorbidities in Gaucher disease: a pharmacogenomic approach to safety and efficacy. (PubMed, Front Med (Lausanne)) - "Unlike prior theoretical concerns derived from in vitro ion channel studies, our findings demonstrate that Eliglustat does not induce clinically significant cardiac events when administered according to pharmacogenomic guidelines. The misinformation regarding Eliglustat's cardiotoxicity, largely driven by speculative interpretations rather than clinical data, is effectively countered by our findings, which show no significant QT prolongation or arrhythmias over a median treatment duration of 8 years."

Biomarker • Journal • Atrial Fibrillation • Cardiovascular • CNS Disorders • Gaucher Disease • Genetic Disorders • Hypertension • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Myocardial Infarction • Pulmonary Arterial Hypertension • Pulmonary Disease • Rare Diseases • Respiratory Diseases • Type 1 Gaucher Disease • GBA

Challenges in Gaucher disease: Perspectives from an expert panel. (PubMed, Mol Genet Metab) - "Studies of switching from ERT to eliglustat, or between different ERT products, have indicated that changing treatment is safe, although efficacy outcomes vary. A critical remaining issue is the lack of treatments capable of reaching the CNS to slow or halt the progression of neuronopathic disease in patients with GD type 2 or 3 and potentially reduce the risk of Parkinson's disease in GD type 1 patients and heterozygotes for GBA1 variants."

Journal • Review • CNS Disorders • Gaucher Disease • Genetic Disorders • Hematological Malignancies • Lymphoma • Metabolic Disorders • Monoclonal Gammopathy • Movement Disorders • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • Parkinson's Disease • Pediatrics

Eliglustat substrate reduction therapy in children with Gaucher disease type 1. (PubMed, Front Pediatr) - "The therapy showed a favorable safety profile comparable to that observed in adults. These findings suggest eliglustat is a promising therapeutic option for pediatric GD1 patients, providing an effective alternative to ERT."

Journal • Gastroenterology • Gastroesophageal Reflux Disease • Gaucher Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Pediatrics • Rare Diseases • Type 1 Gaucher Disease

Model-informed repurposing of eliglustat for treatment and prophylaxis of Shiga toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS) in children. (PubMed, Pediatr Nephrol) - "Based on pharmacokinetic modeling, we developed oral and intravenous eliglustat dosing regimens that are likely safe and effective for treatment of STEC-HUS and prophylaxis in case of outbreaks of STEC infections. Clinical evaluation of these dosing regimens in children suspected of or diagnosed with STEC-HUS is required and should include assessment of pharmacokinetics, efficacy, and safety (e.g., ECG monitoring)."

Journal • Atypical Hemolytic Uremic Syndrome • Cardiovascular • Gaucher Disease • Genetic Disorders • Infectious Disease • Metabolic Disorders • Nephrology • Pediatrics

UPLC-MS/MS Method for Givinostat in Rat Plasma: Development, Validation, in vivo Pharmacokinetics Study and in vitro Metabolic Stability Research. (PubMed, Drug Des Devel Ther) - "This study aimed to develop and verify a quick assay for the measurement of givinostat concentration using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) with eliglustat as the internal standard (IS), establishing a basic pharmacokinetic profile for its pre-clinical application and metabolic stability in vitro. Givinostat was rapidly absorbed and cleared slowly in vivo, and it was confirmed by in vitro experiments. This study provides a potential reference for givinostat in clinical studies."

Journal • PK/PD data • Preclinical • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

Inhibiting UGCG prevents PRV infection by decreasing lysosome-associated autophage. (PubMed, Int J Biol Macromol) - "Finally, through in vivo evaluation, this study revealed that UGCG inhibitors, Eliglustat hemitartrate and Ibiglustat, hold promise as potential therapeutics for the treatment of PRV infection. In summary, this study preliminarily elucidates the impact of UGCG on PRV infection and its associated molecular mechanisms, suggesting UGCG could serve as a potential novel target for the prevention and treatment of viral diseases such as PRV."

Journal • Infectious Disease • Metabolic Disorders

Building Confidence in Physiologically Based Pharmacokinetic Modeling of CYP3A Induction Mediated by Rifampin: An Industry Perspective. (PubMed, Clin Pharmacol Ther) - "Case studies for three challenging DDI predictions (i.e., for eliglustat, tofacitinib, and ribociclib) are presented. PBPK modeling was shown to be an effective tool to predict induction DDIs with rifampin for CYP3A substrates with limited mechanistic complications, increasing confidence in the rifampin model. While this analysis focused on rifampin, the learnings may apply to other inducers."

Journal • PK/PD data • Review • CYP3A4

LONG-TERM SAFETY OUTCOMES OF ELIGLUSTAT IN PATIENTS WITH GAUCHER DISEASE: PROSPECTIVE, MULTICENTER, OBSERVATIONAL, POST AUTHORIZATION SAFETY SUB-REGISTRY STUDY (SSIEM 2024) - "Eliglustat was well-tolerated by GD1 patients in real-world and safety profile was consistent with that observed during clinical development."

Clinical • Back Pain • Gaucher Disease • Genetic Disorders • Infectious Disease • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Novel Coronavirus Disease • Pain • Pneumonia • Respiratory Diseases • Rheumatology • Type 1 Gaucher Disease

SAFETY AND PHARMACOKINETICS OF ELIGLUSTAT ADMINISTERED WITH AND WITHOUT IMIGLUCERASE IN PAEDIATRIC PATIENTS WITH GAUCHER DISEASE TYPE 1/3: ELIKIDS STUDY (SSIEM 2024) - P3 | "Eliglustat was well tolerated in paediatric participants with GD1 and GD3. The safety profile of eliglustat observed in paediatric participants with GD1 and GD3 is in line with the established safety profile seen in adults with GD1. PK exposure is aligned with the target exposure seen in the adult eliglustat clinical trials."

Clinical • PK/PD data • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Pediatrics • Type 1 Gaucher Disease

HETEROGENEITY OF GAUCHER DISEASE PHENOTYPES IN PATIENTS WITH THE C.1880T>G (D409H) VARIANT IN GBA1. (SSIEM 2024) - "Adult type 1 patients currently receive eliglustat treatment, maintaining therapeutic objectives without adverse events. Heterozygous patients with neurological manifestations received miglustat in addition with ERT in 3 cases, and 3 receiving ambroxol... Comprehensive genetic sequencing is imperative for identifying detected combinations and offering appropriate genetic assessment."

Clinical • Heterogeneity • CNS Disorders • Epilepsy • Gaucher Disease • Genetic Disorders • Metabolic Disorders

EFFICACY OF ELIGLUSTAT ADMINISTERED WITH AND WITHOUT IMIGLUCERASE IN PAEDIATRIC PATIENTS WITH GAUCHER DISEASE TYPE 1 OR 3: ELIKIDS STUDY (SSIEM 2024) - P3 | "The majority of study participants who received eliglustat monotherapy and eliglustat in combination with imiglucerase maintained Gaucher-related clinical parameters within the prespecified therapeutic goals during the 52-week PAP."

Clinical • Gaucher Disease • Genetic Disorders • Hematological Disorders • Metabolic Disorders • Pediatrics • Type 1 Gaucher Disease

Glucosylceramide regulates mitochondria function and inflammation in diabetic kidneys (KLC 2024) - "The overexpression of UGCG caused significantly increased inflammation and decreased mitochondrial gene expression. To test whether the inhibition of glucosylceramide synthase could mediate the beneficial effects of reduced glucosylceramide level in the kidney, we treated the diabetic mice with UGCG inhibitor eliglustat and found that the short-term treatment of eligludtat successfully decreased the overall glucosylceramide level in the diabetic kidneys.In this study, we explored the potential impact of UGCG-mediated glucosylceramide synthesis in the diabetic kidneys and provided evidence to support a novel treatment avenue to use UGCG inhibitor eliglustat."

Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus

GSL Synthetase Inhibitor Plus Immune Checkpoint Inhibitor and/or Regorafenib in Previously Treated pMMR/MSS CRC. (clinicaltrials.gov) - P2 | N=120 | Not yet recruiting | Sponsor: Chinese PLA General Hospital

Checkpoint inhibition • Combination therapy • IO biomarker • Metastases • New P2 trial • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD4 • CD8 • IL2 • IL6 • TNFA

Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial. (PubMed, Nat Commun) - P1 | "Of the 8 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer, one achieved complete response and two each had partial response and stable disease. In summary, inhibiting the synthesis of GSLs might represent an effective immunotherapy approach."

Checkpoint inhibition • Combination therapy • Journal • Metastases • P1 data • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Ceramide metabolism alterations contribute to Tumor Necrosis Factor-induced melanoma dedifferentiation and predict resistance to immune checkpoint inhibitors in advanced melanoma patients. (PubMed, Front Immunol) - "Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation...Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy. Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy."

Checkpoint inhibition • IO biomarker • Journal • Metastases • Cutaneous Melanoma • Genetic Disorders • Melanoma • Metabolic Disorders • Oncology • Ophthalmology • Skin Cancer • Solid Tumor • ASAH1 • MITF • TNFA

Presentation of ichthyosis after substrate reduction therapy in Gaucher type 1. (PubMed, Am J Med Genet A) - "We describe a case in which a type 1 Gaucher patient developed ichthyosis weeks after starting substrate reduction therapy (SRT) with eliglustat...Ichthyosis is seen with type 2 and 3 Gaucher disease, but not type 1. This raises the question: Why would a patient develop ichthyosis after starting SRT?"

Journal • Atopic Dermatitis • Dermatology • Gaucher Disease • Genetic Disorders • Immunology • Metabolic Disorders • Type 1 Gaucher Disease • Vitiligo

Targeting sphingolipid metabolism in chronic lymphocytic leukemia. (PubMed, Clin Exp Med) - "To evaluate the therapeutic potential of inhibiting GluCer synthesis, we genetically repressed the UGCG pathway using in vitro models of leukemic B cells, in addition to UGCG pharmacological inhibition with approved drugs such as eliglustat and ibiglustat, both individually and in combination with ibrutinib, assessed in cell models and primary CLL patient cells. Inhibitors that target alternative pathways within sphingolipid metabolism, like sphingosine kinases inhibitor SKI-II, also demonstrated promising therapeutic effects both alone and when used in combination with ibrutinib, reinforcing the oncogenic impact of sphingolipids in CLL cells. Targeting sphingolipid metabolism, especially the UGCG pathway, represents a promising therapeutic strategy and as a combination therapy for potential treatment of CLL patients, warranting further investigation."

Journal • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology

Efficacy and Safety of Eliglustat in Chinese Pediatric Patients With Gaucher Disease Type 1 and Type 3 (clinicaltrials.gov) - P2 | N=5 | Not yet recruiting | Sponsor: Peking Union Medical College Hospital

New P2 trial • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Pediatrics • Type 1 Gaucher Disease

Histologic and ultrastructural study of intracranial Gaucheroma causing deafness in a patient with Gaucher disease type 3: Effects of substrate reduction therapy. (PubMed, Mol Genet Metab Rep) - "Combination therapy of ERT with imiglucerase and substrate reduction therapy (SRT) with eliglustat significantly decreased the size of Gaucher cells and cleared the characteristic microtubular structures in the lysosomes in Gaucher cells. Early implementation of SRT may prevent at least conductive hearing impairment in GD although it may not prevent sensorineural hearing loss due to inner hair cell dysfunction which is also known to be associated with neuronopathic GD."

Journal • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Otorhinolaryngology

LONG-TERM SAFETY OUTCOMES OF ELIGLUSTAT IN PATIENTS WITH GAUCHER DISEASE: PROSPECTIVE, MULTICENTER, OBSERVATIONAL, POST AUTHORIZATION SAFETY SUB-REGISTRY STUDY (EHA 2024) - "Eliglustat was well-tolerated by GD1 patients in real-world and safety profile wasconsistent with that observed during clinical development. Table 1. Exposure-adjusted incidence rate of AEs and SAEs for any eliglustat and imiglucerase treatments"

Clinical • Back Pain • Gastroenterology • Gastrointestinal Disorder • Gaucher Disease • Genetic Disorders • Immunology • Infectious Disease • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Novel Coronavirus Disease • Pain • Pneumonia • Respiratory Diseases • Rheumatology • Type 1 Gaucher Disease

SAFETY, PHARMACOKINETICS, AND EFFICACY OF ELIGLUSTAT ADMINISTERED WITH AND WITHOUT IMIGLUCERASE IN PAEDIATRIC PARTICIPANTS WITH GAUCHER DISEASE TYPE 1 OR 3: THE ELIKIDS STUDY (EHA 2024) - P3 | "Eliglustat was well tolerated in paediatric participants with GD1 and GD3 and no new safety issues wereidentified during the PAP."

Clinical • PK/PD data • Gaucher Disease • Genetic Disorders • Hematological Disorders • Metabolic Disorders • Orthopedics • Pediatrics • Pulmonary Disease • Respiratory Diseases • Thrombocytopenia • Type 1 Gaucher Disease

Increasing the immunogenicity of neuroblastoma by modulating ganglioside expression (CIMT 2024) - "Their expression can be regulated by glucosylceramide synthase inhibitors such as eliglustat, which are used for treating patients with Gaucher’s disease...As the drug is already used in paediatric patients with Gaucher syndrome, it could be easily tested whether it is also effective in the treatment of tumours. Moreover, the effect of gangliosides expression on the MHC expression could be relevant also for adult tumour entities with a neuroendocrine origin such as small cell lung cancer (SCLC), which has an altered ganglioside expression and a low intrinsic expression of MHC-1."

Tumor mutational burden • CNS Tumor • Gaucher Disease • Lung Cancer • Metabolic Disorders • Neuroblastoma • Oncology • Pediatrics • Small Cell Lung Cancer • Solid Tumor • IFNG • TMB

Long-term effectiveness of eliglustat treatment: A real-world analysis from the International Collaborative Gaucher Group Gaucher Registry. (PubMed, Am J Hematol) - "Among splenectomized switch patients, clinical parameters were stable over time. These long-term, real-world outcomes are consistent with the eliglustat clinical trials and emerging real-world experience across the GD phenotypic spectrum."

Journal • Real-world • Real-world evidence • Gaucher Disease • Genetic Disorders • Metabolic Disorders • Type 1 Gaucher Disease

Cost-Effectiveness of Eliglustat Tartrate for the Treatment of Type 1 Gaucher Disease in China Using a Semi-Markov Model (ISPOR 2024) - "Using the threshold of 2 times per capita GDP (2022, CN¥171,396), Eliglustat Tartrate was predicted to improve outcomes and be a cost-effective treatment option compared with standard care without Eliglustat Tartrate for GD-1 patients in China. Considering that Eliglustat Tartrate was added to the NRDL in 2023, the introduction of Eliglustat Tartrate would benefit more GD-1 patients."

Cost effectiveness • HEOR • Gaucher Disease • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases • Type 1 Gaucher Disease