Acid sphingomyelinase deficiency (ASMD) (also known as Niemann-Pick disease types A and B) is a rare and debilitating lysosomal storage disorder. This prospective, multi-center, multinational ...longitudinal study aimed to characterize the clinical features of chronic forms of ASMD and disease burden over time in children and adults.
Fifty-nine patients (31 males/28 females) ranging in age from 7 to 64 years with chronic ASMD types A/B and B and at least two disease symptoms participated from 5 countries. Disease characteristics were assessed at baseline, after 1 year, and at the final visit (ranging from 4.5 to 11 years). Thirty patients (51%) were < 18 years at baseline (median age 12 years), and 29 were adults (median age 32 years). Overall, 32/59 patients completed the final visit, 9 died, 9 discontinued, and 9 were lost to follow up. Common clinical characteristics that tended to worsen gradually with time were splenomegaly, hepatomegaly, interstitial lung disease, lung diffusion capacity (DL
), and dyslipidemia. Spleen volumes ranged from 4 to 29 multiples of normal at baseline, and splenomegaly was moderate or severe in 86%, 83%, and 90% of individuals at baseline, year 1, and final visits, respectively. The proportion of all individuals with interstitial lung disease was 66% (39/59) at baseline and 78% (25/32) at the final visit, while median % predicted DL
decreased by > 10% from baseline to the final visit. Nine patients died (15%), eight of causes related to ASMD (most commonly pneumonia); of these eight patients, five (63%) had symptom onset at or before age 2. Overall, six of the nine deaths occurred before age 50 with three occurring before age 20. Individuals with either severe splenomegaly or prior splenectomy were ten times more likely to have died during the follow-up period than those with smaller or intact spleens (odds ratio 10.29, 95% CI 1.7, 62.7). Most children had growth deficits that persisted into adulthood.
This study provides important information about the natural history of chronic ASMD and provides a longitudinal view of the spectrum of disease manifestations and major morbidities in children and adults and supports the selection of clinically meaningful endpoints in therapeutic trials.
Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have an extensive, intermediate or poor CYP2D6 metabolizer phenotype (> 90% of patients). Whereas enzyme ...replacement therapy for Gaucher disease has been widely used for more than two decades, eliglustat has only been in commercial use since 2014. Clinicians and patients want to better understand which adverse events are most commonly associated with eliglustat, as well as their severity, frequency, and duration.
This pooled analysis of treatment-emergent adverse events combines data from four completed eliglustat clinical trials involving 393 Gaucher disease type 1 patients. It represents 1400 patient-years of eliglustat exposure and a mean treatment duration of 3.6 years (maximum: 9.3 years).
Eighty-one percent of patients remained in their respective trial until commercial availability of eliglustat (US patients only) or until trial completion. Nine patients (2.3%) withdrew from their respective trial due to one or more adverse events reported as eliglustat treatment-related; all but one of these events were mild or moderate. Overall, 97% of adverse events were mild or moderate and 86% were reported by the investigator as unrelated to eliglustat treatment. The overall rate of adverse events decreased over time and did not increase with increasing eliglustat dose. We evaluated frequency, duration, and severity of 14 adverse event terms reported at least once as treatment-related in 2% or more of all patients: dyspepsia (5.9%), headache (5.3%), abdominal pain upper (5.1%), dizziness (5.1%), diarrhea (4.6%), nausea (4.6%), arthralgia (3.6%), constipation (3.3%), abdominal pain (2.8%), gastroesophageal reflux disease (2.8%), fatigue (2.8%), palpitations (2.8%), abdominal distension (2.5%), and gastritis (2.3%). For abdominal pain upper, diarrhea, nausea, abdominal pain, and headache events, median duration was less than 14 days. All 14 adverse event terms, except for arthralgia and headache, were reported only once per patient in more than 70% of patients experiencing the event.
This final pooled analysis of treatment-emergent adverse events reinforces the favorable safety profile of eliglustat. The majority of the most frequently reported treatment-related adverse events were mild or moderate, transient, and occurred only once per patient.
Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, ...open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval CI = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (−38.5%; 95% CI = −43.5%-−33.5%), liver volume (−17.0%; 95% CI = −21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1. This study is registered at www.clinicaltrials.gov as #NCT00358150.
Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naïve patients have now completed 4years of an open-label study (NCT00358150). ...Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of eliglustat reported at 1 and 2 years to 4 years.
Gaucher’s disease type 1 (GD1) leads to significant morbidity and mortality through clinical manifestations, such as splenomegaly, hematological complications, and bone disease. Two types of ...therapies are currently approved for GD1: enzyme replacement therapy (ERT), and substrate reduction therapy (SRT). In this study, we have developed a quantitative systems pharmacology (QSP) model, which recapitulates the effects of eliglustat, the only first‐line SRT approved for GD1, on treatment‐naïve or patients with ERT‐stabilized adult GD1. This multiscale model represents the mechanism of action of eliglustat that leads toward reduction of spleen volume. Model capabilities were illustrated through the application of the model to predict ERT and eliglustat responses in virtual populations of adult patients with GD1, representing patients across a spectrum of disease severity as defined by genotype‐phenotype relationships. In summary, the QSP model provides a mechanistic computational platform for predicting treatment response via different modalities within the heterogeneous GD1 patient population.
Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the ...increasing availability of real-world data, and advances in natural language processing, particularly large language models, allow for a more granular comparison of populations than previously possible. This study includes two research populations and two real-world data-derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using a manually validated natural language processing with a large language model to extract measurements of PD progression. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p < 0.001; mini-mental state exam median decline 0.28 vs. 0.11, p < 0.001; and clinically recognized cognitive decline, p = 0.001). In real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p < 0.001). After diagnosis, in real-world cohorts, treatment with PD medications has initiated an average of 2.3 years later (95% CI: 2.1-2.4; p < 0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real-world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.
Eliglustat is an oral glucosylceramide synthase inhibitor indicated for the long-term treatment of adults with Gaucher disease type 1 and CYP2D6 extensive, intermediate, or poor metabolizer ...phenotypes. Eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4 and is a substrate of P-glycoprotein (P-gp). Three studies evaluated the effects of paroxetine (strong CYP2D6 inhibitor), ketoconazole (strong CYP3A4 and P-gp inhibitor), and rifampin (strong CYP3A4/P-gp inducer; OATP inhibitor) on the pharmacokinetics of orally administered eliglustat in healthy adults. An 8.9-fold increase in eliglustat exposure following co-administration of multiple-dose eliglustat and paroxetine is attributed to inhibition of CYP2D6-mediated metabolism of eliglustat by paroxetine. A 4.3-fold increase in eliglustat exposure following co-administration of multiple-dose eliglustat and ketoconazole is attributed to inhibition of CYP3A4-mediated metabolism and/or P-gp-mediated transport of eliglustat by ketoconazole. Co-administration of eliglustat with oral doses of rifampin reduced eliglustat exposure by >85% due to induction of CYP3A4/P-gp by rifampin, while a single intravenous dose of rifampin had no effect on eliglustat, confirming that eliglustat is not an OATP substrate. Depending on CYP2D6 metabolizer phenotype, co-administration of eliglustat with CYP2D6 and/or CYP3A inhibitors or CYP3A inducers may alter eliglustat exposure, warrant dosage adjustment or use with caution, or be contraindicated.
•Co-administration of multiple-dose eliglustat and paroxetine (CYP2D6 inhibitor) increased eliglustat exposure.•Co-administration of multiple-dose eliglustat and ketoconazole (inhibitor of CYP3A and P-gp) increased eliglustat exposure.•Co-administration of eliglustat with oral rifampin (inducer of CYP3A and intestinal P-gp) reduced eliglustat exposure.•A single intravenous dose of rifampin had no effect on eliglustat exposure.•Eliglustat label contains dose adjustments/contraindications for co-administration with CYP2D6/3A inhibitors or inducers.
Three phase 1 studies of eliglustat tartrate (Genz‐112638), an oral inhibitor of glucosylceramide synthase under development for treating Gaucher disease type 1 (GD1), evaluated the safety, ...tolerability, and pharmacokinetics in healthy volunteers after escalating single doses (n = 99), escalating multiple doses (n = 36), and food (n = 24). Eliglustat tartrate was well tolerated at single doses ≤20 mg/kg and multiple doses ≤200 mg bid, with 50 mg bid producing plasma concentrations in the predicted therapeutic range. No serious adverse events occurred. Mild to moderate events of nausea, dizziness, and vomiting increased in frequency with escalating single and multiple doses. Single doses ≥10 mg/kg caused mild increases in electrocardiogram PR, QRS, and QT/QTc intervals. Single‐dose pharmacokinetics showed dose linearity but not proportionality. Maximum plasma concentrations occurred at ∼2 hours, followed by a monophasic decline with a ∼6‐hour terminal half‐life. Unchanged drug in 8‐hour urine collections was <1.5% of administered doses. Food did not significantly affect the rate or extent of absorption. Multiple‐dose pharmacokinetics was nonlinear, showing higher than expected plasma drug concentrations. Steady state was reached ∼60 hours after bid dosing. Higher drug exposure occurred in slower CYP2D6 metabolizers. Based on favorable results in healthy participants, a phase 2 trial of eliglustat tartrate was initiated in GD1 patients.
In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was ...noninferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in ≥85% of patients as well as individually in ≥92%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as #NCT00943111.
•Eliglustat treatment resulted in stable mean hemoglobin concentration, platelet count, and spleen and liver volumes for up to 4 years.•Mean bone mineral density z scores also remained stable and were maintained in the healthy reference range for up to 4 years.
PDF
