Reply to Mistry et al. The Two Substrate Reduction Therapies for Type 1 Gaucher Disease Are Not Equivalent. Comment on "Hughes et al. Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS). J. Clin. Med. 2022, 11, 5158".

Thank you for allowing us the opportunity to respond to the commentary from Mistry and colleagues (Comment: The two substrate reduction therapies for type 1 Gaucher disease are not equivalent) [...].

Complement Inhibition in Paroxysmal Nocturnal Hemoglobinuria (PNH): A Systematic Review and Expert Opinion from Central Europe on Special Patient Populations.

INTRODUCTION: Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition. METHODS: The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement. RESULTS: Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence. CONCLUSION: Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.

Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1.

PURPOSE: Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1. METHODS: Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naïve patients or patients switching to eliglustat from enzyme replacement therapy (ERT). RESULTS: Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available. Mean eliglustat treatment duration ranged from 3.3 to 6.5 years. In treatment-naïve patients and ERT-switch patients, frequency and severity of bone pain decreased during eliglustat treatment. Mean lumbar spine T-scores shifted from abnormal to normal in treatment-naïve patients and remained in the healthy reference range or improved modestly in ERT-switch patients. Mean total bone marrow burden score shifted from marked-to-severe to moderate in treatment-naïve patients and remained moderate in ERT-switch patients. MIP-1ß (marker of active bone disease) was elevated at baseline and decreased to the healthy reference range in treatment-naïve patients and remained in the healthy reference range among ERT-switch patients. CONCLUSION: These findings confirm the long-term efficacy of eliglustat on skeletal complications of Gaucher disease in treatment-naïve and ERT-switch patients.

Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study.

Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.

Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS).

Switching between enzyme replacement therapies (ERT) and substrate reduction therapies (SRT) in patients with type 1 Gaucher disease (GD1) is not uncommon; however, the reasons for switchng treatments have not been explored in detail. Data from the Gaucher Outcome Survey (GOS), an international registry for patients with confirmed GD, were used to evaluate the reasons for, and consequences of, switching between these treatment types. Of the 1843 patients enrolled in GOS on 25 February 2020, 245 had undergone a treatment switch: 222 from initial ERT to SRT (of whom 88 later switched back to ERT) and 23 from initial SRT to ERT. The most common reasons for ERT-SRT switching were duration of infusion (25.4%), drug shortage (22.0%), and adverse events (AEs; 11.9%), and for SRT-ERT switching, AEs (63.6%), lack of beneficial effect (16.4%), and participation in a clinical trial (9.1%). Bodyweight and hematologic parameters largely remained stable before and after switching between ERT and SRT, although with substantial variation between patients. These findings contribute to understanding why treatment switching occurs in patients with GD, and may help physicians recognize the real-world impact of treatment switching between ERT and SRT for patients with GD.

Development of antibody resistance in emerging mutant strains of SARS CoV-2: Impediment for COVID-19 vaccines.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a highly infectious agent associated with unprecedented morbidity and mortality. A failure to stop growth of COVID-19-linked morbidity rates is caused by SARS-CoV-2 mutations and the emergence of new highly virulent SARS-CoV-2 strains. Several acquired SARS-CoV-2 mutations reflect viral adaptations to host immune defence. Mutations in the virus Spike-protein were associated with the lowered effectiveness of current preventive therapies, including vaccines. Recent in vitro studies detected diminished neutralisation capacity of vaccine-induced antibodies, which are targeted to bind Spike receptor-binding and N-terminal domains in the emerging strains. Lower than expected inhibitory activity of antibodies was reported against viruses with E484K Spike mutation, including B.1.1.7 (UK), P.1 (Brazil), B.1.351 (South African), and new Omicron variant (B.1.1.529) with E484A mutation. The vaccine effectiveness is yet to be examined against new mutant strains of SARS-CoV-2 originating in Europe, Nigeria, Brazil, South Africa, and India. To prevent the loss of anti-viral protection in vivo, often defined as antibody resistance, it is required to target highly conserved viral sequences (including Spike protein) and enhance the potency of antibody cocktails. In this review, we assess the reported mutation-acquiring potential of coronaviruses and compare efficacies of current COVID-19 vaccines against 'parent' and 'mutant' strains of SARS-CoV-2 (Kappa (B.1.617.1), Delta (B.1.617.2), and Omicron (B.1.1.529)).

The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives.

Breast cancer (BC) cell de-sensitization to Tamoxifen (TAM) or other selective estrogen receptor (ER) modulators (SERM) is a complex process associated with BC heterogeneity and the transformation of ER signalling. The most influential resistance-related mechanisms include modifications in ER expression and gene regulation patterns. During TAM/SERM treatment, epigenetic mechanisms can effectively silence ER expression and facilitate the development of endocrine resistance. ER status is efficiently regulated by specific epigenetic tools including hypermethylation of CpG islands within ER promoters, increased histone deacetylase activity in the ER promoter, and/or translational repression by miRNAs. Over-methylation of the ER α gene (ESR1) promoter by DNA methyltransferases was associated with poor prognosis and indicated the development of resistance. Moreover, BC progression and spreading were marked by transformed chromatin remodelling, post-translational histone modifications, and expression of specific miRNAs and/or long non-coding RNAs. Therefore, targeted inhibition of histone acetyltransferases (e.g. MYST3), deacetylases (e.g. HDAC1), and/or demethylases (e.g. lysine-specific demethylase LSD1) was shown to recover and increase BC sensitivity to anti-estrogens. Indicated as a powerful molecular instrument, the administration of epigenetic drugs can regain ER expression along with the activation of tumour suppressor genes, which can in turn prevent selection of resistant cells and cancer stem cell survival. This review examines recent advances in the epigenetic regulation of endocrine drug resistance and evaluates novel anti-resistance strategies. Underlying molecular mechanisms of epigenetic regulation will be discussed, emphasising the utilization of epigenetic enzymes and their inhibitors to re-program irresponsive BCs.

Randomized multicenter noninferiority phase III clinical trial of the first biosimilar of eculizumab.

Currently, eculizumab is the main effective treatment for paroxysmal nocturnal hemoglobinuria (PNH). The aim of this randomized multicenter noninferiority study was to evaluate the efficacy and safety of the Biosimilar (Elizaria) in comparison with the Originator (Soliris) in patients with PNH. Biosimilar and Originator were administered at a dose of 600 mg weekly for 4 weeks at the initial stage in naive patients, as well as for maintenance therapy at a dose of 900 mg every 2 weeks in all patients. The primary endpoint was a comparative assessment of hemolytic activity based on the area under the lactate dehydrogenase (LDH) concentration-time curve during the maintenance therapy. Thirty-two (32) patients were randomized for therapy with Biosimilar (n = 16) or Originator (n = 16). The mean values of LDH concentration-time curve were similar in both treatment groups without statistically significant differences (p > 0.05). Evaluation of secondary endpoints has shown no statistically significant differences between the groups. Safety values were comparable in both treatment groups. The data obtained confirm that the Biosimilar is not inferior to the Originator in terms of the main efficacy parameter, and is also comparable with it in terms of safety and additional efficacy parameters. Clinicaltrials.gov identifier: NCT04463056.

Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results.

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3-6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109 /L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 µg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.

Pregnancy outcome in women with Gaucher disease type 1 who had unplanned pregnancies during eliglustat clinical trials.

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficient enzymatic activity of acid ß-glucosidase, resulting in accumulation of its substrate glucosylceramide, leading to debilitating visceral, hematologic, and skeletal manifestations. Women with GD1 are at increased risk for complications during pregnancy, delivery, and postpartum. Treatment with enzyme replacement therapy is generally recommended before and during pregnancy to reduce risks. Eliglustat, an oral substrate-reduction therapy, is a first-line treatment for adults with GD1 adults who have extensive, intermediate, or poor CYP2D6-metabolizer phenotypes (>90% of patients). We report on pregnancy outcomes among women in eliglustat trials who had unplanned pregnancies and female partners of men in the trials. In four phase 2 and 3 eliglustat trials of 393 adults with GD1, women of childbearing potential were required to use contraception, have monthly pregnancy tests, and discontinue eliglustat promptly if pregnant. In phase 2 and 3 trials, 18 women had 19 pregnancies, resulting in 14 healthy infants from 13 pregnancies (one set of twins), three elective terminations, one ectopic pregnancy, one spontaneous abortion, and one in utero death. Median estimated eliglustat exposure duration during pregnancy was 38 days. In phase 1 trials (non-GD1 subjects), one woman had a spontaneous abortion. Partners of 16 eliglustat-treated men with GD1 had 18 pregnancies, all resulting in healthy infants. Eliglustat is not approved during pregnancy due to limited data. Guidelines for clinicians and patients with GD that address use of eliglustat in women of childbearing potential are needed.

Diagnostic significance of flow cytometry scales in diagnostics of myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) can present a challenge for clinicians. Multicolor flow cytometry (MFC) can aid in establishing a diagnosis. The aim of this study was to determine the optimal MFC approach for MDS. METHODS: The study included 102 MDS (39 low-grade MDS), 83 cytopenic patients without myeloid neoplastic disorders (control group), and 35 healthy donors. Bone marrow was analyzed using a six-color MFC. Analysis was conducted according to the "Ogata score," "Wells score," and the integrated flow cytometry (iFC) score. RESULTS: The respective sensitivity and specificity values were 77.5% and 90.4% for the Ogata score, 79.4% and 81.9% for the Wells score, and 87.3% and 87.6% for the iFC score. Specificity was not 100% due to deviations of MFC parameters in the control group. Patients with paroxysmal nocturnal hemoglobinuria (PNH) had higher levels of CD34+ CD7+ myeloid cells than donors. Aplastic anemia and PNH were characterized by a high proportion of CD56+ cells among CD34+ precursors and neutrophils. The proportion of MDS-related features increased with the progression of MDS. The highest number of CD34+ blasts was found in MDS with excess blasts. MDS with isolated del(5q) was characterized by a high proportion of CD34+ CD7+ cells and low granularity of neutrophils. In 39 low-grade MDS, the sensitivities were 53.8%, 61.5%, and 71.8% for Ogata score, Wells score, and iFC, respectively. CONCLUSION: The results support iFC as a useful diagnostic tool in MDS.

The definition of neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.

Sphingolipids as mediators of inflammation and novel therapeutic target in inflammatory bowel disease.

Morbidity of inflammatory gastrointestinal (GI) diseases continues to grow resulting in worsen quality of life and increased burden on public medical systems. Complex and heterogenous illnesses, inflammatory bowel diseases (IBDs) encompass several inflammation -associated pathologies including Crohn's disease and ulcerative colitis. IBD is often initiated by a complex interplay between host genetic and environmental factors, lifestyle and diet, and intestinal bacterial components. IBD inflammatory signature was linked to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) signaling pathway that is currently targeted by IBD therapies. Sphingolipid signaling was identified as one of the key mediators and regulators of pro-inflammatory conditions, and, specifically, TNF-α related signaling. All GI tissues and circulating immune/blood cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinases (SphK1 and SphK2) that generate sphingosine-1-phosphate (S1P), a bioactive lipid and ligand for five G-protein coupled membrane S1P receptors (S1PRs). Numerous normal and pathogenic inflammatory responses are mediated by SphK/S1P/S1PRs signaling axis including lymphocyte trafficking and activation of cytokine signaling machinery. SphK1/S1P/S1PRs axis has recently been defined as a target for the treatment of GI diseases including IBD/colitis. Several SphK1 inhibitors and S1PRs antagonists have been developed as novel anti-inflammatory agents. In this review, we discuss the mechanisms of SphK/S1P signaling in inflammation-linked GI disorders. The potential role of SphK/S1PRs inhibitors in the prevention and treatment of IBD/colitis is critically evaluated.

Biocompatible Organic Coatings Based on Bisphosphonic Acid RGD-Derivatives for PEO-Modified Titanium Implants.

Currently, significant attention is attracted to the problem of the development of the specific architecture and composition of the surface layer in order to control the biocompatibility of implants made of titanium and its alloys. The titanium surface properties can be tuned both by creating an inorganic sublayer with the desired morphology and by organic top coating contributing to bioactivity. In this work, we developed a composite biologically active coatings based on hybrid molecules obtained by chemical cross-linking of amino acid bisphosphonates with a linear tripeptide RGD, in combination with inorganic porous sublayer created on titanium by plasma electrolytic oxidation (PEO). After the addition of organic molecules, the PEO coated surface gets nobler, but corrosion currents increase. In vitro studies on proliferation and viability of fibroblasts, mesenchymal stem cells and osteoblast-like cells showed the significant dependence of the molecule bioactivity on the structure of bisphosphonate anchor and the linker. Several RGD-modified bisphosphonates of ß-alanine, γ-aminobutyric and ε-aminocaproic acids with BMPS or SMCC linkers can be recommended as promising candidates for further in vivo research.

Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate-to-severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Biomarker median percent changes from baseline were -91% for chitotriosidase, -87% for CCL18, -92% for glucosylsphingosine, and -80% for plasma glucosylceramide. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Presenting signs and patient co-variables in Gaucher disease: outcome of the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi initiative.

BACKGROUND: Gaucher disease (GD) presents with a range of signs and symptoms. Physicians can fail to recognise the early stages of GD owing to a lack of disease awareness, which can lead to significant diagnostic delays and sometimes irreversible but avoidable morbidities. AIM: The Gaucher Earlier Diagnosis Consensus (GED-C) initiative aimed to identify signs and co-variables considered most indicative of early type 1 and type 3 GD, to help non-specialists identify 'at-risk' patients who may benefit from diagnostic testing. METHODS: An anonymous, three-round Delphi consensus process was deployed among a global panel of 22 specialists in GD (median experience 17.5 years, collectively managing almost 3000 patients). The rounds entailed data gathering, then importance ranking and establishment of consensus, using 5-point Likert scales and scoring thresholds defined a priori. RESULTS: For type 1 disease, seven major signs (splenomegaly, thrombocytopenia, bone-related manifestations, anaemia, hyperferritinaemia, hepatomegaly and gammopathy) and two major co-variables (family history of GD and Ashkenazi-Jewish ancestry) were identified. For type 3 disease, nine major signs (splenomegaly, oculomotor disturbances, thrombocytopenia, epilepsy, anaemia, hepatomegaly, bone pain, motor disturbances and kyphosis) and one major co-variable (family history of GD) were identified. Lack of disease awareness, overlooking mild early signs and failure to consider GD as a diagnostic differential were considered major barriers to early diagnosis. CONCLUSION: The signs and co-variables identified in the GED-C initiative as potentially indicative of early GD will help to guide non-specialists and raise their index of suspicion in identifying patients potentially suitable for diagnostic testing for GD.

Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (>90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing. Of 170 enrolled patients, 156 completed the lead-in period and 131 met all requirements to enter the double-blind treatment period. To achieve the composite primary endpoint in the double-blind period, patients had to maintain clinical stability relative to baseline on all five endpoints (hemoglobin, platelet count, spleen and liver volumes, and bone symptoms) and meet pharmacokinetic and other tolerability requirements as determined by the investigator after 1year of eliglustat treatment. After 1year, 80.4% (95% CI: 67.6, 89.8) of once-daily patients were stable compared with 83.1% (95% CI: 71.0, 91.6) of twice-daily patients. The 95% CI for the mean difference of -2.7% between groups was -17.7, 11.9. Because the lower bound of the CI exceeded the pre-defined non-inferiority margin of -15%, once-daily dosing could not be declared non-inferior to twice-daily dosing. Both once-daily and twice-daily patients maintained mean values for hematologic and visceral measures within established therapeutic goals during the double-blind treatment and long-term extension periods. Eliglustat was generally well-tolerated during this long-term trial (mean treatment duration: 3.3years), with just four withdrawals (2%) for related adverse events (AE), and similar AE profiles for both dosing regimens. Patients on twice-daily eliglustat showed more stability overall, and this dose regimen was better tolerated, confirming the dosing regimen for most patients specified in the drug label.

Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

Gaucher disease is an inherited metabolic disease characterized by ß-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427.