Twelve Years of the Gaucher Outcomes Survey (GOS): Insights, Achievements, and Lessons Learned from a Global Patient Registry.

Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.

Long-Term Treatment of Gaucher Disease with Velaglucerase Alfa in ERT-Naïve Patients from the Gaucher Outcome Survey (GOS) Registry.

Background: Gaucher disease (GD) is a rare, autosomal, recessive condition characterized by hepatosplenomegaly, thrombocytopenia, anemia, and bone abnormalities, often requiring life-long treatment. Velaglucerase alfa has improved hematologic and visceral parameters in clinical trials; however, limited long-term efficacy and safety data are available. Methods: The Gaucher Outcome Survey (GOS), a structured and validated international registry for patients with confirmed GD, provides an opportunity to evaluate long-term data from patients receiving velaglucerase alfa. Results: This analysis included 376 treatment-naïve children and adults with GD enrolled in GOS, including 20 with type 3 GD, who initiated velaglucerase alfa through participation in clinical trials or as part of their clinical management and continued treatment for a mean (range) time of 6.6 (0.003-18.6) years. Initial improvements in hematologic and visceral parameters and the biomarkers glucosylsphingosine (lyso-GL1) and chitotriosidase were observed after one year of treatment and were maintained throughout the follow-up period. Of 129 (34.3%) patients who developed adverse events during the follow-up period, events were considered related to treatment in 33 (8.8%). None led to treatment discontinuation. There were 21 deaths overall, none of which were considered related to treatment. Conclusions: This analysis of data from the GOS registry supports the safety and efficacy of velaglucerase alfa in patients with GD.

A global neuronopathic gaucher disease registry (GARDIAN): a patient-led initiative.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder. GD types 2 and 3 are known as neuronopathic Gaucher disease (nGD) because they have brain involvement that progresses over time. Implementing a systematic approach to the collection of real-world clinical and patient-relevant outcomes data in nGD presents an opportunity to fill critical knowledge gaps and ultimately help healthcare providers in the management of this patient population. This paper summarizes the development of a patient-initiated Gaucher Registry for Development Innovation and Analysis of Neuronopathic Disease (GARDIAN). METHODS: The International Gaucher Alliance led the GARDIAN planning, including governance, scope, stakeholder involvement, platform, and reporting. Registry element input was determined in a series of meetings with clinical experts, patients, and caregivers, who identified key clinical variables and the draft content of nGD patient-reported outcomes (PRO) and observer-reported outcomes (ObsRO) focusing on symptoms, patient physical and emotional functioning. These were then tested in cognitive interviews with patients with nGD (> 12 years of age) and caregivers. RESULTS: Core registry data elements (n = 138) were identified by seven global clinical experts from Egypt, Germany, Israel, Japan, United Kingdom (UK), and United State (US) and reviewed via online Delphi method by 14 additional clinicians with experience of nGD from six countries and three pharmaceutical representatives. The elements were consistent with those identified via interviews with 10 patients/caregivers with nGD from Japan, Sweden, UK, and US. Key domains identified were demographics, diagnostic information, health status, clinical symptomatology, laboratory testing, treatment, healthcare resource utilization, aids/home improvements, and patient/caregiver burden and quality of life, specifically physical functioning, self-care, daily and social activities, emotional impacts, support services, and caregiver-specific impacts. Nine caregivers and six patients from the US, UK, China, Mexico, Egypt, and Japan participated in the cognitive interviews that informed revisions to ensure that all items are understandable and interpreted as intended. CONCLUSIONS: The comprehensive set of clinical and patient relevant outcomes data, developed collaboratively among all stakeholders, to be reported using GARDIAN will bridge the many gaps in the understanding of nGD and align with regulatory frameworks on real-world data needs.

FindZebra online search delving into rare disease case reports using natural language processing.

Early diagnosis is crucial for well-being and life quality of the rare disease patient. Access to the most complete knowledge about diseases through intelligent user interfaces can play an important role in supporting the physician reaching the correct diagnosis. Case reports may offer information about heterogeneous phenotypes which often further complicate rare disease diagnosis. The rare disease search engine FindZebra.com is extended to also access case report abstracts extracted from PubMed for several diseases. A search index for each disease is built in Apache Solr adding age, sex and clinical features extracted using text segmentation to enhance the specificity of search. Clinical experts performed retrospective validation of the search engine, utilising real-world Outcomes Survey data on Gaucher and Fabry patients. Medical experts evaluated the search results as being clinically relevant for the Fabry patients and less clinically relevant for the Gaucher patients. The shortcomings for Gaucher patients mainly reflect a mismatch between the current understanding and treatment of the disease and how it is reported in PubMed, notably in the older case reports. In response to this observation, a filter for the publication date was added in the final version of the tool available from deep.findzebra.com/ with = gaucher, fabry, hae (Hereditary angioedema).

Development and validation of Gaucher disease type 1 (GD1)-specific patient-reported outcome measures (PROMs) for clinical monitoring and for clinical trials.

BACKGROUND: Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. RESULTS AND DISCUSSION: The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients' understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test-retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test-retest reliability. CONCLUSIONS: Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment.

Impact of the COVID-19 pandemic on the standard of care for patients with lysosomal storage diseases: A survey of healthcare professionals in the Fabry, Gaucher, and Hunter Outcome Survey registries.

The impact of the COVID-19 pandemic on the standards of care of patients with lysosomal storage diseases and the needs of their healthcare providers were explored using a 12-question survey. Overall, 80/91 respondents (88%) indicated that the pandemic had negatively affected standards of care. With increased reliance on telemedicine, the respondents highlighted the need for a personalized approach to care, direct and frequent communication with patients, and greater involvement of patients and caregivers.

Plasma adiponectin is a potential biomarker for organ involvement in male Fabry disease patients.

Fabry disease is an X-linked lysosomal storage disorder caused by pathogenic variants in GLA. It manifests in hemizygous males and in many heterozygous females. Cardiovascular and renal involvement are frequent. Adiponectin is a circulating hormone that has been linked to numerous disease conditions including heart and kidney failure. In the present pilot study, we investigated plasma adiponectin levels in a cohort of 56 individuals with a genetic diagnosis of Fabry disease. Adiponectin levels did not differ between patients and controls. However, in male patients, significantly decreased adiponectin levels were associated with cardiovascular manifestation, while increased levels were associated with renal involvement. Similar trends in female patients did not reach statistical significance. Lyso-Gb3, a metabolite with good diagnostic/screening performance, was not indicative of organ involvement. In combination, adiponectin and Lyso-Gb3 may be of value for identification and stratification of Fabry patients. A potential additional relevance for prognosis and monitoring should be addressed by future studies in larger cohorts.

Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS).

The Gaucher Outcome Survey (GOS) is an international Gaucher disease (GD) registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status, designed to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments. As of February 25, 2017, 1209 patients had enrolled, the majority from Israel (44.3%) and the US (31.4%). Median age at GOS entry was 40.4 years, 44.1% were male, and 13.3% had undergone a total splenectomy. Most patients had type 1 GD (91.5%) and were of Ashkenazi Jewish ethnicity (55.8%). N370S/N370S was the most prevalent genotype, accounting for 44.2% of genotype-confirmed individuals (n = 847); however, there was considerable variation between countries. A total of 887 (73.4%) patients had received ≥1 GD-specific treatment at any time, most commonly imiglucerase (n = 587), velaglucerase alfa (n = 507), and alglucerase (n = 102). Hematological and visceral findings at the time of GOS entry were close to normal for most patients, probably a result of previous treatment; however, spleen volume of patients in Israel was almost double that of patients elsewhere (7.2 multiples of normal [MN] vs. 2.7, 2.9 and 4.9 MN in the US, UK and rest of world), which may be explained by a greater disease severity in this cohort. This analysis aimed to provide an overview of GOS and present baseline demographic and disease characteristics of participating patients to help improve the understanding of the natural history of GD and inform the overall management of patients with the disease.

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.

Liver involvement in Gaucher disease - Review and clinical approach.

Gaucher disease (GD), one of the most prevalent lysosomal storage diseases, is associated with glucocerebroside accumulation in cells of the monocyte-macrophage system in various organs, including the liver. Evaluating and managing liver disease in patients with Gaucher disease may be challenging. While hepatic involvement is common in Gaucher disease, its severity, and clinical significance span a wide spectrum, ranging from sub-clinical involvement to liver cirrhosis with its associated complications including portal hypertension. Apart from liver involvement in Gaucher disease, patients with may also suffer from other comorbidities involving the liver. That Gaucher disease itself can mimic hepatic lesions, affect laboratory tests used to characterize liver disease, and may be associated with non-cirrhotic portal hypertension, complicates the diagnostic approach even more. Better understanding of liver involvement in Gaucher disease can spare patients unnecessary invasive testing, and assist physicians in decision making when evaluating patients with Gaucher disease suspected for significant liver disease. This review describes the various clinical manifestations, laboratory and imaging abnormalities that may be encountered when following patients with Gaucher disease for liver involvement. The mechanism for liver disease are discussed, as well as the possible hepato-protective effect of glucocerebroside, and the a diagnostic and treatment approaches.

Growth and final height of children with Gaucher disease: A 15-year follow-up at an Israeli Gaucher center.

BACKGROUND: It is held that enzyme replacement therapy (ERT) accelerates the growth rate in children with Gaucher disease, but its effect on final height has not been established with certainty. This study presents final heights of Gaucher patients followed up for 15years. METHODS: The study included 41 adults with non-neuronopathic Gaucher disease. The final height of the patients and age at puberty was compared to their mid-parental target height and to their siblings' heights. RESULTS: Mean final height standard deviation score (HSDS) in the patients was -0.22, but none of the patients was abnormally short (HSDS of less than -2.2). Mean age at menarche of the female patients (14.7years) was significantly delayed compared to that of their mothers (P=0.0005), and mean age at first shaving in the boys was 16years. CONCLUSION: Our study showed that the mean final height of Gaucher patients fell below the mean of the 2000 CDC growth charts, but the patients were not of short stature (height less than the 3rd percentile). ERT treatment did not significantly impact the mean final HSDS. The onset of puberty, as indicated by the age at menarche, was delayed in girls with Gaucher disease.

Children with type 1 Gaucher disease: Changing profiles in the 21st century.

Gaucher disease (GD) has phenotypic variability. Increased GD awareness especially among at-risk Ashkenazi Jews (AJ) and availability of non-invasive diagnosis induced trend to prenatal screening. We retrospectively assessed pediatric (<16years) Israeli AJ GD patients to ascertain demographics and phenotype at presentation and over-time because many were identified by large-scale screening. 55/67 patients born since 01/01/2000 are AJ with non-neuronopathic GD: 28 (50.9%) are N370S/N370S; 24 (43.6%) are N370S/other; 3 (3.5%) have no N370S allele. 30 (54.5%) diagnosed by screening; 10 (18.2%) with sibling diagnosed by screening. Of 19 (34.5%) receiving enzyme replacement therapy (ERT), 4/19 (21.1%) were by screening (N370S/N370S; N370S/L444P, N370S/84GG, N370S/IVS2+1); 15/19 (78.9%) diagnosed by symptoms and/or symptomatic sibling. 4/19 (21.1%) began ERT at age <2years; 9/19 (47.4%) at 3-5years; 6/19 (31.6%) at 6-12years. 49% presented with height/weight growth percentiles ≤25%, but group means were comparable up to 12years follow-up including 10 receiving ERT (8 for >5years). 22% presented with anemia, 20% with thrombocytopenia; at last follow-up 4% and 6%, respectively, remained cytopenic. We present a new demographic profile for pediatric GD because many identified by screening had/have few GD signs/symptoms. Nonetheless, early diagnosis is important, especially for non-N370S, non-mild genotypes.

Exploring the patient journey to diagnosis of Gaucher disease from the perspective of 212 patients with Gaucher disease and 16 Gaucher expert physicians.

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme ß-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD.

Reductions in glucosylsphingosine (lyso-Gb1) in treatment-naïve and previously treated patients receiving velaglucerase alfa for type 1 Gaucher disease: Data from phase 3 clinical trials.

Gaucher disease (GD), an autosomal recessive lipid storage disorder, arises from mutations in the GBA1 (ß-glucocerebrosidase) gene, resulting in glucosylceramide accumulation in tissue macrophages. Lyso-Gb1 (glucosylsphingosine, lyso-GL1), a downstream metabolic product of glucosylceramide, has been identified as a promising biomarker for the diagnosis and monitoring of patients with GD. This retrospective, exploratory analysis of data from phase 3 clinical trials of velaglucerase alfa in patients with type 1 GD evaluated the potential of lyso-Gb1 as a specific and sensitive biomarker for GD. A total of 22 treatment-naïve patients and 21 patients previously treated with imiglucerase (switch patients) were included in the analysis. Overall, demographics between the two groups were similar. Mean lyso-Gb1 concentrations were reduced by 302.2ng/mL from baseline to week 209 in treatment-naïve patients and by 57.3ng/mL from baseline to week 161 in switch patients, corresponding to relative reductions of 82.7% and 52.0%, respectively. In both the treatment-naïve and switch groups, baseline mean lyso-Gb1 was higher for patients with at least one N370S mutation (363.9ng/mL and 90.7ng/mL, respectively) than for patients with non-N370S mutations (184.6ng/mL and 28.3ng/mL, respectively). Moderate correlations between decreasing lyso-Gb1 levels and increasing platelet counts, and with decreasing spleen volumes, were observed at some time points in the treatment-naïve group but not in the switch group. These findings support the utility of lyso-Gb1 as a sensitive and reliable biomarker for GD, and suggest that quantitation of this biomarker could serve as an indicator of disease burden and response to treatment.

Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease.

The introduction of a home therapy option during clinical trials of velaglucerase alfa in patients with type 1 Gaucher disease marked the first time that home infusions have been permitted during a clinical trial for an investigational drug for Gaucher disease. Home infusions were an available option in 4 open-label velaglucerase alfa clinical studies to eligible patients who received their initial infusions at a clinic. Patients who participated in the home therapy option and received at least 10% of their infusions at home (n=100) received a range of 11.6%-100% of their scheduled infusions at home (median 87.5%), excluding infusions received at the clinic during protocol-mandated visits. The length of time over which individual patients received home therapy ranged from 13days to 4.56years (median 0.57years). During the time that home therapy was available, 2904 of 3572 (81.3%) infusions were administered at home. Ten patients experienced 62 infusion-related adverse events (IRAEs) during 38 home infusions, with malaise, pain, hypertension, fatigue, and headache being reported most frequently. No notable differences were found between the type and severity of IRAEs experienced at home and those experienced at the clinic. Home infusions administered by trained and qualified medical personnel were successfully introduced into the velaglucerase alfa clinical development program, and fewer than 10% of patients experienced IRAEs in the home setting. Local labeling and practice guidelines should be consulted for administration of velaglucerase alfa infusions at home.

ASPECTS OF PATIENT REPORTED OUTCOMES IN RARE DISEASES: A DISCUSSION PAPER.

OBJECTIVES: A patient reported outcome (PRO) is "any report of the status of a patient's health condition that comes directly from the patient without interpretation of the patient's response by a clinician or anyone else" (USFDA 2009). PROs are discussed widely, and many regard the patients' perspective on treatment benefit as very valuable. Although many PROs have shown satisfactory measurement properties including reliability, validity, and responsiveness, there is great concern about risk of bias, that is, in clinical trials. METHODS: Differences in perspectives of PRO measurement in rare diseases are given arising from methodology, clinical, HTA, and patient advocacy views. RESULTS: PROs are playing an important role in dealing with treatment benefit especially in small sample size as occurring often in rare diseases. Challenges remain especially regarding lack of responsiveness of generic measures, limited capture of all patient relevant aspects, study design and high risk of bias. CONCLUSIONS: PROs seem a valuable instrument to detect patient relevant aspects in rare diseases. They should be seen in addition to other approved assessment methods as randomized controlled trials but not as their substitute.

New Directions in Gaucher Disease.

In Gaucher disease (GD), mutant lysosomal acid ß-glucocerebrosidase fails to properly hydrolyze its substrate, glucosylceramide, which accumulates in the lysosomes. Due to its phenotypic heterogeneity, GD has been classified into type 1, non-neuronopathic, and types 2 and 3, the neuronopathic forms, based on the primary involvement of the central nervous system. Neuroinflammation and necroptotic death may appear in the neuronopathic forms of GD, whereas type 1 GD patients may develop Parkinson disease (PD), a prototype of protein misfolding disorders of the nervous system. PD is significantly more prevalent among GD carriers and patients than among the non-GD populations. It is apparent that the amount of mutant enzyme present in lysosomes depends on the amount of mutant enzyme recognized as correctly folded in the endoplasmic reticulum (ER) for physiologically correct transport through the Golgi apparatus to the lysosome. Mutant enzyme recognized as misfolded is retained in the ER, inducing the Unfolded Protein Response. In the current review, we present three discrete areas of interest: molecular and cellular mechanisms underlying the association between GD and PD; the clinical and genetic associations between GD and PD; and treatment options for GD. We also discuss the relevance of induced pleuripotent stem cells to the above associations.

The association between ABO blood group and obstetric hemorrhage.

UNLABELLED: Whether intra- and early post-partum hemorrhage is influenced by ABO blood groups remains unknown. Therefore, we compared women with O to non-O blood groups with regard to maternal post-partum hemorrhage and transfusion need. This retrospective study was conducted in a single tertiary center between 2005 and 2014. For the purpose of the study, parturients were categorized as O and non-O blood groups. Data included all deliveries but excluded patients with missing blood grouping or hemoglobin values, and/or stillbirth. Drop in hemoglobin was defined as hemoglobin concentration at admission for delivery minus lowest hemoglobin concentration post-delivery. Study outcomes were postpartum hemorrhage, hemoglobin drop >2-7 g/dL inclusive, and packed red blood cells transfusion. STATISTICS: descriptive, χ(2) (p < 0.05 significant) and multivariable regression models [odds ratio (OR), 95 % confidence interval (CI), p value]. 125,768 deliveries were included. After multivariable analysis, women with O blood type relative to women with non-O blood type had significantly higher odds of postpartum hemorrhage (OR 1.14; 95 % CI 1.05-1.23, p < 0.001), higher odds of statistically significant hemoglobin decreases of >2, 3, or 4 g/dL (OR 1.07; 95 % CI 1.04-1.11, p < 0.001, OR 1.08; 95 % CI 1.03-1.14, p = 0.002, OR 1.14; 95 % CI 1.05-1.23, p = 0.001; respectively), and higher odds, albeit not statistically significant of 5, 6, or 7 g/dL decreases in hemoglobin (OR 1.13; 95 % CI 1.00-1.29, p = 0.055, OR 1.05; 95 % CI 0.84-1.32, p = 0.66, OR 1.15; 95 % CI 0.79-1.68, p = 0.46; respectively), but no difference in blood products transfusion (OR 1.03; 95 % CI 0.92-1.16, p = 0.58). In conclusion, women with blood type O may be at greater risk of obstetrical hemorrhage.