A simplified pneumonia severity index (PSI) for clinical outcome prediction in COVID-19.

BACKGROUND: The Pneumonia Score Index (PSI) was developed to estimate the risk of dying within 30 days of presentation for community-acquired pneumonia patients and is a strong predictor of 30-day mortality after COVID-19. However, three of its required 20 variables (skilled nursing home, altered mental status and pleural effusion) are not discreetly available in the electronic medical record (EMR), resulting in manual chart review for these 3 factors. The goal of this study is to compare a simplified 17-factor version (PSI-17) to the original (denoted PSI-20) in terms of prediction of 30-day mortality in COVID-19. METHODS: In this retrospective cohort study, the hospitalized patients with confirmed SARS-CoV-2 infection between 2/28/20-5/28/20 were identified to compare the predictive performance between PSI-17 and PSI-20. Correlation was assessed between PSI-17 and PSI-20, and logistic regressions were performed for 30-day mortality. The predictive abilities were compared by discrimination, calibration, and overall performance. RESULTS: Based on 1,138 COVID-19 patients, the correlation between PSI-17 and PSI-20 was 0.95. Univariate logistic regression showed that PSI-17 had performance similar to PSI-20, based on AUC, ICI and Brier Score. After adjusting for confounding variables by multivariable logistic regression, PSI-17 and PSI-20 had AUCs (95% CI) of 0.85 (0.83-0.88) and 0.86 (0.84-0.89), respectively, indicating no significant difference in AUC at significance level of 0.05. CONCLUSION: PSI-17 and PSI-20 are equally effective predictors of 30-day mortality in terms of several performance metrics. PSI-17 can be obtained without the manual chart review, which allows for automated risk calculations within an EMR. PSI-17 can be easily obtained and may be a comparable alternative to PSI-20.

Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial.

Background: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes. Methods: This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses. Findings: From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 µmol/L to 86.4 µmol/L at Week 24 vs 464.7 to 426.6 µmol/L for placebo (95% CI: -67.1%, -83.5%; p < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity. Interpretation: These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility. Funding: Aeglea BioTherapeutics.

Patient and Provider Experiences and Views on the Use of Telehealth in Genetics Clinics in Response to the COVID-19 Pandemic.

Introduction: The 2019 Coronavirus Disease (COVID-19) pandemic necessitated a mass transition in genetics clinics nationwide from in-person care to virtual care through telehealth. Before the COVID-19 pandemic, there was limited research on the use of telehealth in genetics specialties. Therefore, the COVID-19 pandemic presented a unique opportunity to study this emerging mode of care delivery in the setting of genetics clinics. This study described the scope of telehealth use in genetics clinics nationally and determined how COVID-19 influenced patients' decisions regarding their genetic care. Methods: Two anonymous surveys for patients and providers were developed. The patient survey was offered online to all genetics patients seen through telehealth at a Manhattan-based practice between March and December 2020. The provider survey was distributed through several listservs to genetics providers nationwide. Results: Patients (n = 242) and providers (n = 150) responded. Telehealth was used in all specialty genetics clinics for both initial and follow-up visits. Telehealth was both effective and satisfactory to patients for both visit types and across specialties; however, Asian and Hispanic/Latino patients had significantly lower mean satisfaction scores compared with White patients (p = 0.03 and 0.04, respectively). Patients appreciated telehealth for its convenience and to avoid COVID-19 exposure. Providers across specialties and provider types preferred telehealth for follow-up rather than initial visits. Several clinic initiatives related to telehealth were identified. Discussion: Telehealth was generally well received by both patients and providers, and is expected to become permanent option in genetics clinics. Further studies are needed to identify barriers to accessing telehealth.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic results disclosure in diverse families.

Digital solutions are needed to support rapid increases in the application of genetic/genomic tests (GTs) in diverse clinical settings and patient populations. We developed GUÍA, a bilingual digital application that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GTs. The trial evaluated GUÍA's impact on understanding the GT results by randomizing families to results disclosure genetic counseling with GUÍA (intervention) or standard of care (SOC). Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6 months later. Survey measures assessed the primary study outcomes of participants' perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. The analysis included 551 diverse participants, 270 in the GUÍA arm and 281 in SOC. Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR = 2.8, CI[1.004, 7.617], p = 0.049) and maintained higher objective understanding over time (OR = 1.1, CI[1.004, 1.127], p = 0.038) compared to SOC. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR = 3.9, CI[1.603, 9.254], p = 0.003), confidence (OR = 2.7, CI[1.021, 7.277], p = 0.046), and objective understanding (OR = 1.1, CI[1.009, 1.212], p = 0.032) compared to SOC. This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions and builds a case for utilizing GUÍA to deliver complex results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics.

Efficacy and safety of a synthetic biotic for treatment of phenylketonuria: a phase 2 clinical trial.

Despite available treatment options, many patients with phenylketonuria (PKU) cannot achieve target plasma phenylalanine (Phe) levels1. We previously modified Escherichia coli Nissle 1917 to metabolize Phe in the gut after oral administration (SYNB1618) and designed a second strain (SYNB1934) with enhanced activity of phenylalanine ammonia lyase2,3. In a 14-day open-label dose-escalation study (Synpheny-1, NCT04534842 ), we test a primary endpoint of change from baseline in labeled Phe (D5-Phe AUC0-24; D5-Phe area under the curve (AUC) over 24 hours after D5-Phe administration) in plasma after D5-Phe challenge in adult participants with screening Phe of greater than 600 µM. Secondary endpoints were the change from baseline in fasting plasma Phe and the incidence of treatment-emergent adverse events. A total of 20 participants (ten male and ten female) were enrolled and 15 completed the study treatment. Here, we show that both strains lower Phe levels in participants with PKU: D5-Phe AUC0-24 was reduced by 43% from baseline with SYNB1934 and by 34% from baseline with SYNB1618. SYNB1934 led to a decrease in fasting plasma Phe of 40% (95% CI, -52, -24). There were no serious adverse events or infections. Four participants discontinued because of adverse events, and one withdrew during the baseline period. We show that synthetic biotics can metabolize Phe in the gut, lower post-prandial plasma Phe levels and lower fasting plasma Phe in patients with PKU.

The NYCKidSeq randomized controlled trial: Impact of GUÍA digitally enhanced genetic counseling in racially and ethnically diverse families.

Background: Digital solutions are needed to support rapid increases in the application of genetic and genomic tests (GT) in diverse clinical settings and patient populations. We developed GUÍA, a bi-lingual web-based platform that facilitates disclosure of GT results. The NYCKidSeq randomized controlled trial evaluated GUÍA's impact on understanding of GT results. Methods: NYCKidSeq enrolled diverse children with neurologic, cardiac, and immunologic conditions who underwent GT. Families were randomized to genetic counseling with GUÍA (intervention) or standard of care (SOC) genetic counseling for results disclosure. Parents/legal guardians (participants) completed surveys at baseline, post-results disclosure, and 6-months later. Survey measures assessed the primary study outcomes of perceived understanding of and confidence in explaining their child's GT results and the secondary outcome of objective understanding. We used regression models to evaluate the association between the intervention and the study outcomes. Results: The analysis included 551 participants, 270 in the GUÍA arm and 281 in SOC. Participants' mean age was 41.1 years and 88.6% were mothers. Most participants were Hispanic/Latino(a) (46.3%), White/European American (24.5%), or Black/African American (15.8%). Participants in the GUÍA arm had significantly higher perceived understanding post-results (OR=2.8, CI[1.004,7.617], P=0.049) and maintained higher objective understanding over time (OR=1.1, CI[1.004, 1.127], P=0.038) compared to those in the SOC arm. There was no impact on perceived confidence. Hispanic/Latino(a) individuals in the GUÍA arm maintained higher perceived understanding (OR=3.9, CI[1.6, 9.3], P=0.003), confidence (OR=2.7, CI[1.021, 7.277], P=0.046), and objective understanding (OR=1.1, CI[1.009, 1.212], P=0.032) compared to SOC . Conclusions: This trial demonstrates that GUÍA positively impacts understanding of GT results in diverse parents of children with suspected genetic conditions. These findings build a case for utilizing GUÍA to deliver complex and often ambiguous genetic results. Continued development and evaluation of digital applications in diverse populations are critical for equitably scaling GT offerings in specialty clinics. Trial Registration: Clinicaltrials.gov identifier NCT03738098.

Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program.

Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0-21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

PURPOSE: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. METHODS: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. RESULTS: A total of 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs TGPs in Hispanic/Latino(a) (17.2% vs 9.5%, P < .001) and White/European American (19.8% vs 7.9%, P < .001) but not in Black/African American (11.5% vs 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. CONCLUSION: GS may yield up to twice as many diagnoses in pediatric patients compared with TGP testing but not yet across all population groups.

Clinical, biochemical and molecular characterization of 12 patients with pyruvate carboxylase deficiency treated with triheptanoin.

Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive mitochondrial neurometabolic disorder of energy deficit resulting in high morbidity and mortality, with limited therapeutic options. The PC homotetramer has a critical role in gluconeogenesis, anaplerosis, neurotransmitter synthesis, and lipogenesis. The main biochemical and clinical findings in PC deficiency (PCD) include lactic acidosis, ketonuria, failure to thrive, and neurological dysfunction. Use of the anaplerotic agent triheptanoin on a limited number of individuals with PCD has had mixed results. We expand on the potential utility of triheptanoin in PCD by examining the clinical, biochemical, molecular, and health-related quality-of-life (HRQoL) findings in a cohort of 12 individuals with PCD (eight with Type A and two each with Types B and C) treated with triheptanoin ranging for 6 days to about 7 years. The main endpoints were changes in blood lactate and HRQoL scores, but collection of useful data was limited to about half of subjects. An overall trend of lactate reduction with time on triheptanoin was noted, but with significant variability among subjects and only one subject reaching close to statistical significance for this endpoint. Parent reported HRQoL assessments with treatment showed mixed results, with some subjects showing no change, some improvement, and some worsening of overall scores. Subjects with buried amino acids in the pyruvate carboxyltransferase domain of PC that undergo destabilizing replacements may be more likely to respond (with lactate reduction or HRQoL improvement) to triheptanoin compared to those with replacements that disrupt tetramerization or subunit-subunit interface contacts. The reason for this difference is unclear and requires further validation. We observed significant variability but an overall trend of lactate reduction with time on triheptanoin and mixed parent reported outcome changes by HRQoL assessments for subjects with PCD on long-term triheptanoin. The mixed results noted with triheptanoin therapy in this study could be due to endpoint data limitation, variability of disease severity between subjects, limitation of the parent reported HRQoL tool, or subject genotype variability. Alternative designed trials and more study subjects with PCD will be needed to validate important observations from this work.

Olipudase alfa enzyme replacement therapy for acid sphingomyelinase deficiency (ASMD): sustained improvements in clinical outcomes after 6.5 years of treatment in adults.

BACKGROUND: Enzyme replacement therapy with olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children and adults. An ongoing, open-label, long-term study (NCT02004704) assessed the safety and efficacy of olipudase alfa in 5 adults with ASMD. RESULTS: After 6.5 years of treatment, there were no discontinuations, no olipudase-alfa-related serious adverse events, and no new safety signals compared to earlier assessments. Most treatment-emergent adverse events were mild in intensity (1742/1766, 98.6%). Among treatment-related adverse events (n = 657), more than half were considered infusion-associated reactions (n = 403, 61.3%) such as headache, nausea, abdominal pain, arthralgia, pyrexia, and fatigue. No patient developed neutralizing anti-drug antibodies to cellular uptake, and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Improvements (decreases) in spleen and liver volumes progressed through 6.5 years (mean changes from baseline of -59.5% and -43.7%, respectively). There was a mean increase in diffusing capacity of the lung for carbon monoxide from baseline of 55.3%, accompanied by improvements in interstitial lung disease parameters. Lipid profiles at baseline indicated dyslipidemia. All patients had sustained decreases in pro-atherogenic lipid levels and increases in anti-atherogenic lipid levels following olipudase alfa treatment. CONCLUSIONS: Olipudase alfa is the first disease-specific treatment for ASMD. This study demonstrates that long-term treatment with olipudase alfa is well-tolerated and is associated with sustained improvements in relevant disease clinical measures. NCT02004704 registered 26 November 2013, https://clinicaltrials.gov/ct2/show/NCT02004704?term=NCT02004704&draw=2&rank=1 .

TRPC6 inhibitor (BI 764198) to reduce risk and severity of ARDS due to COVID-19: a phase II randomised controlled trial.

BACKGROUND: Despite the availability of COVID-19 vaccinations, there remains a need to investigate treatments to reduce the risk or severity of potentially fatal complications of COVID-19, such as acute respiratory distress syndrome (ARDS). This study evaluated the efficacy and safety of the transient receptor potential channel C6 (TRPC6) inhibitor, BI 764198, in reducing the risk and/or severity of ARDS in patients hospitalised for COVID-19 and requiring non-invasive, supplemental oxygen support (oxygen by mask or nasal prongs, oxygen by non-invasive ventilation or high-flow nasal oxygen). METHODS: Multicentre, double-blind, randomised phase II trial comparing once-daily oral BI 764198 (n=65) with placebo (n=64) for 28 days (+2-month follow-up). PRIMARY ENDPOINT: proportion of patients alive and free of mechanical ventilation at day 29. Secondary endpoints: proportion of patients alive and discharged without oxygen (day 29); occurrence of either in-hospital mortality, intensive care unit admission or mechanical ventilation (day 29); time to first response (clinical improvement/recovery); ventilator-free days (day 29); and mortality (days 15, 29, 60 and 90). RESULTS: No difference was observed for the primary endpoint: BI 764198 (83.1%) versus placebo (87.5%) (estimated risk difference -5.39%; 95% CI -16.08 to 5.30; p=0.323). For secondary endpoints, a longer time to first response (rate ratio 0.67; 95% CI 0.46 to 0.99; p=0.045) and longer hospitalisation (+3.41 days; 95% CI 0.49 to 6.34; p=0.023) for BI 764198 versus placebo was observed; no other significant differences were observed. On-treatment adverse events were similar between trial arms and more fatal events were reported for BI 764198 (n=7) versus placebo (n=2). Treatment was stopped early based on an interim observation of a lack of efficacy and an imbalance of fatal events (Data Monitoring Committee recommendation). CONCLUSIONS: TRPC6 inhibition was not effective in reducing the risk and/or severity of ARDS in patients with COVID-19 requiring non-invasive, supplemental oxygen support. TRIAL REGISTRATION NUMBER: NCT04604184.

Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients.

Purpose: Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. Methods: Probands with neurologic, cardiac, or immunologic conditions were offered GS and TGP testing. Diagnostic yield was compared using a fully paired study design. Results: 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses ( P < .001). Yield was greater for GS vs . TGPs in Hispanic/Latino(a) (17.2% vs . 9.5%, P < .001) and White/European American (19.8% vs . 7.9%, P < .001), but not in Black/African American (11.5% vs . 7.7%, P = .22) population groups by self-report. A higher rate of inconclusive results was seen in the Black/African American (63.8%) vs . White/European American (47.6%; P = .01) population group. Most causal copy number variants (17 of 19) and mosaic variants (6 of 8) were detected only by GS. Conclusion: GS may yield up to twice as many diagnoses in pediatric patients compared to TGP testing, but not yet across all population groups.

The TeleKidSeq pilot study: incorporating telehealth into clinical care of children from diverse backgrounds undergoing whole genome sequencing.

BACKGROUND: The COVID-19 pandemic forced healthcare institutions and many clinical research programs to adopt telehealth modalities in order to mitigate viral spread. With the expanded use of telehealth, there is the potential to increase access to genomic medicine to medically underserved populations, yet little is known about how best to communicate genomic results via telehealth while also ensuring equitable access. NYCKidSeq, a multi-institutional clinical genomics research program in New York City, launched the TeleKidSeq pilot study to assess alternative forms of genomic communication and telehealth service delivery models with families from medically underserved populations. METHODS: We aim to enroll 496 participants between 0 and 21 years old to receive clinical genome sequencing. These individuals have a neurologic, cardiovascular, and/or immunologic disease. Participants will be English- or Spanish-speaking and predominantly from underrepresented groups who receive care in the New York metropolitan area. Prior to enrollment, participants will be randomized to either genetic counseling via videoconferencing with screen-sharing or genetic counseling via videoconferencing without screen-sharing. Using surveys administered at baseline, results disclosure, and 6-months post-results disclosure, we will evaluate the impact of the use of screen-sharing on participant understanding, satisfaction, and uptake of medical recommendations, as well as the psychological and socioeconomic implications of obtaining genome sequencing. Clinical utility, cost, and diagnostic yield of genome sequencing will also be assessed. DISCUSSION: The TeleKidSeq pilot study will contribute to innovations in communicating genomic test results to diverse populations through telehealth technology. In conjunction with NYCKidSeq, this work will inform best practices for the implementation of genomic medicine in diverse, English- and Spanish-speaking populations.

Detection of mosaic variants using genome sequencing in a large pediatric cohort.

The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.

The role and control of arginine levels in arginase 1 deficiency.

Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae. Nearly five decades of clinical experience with ARG1-D and empirical studies in genetically manipulated models have generated a large body of evidence that, when considered in aggregate, implicates arginine directly in disease pathophysiology. Severe dietary protein restriction to minimize arginine intake and diversion of ammonia from the urea cycle are the mainstay of care. Although this approach does reduce plasma arginine and improve patients' cognitive and motor/mobility manifestations, it is inadequate to achieve and maintain sufficiently low arginine levels and prevent progression in the long term. This review presents a comprehensive discussion of the clinical and scientific literature, the effects and limitations of the current standard of care, and the authors' perspectives regarding the past, current, and future management of ARG1-D.

Long-term safety and clinical outcomes of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency: two-year results.

BACKGROUND: Olipudase alfa is a recombinant human acid sphingomyelinase (ASM) enzyme replacement therapy (ERT) for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). We report 2-year cumulative safety and efficacy data after olipudase alfa treatment in 20 children (four adolescents [12-17 year], nine children [6-11 year], and seven infants/early child [1-5 year]) with baseline splenomegaly and growth deficits who completed the 1-year ASCEND-Peds clinical trial (NCT02292654) and who continue to receive olipudase alfa in a long-term study (NCT02004704). Efficacy endpoints include spleen and liver volumes, diffusing capacity of the lung for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) lung imaging, lipid profiles, liver function tests, and height Z-scores. RESULTS: All 20 former ASCEND-Peds patients completed at least 2 years of olipudase alfa treatment. No patient discontinued and no new safety issue arose during the second year of treatment; 99% of adverse events were mild or moderate. During year 2, one patient had two treatment-related serious events of hypersensitivity that resolved. Mean reductions from baseline in spleen and liver volumes were 61% and 49%, respectively (p < 0.0001) and mean percent-predicted-DLCO increased by 46.6% (p < 0.0001) in nine patients who performed the test at baseline. Lipid profiles and elevated liver transaminase levels that improved or normalized by 1 year remained stable. Mean height Z-scores improved in all age groups (mean change from baseline 1.17, P < 0.0001). CONCLUSION: Olipudase alfa was generally well-tolerated during 2 years of treatment. Improvements in clinically relevant disease endpoints observed during the first year of treatment were maintained or augmented in the second year. Trial registration NCT02004704 registered 26 Nov 2013, https://clinicaltrials.gov/ct2/show/record/NCT02004704 .

Health insurance literacy and health services access barriers in Niemann-Pick disease: the patient and caregiver voice.

BACKGROUND: Major challenges to health care access include low health insurance literacy, prohibitive costs, and insurance barriers. Niemann-Pick disease (NPD), comprising acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C (NPC), is a group of rare, autosomal recessive, highly heterogeneous, neurovisceral, life-threatening, relentlessly progressive lysosomal disorders. Patients experience debilitating systemic and neurological symptoms and substantial emotional and financial stress. Currently, these multifaceted disorders are managed symptomatically as there are no approved therapies. Given the considerable disease burden of NPD, timely access to quality health care is paramount for improving outcomes in these life-threatening disorders. Understanding health insurance literacy and access challenges among patients with NPD and their caregivers is a first step to overcoming treatment barriers. RESULTS: Patients from the Niemann-Pick community participated in a health insurance literacy survey and follow-up telephone interviews on perceived access challenges. Of the 79 respondents who completed the survey, 67 participated in interviews. All respondents had stable health insurance coverage. However, 61% of respondents were unaware of Medicaid waivers and did not avail of them. Overall, 50% of respondents with childhood onset NPC selected Medicaid/Medicare and private insurance; 35% utilized Medicaid waivers. Most respondents with ASMD had private insurance only. Although the Niemann-Pick community demonstrated greater health insurance literacy than the general population, knowledge gaps exist in calculating insurance coverage, out-of-pocket maximums, and defining a formulary. The most frequently cited access burden was the process of obtaining medical care and services. Among respondents with ASMD, the greatest access burden was fear of unavailability of or access to medications and treatment. Access challenges adversely impacted patients' mental health and exacerbated physical symptoms. Delays and denials in obtaining essential medication, equipment, and services contributed to disease progression. Caregivers faced burnout and often questioned the utility of their advocacy. CONCLUSIONS: This study identified knowledge gaps in health insurance literacy and challenges to access medication and health care services among individuals impacted by NPD. Patients and caregivers need the knowledge and skills to navigate a complicated health care system, understand their rights to medication and services and, ultimately, benefit from improved outcomes, especially in a post-drug approval era.

Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): A systematic review.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.