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Background and ObjectivesPompe disease is a rare, progressive neuromuscular disorder caused by deficiency of lysosomal acid α-glucosidase (GAA) and subsequent glycogen accumulation. Avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy designed for increased cellular uptake and glycogen clearance, has been studied for long-term efficacy and safety in patients with late-onset Pompe disease (LOPD). Here, we report up to 6.5 years' experience with avalglucosidase alfa during the NEO1 and NEO-EXT studies.MethodsNEO1 participants with LOPD, either treatment naive (Naive Group) or receiving alglucosidase alfa for ≥9 months (Switch Group), received avalglucosidase alfa (5, 10, or 20 mg/kg every other week [qow]) for 6 months before entering NEO-EXT and continued their NEO1 dose until all proceeded with 20 mg/kg qow. Safety and efficacy, a prespecified exploratory secondary outcome, were assessed; slopes of change for efficacy outcomes were calculated from a repeated mixed-measures model.ResultsTwenty-four participants enrolled in NEO1 (Naive Group, n = 10; Switch Group, n = 14); 21 completed and 19 entered NEO-EXT; in February 2020, 17 participants remained in NEO-EXT, with data up to 6.5 years. Avalglucosidase alfa was generally well tolerated during NEO-EXT, with a safety profile consistent with that in NEO1. No deaths or treatment-related life-threatening serious adverse events occurred. Eighteen participants developed antidrug antibodies without apparent effect on clinical outcomes. No participants who were tested developed immunoglobulin E antibodies. Upright forced vital capacity %predicted remained stable in most participants, with slope estimates (95% CIs) of −0.473 per year (−1.188 to 0.242) and −0.648 per year (−1.061 to −0.236) in the Naive and Switch Groups, respectively. Six-minute walk test (6MWT) %predicted was also stable for most participants, with slope estimates of −0.701 per year (−1.571 to 0.169) and −0.846 per year (−1.567 to −0.125) for the Naive and Switch Groups, respectively. Improvements in 6MWT distance were observed in most participants aged DiscussionAvalglucosidase alfa was generally well tolerated for up to 6.5 years in adult participants with LOPD either naive to alglucosidase alfa or who had previously received alglucosidase alfa for ≥9 months.Classification of EvidenceThis study provides Class IV evidence of long-term tolerability and sustained efficacy of avalglucosidase alfa in patients with LOPD after up to 6.5 years.Trial Registration InformationNCT01898364 (NEO1 first posted: July 12, 2013; clinicaltrials.gov/ct2/show/NCT01898364); NCT02032524 (NEO-EXT first posted: January 10, 2014; clinicaltrials.gov/ct2/show/NCT02032524). First participant enrollment: NEO1—August 19, 2013; NEO-EXT—February 27, 2014.

Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.Observational cohort.Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 mADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.The mean baseline eGFR was 44 mL/min/1.73 mSingle cohort, restricted to patients with diabetes and eGFR 60 mL/min/1.73 mHigher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

Introduction: Hemophilia B is a bleeding disorder characterized by coagulation factor IX (FIX) deficiency and is associated with symptoms of prolonged bleeding upon trauma and spontaneous bleed events. The current standard of care for people with hemophilia B is prophylactic FIX replacement therapy for the prevention of bleed events (Goodeve et al. J Thromb Haemost. 2015; Saini et al. Haemophilia. 2015; Castaman. Expert Rev Hematol. 2018). The aim of this study is to present a descriptive post hoc analysis of spontaneous bleed events in the context of treatment regimen (eg, prophylaxis [PPX] versus on-demand [OD]) in previously untreated participants (PUPs) with hemophilia B treated with extended half-life recombinant factor IX Fc fusion protein (rFIXFc, Alprolix) from the PUPs B-LONG study. Methods: The PUPs B-LONG study (NCT02234310) enrolled 33 previously untreated male participants Results: In PUPs B-LONG, 11 participants began on PPX, with 22 participants beginning with OD regimens. Of the 22 who began OD, 17 switched to PPX, for a total of 28 participants on PPX during the study. Six participants discontinued early, for reasons such as withdrawn consent (n=2 [6.1%]), eligibility criteria not fulfilled (n=2 [6.1%]), an adverse event (n=1 [3.0%]), or physician decision (n=1 [3.0%]). A total of 24 spontaneous bleed events occurred. The baseline age of PUPs was not a statistically significant factor for time to first spontaneous bleed event for either regimen or for those who switched from rFIXFc OD to PPX. KM analyses showed that participants receiving PPX had a reduced frequency and extended time to first spontaneous bleed event compared with those receiving OD therapy (Figure 1A). Median (range) time to first spontaneous bleed event was 341.5 (64.0-378.0) days for those on PPX (n=4) and was 183.0 (15.0-832.0) days for those on OD (n=9) who experienced a spontaneous bleed event. Four participants on PPX had first spontaneous bleed events in a joint or in skin/mucosa (n=2 [50%] participants for each location). Nine participants on OD had a first spontaneous bleed event in the skin/mucosa (n=4, 44%), internal or joint bleeds (n=2 [22%] participants for each location), or other locations (n=1 [11%]). Furthermore, during their PPX treatment period, participants on primary PPX had a lower frequency and longer time to first spontaneous bleed event than those who switched from OD to PPX (Figure 1B). Conclusions: rFIXFc PPX prolonged the time to first spontaneous bleed event and reduced the frequency of first bleed events versus OD in PUPs with hemophilia B. In participants who received primary PPX, the frequency of a first spontaneous bleed event during the study was lower than in those receiving OD treatment initially. Although these results are limited to a small patient group, they suggest that the type of treatment regimen impacts bleed pattern in pediatric PUPs. Funding: This study was funded by Sanofi and Sobi. Figure 1 Figure 1. Disclosures Nolan: Sobi: Other: Personal fees; Bayer: Other: Sponsorship; CSL Behring: Other: Sponsorship; Sanofi: Other: Sponsorship. Recht: Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; uniQure: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment. Rendo: Sanofi: Current Employment, Other: May hold shares and/or stock options . Falk: Sobi: Current Employment, Other: May hold shares and/or stock options. Foster: Sanofi: Current Employment, Other: May hold shares and/or stock options in the company. Casiano: Sanofi: Current Employment, Other: May hold shares and/or stock options. Rauch: BioMarin: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees. Shapiro: Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Glover Blood Therapeutics: Research Funding; Kedrion Biopharma: Research Funding; Novartis: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; BioMarin: Research Funding; Agios: Research Funding; Octapharma: Research Funding; OPKO: Research Funding; Pfizer: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Takeda: Research Funding.

RATIONALE & OBJECTIVE: Determining whether a change in estimated glomerular filtration rate (eGFR) or albuminuria is clinically significant requires knowledge of short-term within-person variability of the measurements, which few studies have addressed in the setting of chronic kidney disease. STUDY DESIGN: Cross-sectional study with multiple collections over less than 4 weeks. SETTING & PARTICIPANTS: Clinically stable outpatients with chronic kidney disease (N = 50; mean age, 56.8 years; median eGFR, 40 mL/min/1.73 m(2); median urinary albumin-creatinine ratio (UACR), 173 mg/g). EXPOSURE: Repeat measurements from serially collected samples across 3 study visits. OUTCOMES: Measurements of urine albumin concentration (UAC), UACR, and plasma creatinine, cystatin C, β(2)-microglobulin (B2M), and beta trace protein (BTP). ANALYTICAL APPROACH: We calculated within-person coefficients of variation (CV(w)) values and corresponding reference change positive and negative (RCV(pos) and RCV(neg)) values using log-transformed measurements. RESULTS: Median CV(w) (RCV(pos); RCV(neg)) values of filtration markers were 5.4% (+16%; –14%) for serum creatinine, 4.1% (+12%; –11%) for cystatin C, 7.4% (+23%; –18%) for BTP, and 5.6% (+17%; –14%) for B2M. Results for albuminuria were 33.2% (+145%; –59%) for first-morning UAC, 50.6% (+276%; –73%) for random spot UAC, 32.5% (+141%; –58%) for first-morning UACR, and 29.7% (124%; –55%) for random spot UACR. CV(w) values for filtration markers were comparable across the range of baseline eGFRs. CV(w) values for UAC and UACR were comparable across the range of baseline albuminuria values. LIMITATIONS: Small sample size limits the ability to detect differences in variability across markers. Participants were recruited and followed up in a clinical and not research setting, so some preanalytical factors could not be controlled. CONCLUSIONS: eGFR markers appear to have relatively low short-term within-person variability, whereas variability in albuminuria appears to be high, making it difficult to distinguish random variability from meaningful biologic changes.