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Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report

Open AccessPublished:December 20, 2022DOI:https://doi.org/10.1016/j.gim.2022.10.010

      Abstract

      Purpose

      Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3).

      Methods

      During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase alfa 40 mg/kg every other week or alglucosidase alfa (current stable dose) for 6 months.

      Results

      In total, 22 individuals were enrolled (cohort 1 [n = 6], cohort 2 [n = 5], cohort 3—avalglucosidase alfa [n = 5], and cohort 3—alglucosidase alfa [n = 6]). Median treatment compliance was 100%. None of the individuals discontinued treatment or died. Percentages of individuals with treatment-emergent adverse events were similar across dose and treatment groups. No serious or severe treatment-related treatment-emergent adverse events occurred. Trends for better motor function from baseline to week 25 were observed for 40 mg/kg every other week avalglucosidase alfa compared with either 20 mg/kg every other week avalglucosidase alfa or alglucosidase alfa up to 40 mg/kg weekly.

      Conclusion

      These data support the positive clinical effect of avalglucosidase alfa in patients with infantile-onset Pompe disease previously declining on alglucosidase alfa.

      Graphical abstract

      Keywords

      Introduction

      Pompe disease (OMIM 232300) is a progressive neuromuscular disorder caused by enzyme deficiency of acid α-glucosidase (GAA), which breaks down lysosomal glycogen, resulting in cellular dysfunction, progressive muscle damage, and functional disabilities.
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      Classic infantile-onset Pompe disease (IOPD), the most severe, rapidly progressive form, presents generally in the first few days to weeks of life (cardiomyopathy may even be prenatal
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      Enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme/Lumizyme, Genzyme Corporation/Genzyme Europe B.V.), approved in 2006 for Pompe disease,
      Genzyme Corporation
      LUMIZYME® (alglucosidase alfa) for injection, for intravenous use. Prescribing Information. Initial US approval 2010. Revised May 2022.
      ,
      Genzyme Corporation
      MYOZYME® (alglucosidase alfa) injection, for intravenous infusion. Prescribing Information. Initial US approval 2006. Revised May 2019.
      has significantly improved invasive-ventilator-free survival among patients with IOPD. However, some patients continue to decline during treatment,
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      and studies have shown that higher and/or more frequent alglucosidase alfa doses may improve motor, respiratory, and biomarker outcomes.
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      This variable response and disease progression in some patients during alglucosidase alfa treatment represents an unmet need.
      Avalglucosidase alfa is a recombinant human GAA ERT, specifically designed for enhanced mannose-6-phosphate receptor targeting and enzyme uptake (≈15-fold increase in mannose-6-phosphate) to increase glycogen clearance (5-fold greater muscle glycogen clearance in preclinical models) and improve on clinical efficacy achieved with alglucosidase alfa.
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      Avalglucosidase alfa (Nexviazyme/Nexviadyme, Genzyme Corporation/Genzyme Europe B.V.) has been studied in late-onset Pompe disease (LOPD) in NEO1 (NCT01898364),
      • Pena L.D.M.
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      Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naive and alglucosidase alfa-treated patients with late-onset Pompe disease: a phase 1, open-label, multicenter, multinational, ascending dose study.
      NEO-EXT (NCT02032524),
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      NEO1 and NEO-EXT studies: long-term safety and exploratory efficacy of repeat avalglucosidase alfa dosing for 5.5 years in late-onset Pompe disease patients.
      and phase 3 COMET (NCT0278274)
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      studies and has received marketing authorization in several countries for LOPD and/or IOPD. In the United States, it was approved in August 2021 for patients with LOPD aged ≥1 year.

      Genzyme Corporation. NEXVIAZYME™ (avalglucosidase alfa-ngpt) for injection, for intravenous use. Prescribing Information. Initial US approval 2021. Revised August 2021. Accessed November 29, 2022. https://products.sanofi.us/nexviazyme/nexviazyme.pdf

      Mini-COMET (NCT03019406) is the first study assessing avalglucosidase alfa safety, pharmacokinetics (PK), and efficacy in children with IOPD aged <18 years. We report the primary analysis period (PAP) results after 25 weeks of avalglucosidase alfa treatment.

      Materials and Methods

      Study design

      Mini-COMET is an ongoing, phase 2, multistage, open-label, multicenter, multinational, ascending-dose cohort, repeated intravenous infusion study, primarily evaluating the safety of avalglucosidase alfa in alglucosidase alfa-experienced children with IOPD who showed clinical decline (stage 1) or suboptimal clinical response (stage 2). In stage 1, avalglucosidase alfa was administered in an ascending-dose manner supported by safety monitoring in cohort 1 (20 mg/kg every other week) and cohort 2 (40 mg/kg every other week). In stage 2, cohort 3 was initiated after determining the highest tolerated avalglucosidase alfa dose in stage 1. Cohort 3 individuals were randomized 1:1 to receive 40 mg/kg avalglucosidase alfa every other week or continue their current stable alglucosidase alfa dose (20 mg/kg every other week to 40 mg/kg weekly) in the PAP. Randomization using interactive response technology was stratified by sex. Each investigator confirmed randomization eligibility.
      Although Mini-COMET was not masked at site level, measures were taken to reduce observation bias where feasible (eg, central reading of echocardiograms and laboratory testing, except for PK and immunogenicity measurements, were masked to treatment).
      Individuals had IOPD diagnosis confirmed through the detection of GAA deficiency in any tissue, were <18 years old, had cardiomyopathy at diagnosis in the first year of life, and received a stable alglucosidase alfa dose regularly for ≥6 months immediately before enrollment. Cohorts 1 and 2 had documented evidence of clinical decline in ≥1 of respiratory function, motor skills, and/or cardiac parameters related to IOPD and not to intercurrent illness. Cohort 3 had documented evidence of suboptimal clinical response in ≥1 of respiratory function, motor skills, and/or new onset of ptosis (drooping eyelid, confirmed by ≥2 sequential assessments) related to IOPD and not to intercurrent illness. Decline or suboptimal clinical response required ≥2 recent consecutive assessments ≥2 weeks apart before enrollment and ≥1 assessment before the onset of decline. Exclusion criteria were antialglucosidase alfa antibody titers of ≥25,600 at 2 consecutive time points >1 month apart, clinically significant non-Pompe organic disease causing abnormal laboratory parameters or potentially decreased survival, or high risk for severe allergic reaction to avalglucosidase alfa (previous moderate/severe anaphylactic reaction, immunoglobulin [Ig]E antibodies, or history of high IgG antibodies to alglucosidase alfa). Criteria for the ascertainment of clinical decline and suboptimal clinical response are presented in the Appendix. CRIM status was ascertained from historical data or interpretation of GAA variants in blood testing by a central laboratory. GAA variant analysis was mandatory either at entry or from prestudy history.

      Treatments

      The starting avalglucosidase alfa dose (20 mg/kg every other week) aligned with adult dosing in the completed NEO1 study.
      • Pena L.D.M.
      • Barohn R.J.
      • Byrne B.J.
      • et al.
      Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naive and alglucosidase alfa-treated patients with late-onset Pompe disease: a phase 1, open-label, multicenter, multinational, ascending dose study.
      The avalglucosidase alfa dose of 40 mg/kg every other week is based on overall good tolerance of 40 mg/kg alglucosidase alfa in clinical practice and trial settings, and is consistent with clinical practice observations when patients with IOPD do not respond to 20 mg/kg alglucosidase alfa every other week and then receive 40 mg/kg every other week.
      • Chien Y.H.
      • Tsai W.H.
      • Chang C.L.
      • et al.
      Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: evidence from real-world experiences.
      ,
      • van Gelder C.M.
      • Poelman E.
      • Plug I.
      • et al.
      Effects of a higher dose of alglucosidase alfa on ventilator-free survival and motor outcome in classic infantile Pompe disease: an open-label single-center study.
      ,
      • Hahn S.H.
      • Kronn D.
      • Leslie N.D.
      • et al.
      Efficacy, safety profile, and immunogenicity of alglucosidase alfa produced at the 4,000-liter scale in US children and adolescents with Pompe disease: ADVANCE, a phase IV, open-label, prospective study.
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      • Geddes G.C.
      Pompe disease treatment with twice a week high dose alglucoside alfa in a patient with severe dilated cardiomyopathy.
      • Yanovitch T.L.
      • Casey R.
      • Banugaria S.G.
      • Kishnani P.S.
      Improvement of bilateral ptosis on higher dose enzyme replacement therapy in Pompe disease.
      Cohort 3 alglucosidase alfa recipients received current stable doses, ie, alglucosidase alfa dose administered regularly for ≥6 months immediately before enrollment (20 mg/kg every other week [n = 1], 40 mg/kg every other week [n = 2], 20 mg/kg weekly [n = 1], 30 mg/kg weekly [n = 1], 40 mg/kg weekly [n = 1]).

      Outcomes

      The PAP was 6 months (25 weeks) from study treatment initiation. Outcomes are reported as changes from baseline to week 25. The primary objective was to assess safety and tolerability of avalglucosidase alfa. Assessments included adverse events (AEs), serious AEs, including medically important events such as new invasive ventilatory support, and AEs of special interest, including infusion-associated reactions (IARs), immunogenicity, physical examinations (weight, height, and head circumference), clinical laboratory evaluations (biochemistry, hematology, and urinalysis), vital sign measurements, and 12-lead electrocardiogram.
      Secondary objectives were to characterize the PK profile of avalglucosidase alfa and evaluate its efficacy compared with that of alglucosidase alfa. Secondary efficacy end points included changes in motor parameters (Gross Motor Function Measure-88 [GMFM-88], Gross Motor Function Classification System-Expanded and Revised [GMFCS-E&R], Quick Motor Function Test [QMFT], and Pompe Pediatric Evaluation of Disability Inventory [Pompe-PEDI] Functional Skills Scale: Mobility Domain), echocardiography (left ventricular mass index [LVMI] and left ventricular mass [LVM] z-score), eyelid position measurements (presence/absence of ptosis), and creatine kinase (CK) and urinary hexose tetrasaccharide (Hex4).
      Tertiary objectives were to determine exploratory pharmacodynamics, pharmacogenetics, and avalglucosidase alfa effect on functional endurance (6-minute walk test [6MWT]), respiratory function (pulmonary function testing and ventilator use [invasive or noninvasive]), health-related quality of life, pain, developmental disability, and hearing (Appendix).

      Statistical analyses

      Descriptive summaries of safety results reflect the safety population (ie, everyone receiving ≥1 infusion). AE analyses focused on treatment-emergent AEs (TEAEs), AEs that developed, worsened, or became serious during treatment. IARs occurring during infusion or 2 hours after infusion were considered AEs related/possibly related to treatment.
      Descriptive summaries of immunogenicity, efficacy, PK, and pharmacodynamic end points are provided by cohort and treatment group. To evaluate the effect of switching from a prior stable dose of alglucosidase alfa to avalglucosidase alfa, an exploratory composite score and other efficacy end points were assessed using the intent-to-treat population (Appendix). Efficacy results are reported as group-level and individual responses.
      Nominal P values are provided via a rerandomization approach. SAS (v9.4, SAS Institute Inc) was used to calculate P values and 95% CIs. No formal sample size calculations were performed.

      Results

      Mini-COMET comprises 10 sites in 5 countries (France, Japan, Taiwan, United Kingdom, and United States) and the PAP lasted from October 12, 2017 to September 30, 2019. All 22 screened children were enrolled, treated (Figure 1), and assigned as follows: cohort 1, n = 6; cohort 2, n = 5; cohort 3, n = 11 (avalglucosidase alfa [n = 5]; alglucosidase alfa [n = 6]).
      Figure thumbnail gr1
      Figure 1Patient disposition and analysis population. ETP, extended treatment period; PAP, primary analysis period.
      No one discontinued treatment during the PAP. All enrolled in the Mini-COMET extension treatment period (ETP). Median treatment compliance was 100%. No one missed infusions or had dose decreases because of safety concerns.

      Demographics and baseline characteristics

      Patient demographics and baseline characteristics are shown in Table 1. Cohort 3 alglucosidase alfa recipients were numerically younger at enrollment (median [range] = 3.6 [1-10] years) than those in cohort 3 avalglucosidase alfa and cohorts 1 and 2 (8.0 [4-10], 8.2 [2-11], and 9.8 [1-12] years, respectively). Cohort 3 alglucosidase alfa recipients had the longest durations between symptom onset and alglucosidase alfa initiation. Cohort 3 avalglucosidase alfa recipients were generally younger at symptom onset, diagnosis, and alglucosidase alfa initiation than those in cohorts 1, 2, and 3 (alglucosidase alfa recipients). Cohort 3 received higher average pre-enrollment doses of alglucosidase alfa. Cohorts 1 and 2 had more males and cohort 3 more females; cohort 3, with sex-stratified randomization, was nearly balanced between the sexes. Cohorts 1 and 2 had more Asians than cohort 3. Growth parameters were normal across cohorts and treatment groups.
      Table 1Baseline demographics, individual characteristics, disease history, and functional status
      ParameterCohort 1 (N = 6)Cohort 2 (N = 5)Cohort 3
      Avalglucosidase alfa (N = 5)Alglucosidase alfa (N = 6)
      Country, n (%)
       France2 (33)1 (20)01 (17)
       Japan1 (17)1 (20)00
       Taiwan2 (33)2 (40)1 (20)0
       United Kingdom001 (20)1 (17)
       United States1 (17)1 (20)3 (60)4 (67)
      Age, y
       Mean (SD)7.6 (3.4)8.1 (4.1)6.9 (2.7)4.7 (3.2)
       Median (range)8.2 (2-11)9.8 (1-12)8.0 (4-10)3.6 (1-10)
      Sex, male, n (%)5 (83)3 (60)2 (40)2 (33)
      Race, n (%)
       White3 (50)2 (40)3 (60)4 (67)
       Black/African American0002 (33)
       Asian3 (50)3 (60)2 (40)0
      Ethnicity, n (%)
       Hispanic/Latino01 (20)1 (20)1 (17)
       Not Hispanic/Latino6 (100)4 (80)4 (80)5 (83)
      Height, z-score
       Mean (SD)–0.2 (0.7)0.0 (1.4)–0.8 (0.8)–0.1 (1.2)
       Median (range)–0.3 (–1 to 1)–0.3 (–1 to 2)–1.2 (–2 to 0)0.3 (–2 to 1)
      Weight, z-score
       Mean (SD)–0.1 (1.4)–-0.2 (2.1)0.4 (0.9)0.1 (0.9)
       Median (range)0.0 (–2 to 2)–0.1 (–3 to 3)0.5 (–1 to 1)0.4 (–1 to 1)
      BMI, z-score
       Mean (SD)–0.16 (1.91)–0.06 (2.57)1.07 (1.25)0.48 (0.36)
       Median (range)0.41 (–2.7 to 1.6)0.64 (–3.7 to 2.2)0.98 (–0.7 to 2.4)0.50 (0.1-1.0)
      Head circumference, cm
      Head circumference z-scores were only available for individuals aged between 0 and 35 months (inclusive) (n = 4) (World Health Organization head circumference z-score tables).
       Mean (SD)53.4 (3.4)51.7 (2.7)53.2 (1.5)50.6 (2.5)
       Median (range)54.0 (48-58)52.0 (49-56)53.2 (52-56)50.9 (46-54)
      Ptosis
       Unilateral01 (20)03 (50)
       Bilateral2 (33)01 (20)0
       Right eye2 (33)1 (20)1 (20)2 (33)
       Left eye2 (33)01 (20)1 (17)
      CRIM status, n (%)
       Positive6 (100)4 (80)4 (100)5 (83)
       Negative01 (20)01 (17)
      Age at first symptoms of Pompe disease, mo
       Mean (SD)1.23 (1.70)3.33 (2.93)0.18 (0.41)1.79 (1.72)
       Median (range)0.34 (0.0-4.4)4.40 (0.1-6.5)0.0 (0.0-0.9)1.79 (0.0-3.7)
      Age at diagnosis of Pompe disease, mo
       Mean (SD)1.93 (2.07)4.29 (3.75)1.54 (1.49)5.12 (5.46)
       Median (range)1.10 (0.3-5.5)4.47 (0.3-8.7)1.84 (0.0-3.5)3.45 (0.3-15.9)
      Age at first treatment with alglucosidase alfa, mo
       Mean (SD)2.85 (2.35)5.32 (4.76)2.12 (2.22)6.19 (6.65)
       Median (range)2.41 (0.4-5.7)4.63 (0.5-10.4)1.94 (0.2-5.7)4.44 (0.3-19.4)
      Time from first symptom to first treatment with alglucosidase alfa, mo
       Mean (SD)1.65 (1.35)2.02 (2.17)1.94 (2.27)4.46 (5.73)
       Median (range)1.54 (0.2-3.5)0.69 (0.3-4.8)1.05 (0.2-5.7)2.64 (0.5-15.7)
      Treatment with alglucosidase alfa before enrollment, n (%)
       20 mg/kg every other week3 (50)2 (40)1 (20)1 (17)
       20 mg/kg weekly3 (50)2 (40)01 (17)
       25 mg/kg weekly002 (40)0
       30 mg/kg weekly0001 (17)
       35 mg/kg weekly001 (20)0
       40 mg/kg every other week01 (20)02 (33)
       40 mg/kg weekly0001 (17)
       42.6 mg/kg weekly001 (20)0
      CK, IU/L
       Mean (SD)1102.17 (932.43)1444.80 (164.17)1211.40 (597.45)1136.17 (672.61)
       Median (range)750.00 (318.0-2607.0)1472.00 (1188.0-1645.0)1528.00 (347.0-1704.0)1179.00 (273.0-1830.0)
      Hex4, mmol/mol
      Hex4 normal range for age >1 years ≤ 4 mmols/mols creatinine (Duke Biochemicals Genetics Laboratory).
       Mean (SD)80.25 (48.38)63.43 (30.71)54.81 (50.41)52.16 (33.93)
       Median (range)73.12 (16.1-143.3)71.31 (20.0-97.3)42.54 (11.9-141.0)69.17 (4.2-80.6)
      GMFCS-E&R, n
       Level I (walks without limitations)1 (17)1 (20)2 (40)3 (50)
       Level II (walks with limitations)1 (17)2 (40)1 (20)0
       Level III (walks using a hand-held mobility device)1 (17)01 (20)1 (17)
       Level IV (self-mobility with limitations, may use powered mobility)2 (33)2 (40)01 (17)
       Level V (transported in a manual wheelchair)1 (17)01 (20)1 (17)
      GMFM-88 total percent score
       Mean (SD)54.81 (31.44)67.43 (33.84)78.69 (20.99)50.44 (26.45)
       Median (range)56.25 (0.8-86.2)86.63 (19.1-96.3)82.76 (52.6-96.6)59.63 (5.1-73.4)
      QMFT
       Mean (SD)23.33 (14.76)31.20 (19.98)30.75 (17.52)20.67 (12.03)
       Median (range)25 (1-41)38 (10-52)33 (11-46)24 (3-36)
      6MWT (distance walked, m)
      Performed for individuals who were ambulatory, defined as the ability to ambulate 40 m (∼130 feet) without stopping and without an assistive device.
       Number of individuals, n4333
       Mean (SD)247.40 (111.63)395.94 (71.21)340.20 (76.77)215.33 (36.56)
       Median (range)259.50 (105.8-364.7)420.00 (315.8-452.0)370.00 (253.0-397.6)213.00 (180.0-253.0)
      Inclusion criteria met at enrollment, n (%)
       Motor function5 (83)5 (100)5 (100)2 (33)
       Respiratory function2 (33)01 (20)1 (17)
       PtosisN/AN/A1 (20)4 (67)
       Missing data0001 (17)
      Cohort 1: avalglucosidase alfa 20 mg/kg every other week. Cohort 2: avalglucosidase alfa 40 mg/kg every other week. Cohort 3: avalglucosidase alfa 40 mg/kg every other week. Cohort 3: alglucosidase alfa 20 mg/kg every other week to 40 mg/kg weekly. The n values reflect the number of individuals with data reported for specific parameters.
      6MWT, 6-minute walk test; BMI, body mass index; CK, creatine kinase; CRIM, cross-reactive immunologic material; GMFCS-E&R, Gross Motor Function Classification System—Expanded and Revised; GMFM-8, Gross Motor Function Measure-88; Hex4, urinary hexose tetrasaccharide; N/A, not applicable; QMFT, Quick Motor Function Test.
      a Head circumference z-scores were only available for individuals aged between 0 and 35 months (inclusive) (n = 4) (World Health Organization head circumference z-score tables).
      b Hex4 normal range for age >1 years ≤ 4 mmols/mols creatinine (Duke Biochemicals Genetics Laboratory).
      c Performed for individuals who were ambulatory, defined as the ability to ambulate 40 m (∼130 feet) without stopping and without an assistive device.
      In total, 19 individuals were CRIM-positive and 2 were CRIM-negative (1 in cohort 2 and 1 in cohort 3 alglucosidase alfa group). The 2 CRIM-negative children had received rituximab/methotrexate before first administration of alglucosidase alfa but were not receiving immunomodulation at study initiation. The cohort 2 individual (who ceased immunomodulation 4 weeks before study initiation, had developed immunodeficiency, and continues receiving polyclonal immunoglobulins) was antidrug antibody (ADA) negative at enrollment, with an initial titer of 200 (week 9) and a last titer of 800 (week 25). The cohort 3 individual ceased immunomodulation 5 weeks before study initiation and was ADA negative from enrollment onward. Thus, although B-cells were not measured, the 2 immunomodulated CRIM-negative individuals were, respectively, low-ADA and immunotolerant by week 25.
      One cohort 3 avalglucosidase alfa recipient had missing CRIM data and was considered CRIM-positive based on genotype.
      One CRIM-positive individual (cohort 1) was immunomodulated before enrollment with 2 courses of immunomodulation (rituximab, methotrexate, and polyclonal immunoglobulins) for elevated antialglucosidase alfa ADAs. The first course started ≈10 months after alglucosidase alfa initiation and continued until ≈24 months after the initiation; the second started ≈33 months after alglucosidase alfa initiation and continued for a further ≈22 months. The individual tolerized and ceased receiving immunomodulation before study initiation; ADA titer was 100 at enrollment and was ADA negative thereafter.
      Baseline GMFCS functional levels were lower in cohorts 1 and 2 than in cohort 3, demonstrating prestudy motor decline or suboptimal response to alglucosidase alfa.
      In cohort 1 (n = 6), 4 individuals enrolled solely for motor decline, 1 solely for respiratory decline, and 1 for both. All 5 cohort 2 individuals enrolled solely for motor decline. Among cohort 3 avalglucosidase alfa recipients (n = 5), 3 enrolled solely for motor suboptimal response, 1 for both motor and respiratory suboptimal response, and 1 for both motor suboptimal response and ptosis. Of cohort 3 alglucosidase alfa recipients (n = 6), 1 enrolled solely for motor suboptimal response, 3 solely for ptosis, and 1 for motor and respiratory suboptimal responses and ptosis. No assessment scale was available at inclusion for 1 individual, who was included by the principal investigator’s overall clinical evaluation confirming a plateau of motor development.
      Although all enrollees had evidence of cardiac involvement at diagnosis (Supplemental Table 1), none were enrolled for declining cardiac parameters (LVM z-score range = −2 to 2.8 [normal range = −2 to 2]).
      Most enrollees had sensorineural hearing loss and muscle weakness (Supplemental Table 1). Baseline functional levels were heterogeneous. The most severely affected individuals were in cohorts 1 and 2 (Supplemental Table 1).
      All 5 Taiwanese individuals had the most frequent GAA variant, NM_000152.5:c.(1726G>A;1935C>A), translation NP_000143.2:p.(Gly576Ser) and p.(Asp645Glu). All variants in the White, Asian, and Black/African American subpopulations were unique to those subpopulations within the study.

      Safety

      Safety results aligned with known safety profiles for avalglucosidase alfa, IOPD, and alglucosidase alfa. Similar numbers of individuals had any TEAE across dose and treatment groups (Table 2). No serious or severe treatment-related TEAEs occurred. IARs (affecting 4 individuals) were mild. IAR incidence on avalglucosidase alfa was higher at 40 mg/kg than at 20 mg/kg, but few individuals had IARs (3 of 10 [30%] vs 0 of 6 [0%]). Among cohort 3 alglucosidase alfa recipients, only 1 of 6 (17%) individuals experienced IARs; prestudy exposure time was by definition longer with alglucosidase alfa. Percentages of IAR-affected individuals appeared similar between doses and treatments.
      Table 2Safety overview: TEAEs during the primary analysis period of the Mini-COMET study
      Parameter, n (%)Cohort 1 (N = 6)Cohort 2 (N = 5)Cohort 3
      Avalglucosidase alfa (N = 5)Alglucosidase alfa (N = 6)
      TEAEs5 (83)5 (100)5 (100)5 (83)
      TEAEs potentially related to treatment02 (40)1 (20)1 (17)
      Serious TEAEs1 (17)3 (60)02 (33)
       Serious TEAEs potentially related to treatment0000
      Severe TEAEs02 (40)01 (17)
       Severe TEAEs potentially related to treatment0000
      TEAEs leading to study discontinuation0000
      TEAEs leading to death0000
      Infusion-associated reactions
      An individual could have more than 1 infusion-associated reaction.
      02 (40)1 (20)1 (17)
       Rash01 (20)1 (20)1 (17)
       Urticaria01 (20)00
       Pruritus0001 (17)
      Cohort 1: avalglucosidase alfa 20 mg/kg every other week. Cohort 2: avalglucosidase alfa 40 mg/kg every other week. Cohort 3: avalglucosidase alfa 40 mg/kg every other week. Cohort 3: alglucosidase alfa 20 mg/kg every other week to 40 mg/kg weekly.
      TEAE, treatment-emergent adverse event.
      a An individual could have more than 1 infusion-associated reaction.
      The 3 most common TEAEs were vomiting, pyrexia, and upper respiratory tract infection (Supplemental Table 2). No individual died, and no TEAE prompted treatment discontinuation.

      Immunogenicity

      The immunogenicity results are summarized in Table 3. During the PAP, 16 individuals received avalglucosidase alfa and 6 alglucosidase alfa. Five had pre-existing ADA to their respective treatments: avalglucosidase alfa treatment in 2 and alglucosidase alfa treatment in 3. One avalglucosidase alfa recipient had baseline ADA titer of 100 and became ADA negative at week 25, whereas the second had baseline titer of 200 and boosted to 6400. Cohort 1, 20 mg/kg every other week avalglucosidase alfa recipients, remained ADA negative, whereas 5 of 10 (50%) 40 mg/kg every other week recipients in cohorts 2 and 3 developed antiavalglucosidase alfa ADA (1 boosted and 4 seroconverted) with titers of 100 to 6400. All 16 avalglucosidase alfa recipients were also evaluated for ADA cross-reactive to alglucosidase alfa; 7 of 16 (44%) had pre-existing cross-reactive ADA and 3 additional individuals subsequently developed cross-reactive ADA. On-study alglucosidase alfa ADA titers (including treatment-boosted) were 100 to 25,600; treatment-induced avalglucosidase alfa titers were 100 to 800.
      Table 3Immunogenicity to treatment administered during the primary analysis period of the Mini-COMET study
      ParameterCohort 1 (N = 6)Cohort 2 (N = 5)Cohort 3
      Avalglucosidase alfa (N = 5)Alglucosidase alfa (N = 6)
      Avalglucosidase alfa ADAs (n = 6)Avalglucosidase alfa ADAs (n = 5)Avalglucosidase alfa ADAs (n = 5)Alglucosidase alfa ADAs (n = 6)
      Number of individuals with ≥2 postbaseline samples, n (%)6 (100)5 (100)5 (100)6 (100)
      ADA status, n (%)
       Positive at baseline1 (17)01 (20)3 (50)
       Negative at baseline5 (83)5 (100)4 (80)3 (50)
      ADA after treatment
       Treatment-boosted ADAs
      Treatment-boosted ADA = pre-existing ADA positive was boosted to a higher level after administration of the study drug.
      , n (%)
      001 (20)2 (33)
       Treatment-induced ADA positive
      Treatment induced ADA incidence = treatment-induced ADA individuals/number of evaluable individuals ADA negative at baseline.
      , n (%)
      01 (20)3 (75)1 (33)
       Treatment-emergent ADA positive
      Treatment-emergent ADA = treatment-boosted ADA + treatment-induced ADA.
      , n
      0143
       Treatment-emergent ADA negative
      Individuals with no treatment-induced or boosted ADA response detected after baseline during the primary analysis period.
      , n (%)
      6 (100)4 (80)1 (20)3 (50)
      Cohort 1: avalglucosidase alfa 20 mg/kg every other week. Cohort 2: avalglucosidase alfa 40 mg/kg every other week. Cohort 3: avalglucosidase alfa 40 mg/kg every other week. Cohort 3: alglucosidase alfa 20 mg/kg every other week to 40 mg/kg weekly. The percentage calculations are based on denominator of total number of individuals in the ADA evaluable population of the treatment group.
      ADA, antidrug antibodies.
      a Treatment-boosted ADA = pre-existing ADA positive was boosted to a higher level after administration of the study drug.
      b Treatment induced ADA incidence = treatment-induced ADA individuals/number of evaluable individuals ADA negative at baseline.
      c Treatment-emergent ADA = treatment-boosted ADA + treatment-induced ADA.
      d Individuals with no treatment-induced or boosted ADA response detected after baseline during the primary analysis period.
      In cohort 3 alglucosidase alfa recipients, 3 of 6 (50%) had baseline alglucosidase alfa ADA and 2 of these subsequently boosted; 1 additional individual (1/6; 17%) subsequently seroconverted. Peak titers in alglucosidase alfa recipients were 400 to 1600. Cross-reactive avalglucosidase alfa ADA pre-existed in 1 of 6 (17%) and subsequently developed in 1 additional individual. Both had cross-reactive ADA titer of 100.

      Efficacy

      Motor function

      Fewer cohort 3 alglucosidase alfa recipients were included for motor decline than in other groups. GMFM-88 improved across all cohorts despite heterogeneous baseline functional levels and greater severity in cohorts 1 and 2 (Table 1). GMFM-88 total percent score (mean) improved modestly in all cohorts, with high interindividual variability (Figure 2A, C, and E). QMFT total score improved in cohorts 2 and 3, whereas mean score in cohort 1 remained stable (Figure 2B). Correlations were observed and were nominally significant between the GMFM-88 total score and the 16-item QMFT total score at baseline (Spearman’s correlation = 0.907, P < .0001) and at week 25 (Spearman’s correlation = 0.878, P < .0001) and for change from baseline to week 25 (Spearman’s correlation = 0.863, P < .0001; Supplemental Figure 1), showing sensitivity and consistency. Individual results are presented in Figure 2C to F. GMFM-88 and QMFT appeared to improve the most in individuals with baseline scores between 20% to 70% (scale: 0%-100%) and 10 to 45 (scale: 0-64), respectively (Figure 2E and F). Two children (both in cohort 1 on 20 mg/kg every other week avalglucosidase alfa, included for motor decline and on 20 mg/kg weekly alglucosidase alfa prestudy) had worsened GMFM-88 scores from baseline to week 25. QMFT scores worsened at week 25 in 4 individuals (3 in cohort 1 and 1 in cohort 2), and 2 had worsening GMFM-88 and QMFT scores. Only 1 of these, who had started ERT at age 6 years, in cohort 1, declined >4 points on GMFM-88 and >2 points on QMFT.
      Figure thumbnail gr2
      Figure 2Changes over time in motor function in GMFM-88 and QMFT. Group-level results for GMFM-88 total percent score (A) and QMFT total score (B). Individual responses ordered by cohort for GMFM-88 total percent score (C) and QMFT total score (D). Individual responses ordered by baseline level for GMFM-88 total percent score (E) and QMFT total score (F). For both instruments, higher scores indicate higher functional level. GMFM-88, Gross Motor Function Measure-88; QMFT, Quick Motor Function Test.
      Among ambulatory individuals aged ≥6 years at baseline, 6MWT distance improved for all receiving 40 mg/kg of avalglucosidase alfa every other week in cohorts 2 and 3. Cohort 1 and the cohort 3 alglucosidase alfa recipients were stable or declined during the PAP (Supplemental Figure 2A and B). Pompe-PEDI functional skills improved or stabilized across all cohorts (Supplemental Figure 3).

      Pompe disease burden biomarkers

      Median CK (muscle damage) and Hex4 (glycogen burden) decreased over time in 40 mg/kg every other week avalglucosidase alfa recipients (Supplemental Figure 4A and B, respectively). CK decreases were less pronounced and responses were more variable with 20 mg/kg every other week avalglucosidase alfa (cohort 1, median [range] change from baseline to week 25, −106 [−809 to 280] IU/L) or alglucosidase alfa (cohort 3 alglucosidase alfa recipients, −9.5 [−54 to 65] IU/L) than for 40 mg/kg every other week avalglucosidase alfa (cohort 2, −588 [−1021 to 113] IU/L; cohort 3 avalglucosidase alfa recipients, −149 [−925 to −81] IU/L). (For CK, multiply by 0.0167 to convert conventional units [IU/L] to SI units [μkat/L].) CK decreased primarily in individuals with baseline levels of >900 IU/L, tended to decrease on either dose of avalglucosidase alfa, and remained stable on alglucosidase alfa (Supplemental Figure 4C). There was a trend for greater Hex4 decreases with 40 mg/kg every other week avalglucosidase alfa (median [range] change from baseline to week 25 for cohort 2, −27.44 [−39.0 to −11.2] mmol/mol; for cohort 3 avalglucosidase alfa recipients, −18.49 [−61.3 to −3.7] mmol/mol) vs 20 mg/kg every other week avalglucosidase alfa (1.59 [−55.6 to 32.8] mmol/mol) and alglucosidase alfa (−2.70 [−41.5 to 41.2] mmol/mol). Hex4 decreases were largest in recipients of avalglucosidase alfa 40 mg/kg every other week with baseline values of >40 mmol/mol and were more variable for those receiving alglucosidase alfa or 20 mg/kg avalglucosidase alfa every other week (Supplemental Figure 4D).

      Cardiac parameters

      Cardiac mass index was normal at baseline in all but one child, a CRIM-negative cohort 2 individual with abnormal baseline LVM and LVMI z-scores of >2, which improved to normal range by week 25. This child had started alglucosidase alfa at age 10 months (7 months before enrollment), with a LVM z-score of 2.8 at baseline and 1.7 at week 25 and antiavalglucosidase alfa ADA titers of 100 and 1600 at these respective timepoints. All others with available baseline M-mode echocardiography had normal baseline LVM and LVMI z-scores. Median LVM z-scores did not increase (ie, did not worsen) from baseline to week 25 (Supplemental Table 3). Everyone’s heart size remained within the normal range or improved.

      Presence/absence of ptosis

      In cohort 1, unilateral ptosis was reported in none of the individuals at baseline and in 1 at week 25, and bilateral ptosis was reported in 2 at baseline and in 3 at week 25. In cohort 2, unilateral ptosis was reported for 1 individual at baseline and in no one at week 25. Among cohort 3 avalglucosidase alfa recipients, bilateral ptosis was reported in 1 individual at baseline, which resolved by week 25, whereas 1 additional individual developed unilateral ptosis between baseline and week 25. Among cohort 3 alglucosidase alfa recipients, unilateral ptosis was reported in 3 individuals at baseline; at week 25, it persisted in 2 and had resolved in 1. Eyelid position measurements will be the focus of a separate article.

      Respiratory function

      Limited pulmonary function testing data were available based on age-related limitations in reliable test performance ability. A total of 5 individuals were receiving ventilation at baseline, and no new invasive ventilator use was reported during the PAP. Few changes without respiratory decline were observed.

      Composite score analysis and evaluation of declining parameters at entry

      Results from the composite score analysis and evaluation of declining parameters at entry are described in Supplemental Table 4. Composite scores for cohort 3 were numerically higher for the alglucosidase alfa group than for the avalglucosidase alfa group, as well as compared with all avalglucosidase alfa recipients, although not statistically significant (Supplemental Tables 5 and 6, respectively).

      Pharmacokinetic parameters

      After 20 mg/kg avalglucosidase alfa every other week treatment, mean terminal half-life (t1/2z) was similar at weeks 1 and 25 (0.7 and 0.6 hour, respectively), as were mean systemic plasma clearance (0.67 and 0.70 L/hour, respectively) and mean steady-state volume of distribution (both 3.5 L). At weeks 1 and 25, after 40 mg/kg avalglucosidase alfa every other week treatment, mean t1/2z ranged from 0.8 to 1.2 hours, mean plasma clearance from 0.53 to 0.68 L/hour, and mean steady-state volume of distribution from 4.0 to 5.4 L. Avalglucosidase alfa exposure increased dose-proportionally without apparent deviation (Supplemental Table 7).

      Discussion

      The Mini-COMET study enrolled long-term IOPD survivors, aged 1 to 12 years, incompletely responsive to alglucosidase alfa at doses from 20 mg/kg every other week to 42.6 mg/kg weekly. Children showed individual patterns of decline at enrollment because of inevitable disease heterogeneity, inducing cohort-level interpatient variability. Before enrollment, most individuals had prominent motor function declines, and some demonstrated respiratory function decline or new onset of ptosis. Only 1 child (CRIM-negative in cohort 2; on alglucosidase alfa treatment for 7 months before study initiation) had abnormal baseline LVM and LVMI z-scores at enrollment (z-score > 2).
      Disease biomarkers and exploratory efficacy assessments improved in most avalglucosidase alfa recipients, especially at 40 mg/kg every other week. Exploratory efficacy outcomes (6MWT, GMFM-88, QMFT, Pompe-PEDI, ptosis, and LVM z-score) improved or stabilized at avalglucosidase alfa 40 mg/kg every other week, whereas these parameters stabilized or declined in the PAP with avalglucosidase alfa 20 mg/kg every other week or alglucosidase alfa. Heterogeneous ages and functional levels made it challenging to select motor assessments encompassing the range of potential changes. Small GMFM-88 or Pompe-PEDI changes can represent skills important to patients and families but may be difficult to interpret meaningfully in a heterogeneous group. The GMFM-88 comprises 88 items and the Pompe-PEDI Functional Skills Scale Mobility Domain has 160 items, whereas these tools were developed to capture functional changes important to a child’s mobility and independence, each item contributing a small numeric change. Younger ages among cohort 3 alglucosidase alfa recipients increased interpatient variability without affecting the validity of group results. Apparent absence of GMFM-88 difference between the 2 cohort 3 groups may reflect baseline age imbalance and IOPD population heterogeneity but also the 25-week PAP duration. Of the 6 cohort 3 alglucosidase alfa recipients, the 3 who enrolled because of ptosis alone experienced motor improvement in the PAP while continuing the highest pre-enrollment alglucosidase alfa doses (20 mg/kg weekly to 40 mg/kg weekly).
      Avalglucosidase alfa was generally safe and well-tolerated at 20 and 40 mg/kg every other week in severely affected children with incomplete response to previous alglucosidase alfa treatment at doses from 20 mg/kg every other week to 42.6 mg/kg weekly. No serious or severe treatment-related TEAEs occurred (including deaths). No TEAEs resulted in treatment modification or discontinuation. Avalglucosidase alfa PK parameters appeared similar at weeks 1 and 25, indicating no apparent accumulative effect of every other week dosing.
      A total of 6 avalglucosidase alfa recipients developed treatment-emergent ADA to avalglucosidase alfa with titers from 100 to 6400. This relatively low immunogenicity could reflect several factors, including prior immunomodulation, previous long-term alglucosidase alfa treatment, exclusion of individuals with antibody titers of ≥25,600, and differences in immunoreactivity. Importantly, antibody titers formed on study remained low.
      The highest avalglucosidase alfa dose tested, 40 mg/kg every other week, appears to afford additional benefits in meaningful outcome measures while maintaining a favorable safety profile and acceptable immunogenicity compared with avalglucosidase alfa at 20 mg/kg every other week and alglucosidase alfa at doses from 20 mg/kg every other week to 40 mg/kg weekly in a vulnerable IOPD survivor population with several years’ disease burden. Medically meaningful intraindividual changes in motor outcomes, in which each individual served as their own control, evidenced longitudinal stabilization or improvement after individuals started avalglucosidase alfa after prior clinical decline on alglucosidase alfa. In addition, some individuals’ muscle disease may already have been irreversible at enrollment. Results suggest that early initiation of avalglucosidase alfa may be more beneficial before irreversible muscle damage occurs, underscoring the need to study avalglucosidase alfa in treatment-naïve IOPD and younger patients. Biomarker improvements on 40 mg/kg every other week avalglucosidase alfa, eg, decreased urinary Hex4 output, show improved glycogen burden reduction by this drug and dose (lowest value achieved was 7.4 mmols/mols creatinine).
      • Khan A.A.
      • Case L.E.
      • Herbert M.
      • et al.
      Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.
      ,
      • Young S.P.
      • Zhang H.
      • Corzo D.
      • et al.
      Long-term monitoring of patients with infantile-onset Pompe disease on enzyme replacement therapy using a urinary glucose tetrasaccharide biomarker.

      Study limitations

      Although trial inclusion criteria aimed at including only individuals who had not responded well to alglucosidase alfa without recent intercurrent illnesses, individual variations in disease course were expected, and potential confounding factors (eg, sex, age, disease duration, or functional level) had imbalances. It is also challenging to fully capture pretrial data to document the effect of switching treatment. In addition, selection bias is possible with respect to centers choosing to participate. Only the 25-week PAP results are reported in this article, and further treatment responses may appear during the 120-week ETP and ≤226-week extended long-term treatment period.
      Despite interpatient heterogeneity in disease courses, all individuals showed individual benefit on most outcomes while receiving avalglucosidase alfa. This is also reflected in a median treatment compliance of 100% and mostly positive outcome measures. Positive effects on select outcomes in cohort 3 individuals continuing the same alglucosidase alfa dose they had received for ≥6 months before enrollment with suboptimal response may be biased by confounding factors as well as inclusion of individuals because of new onset of ptosis. With only one relevant timepoint after treatment (week 25), the study could not determine the effect of ADA on PK.

      Conclusion

      Avalglucosidase alfa was generally well-tolerated at 20 and 40 mg/kg every other week in this vulnerable IOPD long-term survivor population. Observed safety aligns with known safety profiles of avalglucosidase alfa and alglucosidase alfa and with underlying IOPD. Results from the 16 avalglucosidase alfa recipients confirm the exploratory efficacy of avalglucosidase alfa to be similar or better than alglucosidase alfa based on data from biomarker and motor evaluations. The results suggest avalglucosidase alfa 40 mg/kg every other week can potentially improve clinical outcomes in patients with IOPD who showed prior clinical decline or suboptimal response on alglucosidase alfa doses between 20 mg/kg every other week and 42.6 mg/kg weekly. Data support avalglucosidase alfa’s positive clinical effect in IOPD patients, the most severely affected patients with this progressive disease.

      Data Availability

      Qualified researchers may request access to individual-level data and related study documents. Individual-level data will be anonymized, and study documents will be redacted to protect the privacy of trial individuals. Further details on Sanofi’s data sharing criteria, eligible studies, and process for requesting access can be found at https://www.vivli.org/

      Mini-COMET Study Investigators

      Principal investigators

      Yin-Hsiu Chien, François Labarthe, Evelyne Jacqz-Aigrain, Manuel Schiff, Anaïs Brassier, Satoko Kumada, Hirotaka Ohki, James Edward Davison, Alexander Allen Broomfield, Priya Kishnani, David F. Kronn, Si Houn Hahn.

      Subinvestigators

      Wuh-Liang Hwu, Chun-An Chen, Zhe-Yi Lin, Hsiang Huang, Ni Chung Lee, Huang Hsiang-Ju, Lin Che-Yi, Laetitia Petit, Aurelie Sabard-Sanchez, Marine Tardieu, Soizick Pondaven-Letour, Elisabeth Dilay, Amelie Mathieu, Emilie Chicoine, Olivia Delrieu, Marie-Dominique Despit, Jérémy Do Cao, Samia Pichard, Florentia Kaguelidou, Francois Martine, Emilie Soulier, Cecilia Martos, Florence Martinache, Sylvain Bidaud, Delphine Sitbon, Lea Etchebarren, Jean-Baptiste Arnoux, Juliette Bouchereau, Pascale De Lonlay, Camille Wicker, Manuel Schiff, Nathalie Loundon, Elodie Deladrière, Virginie Germa, Marie France De Champagne, Valerie Barbier, Marion Maquet, Hideaki Mashimo, Kenji Inoue, Atsuko Arisaka, Yohane Miyata, Hiroya Nishida, Ikuko Shirai, Mari Inoue, Mika Kanazashi, Masaru Miura, Naoya Fukushima, Koichi Miyata, Naofumi Sumitomo, Hiroki Nagamine, Satoshi Takasago, Yoshihiko Morikawa, Jun Maeda, Maasa Sato, Yutaro Koyama, Noriyuki Morikawa, Tomosato Yamagata, Kayoko Osuga, Toshio Inagaki, Masahide Watanabe, Yukiko Uchiyama, Aki Komatsu, Ryoko Mayama, Emiko Saitou, Spyros Batzios, Ciancio Jose Ignacio Rodriguez, Svetlana Tuslova, Nimmi Parikh, Rebecca Greenaway, Gillian Waite, Deepti Chugh, Brindha Anandanadarajah, Herra Bhutta, Anita Wong, Phillip Harniess, Arunabha Ghosh, Simon Allan Jones, Pauline Hensman, Clare Convery, Rachel Booth, Stewart Robert Rust, Mai Kamal El Mallah, Stephanie DeArmey, Laura Elizabeth Case, Crista Walters, Jennifer S. Li, Rebecca Quinones, Gail Spiridigliozzi, Julie Coats, Rachel Gandy, Daniel King, Valerie M. Marrero-Stein, Keith Villacorta, Mariam Magda, Vanessa Vargas-Fajardo, Lianne De Serres, Christina Tsui-Shan Lam, Irene Chang, Jenny Howell, Lawrence Merritt II, Angela Sun, Leslie Vogel, Alison Paolozzi.

      Conflict of Interest

      P.S.K. reports advisory board participation for Amicus Therapeutics, Baebies, and Sanofi; receiving consulting fees from Amicus Therapeutics, Asklepios Biopharmaceutical Inc (AskBio), JCR Pharma Co Ltd, Maze Therapeutics, and Sanofi; performing contracted research for Amicus Therapeutics and Sanofi; receiving honoraria from Amicus Therapeutics, AskBio, Maze Therapeutics, and Sanofi; having ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in AskBio and Maze Therapeutics; and receiving travel expenses from Amicus Therapeutics and Sanofi. D.K. reports advisory board participation for AskBio and Sanofi; performing contracted research for Sanofi; serving on the Speaker’s bureau for Sanofi; and receiving travel expenses from AskBio and Sanofi. A.Bra. reports advisory board participation for Alexion, Sanofi, and Shire; receiving consulting fees from Alexion; and receiving travel expenses from Alexion, BioMarin, Orphan Europe, Sanofi, and Shire. A.Bro. reports advisory board participation for Sanofi and receiving honoraria from Orchard Therapeutics and Sanofi. J.D. reports advisory board participation for Sanofi, Recordati RRD, and Orchard Therapeutics; receiving consulting fees from bluebird bio Inc; and serving on the Speaker’s bureau for Sanofi, Recordati RRD, and FYMCA Medical Ltd. S.H.H. reports advisory board participation for Alexion Pharmaceutical Inc; performing contracted research for Sanofi; receiving honoraria from Alexion Pharmaceutical Inc; membership of the Seattle Children’s Hospital workforce; serving as temporary CEO of KEY PROTEO, Inc; being an inventor of intellectual property that has been licensed to KEY PROTEO, Inc; being a founder of KEY PROTEO, Inc and having ownership equity interests in the company; and receiving royalties from UpToDate. S.K., F.L., and H.O. declare no conflicts of interest. S.P. reports receiving travel expenses from Sanofi. S.G.P. reports performing contracted research for Sanofi and receiving consulting fees from Sanofi. K.A.H. and her spouse are employees of Sanofi and both have ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi. B.K. is an employee of Sanofi and has ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi. X.M. is an employee of TechData Service LLC (contracted to Sanofi). S.S. is an employee of Sanofi and has ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi. C.W. reports receiving consulting fees from Sanofi and Regenxbio. A.Z. is an employee of Sanofi and has ownership interest of <5% (stocks, stock options, or other ownership interest excluding diversified mutual funds) in Sanofi Canada. Y.-H.C. reports advisory board participation for Amicus Therapeutics and Sanofi; receiving consulting fees from Amicus Therapeutics and Sanofi; performing contracted research for Sanofi; and receiving honoraria from Biogen, Novartis, Sanofi, and Takeda.

      Acknowledgments

      The authors acknowledge medical writing and publication support provided by Marianne B. Zajdel, formerly of Sanofi, and Jane M. Gilbert of Elevate Scientific Solutions, contracted by Sanofi for publication support services. The authors exerted sole scientific control, were responsible for all content and editorial decisions, and received no honoraria related to the development of this article. This study was funded by Sanofi.

      Author Information

      Conceptualization: P.S.K., S.G.P., K.A.H., C.W., A.Z., Y.-H.C.; Data Curation: S.G.P., K.A.H., X.M., C.W., A.Z.; Formal Analysis: K.A.H., X.M., C.W., A.Z.; Funding Acquisition: K.A.H.; Investigation: P.S.K., D.K., A.Bra., A.Bro., J.D., S.H.H., S.K., F.L., H.O., S.P., S.G.P., K.A.H., B.K., X.M., S.S., C.W., A.Z., Y.-H.C.; Methodology: P.S.K., S.G.P., K.A.H., X.M., C.W., A.Z., Y.-H.C.; Project Administration: K.A.H., Y.-H.C.; Resources: P.S.K., D.K., A.Bra., A.Bro., J.D., S.H.H., S.K., F.L., H.O., S.P., S.G.P., Y.-H.C.; Supervision: P.S.K., K.A.H., Y.-H.C.; Validation: K.A.H., X.M., A.Z.; Visualization: P.S.K., D.K., A.Bra., A.Bro., J.D., S.H.H., S.K., F.L., H.O., S.P., S.G.P., K.A.H., B.K., X.M., S.S., C.W., A.Z., Y.-H.C.; Writing-original draft: P.S.K., D.K., A.Bra., A.Bro., J.D., S.H.H., S.K., F.L., H.O., S.P., K.A.H., B.K., X.M., S.S., C.W., A.Z., Y.-H.C.; Writing-review and editing: P.S.K., D.K., A.Bra., A.Bro., J.D., S.H.H., S.K., F.L., H.O., S.P., S.G.P., K.A.H., B.K., X.M., S.S., C.W., A.Z., Y.-H.C.

      Ethics Declaration

      The study was conducted in accordance with the Declaration of Helsinki and the International Council for Harmonisation guidelines for good clinical practice. The study protocol was reviewed and approved by the Duke University Health Systems Institutional Review Board. All participating institutions received appropriate independent ethics committee/institutional review board approval. Written informed individual consent was obtained before any study-related procedures.

      Supplementary Material

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