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Background: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures., Methods: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement)., Results: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05)., Conclusions: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD., Competing Interests: Declaration of Competing Interest KAH: is an employee and may hold stock and/or stock options in Sanofi. KIB: has served as a consultant to Sanofi, Amicus Therapeutics, Takeda, Valerion, and has participated in advisory boards for Sanofi, AskBio, Spark Therapeutics and Takeda; he is currently an employee of Sanofi. PD: is an employee and may hold stock and/or stock options in Sanofi. MMD: serves or recently served as a consultant for Abcuro, Amazentis/Vandria, ArgenX, Astellas, Catalyst, Cello, CNSA, Covance/Labcorp, CSL-Behring, Dianthus, EcoR1, EMD Serono/Merck, Janssen, Kezar, MDA, Medlink, Momenta, NuFactor, Octapharma, Priovant, RaPharma/UCB, Roivant Sciences Inc., Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, TACT, Abata/Third Rock, UCB Biopharma, and UpToDate. MMD received research grants, contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, The Myositis Association, UCB Biopharma/RaPharma, Viromed/Healixmith & TMA. AH: is an employee and may hold stock and/or stock options in Sanofi. PSK: has received research/grant support from Sanofi Genzyme and Amicus Therapeutics; has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, Bayer and Asklepios Biopharmaceutical, Inc. (AskBio); is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Pompe Disease Advisory Board for Amicus Therapeutics, and Advisory Board for Baebies; and has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals, and may receive milestone payments related to that equity in the future. JM: is an employee and may hold stock and/or stock options in Sanofi. LP: is an employee and may hold stock and/or stock options in Sanofi. BS: Unrestricted research grants from Amicus, Astellas, Marigold Foundation, AMDA Foundation. Speaker honoraria from Kedrion, Alexion. Scientific advisor for Amicus, Argenx, Astellas, Maze, Pepgen, Sanofi, Spark, and Taysha. No stocks or shares. NT: is an employee and may hold stock and/or stock options in Sanofi. AT: has received honorarium as a scientific board component (Sanofi, Amicus, and Aro) and as a speaker for Sanofi, Spark, and Amicus. NvdB: received speaker honoraria from Sanofi and Amicus Therapeutics, and has served as scientific advisor for Sanofi under agreements with Erasmus MC University Medical Center and the relevant industry. TZ: is an employee and may hold stock and/or stock options in Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Avalglucosidase alfa (AVAL) was approved in the United States (2021) for patients with late-onset Pompe disease (LOPD), aged ≥ 1 year. In the present study, pharmacokinetic (PK) simulations were conducted to propose alternative dosing regimens for pediatric LOPD patients based on a bodyweight cut-off. Population PK (PopPK) analysis was performed using nonlinear mixed effect modeling approach on pooled data from three clinical trials with LOPD patients, and a phase 2 study (NCT03019406) with infantile-onset Pompe disease (IOPD: 1-12 years) patients. A total of 2257 concentration-time points from 91 patients (LOPD, n = 75; IOPD, n = 16) were included in the analysis. The model was bodyweight dependent allometric scaling with time varying bodyweight included on clearance and distribution volume. Simulations were performed for two dosing regimens (20 mg/kg or 40 mg/kg) with different bodyweight cut-off (25, 30, 35 and 40 kg) by generating virtual pediatric (1-17 years) and adult patients. Corresponding simulated individual exposures (maximal concentration, C max and area under the curve in the 2-week dosing interval, AUC 2W ), and distributions were calculated. It was found that dosing of 40 mg/kg and 20 mg/kg in pediatric patients < 30 kg and ≥ 30 kg, respectively, achieved similar AVAL exposure (based on AUC 2W ) to adult patients receiving 20 mg/kg. PK simulations conducted on the basis of this model provided supporting data for the currently approved US labelling for dosing adapted bodyweight in LOPD patients ≥ 1 year by USFDA., (© 2023. The Author(s).)

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., Competing Interests: 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Pompe 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., Methods: NEO1 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., Results: Twenty-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 <45 years at NEO1 enrollment in both the Naive and Switch Groups., Discussion: Avalglucosidase 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 Evidence: This 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 Information: NCT01898364 (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., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and accumulation of lysosomal glycogen. We assessed the safety and efficacy of avalglucosidase alfa, a recombinant human GAA enzyme replacement therapy specifically designed for enhanced mannose-6-phosphate-receptor targeting and enzyme uptake aimed at increased glycogen clearance, compared with the current approved standard of care, alglucosidase alfa, in patients with late-onset Pompe disease., Methods: We did a randomised, double-blind, phase 3 trial at 55 sites in 20 countries. We enrolled individuals (aged ≥3 years) with enzymatically confirmed late-onset Pompe disease who had never received treatment. We used a centralised treatment allocation system to randomly allocate participants to either avalglucosidase alfa or alglucosidase alfa. Participants and investigators were unaware of their treatment allocation. The primary outcome measure was change from baseline to week 49 in upright forced vital capacity percent (FVC%) predicted. We used a hierarchical fixed sequential testing strategy, whereby non-inferiority of avalglucosidase alfa compared with alglucosidase alfa was assessed first, with a non-inferiority margin of 1·1. If non-inferiority was seen, then superiority was tested with a 5% significance level. The key secondary objective was effect on functional endurance, measured by the 6-minute walk test (6MWT). Safety was assessed, including treatment-emergent adverse events and infusion-associated reactions. The modified intent-to-treat population was the primary analysis population for all efficacy analyses. The safety population was the analysis population for safety analyses. This trial is registered with ClinicalTrials.gov, NCT02782741. We report results of the 49-week primary analysis period., Findings: Between Nov 2, 2016, and March 29, 2019, 100 participants were randomly allocated avalglucosidase alfa (n=51) or alglucosidase alfa (n=49). Treatment with avalglucosidase alfa resulted in a least-squares mean improvement in upright FVC% predicted of 2·89% (SE 0·88) compared with 0·46% (0·93) with alglucosidase alfa at week 49 (difference 2·43% [95% CI -0·13 to 4·99]). Non-inferiority was shown because the lower bound of the 95% CI for the difference far exceeded the predefined non-inferiority margin but did not exclude 0 (p=0·0074). Superiority was not reached (p=0·063), so formal testing was stopped, as per the testing hierarchy. Improvements were also seen in the 6MWT with avalglucosidase alfa compared with alglucosidase alfa, with greater increases in distance covered (difference 30·01 m [95% CI 1·33 to 58·69]) and percent predicted (4·71% [0·25 to 9·17]). Treatment-emergent adverse events potentially related to treatment were reported in 23 (45%) of 51 participants in the avalglucosidase alfa group and in 24 (49%) of 49 in the alglucosidase alfa group, and infusion-associated reactions were reported in 13 (26%) participants in the avalglucosidase alfa group and 16 (33%) in the alglucosidase alfa group. Of the five trial withdrawals, all in the alglucosidase alfa group, four were due to adverse events, including two infusion-associated reactions. Serious treatment-emergent adverse events were reported in eight (16%) participants who received avalglucosidase alfa and in 12 (25%) who received alglucosidase alfa. One participant treated with alglucosidase alfa died because of acute myocardial infarction determined to be unrelated to treatment. Antidrug antibody responses were similar in both groups. High and persistent titres (≥12 800) and neutralising antibodies were more common with alglucosidase alfa (in 16 [33%] participants) than with avalglucosidase alfa (ten [20%])., Interpretation: We consider that this study provides evidence of clinically meaningful improvement with avalglucosidase alfa therapy over alglucosidase alfa in respiratory function, ambulation, and functional endurance, with no new safety signals reported. An open-label extended-treatment period is ongoing to confirm the long-term safety and efficacy of avalglucosidase alfa, with the aim for this therapy to become the new standard treatment in late-onset Pompe disease., Funding: Sanofi Genzyme., Competing Interests: Declaration of interests SA received reimbursement for attending symposia and other expenses. KB has served on advisory boards for Sanofi Genzyme, AskBio, Spark Therapeutics, and Takeda; and received consultant fees from Sanofi Genzyme, Amicus Therapeutics, AskBio, Spark Therapeutics, Takeda and Valerion. Y-HC has received research support, consulting fees, reimbursement for attending symposium and other expenses, and fees for non-continuing medical education or continuing education services from Sanofi Genzyme. PRC has served as a member of the Pompe Registry North American Advisory Board and undertaken contracted research for Amicus, Sanofi Genzyme, Spark, ReveraGen Biopharma, and NS Pharma. She has been a consultant for Roche and Epirium. She has received travel funding from Roche, Spark, and NS Pharma. JWD has received consulting fees from Audentes, Biogen;, Ionis Pharmaceuticals, Cytokinetics, Pfizer, AveXis, Roche/Genentech Pharmaceuticals, AMO Pharmaceuticals, and Sarepta Therapeutics; and has undertaken contracted research for Biogen, Ionis Pharmaceuticals, Cytokinetics, Roche Pharmaceuticals, AveXis, Sanofi- Genzyme, Sarepta Therapeutics, and Scholar Rock. JD-M has served as a consultant or speaker for Sanofi Genzyme, Lupin, Sarepta, and PTC Therapeutics; and received research support from Boehringer Ingelheim and Sanofi Genzyme. MMD has served as a consultant forArgenX, Catalyst, Cello, CSL Behring, EcoR1, Kezar, Momenta, NuFactor, Octapharma, RaPharma/UCB, RMS Medical, Sanofi Genzyme, Shire Takeda, Spark Therapeutics, and UCB Biopharma; and has received grants from Alexion, Alnylam Pharmaceuticals, Amicus, BioMarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL Behring, US Food and Drug Administration/Office of Orphan Products Development, Genentech, GlaxoSmithKline, Grifols, Kezar, Mitsubishi Tanabe Pharma, Muscular Dystrophy Association, US National Institutes of Health (NIH), Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma, Viromed/Healixmith, and TMA. SE-O has served on advisory boards for Sanofi Genzyme. OG-A has served on advisory boards for Amicus, BioMarin, Sanofi, and Takeda; served on speaker's bureau for Sanofi and Takeda; received consulting fees from Amicus, BioMarin, Sanofi Genzyme, Shire Human Genetics Therapies, and Takeda; and undertaken contracted research for Amicus, Freeline, Genentech, Protalix, Sangamo, Sanofi, and Takeda. SI has received honoraria from Actelion, Boehringher Ingelheim, Ever Pharma, Merz Pharma, Servier, Takeda, and Teva. PSK has served on advisory boards for Amicus, Baebies, and Sanofi Genzyme; received consulting fees from Amicus, AskBio, Sanofi Genzyme, and Vertex; undertaken contracted research for Amicus, Sanofi Genzyme, and Valerion; received honoraria from Amicus, AskBio, Sanofi Genzyme, and Vertex; received travel expenses from Amicus and Sanofi Genzyme; and has ownership interests in AskBio and Baebies. HK has served on advisory boards for Alexion, Catalyst Pharmaceuticals, PTC therapeutics, and Sanofi Genzyme; and is on the speaker's bureau of Akcea, Catalyst Pharmaceuticals, and Sanofi Genzyme. SL has served on advisory boards and speaker's bureau, received consulting fees, and undertaken contracted research for Sanofi Genzyme. TM has served on advisory boards for Amicus, Biomarin, Idera, Novartis, Sanofi Genzyme, Ultragenyx, and received travel subsidies and honoraria for related activities; has served as a consultant to NuFactor, Sarepta Therapeutics, and Walgreens, and received travel subsidies and honoraria; served on the speaker's bureau for Sanofi Genzyme and Grifols and received travel subsidies and honoraria for these; and received research funding from Alexion, Alnylam, Amicus, Baxter, Bio-Blast, Biogen, Biomarin, CSL Behring, Sanofi Genzyme, Grifols, GlaxoSmithKline, Idera, ISIS Pharmaceuticals, NIH, Novartis, and Ultragenyx. MR has received research support from Amicus; received consulting fees, honoraria, and travel reimbursement from Sanofi Genzyme, BioMarin, and Amicus; has received royalties from NIH; is a member of a speaker's bureau for NIH; and is a member of the Pompe Registry Scientific Advisory Board. BS has served within the last 3 years on advisory boards for Amicus Therapeutics, Audentes Therapeutics, Dyne, Lupin, Nexien, Sanofi Genzyme, Spark, and UCB; undertaken contracted research for Amicus, Greenovation Biopharm, and Sanofi Genzyme; received honoraria from Alexion and Kedrion; and travel expenses from Kedrion and Sanofi Genzyme. VS has received consulting fees from AveXis, Exonics Therapeutic, Roche, Sanofi Genzyme, and Sarepta Therapeutics; received honoraria from Sanofi Genzyme; and undertaken contracted research from Sanofi Genzyme and Ultragenyx. AT has received reimbursement for participation either as a speaker for lectures and symposia or as a Pompe Registry board member from Sanofi Genzyme. ATvdP provided consulting services, participated in advisory board meetings, and received grants for pre-marketing studies and research from industries (eg, Sanofi Genzyme, Biomarin, and Amicus, etc) via agreements between Erasmus MC and the industries. KAH and her spouse, CH, OH-B, JJ, NT, and TZ are employees of Sanofi Genzyme. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Late-onset Pompe disease (LOPD) is a rare, metabolic disease primarily affecting the musculoskeletal and respiratory systems. Forced vital capacity (FVC) is commonly used to measure pulmonary function; however, associations between FVC and other LOPD outcomes remain unclear., Methods: A systematic literature review was conducted on November 2015, updated September 2016 and supplemented with clinical trial data from the sponsor. Outcomes included: 6-min walk test distance (6MWT), FVC, maximal inspiratory/expiratory pressure (MIP/MEP), Medical Research Council-skeletal muscle strength score (MRC), 36-item short-form survey-physical component score (SF-36), Rotterdam Handicap Scale (RHS), Fatigue Severity Scale (FSS) and survival. Individual patient data meta-analysis was used for cross-sectional analyses and longitudinal analyses to determine associations between percent of predicted FVC and LOPD measures and outcomes., Results: Fifteen studies were selected. From cross-sectional analyses, FVC and MRC were most strongly associated. Specifically, patients with 10% higher FVC (a round number for illustrative purposes only) were associated with a 4.72% (95% confidence interval [CI]: 3.37, 6.07) higher MRC score, indicating a positive association. Similarly, slopes for the 6MWT and SF-36 relative to a 10% higher FVC were estimated at 33.2 meters (95% CI 24.0, 42.4) and 1.2% (95% CI 0.24, 2.16%), respectively. From longitudinal analyses, a 10% incremental increase in predicted FVC was associated with an average increase of 4.12% in MRC score (95% CI 1.29, 6.95), 35.6 m in the 6MWT (95% CI 19.9, 51.6), and 1.34% in SF-36 (95% CI 0.08, 2.60). There was insufficient data to conduct analyses for RHS, FSS and survival., Conclusions: FVC is positively associated with LOPD measures and outcomes across multiple domains. Additionally, longitudinal changes in FVC are positively associated with changes in the 6MWT, MRC and SF-36.