Efficacy and Safety of Cipaglucosidase Alfa/Miglustat Versus Alglucosidase Alfa in Late-Onset Pompe Disease: a Global, Double-Blind, Randomized Phase 3 Trial (PROPEL)

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Efficacy and safety of cipaglucosidase alfa/miglustat versus alglucosidase alfa in late-onset Pompe disease: A global, double-blind, randomized phase 3 trial (PROPEL)

Tahseen Mozaffar1 1University of California, Irvine, CA, USA

Drago Bratkovic,2 Barry Byrne,3 Pascal Laforet,4 Ans van der Ploeg,5 Mark Roberts,6 Benedikt Schoser,7 Antonio Toscano,8 Hai Jiang,9 Sheela Sitaraman,9 Srilakshmi Kuchipudi,9 Zoheb Kazi,9 Mitchell Goldman,9 Jeff Castelli,9 Priya S. Kishnani10

Affiliations: 2PARC Research Clinic, Royal Adelaide Hospital, Adelaide, SA, Australia; 3University of Florida, Gainesville, FL, USA; 4Raymond-Poincaré Hospital, Garches, France; 5ErasmusMC University Medical Center, Rotterdam, the Netherlands; 6Salford Royal NHS Foundation Trust, Salford, UK; 7Friedrich-Baur-Institut, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; 8Università di Messina, Messina, Italy; 9Amicus Therapeutics, Inc., Cranbury, NJ, USA; 10Duke University Medical Center, Durham, NC, USA 2 Disclosures and Disclaimers

. Dr. Mozaffar has served as a consultant for Amicus Therapeutics, Sanofi Genzyme, Spark Therapeutics and Audentes, and as a speaker for Sanofi Genzyme, and his institution has received grants from Sanofi Genzyme, Valerion, Spark Therapeutics and Audentes for the participation in their clinical trials . This presentation shares information about Amicus Therapeutics’ investigational therapy AT- GAA, which is in development for the treatment of Pompe disease. This investigational therapy is not approved by any regulatory agency at this time . The study was funded by Amicus Therapeutics, Inc. 3 Pompe Disease Overview

. Pompe disease (PD) is a rare, autosomal recessive lysosomal disorder caused by pathogenic variants of the GAA gene1,2 . Functional deficiency of GAA leads to lysosomal accumulation of glycogen in all tissues, especially skeletal, cardiac, and smooth muscles1,3 . The clinical presentation of PD includes 2 phenotypes: infantile-onset (IOPD) and late-onset (LOPD)3 . LOPD is primarily characterized by progressive weakness in the limb-girdle and respiratory muscles, leading to motor and respiratory difficulties2 ̶ Respiratory failure is a common cause of mortality in LOPD3 . LOPD may involve other organ systems, including the central and peripheral nervous system, bone, vasculature, heart, gastrointestinal and urinary tract2,4 . Alglucosidase alfa, a rhGAA, is the only approved treatment that has shown to improve prognosis in patients with IOPD and LOPD5,6 GAA=acid alpha-glucosidase; rhGAA=recombinant human GAA; References: 1. Hers HG. Biochem J. 1963;86(1):11-16. 2. Kishnani PS, et al. J Pediatr. 2004;144(5 Suppl):S35-43. 3. Kishnani PS, et al. Genet Med. 2006;8(5):267-288. 4. Chan J, et al. Mol Genet Metab. 2017;120(3):163-172. 5. Lumizyme® [prescribing information]. Sanofi Genzyme: Cambridge, MA; 2020. 6. Do HV, et al. Ann Transl Med. 2019;7(13):291. 4 AT-GAA: Cipaglucosidase alpha/miglustat

. AT-GAA is an investigational, 2-component therapy comprising cipaglucosidase alfa administered in conjunction with miglustat ̶ Cipaglucosidase alfa is a novel rhGAA with enhanced glycosylation designed for improved uptake and processing ̶ Miglustat is a small molecule that stabilizes cipaglucosidase alfa in blood and enhance delivery of the active enzyme to tissues . In a murine model of PD, AT-GAA was shown to be superior to alglucosidase alfa in reversing or improving all aspects of disease pathogenesis that were measured—glycogen clearance, lysosomal enlargement, autophagic buildup, muscle fiber size and muscle strength Cipaglucosidase alfa Miglustat (intravenous novel ERT) (oral enzyme stabilizer)

AT-GAA=Amicus Therapeutics GAA; ERT=enzyme replacement therapy; rhGAA=recombinant human acid alpha-glucosidase. Reference: Xu S, et al. JCI Insight. 2019;4(5). 5 PROPEL Study Design

. A phase 3, randomized, double-blind, active-controlled trial to assess the efficacy and safety of AT-GAA in adult patients with LOPD compared with alglucosidase alfa/placebo (NCT03729362)

Patients were enrolled in 62 sites across 24 countries

AT-GAA (n=85) 20 mg cipaglucosidase alfa IV a + 260 mg miglustat qowb AT-GAA N=123 Randomization: ERT-experienced 20 mg cipaglucosidase alfa IV & ERT-naive 2:1 Alglucosidase alfa (n=38) + 260 mg miglustat qowb 20 mg/kg alglucosidase alfa IV + placebo qow

Screening and randomization 12-month double-blind Open-label extension (Stratification by prior treatment status) Baselinec Week 52 Key Enrollment Criteria: • ≥18 years old, weighing ≥40 kg at screening with confirmed diagnosis of LOPD • Classified as one of the following with respect to ERT status: • ERT experienced, defined as currently receiving standard of care ERT (alglucosidase alfa) for ≥24 months • ERT naive, defined as never having received ERT • 6MWD ≥75 meters and ≤90% of the predicted value for healthy adults at screening • Sitting FVC ≥30% of the predicted value for healthy adults at screening a2 patients were randomized but not dosed. b195 mg for patients weighing 40-<50 kg. cBaseline values were measured during screening (up to 30 days before dosing). For 6MWD and FVC: the baseline value is the average of last 2 measurements obtained on or prior to 1st dose date. 6MWD=6-minute walk distance; ERT=enzyme replacement therapy; FVC=forced vital capacity; LOPD=late-onset Pompe disease; qow=every other weeks. Reference: ClinicalTrials.gov NCT03729362. Available at: https://clinicaltrials.gov/ct2/show/NCT03729362 6 Efficacy Endpoints

. Primary endpoint: Change from baseline to Week 52 in 6-minute walk distance (6MWD) measured in meters. ̶ The primary endpoint was tested for superiority of AT-GAA vs alglucosidase alpha, using MMRM and pre- specified nonparametric test in case of violation of normality . Key secondary efficacy endpoints in a pre-specified hierarchical order of importance are: ̶ Change from baseline to Week 52 in sitting FVC (% predicted) ̶ Change from baseline to Week 52 in the manual muscle test (MMT) score for the lower extremities ̶ Change from baseline to Week 52 in the total score for the PROMIS– Physical Function ̶ Change from baseline to Week 52 in the total score for the PROMIS – Fatigue ̶ Change from baseline to Week 52 in the total score for the GSGC (Gait, Stairs, Gowers’ maneuver, Chair) Secondary endpoints were analyzed using ANCOVA model with last observation carried forward (ITT LOCF)

ANCOVA=analysis of covariance; FVC=forced vital capacity; ITT=intention to treat; MMRM= mixed-effect model for repeated measures; PROMIS=Patient-reported Outcomes Measurement Information System. Results 8 Patient Disposition

There was a very low drop-out rate Patients Randomized and Dosed and all patients completing the N=123 study subsequently enrolled in the AT-GAA extension study AT-GAA n=85 Alglucosidase Alfa n=38 ERT Experienced n=65 ERT Experienced n=30 ERT Naive n=20 ERT Naive n=8 Discontinued Discontinued n=5 n=1 (IAR=2) (AEb=1) (Othera=3 ) ITT: Primary Analysis ITT: Primary Analysis n=85 n=38

ATB200-07 OLE AT-GAA n=117 AE=adverse event; ERT=enzyme replacement therapy; IAR=infusion-associated reaction; ITT=intention to treat. a1 Covid pneumonia, 2 withdrew, no longer wanting to travel to sites for infusion all unrelated to study drug. b1 stroke, unrelated to study drug. 9 Baseline Demographics

Baseline demographics were representative of the population and generally similar in the 2 treatment arms

AT-GAA Alglucosidase alfa Total n=85 n=38 N=123 Age (years) Mean (SD) 47.6 (13.3) 45.1 (13.3) 46.8 (13.3) Median (Min, Max) 48.0 (19, 74) 46.0 (22, 66) 47.0 (19, 74) Sex, n (%) Male 36 (42.4) 20 (52.6) 56 (45.5) Female 49 (57.6) 18 (47.4) 67 (54.5) Previous ERT Duration (years, ERT-experienced only) Mean (SD) 7.5 (3.4) 7.1 (3.6) 7.4 (3.4) Median (Min, Max) 7.6 (2.0, 13.7) 7.1 (2.1, 13.2) 7.4 (2.0, 13.7) Race, n (%) White 74 (87.1) 30 (78.9) 104 (84.6) Asian 5 (5.8) 5 (13.2) 10 (8.1) Other 6 (7.1) 3 (7.9) 9 (7.3) Regions, n (%) North/South America 26 (30.6) 15 (39.5) 41 (33.3) Europe 43 (50.6) 12 (31.6) 55 (44.7) Asia Pacific 16 (18.8) 11 (28.9) 27 (22.0)

ERT=enzyme replacement therapy; SD=standard deviation. 10 Baseline Characteristics: 6MWD and FVC

Baseline 6MWD and FVC were representative of the population and generally similar in the 2 treatment arms

AT-GAA Alglucosidase alfa Overall population n=85 n=37 6MWD, m Mean (SD) 357.9 (111.8) 351 (121.3) Median (Min, Max) 359.5 (79.0, 575.0) 365.5 (112.5, 623.0) FVC, % predicted Mean (SD) 70.7 (19.6) 69.7 (21.5) Median (Min, Max) 70.0 (30.5, 132.5) 71.0 (31.5, 122.0) AT-GAA Alglucosidase alfa ERT-Experienced n=65 n=30 6MWD, m Mean (SD) 346.9 (110.2) 334.6 (114.0) Median (Min, Max) 352.5 (79.0, 557.5) 343.5 (112.5, 532.3) FVC, % predicted Mean (SD) 67.9 (19.1) 67.5 (21.0) Median (Min, Max) 68 (30.5, 132.5) 69.0 (31.5,122.0) AT-GAA Alglucosidase alfa ERT-Naïve n=20 n=7 6MWD, m Mean (SD) 393.6 (112.4) 420.9 (135.7) Median (Min, Max) 375.2 (154.0, 575.0) 385.5 (201.0, 623.0) FVC, % predicted Mean (SD) 80.2 (18.7) 79.1 (22.6) Median (Min, Max) 82.3 (48.0, 111.0) 93.5 (46.5, 98.0) 11 6MWD and FVC: Overall Population (n=122)

6MWD showed greater improvement with AT-GAA vs alglucosidase alfa but did not reach statistical superiority; FVC demonstrated. Phase 3 aPROPEL nominally statisticallyTopline Results significant & clinically meaningful improvement with AT-GAA vs alglucosidase alfa

6MWD (m) Treatment Baseline CFBL at Week 52 Difference P Value AT-GAA (n=85) 357.9 (111.8) +20.8 (4.6) +13.6 (8.3) P=0.072 Alglucosidase alfa (n=37) 351.0 (121.3) +7.2 (6.6)

FVC (% predicted) Treatment Baseline CFBL at Week 52 Difference P Value AT-GAA (n=85) 70.7 (19.6) -0.9 (0.7) +3.0 (1.2) P=0.023 Alglucosidase alfa (n=37) 69.7 (21.5) -4.0 (0.8)

6MWD=6-minute walk distance; ANCOVA=analysis of covariance; CFBL=change from baseline; FVC=forced vital capacity; LOCF=last observation carried forward; MMRM= mixed-effect model for repeated measures; SD=standard deviation; SE=standard error. Baseline is mean (SD); CFBL is mean LOCF (SE); P values are nominal 2-sided. 6MWD data were not normally distributed and 6MWD P value is for non-parametric ANCOVA; 6MWD parametric MMRM P=0.097. FVC data were normally distributed and P values are from ANCOVA. Results exclude 1 clinically implausible patient who used an investigational anabolic steroid ostarine (selective androgen receptor modulator) just prior to study start. 12 6MWD and FVC Over Time: Overall Population (n=122)

Overall patients treated with AT-GAA demonstrated improvements over time in 6MWD and stabilization over time in FVC versus alglucosidase alfa

6MWD (m): Change from baseline FVC (% predicted): Change from baseline

(n=85, n=37) (n=85, n=37)

30 2.0 p=0.072 1.5 p=0.023

25 1.0 0.5 20.8 0.0 20 -0.5 -0.9 -1.0 15 -1.5 -2.0 10 -2.5 8 7.2 -3.0 6

Mean(SE) Actual Change 6MWD in (m) 4 -3.5 -3.9 2 -4.0 Mean (SE) Actual Change in (m) Change (SE)6MWD Actual Mean Mean(SE) Actual Change % Sitting Predicted in FVC 0 -4.5 -2 -5.0 FVC Predicted % Sitting in Change Actual (SE) Mean Baseline Week 12 Week 26 Week 38 Week 52 LOCF Baseline Week 12 Week 26 Week 38 Week 52 LOCF Visit Visit

Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

6MWD=6-minute walk distance; ANCOVA=analysis of covariance; CFBL=change from baseline; ERT=enzyme-replacement therapy; FVC=forced vital capacity; LOCF=last observation carried forward; MMRM= mixed-effect model for repeated measures; SD=standard deviation; SE=standard error. Baseline is Mean (SD); CFBL is Mean (SE); P values are nominal 2-sided; FVC data normally distributed and P values are from ANCOVA. 6MWD data not normally distributed and 6MWD P value is for non- parametric ANCOVA; 6MWD parametric MMRM P=0.097. Results exclude one clinically implausible patient who used an investigational anabolic steroid ostarine (selective androgen receptor modulator) just prior to study start. 13 6MWD and FVC: ERT-Experienced Population (n=95)

In the ERT-experienced population, 6MWD and FVC demonstrated a nominally statistically significant and clinically meaningful improvement with AT-GAA vs alglucosidase alfa 6MWD (m) Treatment Baseline CFBL at Week 52 Difference P Value AT-GAA (n=65) 346.9 (110.2) +16.9 (5.0) +16.9 (8.8) P=0.046 Alglucosidase alfa (n=30) 334.6 (114.0) 0.0 (7.2)

FVC (% predicted) Treatment Baseline CFBL at Week 52 Difference P Value AT-GAA (n=65) 67.9 (19.1) +0.1 (0.7) +4.1 (1.2) P=0.006 Alglucosidase alfa (n=30) 67.5 (21.0) -4.0 (0.9)

6MWD=6-minute walk distance; ANCOVA=analysis of covariance; CFBL=change from baseline; ERT=enzyme-replacement therapy; FVC=forced vital capacity; MMRM= mixed-effect model for repeated measures; SD=standard deviation; SE=standard error. Baseline is mean (SD); CFBL is mean LOCF (SE); P values are nominal 2-sided. 6MWD data were not normally distributed and 6MWD P value is for non-parametric ANCOVA; 6MWD parametric MMRM P=0.078. FVC data were normally distributed and P values are from ANCOVA. 14 6MWD and FVC Over Time: ERT-Experienced Population (n=95)

ERT-experienced patients treated with AT-GAA demonstrated improvements over time in 6MWD and FVC vs alglucosidase alfa

6MWD (m): Change from baseline FVC (% predicted): Change from baseline (n=65, n=30) (n=65, n=30)

( p ) p p 2.0 30 P=0.046 1.5 P=0.006 25 1.0 0.5 0.1 20 0.0

16.9 -0.5

15 -1.0

-1.5 10 -2.0

-2.5 5 -3.0 0.0 Mean(SE) Actual Change in 6MWD (m) 6MWD in Change Actual Mean(SE) 0 -3.5 -4.0 -2 -4.0 Mean(SE) Actual Change in Sitting % Predicted FVC Predicted % Sitting in Change Actual Mean(SE)

Mean (SE) Actual Change in (m) Change (SE)6MWD Actual Mean -4 -6 -4.5 -8 -5.0 Mean (SE) Actual Change in Sitting % Predicted FVC Predicted % Sitting in Change Actual (SE) Mean BaselineBaseline WeekWeek 12 WeekWeek 2626 WeekWeek 3838 WeekWeek 52 LOCF LOCF BaselineBaseline WeekWeek 12 12 WeekWeek 26 26 Week 38 38 WeekWeek 52 52 LOCF LOCF VisitVisit VisitVisit Treatment: ATB200/AT2221 Alglucosidase Treatment: ATB200/AT2221 Alglucosidase Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

In the smaller ERT-naive population, variability was greater and 6MWD and FVC both numerically favored alglucosidase alfa 6MWD (m) Treatment Baseline CFBL at Week 52 Difference P Value AT-GAA (n=20) 393.6 (112.4) +33.4 (10.9) -4.9 (19.7) P=0.60 Alglucosidase alfa (n=7) 420.9 (135.7) +38.3 (11.1)

FVC (% predicted) Treatment Baseline CFBL at Week 52 Difference P Value AT-GAA (n=20) 80.2 (18.7) -4.1 (1.5) -0.5 (2.7) P=0.57 Alglucosidase alfa (n=7) 79.1 (22.6) -3.6 (1.8)

6MWD=6-minute walk distance; ANCOVA=analysis of covariance; CFBL=change from baseline; ERT=enzyme-replacement therapy; FVC=forced vital capacity; LOCF=last observation carried forward; MMRM= mixed-effect model for repeated measures; SD=standard deviation; SE=standard error. Baseline is mean (SD); CFBL is Mean LOCF (SE); P values are nominal 2-sided; FVC data normally distributed and P values are from ANCOVA. Results exclude 1 clinically implausible patient who used an investigational anabolic steroid ostarine (selective androgen receptor modulator) just prior to study start. 6MWD data not normally distributed and P value is for Wilcoxon test; 6MWD parametric MMRM P=0.75. 16 6MWD and FVC Over Time: ERT-Naive Population (n=27)

ERT naive patients treated with AT-GAA and alglucosidase alfa had similar improvements over time in 6MWD and both declined over time in FVC versus alglucosidase alfa

6MWD (m): Change from baseline FVC (% predicted): Change from baseline

(n=20, n=7) (n=20, n=7) ( p g j ) p 3.5 60 3.0 P=0.60 2.5 P=0.57 2.0 50 1.5 1.0 0.5 40 38.3 0.0 -0.5 33.4 -1.0 30 -1.5 -2.0 -2.5 20 -3.0 -3.5 -3.6 -4.0 Mean(SE) Actual Change in 6MWD (m) 6MWD in Change Actual Mean(SE) -4.1 -4.5

Mean (SE) Actual Change in (m) Change (SE)6MWD Actual Mean 10 -5.0 Mean(SE) Actual Change in Sitting % Predicted FVC Predicted % Sitting in Change Actual Mean(SE) -5.5 -6.0

0 FVC Predicted % Sitting in Change Actual (SE) Mean -6.5 BBaselineaseline WeekWeek 12 12 WeekWeek 26 WeekWeek 38 38 WeekWeek 52 52 LOCF BBaselineaseline WeekWeek 12 12 WeekWeek 26 26 WeekWeek 3838 WeekWeek 52 52 LOCF LOCF Visit Visit

Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

6MWD=6-minute walk distance; ANCOVA=analysis of covariance; CFBL=change from baseline; ERT=enzyme-replacement therapy; FVC=forced vital capacity; LOCF=last observation carried forward; MMRM= mixed-effect model for repeated measures; SD=standard deviation; SE=standard error. Baseline is Mean (SD); CFBL is Mean (SE); P values are nominal 2-sided; FVC data normally distributed and P values are from ANCOVA. 6MWD data not normally distributed and 6MWD P value is for Wilcoxon Text; 6MWD parametric MMRM P=0.75. Results exclude one clinically implausible patient who used an investigational anabolic steroid ostarine (selective androgen receptor modulator) just prior to study start. Key Secondary Endpoints and Biomarkers 18 Baseline characteristics: Key Secondary Endpoints and Biomarkers

Parameters, mean (SD) AT-GAA Alglucosidase alfa

Overall ERT-Experienced Overall ERT-Experienced n=85 n=65 n=37 n=30 MMT lower extremities score 28.0 (5.8)a 26.4 (5.1)b 27.7 (6.2)c 26.1 (5.8)d PROMIS-Physical Function 66.9 (12.3)a 64.4 (11.4)b 68.0 (13.1) 66.9 (12.3) PROMIS- Fatigue 22.3 (8.3) 22.0 (7.9) 21.1 (6.1) 20.4 (5.4) GSGC total score 14.5 (5.2)e 15.6 (4.1)f 14.5 (4.7)g 15.5 (4.4)h

GSGC=Gait, Stairs, Gowers, Chair. Results exclude 1 clinically implausible patient who used an investigational anabolic steroid ostarine (selective androgen receptor modulator) just prior to study start. an=84; bn=64; cn=34; dn=27; en=74; fn=55; gn=32; hn=25. 19 Key Secondary: Lower Extremities MMT All Patients and ERT-Experienced Patients

In the overall population and ERT-experienced population, lower extremities MMT numerically favored AT-GAA

Overall Population ERT-Experienced Population

2.5 2.5 ↑ Improvement ↑ Improvement

2.0 2.0

1.6 1.6 1.5 1.5

1.0 1.0 0.9 0.9

0.5 0.5 Mean(SE) Actual Change in MMT Lower Score MMT Lower in Change Actual Mean(SE) Mean(SE) Actual Change MMT Lower in Score Mean (SE) Actual Change in MMT Lower in Change Lower Score (SE)MMT Actual Mean Mean (SE) Actual Change in MMT Lower in Change Lower Score (SE)MMT Actual Mean 0.0 0.0 BaselineBaseline WeekWeek 1212 WeekWeek 26 26 WeekWeek 3838 WeekWeek 52 52 LOCF LOCF BBaselineaseline WeekWeek 1212 WeekWeek 2626 WeekWeek 38 WeekWeek 52 LOCF LOCF Visit Visit

Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

ERT=enzyme-replacement therapy; LOCF=last observation carried forward; MMT=manual muscle test; SE, standard error. MMT measured via the Medical Research Criteria scale. 20 Key Secondary: PROMIS Physical Function and Fatigue All Patients and ERT-Experienced Patients

Overall Population ERT -Experienced Population ( p g j ) p p 4.0 3.5 3.5 ↑ Improvement 3.0 ↑ Improvement 3.0 2.5 2.0 1.8 2.5 In the overall population and 1.5 2.0 1.9 1.0 1.5 0.5 ERT experienced population, 1.0 0.0 0.5 -0.5 0.2 -1.0 PROMIS physical function 0.0 -1.0 -0.5 -1.5 -2.0 numerically favored AT-GAA -1.0 -2.5 -1.5 -3.0

Mean (SE) Actual Change in Change (SE)Actual Mean -2.0 -3.5 Physical Function Total Total Function Score Physical Mean(SE) Actual Change Physical in Function Total Score -2.5 -4.0

B aselineBaseline Week Week 12 12 Week Week 26 26 WeekWeek 3838 WeekWeek 52 LOCF LOCF Baseline Baseline Week 12 Week Week 26 26 Week Week 3838 WeekWeek 52 52 LOCF LOCF ( p g j ) Week 12 ii p g j ii p p 0.0 1.0

0.5 -0.5

0.0 -0.3 In the overall population and -1.0 -0.5 ERT-experienced population, -1.5 -1.0 -1.7

-1.5 PROMIS fatigue numerically -2.0 -2.0 -1.9 Fatigue Total Score -2.0 favored AT-GAA

-2.5 Score Total Fatigue in Change Actual Mean(SE) Mean(SE) Actual Change Fatigue in Total Score Mean (SE) Actual Change in Change (SE)Actual Mean -2.5 ↓ Improvement ↓ Improvement -3.0 -3.0 BaselineBaseline WeekWeek 12 12 WeekWeek 26 26 WeekWeek 38 38 WeekWeek 52 52 LOCF LOCF BaselineBaseline WeekWeek 12 12 WeekWeek 26 26 WeekWeek 38 38 WeekWeek 52 52 LOCF LOCF

Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

ERT=enzyme-replacement therapy; LOCF=last observation carried forward; PROMIS=Patient-Reported Outcomes Measurement Information System; SE, standard error. PROMIS – Physical Function Short Form 20a (v2.0) comprises 20 questions scored on a scale from 1 to 5: 1=unable to do; 5=without any difficulty; minimum score 20, maximum score 100. PROMIS – Fatigue Short Form 8a comprises 8 questions scored on a scale from 1 to 5: 1=not at all; 5=very much; minimum score 8, maximum score 40. 21 Key Secondary: GSGC (Gait, Stairs, Gowers, Chair) All Patients and ERT-Experienced Patients

In the overall population and ERT-experienced population, clinically and nominally statistically significant improvement was observed in GSGC total score with AT-GAA compared with alglucosidase alfa/placebo

Overall Population ERT-Experienced Population

1.5 1.5 P=0.009 P=0.050

1.0 1.0 Total Total Score 0.8 Total Score

0.6 GSGC 0.5 GSGC 0.5

0.0 0.0

-0.5 -0.5 -0.5 -0.5

Mean(SE) Actual Change in GSGC Total Score Total GSGC in Change Actual Mean(SE) -1.0 -1.0 Mean(SE) Actual Change Total GSGC in Score ↓ Improvement

Mean (SE) Actual Change in Change (SE)Actual Mean ↓ in Change (SE)Actual Mean Improvement -1.5 -1.5 BBaselineaseline WeekWeek 12 12 WeekWeek 2626 WeekWeek 3838 WeekWeek 5252 LOCF LOCF BaselineBaseline WeekWeek 1212 WeekWeek 26 WeekWeek 3838 WeekWeek 52 LOCF LOCF Visit Visit Visit Treatment: ATB200/AT2221 Alglucosidase Treatment: ATB200/AT2221 Alglucosidase Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

ERT=enzyme-replacement therapy; LOCF=last observation carried forward; SE, standard error. GSGC total score is the sum of 4 tests and ranges from a minimum of 4 points (normal performance) to a maximum of 27 points (worst score). 22 Biomarker: Creatine Kinase (CK) and Urinary Hex4 All Patients and ERT-Experienced Patients

Overall Population ERT-Experienced Population

( p ) p p 30 30

20 20 18.0% 15.6%

10 10 In the overall and ERT-experienced

0 0 populations, reductions in CK were

P -10 -10 greater with AT-GAA (nominal -

Mean(SE) Percent Change in CK (U/L) CK in Change Percent Mean(SE) -19.6% value <0.05) -20 -20 -22.4%

↓ Improvement ↓ -30 Improvement -30 Mean (SE) Actual Change in Change (SE)CK Actual Mean (U/L) BaselineB li WeekW k 1212 WeekW k 26 26 WeekW k 38 38 WeekW k52 52 LOCF LOCF BaselineBaseline WeekWeek 12 12 WeekWeek 26 26 WeekWeek 38 38 WeekWeek 52 52 LOCF LOCF ( p g j ) p p p 30 30

20 20 18.4%

11.0% 10 10 In the overall and ERT-experienced 0 0 populations, reductions in Hex4 -10 -10 were greater with AT-GAA (nominal -20 -20

-28.7%

(mmol/mol creatinine) -31.5% P -30 -30 -value <0.05) Mean(SE) Percent Change creatinine) HEX4 (mmol/mol in -40

Mean (SE) Actual Change in Change (SE)Hex4 Actual Mean -40 BaselineB li WeekW k 12 WeekW k 26 WeekW k 38 WeekW 52 k 52 LOCF LOCF Baseline li WeekW k 12 12 WeekW k 26 26 WeekW k 38 38 WeekW 52 k 52 LOCF

Treatment: Cipaglucosidase alfa/miglustat Alglucosidase alfa/placebo

CK=creatine kinase; ERT=enzyme-replacement therapy; Hex4= hexose tetrasaccharide; LOCF=last observation carried forward; SE, standard error. 23 Primary, Key Secondary and Biomarker Endpoint Heat Map Overall & ERT-Experienced Populations

Endpoints across motor function, pulmonary function, muscle strength, PROs and biomarkers favored AT-GAA over alglucosidase alfa in both the overall and ERT-experienced populations and improved from baseline

Overall Population ERT-Experienced

Category Alglucosidase alfa AT-GAA Category Alglucosidase alfa AT-GAA 6MWD 6MWD* %Predicted 6MWD %Predicted 6MWD* GSGC* GSGC* Motor Motor 10-meter walk* 10-meter walk* Function Function 4-stair climb* 4-stair climb Gowers Gowers Rising from Chair Rising from Chair FVC* FVC* Pulmonary Pulmonary MIP MIP Function Function MEP MEP Lower MMT Lower MMT Muscle Muscle Upper MMT Upper MMT Strength Strength Total MMT Total MMT PROMIS-Physical PROMIS-Physical PROs PROs PROMIS-Fatigue PROMIS-Fatigue Hex4* Hex4* Biomarkers Biomarkers CK* CK*

6MWD=6-minute walk distance; CK=creatine kinase; FVC=forced vital capacity; GSGC=Gait, Stairs, Gowers, Chair; Hex4= hexose tetrasaccharide 4; LOCF=last observation carried forward; MEP=maximum expiratory pressure; MIP=maximal inspiratory pressure; MMT=manual muscle test; PRO=patient-reported outcome; PROMIS=Patient-reported Outcomes Measurement Information System. Based on LOCF means; *Nominal P-value <0.05 24 Safety Summary

Safety profile was similar for AT-GAA and alglucosidase alfa

AT-GAA Alglucosidase Alfa n=85 n=38

TEAEs 81 (95.3%) 37 (97.4%) TEAEs Potentially Related to Treatment 26 (30.6%) 14 (36.8%) Serious TEAEs 8 (9.4%) 1 (2.6%) Serious TEAEs Potentially Related to Treatment 1 (1.2%) 0 TEAEs Leading to Study Withdrawal 2 (2.4%) 1 (2.6%) TEAEs Leading to Death 0 0 IARs 21 (24.7%) 10 (26.3%)

• TEAEs leading to withdrawal in the AT-GAA arm were 2 IARs, 1 of which was a serious AE • TEAE leading to withdrawal in the alglucosidase arm was due to stroke (unrelated) • Overall safety profile of AT-GAA is similar to alglucosidase alfa

AE=adverse event; IAR=infusion-associated reaction; TEAE=treatment-emergent adverse event. 25 Conclusions

. In the overall study population of ERT-naive and ERT-experienced patients, AT-GAA showed clinically meaningful improvements on motor and respiratory functions and biomarkers, compared with alglucosidase alfa . Among the ERT-experienced patients (mean ERT duration of 7.4 years), those randomized to AT- GAA showed clinically meaningful improvements on motor and respiratory functions and biomarkers, compared with patients randomized to alglucosidase alfa . Of the 17 efficacy and biomarker endpoints assessed, 16 favored AT-GAA compared with alglucosidase alfa in both the overall study population and ERT-experienced patients . AT-GAA demonstrated a similar safety profile to that of alglucosidase alfa 26 Acknowledgements

. We thank the patients, their families, and Pompe disease patient organizations for their participation in the PROPEL study . We thank the investigators and site staff for their support and contribution to the PROPEL study

Hashiguchi Akihiro MD Patrick Deegan MD Kornblum Cornelia MD Richard Roxburgh MD Hernan Amartino MD Jordi Diaz Manera MD Hani Kushlaf MD Sabrina Sacconi MD Prof. Henning Andersen MD Mazen Dimachkie MD Prof. Laforet Pascal MD, PhD Tomo Sawada MD Aleksandra Dominovic-Kovacevic Stephen Arbogast MD Heather Lau MD Prof. Benedikt Schoser MD MD Shahram Attarian MD Miriam Freimer MD Prof. Christopher Lindberg MD Jin-Hong Shin MD Halina Bartosik-Psujek MD Ozlem Goker-Alpan MD Nicola Longo MD Hideaki Shiraishi MD Martin Bialer MD PhD Robert Henderson MD Wolfgang Löscher MD Celine Tard MD Cynthia Bodkin MD Shinichi Hirose MD Prof. Maria Judit Molnar MD Ivaylo Tarnev MD Francoise Bouhour MD Tarekegn Hiwot MD Tahseen Mozaffar MD Mark Tarnopolsky MD Drago Bratkovic MD Robert Hopkin MD George Konstantinos Papadimas MD Michel Tchan MD Thomas Burrow MD Derralynn Hughes MD Giancarlo Parenti MD Prof. Antonio Toscano MD Ernest Butler, MD Jozsef Janszky MD Helio Pedro MD Prof. Ans van der Ploeg MD Barry Byrne, MD, PhD Aneal Khan MD Alan Pestronk MD Jaime Vengoechea MD Yin-Hsiu Chien MD Priya Kishnani MD Colin Quinn MD Vescei Laszlo MD Prof. Kristl Claeys MD PhD Hiroshi Kobayashi MD Mark Roberts MD Paula R. Clemens MD Blaž Koritnik MD Tobias Ruck MD