Top Line Results From the PROPEL Phase 3 Study

Comparing AT-GAA (cipaglucosidase alfa/miglustat) Versus alglucosidase alfa/placebo In Late Onset Pompe

Disease

Benedikt Schoser

Friedrich-Baur-Institut

Neurologische Klinik und Poliklinik

LMU Munich - Germany

On behalf of the PROPEL investigators

Disclosures for Presenter: Benedikt Schoser

  • • Research Grant(s) from:

Amicus, Greenovation, Nexion, Sanofi Genzyme

  • • Speaker/ Honoraria from:

Amicus, Kedrion, Sanofi Genzyme

  • • Consultant / Advisory Board for:

    Amicus Therapeutics, Alexion, Audentes Therapeutics, Dyne Therapeutics, Lupin Therapeutics, Sanofi Genzyme, Spark Therapeutics

Pompe Disease Overview

Pompe disease is a severe and fatal neuromuscular disease and one of the most prevalent lysosomal disorders. Despite the majority of diagnosed Pompe patients in the addressable geographies in the world being treated with currently approved ERT alglucosidase alfa, there remains significant unmet medical need

AT-GAA: ATB200 (cipaglucosidase alfa) and AT2221 (miglustat)

ATB200 is a novel rhGAA being developed as a next-generation enzyme replacement therapy (ERT) for the treatment of Pompe disease, used in conjunction with AT2221, an iminosugar that stabilizes and enhances the PK of ATB200

PROPEL (ATB200-03): Study Design

Phase 3 double-blind randomized study to assess the efficacy and safety of AT-GAA in adult subjects with late onset Pompe disease compared with alglucosidase alfa/placebo​

Enrollment

52-Week Primary Treatment Period

(Double-Blind)

ClinicalTrials.gov Identifier: NCT03729362

2:1Randomization1

Key Enrollment Criteria:

  • • ≥18 years old, weigh ≥ 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-naïve, 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

12:1 randomization with stratification factors on ERT status, baseline 6MWD

Study Endpoints and Statistical Methods

  • • Change from baseline to Week 52 in the manual muscle test (MMT) score for the lower extremities

    • • Primary endpoint of 6MWD analyzed using MMRM on ITT observed cases

    • • All key secondary endpoints including FVC analyzed by ANCOVA with last observation carried forward (ITT LOCF)

  • • Change from baseline to Week 52 in the PROMIS® - Physical Function domain score

  • • Change from baseline to Week 52 in the PROMIS® - Fatigue domain score

  • • Change from baseline to Week 52 in the GSGC score (Gait, Stairs, Gowers, Chair)

Patient Disposition

There was a very low drop-out rate and all patients completing the study subsequently enrolled in the AT-GAA extension study

Note: * 1 Covid pneumonia, 2 withdrew no longer wanting to travel to sites for infusion all unrelated to study drug; ^1 stroke, unrelated to study drug

Baseline Demographics

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

AT-GAA n=85

Alglucosidase alfa n=38

Total 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)

Gender, n (%)

Male

36 (42.4)

20 (52.6)

56 (45.5)

Female

49 (57.6)

18 (47.4)

67 (54.5)

Previous ERT Duration (ERT Exp. only)

<3 years

4 (6.2)

5 (16.7)

9 (9.5)

3-5 years

16 (24.6)

6 (20.0)

22 (23.2)

>5 years

45 (69.2)

19 (63.3)

64 (67.4)

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)

Baseline Characteristics

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

AT-GAA n=85

Alglucosidase alfa 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)

ERT Experienced

ERT Naive

ERT Experienced

ERT Naive

n=65

n=20

n=30

n=7

Mean (SD)

346.9 (110.2)

393.6 (112.4)

334.6 (114.0)

420.9 (135.7)

Median (Min, Max)

352.5 (79.0, 557.5)

375.2 (154.0, 575.0)

343.5 (112.5, 532.3)

385.5 (201.0, 623.0)

AT-GAA n=85

Alglucosidase alfa n=37

FVC % Predicted, Sitting

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)

ERT Experienced

ERT Naive

ERT Experienced

ERT Naive

n=65

n=20

n=30

n=7

Mean (SD)

67.9 (19.1)

80.2 (18.7)

67.5 (21.0)

79.1 (22.6)

Median (Min, Max)

68 (30.5, 132.5)

82.3 (48.0, 111.0)

69.0 (31.5,122.0)

93.5 (46.5, 98.0)

6MWD=6-minute walk distance; FVC=forced vital capacity

6MWD and FVC Results: Overall Population (n=122)

6MWD showed greater improvement with AT-GAA versus alglucosidase alfa but did not demonstrate statistical superiority;

FVC demonstrated clinically significant improvement with AT-GAA over 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)

NOTES: Baseline is Mean (STDEV); CFBL is Mean LOCF (SE); P-values are nominal 2-sided; FVC data normally distributed and p-values are from ANCOVA.

Results exclude one 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 6MWD p-value is for non-parametric ANCOVA; 6MWD parametric MMRM p-value was p=0.097.

6MWD and FVC Results: ERT Experienced Population (n=95)

In the ERT experienced population (n=95), there was a clinically significant improvement in both

6MWD and FVC with AT-GAA over 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)

NOTE: Baseline is Mean (STDEV); CFBL is Mean LOCF (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-value was p=0.078

6MWD and FVC Plots: ERT Experienced Population (n=95)

ERT experienced 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

(n=65, n=30)

FVC (% predicted): Change from baseline

(n=65, n=30)

(

p

)

p

p

Mean(SE)ActualChangein6MWD(m)

Baseline

Baseline

Mean(SE)ActualChangeinSitting%PredictedFVC

Week 12

Week 26

Week 38

VisitTreatment:

ATB200/AT2221

AlglucosidaseWeek 52 LOCF

NOTE: Baseline is Mean (STDEV); 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-value was p=0.078

Week 12

Week 26

Week 38

VisitTreatment:

ATB200/AT2221

AlglucosidaseWeek 52 LOCF

6MWD and FVC Results: ERT Naive Population (n=27)

In the smaller ERT naive population (n=27), 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)

NOTES: Baseline is Mean (STDEV); CFBL is Mean LOCF (SE); P-values are nominal 2-sided; FVC data normally distributed and p-values are from ANCOVA.

Results exclude one 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-value was p=0.75

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

Overall Population

ERT Experienced Population

Category

Alglucosidase alfa

AT-GAA

Motor Function

6MWD

GSGC*

Pulmonary Function

FVC*

Muscle Strength

Lower MMT

PROs

PROMIS-Physical

PROMIS-Fatigue

Biomarker

Hex4*

CK*

Category

Alglucosidase alfa

AT-GAA

Motor Function

6MWD*

GSGC*

Pulmonary

Function

FVC*

Muscle Strength

Lower MMT

PROs

PROMIS-Physical

PROMIS-Fatigue

Biomarker

Hex4*

CK*

Note: *Nominal P-value <0.05; Based on LOCF means

Safety Summary

Safety profile was similar for AT-GAA and alglucosidase alfa

AT-GAA n=85

Alglucosidase Alfa 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 two IARs, one of which was a serious AE

  • • TEAEs leading to withdrawal in the alglucosidase arm was due to stroke (unrelated)

  • • Overall safety profile of AT-GAA is similar to alglucosidase alfa

Conclusions

  • Topline data demonstrate clinically meaningful improvements with AT-GAA on both motor and respiratory function in the overall population studied

  • In the overall study population, AT-GAA outperformed the currently approved ERT (+21 meters compared to +7 meters) which did not reach statistical significance for superiority on 6MWD

  • In the overall study population, AT-GAA showed a nominally statistically significant and clinically meaningful difference for superiority on the first key secondary endpoint of percent-predicted forced vital capacity (FVC)

  • ERT experienced patients switching to AT-GAA from alglucosidase alfa walked farther and showed stabilization of FVC compared to patients remaining on alglucosidase alfa who showed no improvement in their walking and declined in FVC

  • Improvements in the two important biomarkers of Pompe Disease (Hex-4 and CK) for the overall study population significantly favored AT-GAA compared to the currently approved ERT

  • All key secondary and biomarker endpoints favored AT-GAA compared to alglucosidase alfa in the overall and ERT experienced population

  • Overall safety profile of AT-GAA is similar to alglucosidase alfa

Acknowledgments

  • • The authors thank the patients, their families, and Pompe disease patient organizations for their participation in the PROPEL study sponsored by Amicus Therapeutics

  • • The authors would also like to thank the investigators, and site staff for their support and contributions in the PROPEL study

Hashiguchi Akihiro MD

Ozlem Goker-Alpan MD

Giancarlo Parenti MD

Hernan Amartino MD

Robert Henderson MD

Helio Pedro MD

Prof. Henning Andersen MD

Shinichi Hirose MD

Alan Pestronk MD

Stephen Arbogast MD

Tarekegn Hiwot MD

Colin Quinn MD

Shahram Attarian MD

Robert Hopkin MD

Mark Roberts MD

Halina Bartosik-Psujek MD

Derralynn Hughes MD

Tobias Ruck MD

Martin Bialer MD PhD

Jozsef Janszky MD

Richard Roxburgh MD

Cynthia Bodkin MD

Aneal Khan MD

Sabrina Sacconi MD

Francoise Bouhour MD

Priya Kishnani MD

Tomo Sawada MD

Drago Bratkovic MD

Hiroshi Kobayashi MD

Prof. Benedikt Schoser MD

Thomas Burrow MD

Blaž Koritnik MD

Jin-Hong Shin MD

Ernest Butler, MD

Kornblum Cornelia MD

Hideaki Shiraishi MD

Barry Byrne, MD, PhD

Hani Kushlaf MD

Celine Tard MD

Yin-Hsiu Chien MD

Prof. Laforet Pascal MD, PhD

Ivaylo Tarnev MD

Prof. Kristl Claeys MD PhD

Heather Lau MD

Mark Tarnopolsky MD

Paula R. Clemens MD

Prof. Christopher Lindberg MD

Michel Tchan MD

Patrick Deegan MD

Nicola Longo MD

Prof. Antonio Toscano MD

Jordi Diaz Manera MD

Wolfgang Löscher MD

Prof. Ans van der Ploeg MD

Mazen Dimachkie MD

Prof. Maria Judit Molnar MD

Jaime Vengoechea MD

Aleksandra Dominovic-Kovacevic MD

Tahseen Mozaffar MD

Vescei Laszlo MD

Miriam Freimer MD

George Konstantinos Papadimas MD

Attachments

  • Original document
  • Permalink

Disclaimer

Amicus Therapeutics Inc. published this content on 12 February 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 12 February 2021 17:46:04 UTC.