Poster: Cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease: PROPEL study subgroup analyses

EP.196	Cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo in late-onset Pompe disease: PROPEL study subgroup analyses
	Benedikt Schoser,1 Drago Bratkovic,2 Barry Byrne,3 Jordi Díaz-Manera,4 Pascal Laforet,5 Tahseen Mozaffar,6 Ans van der Ploeg,7 Mark Roberts,8 Antonio Toscano,9 Hai Jiang,10 Sheela Sitaraman,10 Srilakshmi Kuchipudi,10
	Mitchell Goldman,10 Jeff Castelli,10 Priya S. Kishnani11 on behalf of the PROPEL study group
	1Friedrich-Baur-Institut, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; 2PARC Research Clinic, Royal Adelaide Hospital, Adelaide, SA, Australia; 3University of Florida, Gainesville, FL, USA; 4Unitat de Malaties Neuromusculars Servei de Neurologia, Hospital de la Santa Creu i Sant Pau de Barcelona, Barcelona, Spain;
	5Raymond-Poincaré Hospital, Garches, France; 6University of California, Irvine, CA, USA; 7Erasmus MC University Medical Center, Rotterdam, the Netherlands; 8Salford Royal NHS Foundation Trust, Salford, UK; 9Università di Messina, Messina, Italy; 10Amicus Therapeutics, Inc., Cranbury, NJ, USA; 11Duke University Medical Center, Durham, NC, USA. Presenting author: Dr Mark Roberts

OBJECTIVE

• PROPEL (NCT03729362) is a Phase III, randomised, double-blind,active-controlled trial to assess the efficacy and safety of cipaglucosidase alfa/miglustat in adults with late-onset Pompe disease (LOPD) compared with alglucosidase alfa/placebo.
• We report prespecified and post hoc subgroup analyses based on enzyme-replacement therapy (ERT) status, baseline 6-minute walk distance (6MWD), and baseline percent predicted sitting forced vital capacity (FVC).

INTRODUCTION

• Pompe disease is a rare, autosomal recessive lysosomal disorder caused by pathogenic variants of the acid alpha-glucosidase (GAA) gene.1,2
• ERT with the recombinant human GAA (rhGAA), alglucosidase alfa, is the only approved treatment shown to improve prognosis in patients with infantile-onset Pompe disease (IOPD) and LOPD.3,4
• Cipaglucosidase alfa/miglustat is an investigational, two-component therapy comprising cipaglucosidase alfa administered in conjunction with miglustat5
• • Cipaglucosidase alfa is an rhGAA with enhanced glycosylation designed for improved uptake and processing
  • Miglustat is a small molecule that stabilises cipaglucosidase alfa in blood and enhances delivery of the active enzyme to tissues.

Table 1. Baseline characteristics

	Cipaglucosidase alfa/	Alglucosidase alfa/	Total
	miglustat	placebo
	N=123
	n=85	n=38
Median (range) age, years	48.0	(19, 74)	46.0	(22, 66)	47.0	(19, 74)
Male	36	(42.4)	20	(52.6)	56	(45.5)
Female	49	(57.6)	18	(47.4)	67	(54.5)
ERT-naïve	20	(23.5)	8 (21.1)	28	(22.8)
ERT-experienced	65	(76.5)	30	(78.9)	95	(77.2)
Median (range) previous ERT	7.6 (2.0, 13.7)	7.1 (2.1, 13.2)	7.4 (2.0, 13.7)
duration, years, ERT experienced only
Prespecified baseline 6MWD, n (%)
≥75-<150 m	4	(4.7)	4 (10.5)	8	(6.5)
≥150-<400 m	55	(64.7)	22	(57.9)	77	(62.6)
≥400 m	26	(30.6)	12	(31.6)	38	(30.9)

Data are n (%) unless indicated.

Figure 2. Change from baseline in (A) 6MWD and (B) FVC in the overall population (n=122)

Figure 3. Change from baseline in (A) 6MWD and (B) FVC in ERT-experienced patients (n=95)

A	30
Mean(SE) actual change in 6MWD (m)	25
20					16.9
15
10
5
0					0.0
	-2
	-4
	-6
	-8
	Baseline	Week 12		Week 26	Week 38	Week 52 LOCF
	Treatment		Baseline,	CFBL at week 52,	Difference in CFBL at	P value
		(nominal
			mean (SD), m	mean (SE), m	week 52, mean (SE), m
			two-sided)
	Cipaglucosidase		346.9 (110.2)	+16.9 (5.0)
	alfa/miglustat (n=65)	+16.9 (8.8)	0.047
	Alglucosidase
		334.6 (114.0)	0.0 (7.2)
	alfa/placebo (n=30)
B	2.0
	1.5
Mean (SE) actual change (sitting % predicted FVC)	1.0
0.5					0.1
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0					-4.0
	-4.5

Figure 5. Change from baseline in 6MWD and FVC by baseline status in (A) the overall population (n=122) and (B) ERT-experienced patients (n=95)

A		Cipaglucosidase alfa/miglustat (n=85)					Cipaglucosidase alfa/miglustat (n=85)
	30	Alglucosidase alfa/placebo (n=37)					3	Alglucosidase alfa/placebo (n=37)
CFBL in 6MWD (m)	20							2
				(SE) CFBL in FVC % predicted FVC)	1
10					0	n=18	n=11	n=66	n=26
					-1
0
n=23	n=10	n=62	n=27	-2
Mean (SE)	-10					Mean (sitting	-3
-20					-4
				-5
	-30	<300 m	≥300 m			-6	<55%	≥55%
			Baseline 6MWD							Baseline FVC
B		Cipaglucosidase alfa/miglustat (n=65)					Cipaglucosidase alfa/miglustat (n=65)
	30	Alglucosidase alfa/placebo (n=30)					3	Alglucosidase alfa/placebo (n=30)
Mean (SE) CFBL in 6MWD (m)	20							2
				Mean (SE) CFBL in FVC	(sitting % predicted FVC)	1
10					0	n=17	n=9	n=47	n=21
					-1
0
n=21	n=9	n=44	n=21	-2
-10					-3
-20					-4
				-5

METHODS

Figure 1. PROPEL study design6

A

(SE) actual change in 6MWD (m)

30

25

20

15

10

8

20.8

7.2

-5.0

Week

12

Week

26

Baseline

Week 38

Week 52 LOCF

Treatment

Baseline,

CFBL at week 52,

Difference in CFBL at

P value

mean (SD),

mean (SE), %

week 52, mean (SE),

(nominal

% predicted

predicted

% predicted

two-sided)

Cipaglucosidase

67.9 (19.1)

+0.1 (0.7)

alfa/miglustat (n=65)

+4.1 (1.2)

0.006

Alglucosidase

67.5 (21.0)

−4.0 (0.9)

-30	<300 m	≥300 m	-6	<55%	≥55%
	Baseline 6MWD				Baseline FVC

CFBL is mean LOCF (SE) to week 52.

Safety summary

• The safety profile was similar for cipaglucosidase alfa/miglustat and alglucosidase alfa/placebo (Table 2);

N=123*
ERT-experienced and ERT-naïve	Cipaglucosidase alfa/miglustat
• ≥40 kg body weight with confirmed	(n=85)
20 mg/kg cipaglucosidase alfa IV
diagnosis of LOPD; confirmed
	+ 260 mg miglustat Q2W†

Cipaglucosidase

alfa/miglustat

Primary

endpoint: CFBL to

week 52 in

Mean

6

4

2

0 −2

Week

12

Week

26

Baseline

Week 38

Week 52 LOCF

alfa/placebo (n=30)

6MWD data were not normally distributed and the 6MWD P value is from non-parametric ANCOVA; 6MWD parametric MMRM P=0.078. FVC data were normally distributed and the FVC P value is from ANCOVA.

further characterisation of the safety profile is available in Supplementary Table 1.

Table 2. Safety summary

GAA genotype	R: 2:1
• Received alglucosidase alfa at
	Alglucosidase alfa/placebo
20 mg/kg Q2W for ≥2 years
(ERT-experienced group) or		(n=38)
were naïve to ERT	Stratification by	20 mg/kg alglucosidase alfa IV
• Two valid 6-minute walk tests	prior ERT status	+ placebo Q2W
with both screening values ≥75 m	and baseline
and ≤90% of predicted, and the	6MWD
lower value within 20% of
the higher value

20 mg/kg

cipaglucosidase alfa IV + 260 mg miglustat Q2W†

6MWD

First key

secondary

endpoint: CFBL to

week 52 in FVC.

Treatment	Baseline,	CFBL at week 52, Difference in CFBL at	P value
(nominal
	mean (SD), m	mean (SE), m	week 52, mean (SE), m
	two-sided)

	Cipaglucosidase	357.9 (111.8)	+20.8 (4.6)
	alfa/miglustat (n=85)
		+13.6 (8.3)	0.071
	Alglucosidase
	351.0 (121.3)	+7.2 (6.6)
	alfa/placebo (n=37)
B	2.0
	1.5
	1.0

2. Baseline 6MWD categories

• Cipaglucosidase alfa/miglustat was favoured across prespecified baseline 6MWD categories versus alglucosidase alfa/placebo (Figure 4).

Figure 4. Change from baseline in 6MWD by prespecified baseline 6MWD categories in the overall population (n=122)

Cipaglucosidase alfa/miglustat (n=85)

	Cipaglucosidase alfa/miglustat	Alglucosidase alfa/placebo
	n=85	n=38
TEAEs, n (%)	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	1 (1.2)*		0

• FVC ≥30% of predicted at	Baseline‡	Week 52
screening.	12-monthdouble-blind	Open-label extension
62 sites in 24 countries

*Two patients were randomised but not dosed; † 195 mg for patients weighing 40-<50 kg; ‡Baseline values were measured during screening (up to

30 days before dosing). For 6MWD and FVC, the baseline value was the average of the last two measurements obtained on or prior to first dose date. CFBL, change from baseline; IV, intravenous; Q2W, every 2 weeks; R, randomisation.

Statistical methodology

• One ERT-naïve patient (algucosidase alfa/placebo group), deemed clinically implausible by the principal investigator based on baseline assessments, was excluded from all efficacy analyses.
• Additional statistical methodology is available in the Supplement, which is accessible via the QR code.

RESULTS

Patients

• Of the 85 patients randomised to cipaglucosidase alfa/miglustat, 80 completed the study; of the 38 patients randomised to alglucosidase alfa/placebo, 37 completed the study.
• Patient demographics at baseline were representative of the population and generally similar in the two treatment arms (Table 1).

Primary endpoint and first key secondary endpoint

• Overall, patients treated with cipaglucosidase alfa/miglustat showed improvement over time in 6MWD and stabilisation over time in FVC in comparison with those treated with alglucosidase alfa/placebo (Figure 2)
• • 6MWD showed greater improvement with cipaglucosidase alfa/miglustat versus alglucosidase alfa/ placebo but did not reach statistical superiority (P=0.071; Figure 2A)
  • FVC demonstrated a nominally statistically significant and clinically meaningful improvement with cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo (nominal P=0.023; Figure 2B).

Mean (SE) actual change	(sitting % predicted FVC)	0.5
0.0
-0.5				−0.9
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5				−4.0
-4.0
		-4.5
		-5.0
		Baseline	Week 12	Week 26	Week 38	Week 52 LOCF

Treatment	Baseline,	CFBL at week 52,	Difference in CFBL at	P value
mean (SD),	mean (SE), %	week 52, mean (SE),	(nominal
	% predicted	predicted	% predicted	two-sided)
Cipaglucosidase	70.7 (19.6)	−0.9 (0.7)
alfa/miglustat (n=85)	+3.0 (1.2)	0.023
Alglucosidase
69.7 (21.5)	−4.0 (0.8)
alfa/placebo (n=37)

CFBL is mean (SE) LOCF. 6MWD data were not normally distributed and the 6MWD P value is from non-parametric ANCOVA; 6MWD parametric MMRM P=0.097. FVC data were normally distributed and the P value is from ANCOVA. Since the primary endpoint did not meet statistical significance, subsequent analyses of key secondary endpoints that were tested according to the hierarchy of the statistical analysis plan are interpreted as nominal statistical assessments of superiority. ANCOVA, analysis of covariance; LOCF, last observation carried forward; MMRM, mixed-effect model for repeated measures; SE, standard error.

Prespecified subgroup analyses

1. ERT status

• In the ERT-experienced population, 6MWD and FVC showed a nominally statistically significant and clinically meaningful improvement at week 52 with cipaglucosidase alfa/miglustat versus alglucosidase alfa/placebo (nominal P<0.05 for both; Figure 3).
• In the smaller ERT-naïve population (n=27), variability was greater and 6MWD and FVC both numerically favoured alglucosidase alfa/placebo
• • 6MWD: both the cipaglucosidase alfa/miglustat (n=20) and alglucosidase alfa/placebo (n=7) groups
    had similar improvements over time (mean [SE] CFBL to week 52: +33.4 [10.9] m and +38.3 [11.1] m, respectively; nominal two-sidedP=0.60)
  • FVC: both the cipaglucosidase alfa/miglustat (n=20) and alglucosidase alfa/placebo (n=7) groups declined over
    time (mean [SE] CFBL to week 52: −4.1 [1.5] % and −3.6 [1.8] %, respectively; nominal two-sidedP=0.57).

	35	Alglucosidase alfa/placebo (n=37)
	25
(m)	15
6MWD	5
CFBL in
-5	n=4	n=4	n=55	n=21	n=26	n=12
(SE)
Mean	-15
	-25
	-35
			≥75-<150 m	≥150-<400 m		≥400 m
				Baseline 6MWD

CFBL is mean LOCF (SE) to week 52.

Post hoc subgroup analyses

Baseline 6MWD and FVC categories

• Outcomes consistently favoured cipaglucosidase alfa/miglustat in the overall and ERT-experienced populations in patients with baseline 6MWD of <300 m and ≥300 m, and FVC of <55% and ≥55% (Figure 5).
• ERT-naïvepopulation (n=27): three patients had a baseline 6MWD of <300 m and three had a baseline FVC of <55%; analyses of CFBL were not performed in these subgroups owing to the small patient numbers
• • Baseline 6MWD ≥300 m: both the cipaglucosidase alfa/miglustat (n=18) and alglucosidase alfa/placebo
    (n=6) groups had similar improvements over time (mean [SE] CFBL to week 52: +34.4 [12.1] m and +30.8 [9.6] m, respectively)
  • Baseline FVC ≥55%: both the cipaglucosidase alfa/miglustat (n=19) and alglucosidase alfa/placebo (n=5)
    groups declined over time (mean [SE] CFBL to week 52: −3.7 [1.5] % and −3.3 [2.6] %, respectively).

treatment
TEAEs leading to study withdrawal						3 (3.5)†									1 (2.6)‡
TEAEs leading to death	0					0
IARs	21 (24.7)		10 (26.3)

*IAR of anaphylactic reaction; †COVID-19-related pneumonia and IARs of anaphylactic reaction and chills; ‡Stroke, unrelated to treatment. IAR, infusion-associated reaction; TEAE, treatment-emergent adverse event.

CONCLUSIONS

• In the overall study population including ERT-naïve and ERT-experienced patients, cipaglucosidase alfa/miglustat showed positive trends or clinically meaningful improvements on motor and respiratory functions compared with approved ERT, regardless of baseline 6MWD and % FVC assessments, and across both prespecified and post hoc subgroup analyses.
• Cipaglucosidase alfa/miglustat demonstrated a similar safety profile to that of alglucosidase alfa/placebo.

Acknowledgements

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

The PROPEL study was funded by Amicus Therapeutics, Inc.

Medical writing support was provided by Adam Gill, MRes, of Cence, funded by Amicus Therapeutics, Inc.

Some of the primary PROPEL data presented here were previously presented at the 2021 WORLDSymposium™, 7‒12 February 2021, the 2021 MDA Virtual Clinical & Scientific Conference, 15-18 March 2021, and the 2021 ICNMD Virtual Congress, 21-22 and 28-29 May 2021.

This presentation shares information about Amicus Therapeutics' investigational therapy, cipaglucosidase alfa/miglustat, which is in development for the treatment of Pompe disease. This investigational therapy is not approved by any regulatory agency at this time.

The presenter, Dr Mark Roberts, has no conflicts of interest to declare.

References		Scan here to download supplementary	Scan here to download a PDF copy of
	material.	this poster.
1.	Hers HG. Biochem J. 1963;86:11-16.	4.	Do HV et al. Ann Transl Med. 2019;7:291.	Copies of this poster obtained through
QR (Quick Response) code are for
2.	Kishnani PS et al. J Pediatr. 2004;144:S35-43.	5.	Xu S et al. JCI Insight. 2019;4:e125358.	personal use only and may not be
3.	Lumizyme [prescribing information]. Sanofi	6.	ClinicalTrials.gov NCT03729362. Available at:	reproduced without permission of
	Genzyme; 2020.		https://clinicaltrials.gov/ct2/show/NCT03729362.	the authors.

This study was supported by Amicus Therapeutics, Inc.

Presented at the World Muscle Society 2021 Virtual Congress, 20-24 September.