An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy

Figures & data

Table 1 Demographic and baseline clinical characteristics

Characteristic, median (range)	Male, N=5	Female, N=9
Age, years	10.2 (6.7, 14.4)	14.8 (10.1, 15.9)
Height, cm	132.0 (122.0, 167.0)	161.0 (146.0, 163.0)
Weight, kg	37.6 (22.0, 52.0)	60.3 (37.0, 86.0)
SDNN, ms	97.0 (43.0, 116.0)	108.0 (68.0, 172.0)
r-MSSD, ms	63.0 (12.0, 91.0)	78.0 (27.0, 181.0)
pNN50, %	23.5 (0.5, 45.4)	41.1 (5.4, 69.2)
LVMI, g/m^2.7	38.1 (20.2, 57.1)	35.2 (21.0, 44.2)
MFS, %	19.6 (12.4, 20.6)	19.5 (16.1, 22.2)
eGFR, mL/min/1.73 cm^2	113.5 (89.8, 141.9)	116.1 (98.9, 159.1)
Urine protein, mg/dL	4.3 (4.0, 6.7)	4.0 (4.0, 39.1)
Urine microalbumin, mg/dL	0.6 (0.3, 1.2)	0.7 (0.3, 6.9)
Plasma Gb3, nmol/mL	24.2 (20.6, 48.0)	7.3 (4.6, 10.8)
Urine Gb3, nmol/g creatinine	3,518.0 (1,530.0, 13,102.0)	338.0 (183.0, 648.0)
Characteristic, n (%)
LVH	1 (20)	0
Microalbuminuriaa	5 (100.0)	9 (100.0)
Elevated plasma Gb3b	5 (100.0)	8 (88.9)
Elevated urine Gb3c,d	5 (100.0)	9 (100.0)
ACE inhibitor/ARB usage	0	0

Notes:

a Spot urine microalbumin ≥0.3 mg/dL, data from Mehta A et al. and National Kidney Foundation I.^32,33

b Plasma Gb₃ ≥5.26 nmol/mL.

c Urine Gb₃ ≥30 nmol/g creatinine (plasma/urine Gb₃ reference ranges validated in-house, Shire).

d n=2 males missing baseline plasma Gb₃ values. pNN50 represents the percentage of differences between adjacent filtered RR intervals that are >50 ms for the whole analysis. r-MSSD represents the square root of the sum of squares of difference between adjacent filtered RR intervals over the length of the analysis. SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; Gb₃, globotriaosylceramide; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index; MFS, midwall fractional shortening.

Table 2 Summary of efficacy results for the only patient who tested positive for both IgG and neutralizing antibodies

Efficacy endpoint	Baseline	Change from baseline to
		Week 13	Week 25	Week 37	Week 49	Week 55
HRV
SDNN (ms)	76.0	−1.0	−6.0	−12.0	–	17.0
r-MSSD (ms)	63.0	−12.0	−15.0	−17.0	–	3.0
pNN50 (%)	26.7	−9.5	−10.8	−13.7	–	0.6
Cardiac structure
LVMI (g/m^2.7)	48.2	−16.8	−2.2	−16.6	−12.4	−1.0
MFS (%)	15.9	4.0	1.5	3.8	2.8	3.9
Renal function
eGFR (mL/min/1.73 m^2)	104.9	0.0	28.4	3.4	33.8	6.0
Pharmacodynamics
Plasma Gb3 (nmol/mL)	24.2	−10.7	−10.2	−10.5	−11.6	−6.9
Urinary Gb3 (nmol/g creatinine)	NA
Clinical outcomes
BPI-worst pain	9	−9	−9	1	−5	−4
BPI-pain severity	4.75	−4.75	−4.75	−0.50	−2.75	−3.00
Overall HUI2	0.7	0.2	0.3	–	0.0	0.1
Overall HUI3	0.6	0.3	0.3	–	0.2	0.0
CHQ-global health	30	0	30	30	0	30

Notes: pNN50 represents the percentage of differences between adjacent filtered RR intervals that are >50 ms for the whole analysis. r-MSSD represents the square root of the sum of squares of difference between adjacent filtered RR intervals over the length of the analysis. SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis.

Abbreviations: BPI, Brief Pain Inventory; CHQ, Children’s Health Questionnaire; eGFR, estimated glomerular filtration rate; Gb₃, globotriaosylceramide; HRV, heart rate variability; HUI, Health Utilities Index; LVMI, left ventricular mass index; MFS, midwall fractional shortening; NA, not available.

Figure 1 Heart rate variability as assessed by SDNN: individual values at baseline and at 55 weeks.

Notes: (A) Observed values of SDNN (ms). (B) SDNN Z-scores. SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis. The different colored shapes within the figure show individual patient data at baseline and 55 weeks.

Figure 2 LVMI over time for the patient who had LVH at baseline.

Note: SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis.
Abbreviations: LVH, left ventricular hypertrophy; LVMI, left ventricular mass index.

Figure 3 Correlation between change from baseline to week 55 in SDNN and LVMI in patients with baseline SDNN <100 ms.

Notes: *r = Pearson correlation coefficient. SDNN represents the standard deviation of all filtered RR intervals for the length of the analysis.
Abbreviation: LVMI, left ventricular mass index.

Figure 4 Mean (SE) change from baseline in eGFR.

Note: The safety population comprises all enrolled patients who received at least one dose of agalsidase alfa.
Abbreviations: eGFR, estimated glomerular filtration rate; SE, standard error; SP, safety population.

Figure 5 Mean plasma Gb₃ over time for the overall population and by sex.

Notes: (A) Observed values (nmol/mL). (B) Change from baseline.
Abbreviation: Gb₃, globotriaosylceramide.

MehtaAWestMLPintos-MorellGTherapeutic goals in the treatment of Fabry diseaseGenet Med2010121171372020975569

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National Kidney Foundation IKDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease2007 Available from: http://www2.kidney.org/professionals/KDOQI/guideline_diabetes/guide1.htmAccessed September 30, 2015

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