Table 1.
Independent studies of enzyme replacement therapy with agalsidase alfa in patients with Fabry disease
| Study | Study type | Durationa | N and gender; mean age | Primary efficacy endpoint | Primary efficacy results |
|---|---|---|---|---|---|
| Randomized controlled trials | |||||
| Schiffmann et al26 | RCT, double-blind, placebo-controlled | 6 months (12 doses) | 26 (14 agalsidase alfa, 12 placebo) all male; mean age 34 years | Neuropathic pain | BPI score reduced from 6.2 (0.46) to 4.3 (0.73); P = 0.02 |
| Moore et al82 | RCT, double-blind, placebo-controlled | 6 months | 36 all male (26 agalsidase alfa, 10 placebo); mean age 33.7 ± 8 years | Cerebral blood flow | Abnormal resting cerebral blood flow induced by visual stimulation and acetazolamide decreased significantly following ERT; prolonged recovery of cerebral vasculature also decreased significantly following ERT |
| Hajioff et al70 | RCT, double-blind, placebo-controlled | 6 months | 15 all male (7 agalsidase alfa, 8 placebo); aged 25–49 years | Hearing loss | High frequency SNHL deteriorated over the first 6 months in both placebo and agalsidase alfa groups by a median of 6.8 dB (P < 0.0001); hearing loss subsequently improved above baseline by 1.5 dB at 18 months (P = 0.07); by 5 dB at 30 months (P = 0.006) and by 4 dB at 42 months (P = 0.01) |
| Schiffmann et al74 | RCT, double-blind, placebo-controlled | 6 months | 25 all male (14 agalsidase alfa, 11 placebo) | Intraepidermal nerve fiber density | No significant difference in intraepidermal innervation density between treatment groups |
| Hughes et al58 | RCT, double-blind, placebo-controlled | 6 months | 15 (7 agalsidase alfa, 8 placebo) all male | Myocardial Gb3 content | Left ventricular mass was reduced compared with placebo (P = 0.041); mean 20% reduction in myocardial Gb3 compared with a mean 10% increase in patients receiving placebo (0.42) |
| Open-label studies | |||||
| Kampmann et al59 | Open-label | 18 months | 4 (3 female, 1 male) | LVMI | Significant reduction in LVMI (F = 13.67; P = 0.002) and mean ventricular wall thickness (F = 8.81; P < 0.01) |
| Hajioff et al69 | Open-label extension | 2 years | 15 all male (8 placebo); aged 25–49 years | Hearing loss | Hearing loss improved above baseline by 2.1 dB at 18 month (P = 0.02) and by 4.9 dB at 30 months (P = 0.004) |
| Schiffmann et al65 | Open-label extension | 3 year follow-up | 26 all male | Neuropathic pain, sweat function | Overall, 12–18 months ERT reduced pain interference scores of 1.2 ± 0.48 (P = 0.012); sweat function improved 24–72 hours post-agalsidase alfa infusion (0.57 ± 0.71 μL/mm2) and normalized in 4 anhidrotic patients |
| Baehner et al84 | Open-label | Up to 55 weeks | 15 all females | Plasma and urinary Gb3, LVMI | Increased clearance of plasma and urinary Gb3 at 13, 27, and 41 weeks; mean urine sediment Gb3 levels decreased progressively from baseline to 13, 27, and 41 weeks, with a significant decrease from baseline to week 13 (P = 0.03); decrease in plasma Gb3 was also observed in this study, with a significant change from baseline (P = 0.029) and % change from baseline (P < 0.001) at week 13. LVMI reduction from baseline at 27 weeks (P = 0.003) and 41 weeks (P = 0.039), and a reduction in QRS duration at 27 weeks (P = 0.007); other changes included significant improvement in QoL, and no deterioration in renal function |
| Dehout et al67 | Open-label, no controls | Up to 1 year | 11 (9 males and 2 females); mean age 36.2 ± 3 years | Abdominal pain and diarrhea | Severity and frequency (both P < 0.02) of abdominal pain decreased following 6 months of ERT |
| Schiffmann et al42 | Open-label extension | Up to 4.5 years follow-up | 25 all males; mean age 36.8 years | eGFR, and antibody response | eGFR remained stable in subgroups of patients with mild to moderate (GFR > 90 mL/min or 60–89 mL/min, Stage I and II, respectively) baseline CKD; the slope of decline in GFR decreased in patients with more advanced baseline CKD (GFR 30–59 mL/min, Stage III) compared with historical controls; in Stage III patients, mean eGFR fell from 47.1 ± 9.4 mL/min/1.73 m2 to 24.8 ± 14.5 mL/min/1.73 m2 (P = 0.098) after 48 months of treatment (mean rate of decline approximately 5.2 mL/min/1.73 m2/year; 56% of patients showed an IgG antibody response to agalsidase alfa |
| Ries et al22 | Open-label, multicenter | 6 months | 24 children (19 boys and 5 girls); mean ages 11.5 and 13.5 years (boys and girls, respectively) | Plasma Gb3 | Increased clearance of Gb3, particularly in boys; initial beneficial response of cardiac autonomic innervation, microalbuminuria decreased in 3 of 4 children with baseline microalbuminuria |
| Ries et al21 | Open-label, multicenter | 25 weeks | 24 children (19 boys, 5 girls); mean age 11.8 years | Plasma Gb3 | Mean baseline fasting plasma Gb3 was above normal (7.91 ± 0.71 nmol/mL) in boys and normal (2.54 ± 0.25 nmol/mL) in girls; above normal mean baseline fasting plasma Gb3 in boys was significantly reduced by agalsidase alfa therapy (P < 0.001) whereas normal mean baseline fasting plasma Gb3 levels in girls did not change; mean eGFR, cardiac structure and function were normal and unchanged throughout |
| Clarke et al36 | Open-label, multiple dosing | 10 week | 18, all male | Plasma Gb3 | Baseline mean plasma Gb3 (9.12 ± 2.61 nmol/min) was significantly reduced by 50% in all 5 dosing groups; this reduction was independent of dose or dose frequency |
| Schiffmann et al46 | Open-label, weekly dosing of 0.2 mg/kg agalsidase alfa | 24 months | 41, all male | eGFR | During 24 month follow-up period after switching from EOW to weekly infusions, the mean rate of change in GFR was observed to slow from −8.0 ± 0.8 mL/min/1.73 m2/yr to −3.3 ± 4.7 mL/min/1.73 m2/yr (P = 0.01 versus EOW) |
| Ramaswami et al2 | Open-label, multicenter | 23 weeks | 13 children (9 boys, 4 girls), median age 11 years (range 3.5–18 years) | Plasma and urinary Gb3, pain, and sweating | Above normal mean baseline plasma Gb3 in boys were reduced to within normal levels after 12–23 weeks of agalsidase alfa therapy, whereas normal mean baseline plasma Gb3 levels in girls declined slightly; BPI and pain-related QoL scores decreased in most patients; increases in sweat volumes were recorded in most measured patients during the period of treatment |
| Whybra et al6 | Open-label | 4 years | 36 all female; mean age 47 years | Pain, eGFR | Mainz severity score was reduced after 1 year (P < 0.001) and continually improved over 4 years; BPI was reduced after 1 year (P = 0.001) and was sustained through 4 years; mean LVMI decreased from baseline after 1 year (P < 0.001) and remained reduced through 4 years; overall, mean eGFR remained constant during study (from 91.0 ± 31.2 mL/min/1.73 m2 at baseline to 91.0 ± 25.6 mL/min/1.73 m2 after 4 years of ERT) |
| Schiffmann et al20 | Open-label extension | 4 years (6 months, plus up to 3.5 years) | 17 (16 boys and 1 girl); age range 7.3–18.4 years | Plasma and urinary Gb3 | Mean urine sediment Gb3 levels were reduced to normal levels (P < 0.05 compared with baseline during 1.5 to 4 years); BPI scores decreased significantly (P < 0.001); LVM indexed to height and eGFR remained stable throughout |
| West et al47 | Pooled analysis (3 prospective RCT and their open-label extension studies) | Up to 4.5 years (mean 2.0 ± 1.0 year) | 108 males; mean age 34 years | Mean rate of change in GFR | Mean rate of change in GFR for entire study population was −4.8 ± 10.6 mL/min per 1.73 m2/yr (P = 0.0003; when 8 patients with hyperfiltration were removed from analysis, the mean rate of change of GFR was −2.9 ± 8.7 mL/min per 1.73 m2/yr (P = 0.002) |
| Fabry Outcome Survey studies | |||||
| Beck et al48 | Fabry Outcome Survey | Up to 2 years | 545; 314 of whom were receiving treatment | Multiple | Stabilization of renal function following 1–2 years of ERT treatment in patients with mild to moderate renal dysfunction (GFR between 60 and 90 mL/min/1.73 m2 and between 30 and 60 mL/min/1.73 m2, Stages II and III, respectively) baseline renal dysfunction; reduction in LVH from baseline; improved pain scores and quality of life were also reported |
| Hajioff et al71 | Fabry Outcome Survey | 1 year | 26 | Changes in hearing thresholds | In patients with mild or moderate hearing loss at baseline, hearing thresholds improved significantly by 4–7 dB at most frequencies (P < 0.05); no significant change was observed for patients with normal hearing or severe hearing loss at baseline |
| Hoffmann et al64 | Fabry Outcome Survey | 2 years | 545 (264 female and 281 male) | Pain | Statistically significant reduction in pain (P < 0.05), mean health-related QoL utility score was improved and maintained after 2 years (P < 0.05) |
| Schwarting et al49 | Fabry Outcome Survey | up to 4.7 years | 201 (70 female and 131 male); aged 20–60 years | eGFR | Renal function declined significantly (P < 0.05) in the year prior to treatment; renal function decline was halted after 1 year of treatment and sustained for up to 2 years |
| Hoffmann et al63 | Fabry Outcome Survey | 3 years | 752 (393 female, 359 male); 58% of patients treated with agalsidase alfa | Pain | Significant reduction in pain after 3 years of ERT (P < 0.05) |
| Hoffmann et al68 | Fabry Outcome Survey | 2 years | 342 | GI symptoms | Reduced prevalence of abdominal pain, with a statistically significant decrease in male patients and in children after 1 year of ERT |
| Feriozzi et al43 | Fabry Outcome Survey | 3 years | 165 (115 male and 50 female) | eGFR | In males, eGFR declined with Stage I/II renal disease (from 115 ± 22.2 to 98.3 ± 27.3 and from 76.5 ± 8.1 to 66.3 ± 21.6 mL/min/1.73 m2, respectively; both P < 0.01), and was stable in Stage III (from 49.1 ± 6.6 to 42.8 ± 19.9 mL/min/1.73 m2); In females, eGFR was stable in stages I and III renal disease (from 103.2 ± 10.4 to 96.4 ± 17.8 and from 49.5 ± 8.3 to 46.3 ± 13.8 mL/min/1.73 m2, respectively; P = 0.46 and 0.28, respectively) but declined in Stage II (from 72.5 ± 8.3 to 67.3 ± 13.6 mL/min/1.73 m2; P = 0.01) |
| Cybulla et al50 | Fabry Outcome Survey | 2 years | 36 (34 male and 2 female); mean age at transplantation: 37.6 ± 10.9 years | eGFR | During 2 years of ERT, there was a slight decrease in eGFR (from baseline eGFR 59.2 mL/min/1.73 m2 versus 51.1 mL/min/1.73 m2 at 2 years) |
| Kampmann et al61 | Fabry Outcome Survey, pooled analysis, retrospective study | 3 years | 45 (34 male, 11 female); mean age 39.8 years, 93% white | LVM | Data from 45 adult patients who had received ±36 months of ERT with agalsidase alfa were analyzed; of the 14 patients with baseline LVH, LVMI decreased significantly after 1 year (P = 0.008) in 9 patients and after 3 years (P = 0.037) in 10 patients; of the 31 patients without baseline LVH, LVMI significantly increased after 1 year (P = 0.002) and there was no significant change from baseline in 10 patients after 3 years |
| Mehta et al44 | Fabry Outcome Survey | 5 years | 181 (55 female and 126 male); mean age 41.9 ± 14.5 years | Multiple | Sustained reduction in LVM in patients with baseline cardiac hypertrophy (P = 0.0111), BPI, and QoL improved significantly (P = 0.0023 and P = 0.0483, respectively) |
Note:
a
Agalsidase alfa dose at 0.2 mg/kg every other week unless otherwise stated.
Abbreviations: eGFR, estimated glomerular filtration rate; Gb3, globotriaosylceramide; LVM, left ventricular mass; LVMI, left ventricular mass index; GI, gastrointestinal; RCT, randomized controlled trial; BPI, brief pain inventory scores; QoL, quality of life; SNHL, sensorineural hearing loss; ERT, enzyme replacement therapy; CKD, chronic kidney disease; EOW, every other week; LVH, left ventricular hypertrophy.