Phase III Double blind Placebo controlled Study [1]

Please see the full prescribing information in Dutch or in French (PDF) for Aldurazyme®.

Randomised, double blind, placebo-controlled

45 patients, 5 sites in 4 countries

Mean age: 15.5 +/-8.0 years

82% of patients had intermediate disease severity (Hurler-Scheie)

73% pediatric patients (<18 years)

Aldurazyme® (laronidase) 100 U/g (0.58 mg/kg) or placebo IV q week for 26 weeks

Duration study period: 4 years (completed)

MPS I disease, alpha-L-iduronidase deficiency (<10% of the lower limit of normal range)

Forced Vital Capacity (FVC) ≤ 80% predicted, stand independently, walk > 5 meters within 6 minutes

Capable of performing reproducible FVC manoeuvre

To demonstrate reversal of the underlying pathophysiology of MPS I through clearance of glycosaminoglycans (GAG’s) from the body.

To demonstrate clinical improvement in functional measures that might be expected to show change in a short-term clinical study.

To demonstrate a broad treatment effect across multiple organ systems with trends moving in the same direction and to show that individual patients are improving in one or more assessments.

Primary endpoints:

Respiratory function (percent predicted FVC was used to normalise the FVC values)

Functional capacity as assessed by the 6MWT, a widely used submaximal exercise tolerance test that measures the distance walked in 6 minutes

Secondary endpoints:

Sleep study Apnoea/Hypopnoea Index (AHI) (a measure of the degree of sleep apnoea)

Shoulder flexion range of motion as a measure of upper extremity mobility (important for self-care and other activities of daily living)

Liver volume

Tertiary endpoints:

Urinary GAG levels

Baseline patient characteristics were well balanced between the placebo group (n=23) and the treatment group (n=22). The efficacy evaluations of Aldurazyme® can be grouped into four categories: pharmacodynamic parameters, respiratory function, functional capacity, and additional endpoints.

Pharmacodynamic parameters:

Urinary GAG levels:

Aldurazyme® significantly reduced urinary GAG levels versus placebo at week 26. Mean urinary GAG levels decreased by 54.1% in Aldurazyme® patients, compared with an increase of 47.3% in placebo patients (p<0.001).

Liver Size:

Mean decrease of 18.9% in Aldurazyme® patients versus slight increase (1.3%) in placebo patients after 26 weeks (p=0.001)

Respiratory function:

(Percent of predicted normal FVC, co-primary endpoint)

When FVC was calculated using the patient’s baseline height (i.e., the patient’s height at the first study visit), there was a significant (p=0.009) improvement in Aldurazyme® patients versus placebo patients at week 26.

Positive trend toward improvement in apnoea/hypopnoea index (AHI) versus placebo seen in total intent-to-treat study population (p=0.145)

Significant mean decrease in AHI of 11.4 events per hour versus placebo at 26 weeks (p=0.014) in a subset of patients with sleep apnoea at baseline (AHI ≥ 10 for ages ≤ 15 years, AHI ≥ 15 for ages > 15 years).

Functional capacity:

(6-minute walk test, co-primary endpoint)

Aldurazyme® patients had a 38 m mean difference from placebo at 26 weeks. Significance testing was performed on the median difference between groups, which was 38.5 m (p=0.066).

Shoulder flexion (secondary endpoint) improvement in most restricted patients. Improvement in the total study group was not statistically significant.

Pharmacodynamic parameters:

After 1.5 years of treatment with laronidase, normalization of liver volume was observed in 68% of patients who presented with abnormal liver volumes at baseline

Further steady reduction by ~71% of urinary GAG’s was observed after 96 weeks.

Respiratory function:

After 96 weeks treatment with laronidase, the per cent predicted FVC (calculated with current height) showed sustained stabilization at the baseline level. Without treatment, a progressive decrease in lung function would have been expected, thus indicating continued efficacy.

The improvement in AHI, seen in the placeobo controlled group was confirmed by the placebo-crossover group, who showed a 9.2 events per hour decrease after 24 weeks in the extension study.

Functional capacity:

After 96 weeks, the average walking distance further improved for the group initially treated with laronidase (p=0.010) as well as for the group initially treated by placebo and switched to laronidase after 6 months (p=0.190)

In patients with the most severe joint restrictions at baseline, joint range of motion improved with treatment in all assessed movements.

If you would like more information on clinical trials regarding Aldurazyme®, please contact us.

References

1. Wraith JE, Clarke LA, Beck M et al. Enzyme replacement therapy for mucopolysaccharidosis I: A randomized, double-blinded, placebo-controlled, multinational study of recombinant human α-L-Iduronidase (Laronidase) J. Pediatr 2004; 144:581-8

2. Wraith JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin.Pharmacother. (2005) 6 (3): 489-506