Protocol ALID-006-01: A Multicenter, Multinational, Open-Label Extension Study of the Safety and Efficacy of Recombinant Human Alpha-L-iduronidase in Patients with Mucopolysaccharidosis I.

Aldurazyme^® (laronidase)

Drug Name	Generic Name	Studied Indications or Disease	Approved U.S. Drug Label
Aldurazyme®	laronidase	mucopolysaccharidosis I (MPS I)	Prescribing Info

Investigators and Study Center(s)

This was a multicenter study conducted at 2 sites in the United States (US), one site in Canada, and 2 sites in Europe (EU).

The 5 study centers in the US, Canada, and EU that participated in the Phase 3 Double-Blind Study (ALID-003-99) participated in this Phase 3 Open-Label Extension Study, and were responsible for performing all efficacy assessments. Additional study centers local to study patients were initiated to provide laronidase treatment.

Publication (Reference)

None.

Studied Period

First Patient Enrolled 29 May 2001
Last Patient Completed: Ongoing
Results for the primary endpoints (% Predicted forced vital capacity [FVC] and 6 Minute Walk Test (distance walked in meters) are presented through Week 36. All other results are presented through Week 24.

Phase of Development

Phase 3

Objectives

The objective of this Phase 3 Open-Label Extension Study was to collect additional long-term efficacy and safety data on the use of recombinant human α- L-iduronidase (laronidase) in patients with Mucopolysaccharidosis I (MPS I) disease who were previously treated under a Phase 3 Double-Blind Study protocol (ALID-003-99). This report summarizes efficacy and safety data through the first 24 weeks of the ongoing Phase 3 Open-Label Extension Study. Primary efficacy variable data are presented through Week 36.

Methodology

This is a multi-center, multinational Phase 3 Open-Label Extension Study of patients with MPS I disease who had previously been treated under a Phase 3 Double-Blind Study protocol (ALID-003-99). Eligible patients began treatment in the Phase 3 Open-Label Extension Study during the twenty-seventh week following initiation of their treatment in the Phase 3 Double-Blind Study (ALID-003-99). Patients were not informed of their treatment assignment in the Phase 3 Double-Blind Study until after Week 24 of the Phase 3 Open-Label Extension Study. During this Phase 3 Open-Label Extension Study, patients received laronidase treatment once per week for up to 182 consecutive weeks. This interim report covers the first 24 weeks (36 weeks for primary efficacy variables) of the Phase 3 Open-Label Extension Study period. Patients underwent efficacy assessments beginning at Week 12 of the Phase 3 Open-Label Extension Study and will continue through Week 182. Safety is being monitored continuously throughout study participation. Patients began participation in the Phase 3 Open-Label Extension Study at their original study center associated with Study ALID-003-99 and all efficacy evaluations were performed at this original center throughout the Phase 3 Open-Label Extension Study.

Number of Patients (Planned and Analyzed)

Forty–five patients were enrolled in the study. All patients received laronidase. All patients were evaluated for safety and efficacy through the period covered by this report.

Diagnosis and Main Criteria for Inclusion

Patients were eligible to participate in the Phase 3 Open-Label Extension Study if they had successfully completed the previous Phase 3 Double-Blind Study (ALID-003-99), including having received at least 21 of 26 consecutive weekly infusions and if there were no safety issues that would contraindicate Phase 3 Open-Label Extension Study participation. The patient provided written informed consent prior to any protocol-related procedures being performed. Consent of a legally authorized guardian(s) was required for patients under 18 years old. If the patient was under 18 years old and could understand the consent, written informed consent was required from both the patient and the authorized guardian(s). Female patients of childbearing potential were required to have a negative pregnancy test prior to the initial Phase 3 Open-Label Extension Study enzyme infusion and at monthly intervals while participating in this study. All females of childbearing potential and sexually mature males were advised to use a medically accepted method of contraception throughout the study.

Test Product, Dose, and Mode of Administration

Patients received laronidase intravenously at a dose of 100 units/kg (approximately 0.58 mg/kg) over a time period of approximately 4 hours, once weekly.

Duration of Treatment

Total duration of treatment is planned for 182 weeks. This report summarizes efficacy and safety data through the first 24 weeks of the ongoing Phase 3 Open-Label Extension Study. Primary efficacy variable data are presented through Week 36.

Reference Therapy, Dose and Mode of Administration

No reference treatment was used in this open-label study

Criteria for Evaluation
Efficacy

All efficacy variables were evaluated by comparing the mean change from the documented values in the Phase 3 Double-Blind Study (ALID-003-99) at Baseline (last measurement prior to randomization into the Phase 3 Double-Blind Study) and Entry (last measurement in the Phase 3 Double-Blind Study prior to enrollment into the Phase 3 Open-Label Extension Study) to the values assessed during the first 24 weeks (36 weeks for the primary efficacy variables) of the Phase 3 Open-Label Extension Study. The primary efficacy variables were the percent of predicted normal FVC and the 6-Minute Walk Test. Secondary efficacy variables assessed included: sleep apnea/hypopnea index (AHI), liver volume (hepatomegaly), Childhood Health Assessment Questionnaire/Stanford Health Assessment Questionnaire (CHAQ/HAQ) Disability Index, and joint range of motion (ROM) – shoulder flexion. Tertiary efficacy variables included urinary glycosaminoglycan levels (GAGs), the total respiratory event index of the sleep study and the time spent with oxygen saturation below 90% and below 80%, the CHAQ/HAQ Pain Scale, joint ROM – knee extension and flexion and shoulder extension, Child Health Questionnaire/36-Item Short-Form Health Survey (CHQ/SF-36), growth velocity (pre-pubertal patients only), ophthalmology testing, cardiac function tests, forced expiratory volume in 1 second (FEV₁), total lung capacity (TLC), diffusing capacity (D_L), resource utilization, and heart rate, respiratory rate, and O₂ saturation.

Safety

Safety was assessed by monitoring in terms of physical examinations and clinical laboratory evaluations, vital signs, electrocardiograms (ECGs), echocardiograms (ECHOs), adverse events (AEs), and immunogenicity testing.

Statistical Methods

As this Phase 3 Open-Label Extension Study (ALID-006-01) is an extension of the placebo-controlled Phase 3 Double-Blind Study (ALID-003-99), the 2 treatment groups represented in the reporting of the Phase 3 Open-Label Extension Study data are as follows:

laronidase/laronidase treatment group - patients received 26 weeks of laronidase treatment in the Phase 3 Double-Blind Study and are receiving ongoing laronidase treatment in the Phase 3 Open-Label Extension Study; patients had received 36 weeks of laronidase treatment at the time of this interim report, for a total of 62 weeks of laronidase treatment

placebo/laronidase treatment group- patients received 26 weeks of placebo in the Phase 3 Double-Blind Study and are receiving ongoing laronidase treatment in the Phase 3 Open-Label Extension Study; patients had received a total of 36 weeks of laronidase treatment at the time of this interim report

Differences for the laronidase/laronidase and placebo/laronidase treatment groups with respect to the changes from Baseline (last measurement prior to randomization into the Phase 3 Double-Blind Study) and Entry (last measurement in the Phase 3 Double-Blind Study prior to enrollment into the Phase 3 Open-Label Extension Study) to Weeks 12 and 24 (36 for the primary efficacy variables) of the Phase 3 Open-Label Extension Study for the percent of predicted normal FVC and the absolute 6-minute Walk Test distance were assessed using a within-group t-test. Hypothesis testing was performed at the 5% level of significance for 2-sided tests.

Differences for the laronidase/laronidase and placebo/laronidase treatment groups with respect to the changes from Baseline (last measurement prior to randomization into the Phase 3 Double-Blind Study) and Entry (last measurement in the Phase 3 Double-Blind Study prior to entry into the Phase 3 Open-Label Extension Study) to the Phase 3 Open-Label Extension Study time points for all secondary and tertiary efficacy variables were summarized descriptively.

Clinical safety was addressed by comparing the incidence of AEs in the 2 groups, and by summarizing changes from Baseline (last measurement prior to randomization into the Phase 3 Double-Blind Study) and Entry (last measurement in the Phase 3 Double-Blind Study prior to entry into the Phase 3 Open-Label Extension Study) to the Phase 3 Open-Label Extension Study time points for clinical chemistry, hematology, and urinalysis parameters, physical examination results, ECG and ECHO findings, and vital signs.

No rigorous sample size calculations were performed, as this was a Phase 3 Open-Label Extension Study to the Phase 3 Double-Blind Study (ALID-003-99). It was anticipated that most patients randomized into the Phase 3 Double-Blind Study would also enter the Phase 3 Open-Label Extension Study. Forty-five patients were randomized into the Phase 3 Double-Blind Study (ALID-003-99) and subsequently entered the Phase 3 Open-Label Extension Study.

Summary – Conclusions
Efficacy

This ongoing study demonstrates that enzyme replacement therapy with laronidase improves pulmonary function and functional capacity in patients with MPS I.

Primary Efficacy Endpoints

From Entry into the Phase 3 Open-Label Extension Study to Week 24, the mean increase in percent of predicted normal FVC for the laronidase/laronidase group was 1.0 percentage points (p = 0.551). When combined with a mean increase of 4.9 percentage points observed in the Phase 3 Double-Blind Study, a clinically and statistically significant mean improvement of 5.9 percentage points (p = 0.003) after 50 weeks of laronidase treatment resulted. From Entry to Week 24, the placebo/laronidase group had a 0.4 percentage point mean decrease (p = 0.697). The placebo/laronidase patients did not replicate the response of the laronidase patients treated in the Phase 3 Double-Blind Study on FVC, which may be related to their relatively less severe restriction at Baseline or other factors such as seasonal changes or missed infusions.

From Entry into the Phase 3 Open-Label Extension Study to Week 36, the mean increase in percent of predicted normal FVC for the laronidase/laronidase group was 0.5 percentage points (p = 0.773). When combined with a mean increase of 4.9 percentage points observed in the Phase 3 Double-Blind Study, a clinically and statistically significant mean improvement of 5.4 percentage points (p = 0.001) after 62 weeks of laronidase treatment resulted. From Entry to Week 36, the placebo/laronidase group had a 2.6 percentage point mean increase (p = 0.065).

From Entry to Week 24, the mean change in the 6-Minute Walk Test for the laronidase/laronidase group was an increase of 23.2 m (p = 0.015). After 50 weeks of treatment (Baseline to Week 24), the laronidase/laronidase patients had a mean increase in distance walked of 42.9 m (p = 0.005). From Entry to Week 24, the mean increase in 6-Minute Walk distance for the placebo/laronidase group was 23.8 m. (p = 0.073). Both groups had an approximate 20-m increase in mean distance walked in 6 minutes after 24 to 26 weeks of treatment with laronidase, and the laronidase/laronidase group continued to improve during the 24 weeks of the Phase 3 Open-Label Extension Study.

From Entry to Week 36, the mean change in the 6-Minute Walk Test for the laronidase/laronidase group was an increase of 20.3 m (p = 0.146). After 62 weeks of treatment (Baseline to Week 36), the laronidase/laronidase patients had a mean increase in distance walked of 40.0 m (p = 0.005). From Entry to Week 36, the mean increase in 6-Minute Walk distance for the placebo/laronidase group was 32.4 m. (p = 0.023).

Secondary Efficacy Endpoints

The laronidase/laronidase group had a mean increase in AHI of 1.2 events per hour from Entry to Week 24, and an overall mean decrease of 2.0 events per hour over 50 weeks of laronidase treatment. The placebo/laronidase group had a mean decrease of 3.5 events per hour after treatment from Entry to Week 24. In patients with more severe apnea/hypopnea index at Baseline, laronidase/laronidase patients maintained improvements made in the Phase 3 Double-Blind Study, while placebo/laronidase patients improved with a mean decrease of 9.2 events per hour.

Mean liver organ volumes decreased in the laronidase/laronidase group by 3.6% and in the placebo/laronidase group by 12.6% from Entry to Week 24. Overall, there was a mean decrease of 21.7% in the laronidase/laronidase treatment group after 50 weeks of treatment.

Mean changes in the CHAQ/HAQ Disability Index score were small, likely because patients had low mean disability scores at Baseline (2.0 in the laronidase/laronidase group and 1.9 in the placebo/laronidase group).

Both treatment groups demonstrated modest improvement from Entry to Week 24 in mean shoulder flexion ROM measures. In patients with the most severely restricted shoulder ROM at Baseline, mean shoulder flexion increased in the laronidase/laronidase group by 6.6 and in the placebo/laronidase group by 15.2 from Entry to Week 24. Overall, there was a mean increase of 8.7 in the laronidase/laronidase treatment group after 50 weeks of treatment.

Tertiary Efficacy Endpoints

The only tertiary endpoint that showed a significant change was the urinary GAG level. The mean urinary GAG level of the laronidase/laronidase group decreased by 20.2% from Entry to Week 24 and 64.8% from Baseline to Week 24. In the placebo/laronidase group, the mean decrease from Entry to Week 24 was 68.9%. All patients had abnormal urinary GAG levels at Baseline and Entry. By Week 24, 27.3% of patients in the laronidase/laronidase group and 13.0% of patients in the placebo/laronidase group had normal urinary GAG levels.

Safety Results

The evaluation of the various safety parameters monitored during this study that included AEs, physical examination findings, vital signs, ECGs, ECHOs, and standard clinical laboratory and immunogenicity testing indicates that laronidase is well tolerated and has an acceptable long-term safety profile in this patient population.

There was 1 death in a placebo/laronidase patient (030502) at Week 16 due to an upper respiratory tract infection, which was judged by the investigator to be unrelated to laronidase treatment. Nine patients experienced 14 serious adverse events (SAEs), including 11 SAEs in 6 placebo/laronidase patients and 3 SAEs in 3 laronidase/laronidase patients. All SAEs were reported to be unrelated to laronidase treatment.

All patients (100%) in both groups experienced at least 1 AE. The majority of the AEs experienced by the patients were on non-infusion days, with the type and incidence of AEs being similar between the 2 groups. Drug-related AEs (defined as those AEs judged by the investigator to be possibly, probably or definitely related to study medication) were reported in 11 (48%) of the patients in the placebo/laronidase group and 10 (45%) in the laronidase/laronidase group. The most common of these AEs (> 1 patient) in the placebo/laronidase group were arthralgia (9%) and leg pain (9%); the most common (> 1 patient) in the laronidase / laronidase group were arthropathy (14%) and flushing (14%). Severe AEs were experienced by 3 (13%) and 1 (5%) of the placebo/laronidase and laronidase/laronidase patients, respectively. Infusion-associated reactions (IARs) consisted of all drug-related AEs occurring on the day of infusion, excluding those AEs identified by protocol-required assessments performed the day prior to drug infusion (e.g., laboratory and physical examination abnormalities). IARs occurred in 7 (30%) of the placebo/laronidase patients and 8 (36%) of the laronidase/laronidase patients. In both treatment groups the most commonly occurring IAR was flushing (experienced by 1 patient [4%] in the placebo/laronidase group and 3 patients[14%] in the laronidase/laronidase group).. A majority of the IARs in both treatment groups were of mild intensity and none was severe. Also, none of the patients experienced IARs that required treatment interruption, adjustment, or steroid therapy. The lack of significant proteinuria in patients suggests there was no clinical manifestation of immune complex disease.

These safety results indicate that all patients in this patient population experienced some type of AE, which is not unexpected given the underlying disease. There does not appear to be an increased incidence of IARs due to the administration of laronidase, as noted by the similar type and incidence of IARs in the placebo/laronidase group in the Phase 3 Double-Blind Study and the Phase 3 Open-Label Extension Study. The infusions also appeared to be well tolerated for long-term periods, given the decreased incidence of IARs in the laronidase/laronidase group from the Phase 3 Double-Blind Study to the Phase 3 Open-Label Extension Study. When comparing results of the Phase 3 Double-Blind Study and the Phase 3 Open-Label Extension Study, the presence of IgG antibodies does not appear to have an effect on overall safety, as indicated by the low incidence of IARs in patients with IgG-positive status.

Conclusion

The data obtained in this ongoing Phase 3 Open-Label Extension Study demonstrate that enzyme replacement treatment with laronidase is well tolerated and provides clinical benefits when administered for 36 weeks (placebo/laronidase patients) through 62 weeks (laronidase/laronidase patients) to patients with MPS I. Improvements in laronidase/laronidase patients observed during the Phase 3 Double-Blind Study, including improvements in pulmonary function measured by FVC and physical function measured by the 6-Minute Walk Test, were maintained or further improved during this Phase 3 Open-Label Extension Study.