Protocol ALID-003-99: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Multinational, Clinical Study 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), 1 site in Canada, and 2 sites in Europe (EU).

Publication (Reference)

Publications

Studied Period

First Patient Enrolled 07 December 2000
Last Patient Completed 01 March 2001

Phase of Development

Phase 3

Objectives

Primary Objectives The study had 2 primary efficacy objectives. Each was a comparison of the change from Baseline to Week 26 between the recombinant human (rh) α-L-iduronidase (laronidase)-treated group and placebo-control group:

To show an increase in the percent predicted of normal Forced Vital Capacity (FVC)

To show an increase in the absolute distance traveled (in meters) during the 6-Minute Walk Test

Secondary Objectives The study had 4 secondary efficacy objectives. Each of these objectives was evaluated by comparing mean change from Baseline to Week 26 between the laronidase treated group and placebo-control group:

To evaluate the apnea/hypopnea index (AHI) of the sleep study

To evaluate liver organ volume (hepatomegaly)

To evaluate the difference in the change in the Disability Index as assessed between treatment groups, using the Children’s Health Assessment Questionnaire (CHAQ) for patients 5 through age 18 or the Health Assessment Questionnaire (HAQ) for patients aged 19 and above

To evaluate the shoulder flexion variable from the joint range of motion tests.

Tertiary Objectives The study had 12 tertiary efficacy objectives, including an evaluation of the urinary glycosaminoglycan (GAG) levels between-treatment-group evaluation of changes from Baseline to Week 26:

Additional Objectives An additional objective of the study was to perform a pharmacokinetic assessment of the intravenous infusion of laronidase during the 26-week treatment period. This was performed in a subset of study patients.

Safety Objective Clinical safety of treatment with laronidase in MPS I patients was assessed by determination of the incidence of adverse events (AEs) in each treatment group. In addition, changes in standard clinical chemistry, hematology, and urinalysis measurements during the 26-week treatment period were evaluated as safety parameters. Physical examinations, vital signs, cardiac parameters, and immunogenicity results were also used to evaluate the safety of treatment with laronidase.

Methodology

This was a randomized, double-blind, placebo-controlled, multicenter, multinational study to demonstrate the safety and clinical efficacy of treatment with laronidase in MPS I patients. Within 2 weeks following a Baseline evaluation phase (lasting up to 2 weeks), patients were randomized into the second phase of the study, in a double-blind manner, to either a laronidase or a placebo-control group. During Week 1, after randomization, all patients began to receive the first intravenous administration of study solution that was repeated once every week, for a total of 26 consecutive weeks. Patients underwent primary efficacy evaluations at the site at the 4-, 8-, 12-, 16-, 20-, and 26-week time points. Secondary and tertiary variables were evaluated periodically over the 26-week treatment phase. Pharmacokinetic parameters were conducted at 2 of the investigational sites in a subset of patients. Safety was monitored continuously throughout study participation. Patients completing the study were offered the opportunity to participate in an extension protocol.

Number of Patients (Planned and Analyzed)

Forty-two patients were planned to be included in the study. Forty-five patients were randomized into the study. Twenty-three of these patients were randomized to receive placebo and 22 were randomized to receive laronidase. All 45 patients were treated (placebo or laronidase), completed the study, and were evaluated for safety and efficacy.

Diagnosis and Main Criteria for Inclusion

The patient (or patient’s legal guardian) provided written informed consent prior to performing any study-related procedures.

Inclusion Patients who met all of the following inclusion criteria were eligible to participate:

The patient was of either sex and 5 years of age or older.

The patient had a documented diagnosis of MPS I confirmed by measurable clinical signs and symptoms of MPS I and a fibroblast or leukocyte α-l-iduronidase enzyme activity level of less than 10% of the lower limit of the normal range of the measuring laboratory.

Female patients of childbearing potential had a negative pregnancy test (urine bβ-hCG) at Baseline (all female patients of childbearing potential and sexually mature male patients were advised to use a medically accepted method of contraception throughout the study).

The patient was capable of standing independently for 6 minutes and walking a minimum of 5 meters within 6 minutes.

The patient was capable of performing a reproducible FVC maneuver.

The patient had a Baseline FVC value that was less than or equal to 80% of the patient’s predicted normal FVC value, based on Polgar predicted values for standing height for children 5 through 7 years of age and the Hankinson predicted values for patients aged 8 and above.

Test Product, Dose, and Mode of Administration

Patients in the active treatment group 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 for 26 consecutive weeks.

Duration of Treatment

The study duration was 26 weeks.

Reference Therapy, Dose and Mode of Administration

Patients in the placebo-control group received placebo (test product solution without laronidase) intravenously over a time period of approximately 4 hours, once weekly for 26 consecutive weeks.

Criteria for Evaluation
Efficacy, Safety, and Pharmacokinetics

The analyses of the study data were designed to address the following question:

Does the laronidase treatment group differ from the placebo treatment group in terms of the effect of treatment of MPS I in a population of MPS I patients 5 years of age and above?

The effect of treatment of MPS I with laronidase was addressed in terms of the primary efficacy variables of the changes from Baseline (last measurement prior to randomization) to Week 26 of the double-blind treatment period in the percent of predicted normal FVC and the absolute distance traveled (in meters) during the 6-Minute Walk Test.

The effect of treatment of MPS I with laronidase was also addressed in terms of 4 secondary efficacy variables of changes from Baseline (last measurement prior to randomization) to Week 26 of the double-blind treatment period in the AHI of the sleep study, hepatomegaly – liver organ volume, functional status as assessed by the Disability Index component of the CHAQ/HAQ, and shoulder flexion.

In addition, tertiary efficacy variables included changes from Baseline (last measurement prior to randomization) to Week 26 of the double-blind treatment period in urinary glycosaminoglycan (GAG) levels.

Safety was assessed in terms of incidence of reported adverse events (AEs), discontinuations due to AEs, drug-related, serious, and severe AEs, physical examinations, vital signs, cardiac assessments, immunogenicity, and clinical laboratory measurements (serum chemistry, hematology, and urinalysis).

The pharmacokinetic profile of laronidase was described in terms of the elimination rate constant, the area under the activity-time curves, the area under the activity versus time curves, peak laronidase activity, the elimination half-life (t½), total clearance (CL), mean residence time, and volume of distribution at steady state (Vss).

Statistical Methods

All statistical comparisons were carried out as 2-sided tests. Probability values (p-values) were rounded to 3 decimal places. Statistical significance was declared if the p-value was < 0.050.

Efficacy

Primary Efficacy Variables Differences between the laronidase and placebo treatment groups with respect to the changes from Baseline (last measurement prior to randomization) to Week 26 of the double-blind treatment period for the percent of predicted normal FVC and the absolute 6-minute walk distance were assessed using the Wilcoxon rank-sum test. Summary statistics (n, mean, mean change, median, standard deviation, minimum, maximum, and p-value) are presented. In addition, a stratified non-parametric analysis was performed taking into account the Baseline severity. Baseline severity classifications were formed based on the medians of the Baseline values. Values equal to or higher than the median were considered to belong to the mild category and values lower than the median were considered to belong to the more severely affected category.

Differences between the laronidase and placebo treatment groups, with respect to the change from Baseline (last measurement prior to randomization) to the other study time points (Weeks 4, 8, 12, 16, and 20) of the double-blind treatment period for the percent of predicted normal FVC and the absolute 6-minute walk distance, were summarized descriptively (n, mean, median, standard deviation, minimum, and maximum). Summaries were also provided by center, gender, age, race, seroconversion status, and Baseline severity using stratified non-parametric analyses, with graphical presentations when appropriate.

In addition, statistical modeling of the Week-26 values using parametric methods and including the use of covariates (such as Baseline values of the respective parameters) was explored for both primary endpoints. The influence of other covariates on the results of the primary efficacy variables was also explored. Covariates explored for the percent of predicted normal FVC included the AHI, TLC, liver size, and urinary GAG levels. Covariates explored for the 6-minute walk included gender, age, height, knee extension, pain score, liver size, urinary GAG levels, the AHI, left ventricular cardiac function, and oxygen saturation less than 95% at the end of the walk.

Secondary Efficacy Variables Differences between the laronidase and placebo treatment groups with respect to the changes from Baseline (last measurement prior to randomization) to Week 26 of the double-blind treatment period for the Apnea/Hypopnea Index variables of the sleep study, the liver organ volume (hepatomegaly), frequencies of normal and abnormal liver volumes, the Disability Index of the CHAQ/HAQ, and shoulder flexion (mean of the right and left shoulders) were assessed using analysis of variance techniques (ANOVA). Summary statistics (n, mean, median, standard deviation, minimum, maximum, 95% confidence interval of the difference between the laronidase treatment group and the placebo treatment group, and p-value) are presented. Summaries (no hypothesis testing) are also provided by center, with graphical displays when appropriate.

Tertiary Efficacy Variables Differences between the laronidase and placebo treatment groups, with respect to the change from Baseline (last measurement prior to randomization) to Week 26 of the double-blind treatment period for the level of GAG and frequencies of normal and abnormal levels of GAG were assessed using ANOVA techniques. Summary statistics (n, mean, median, standard deviation, minimum, maximum, 95% confidence intervals of the difference between the laronidase treatment group and the placebo treatment group, and p-values) are presented.

Differences between the laronidase and placebo treatment groups, with respect to the change from Baseline (last measurement prior to randomization) to the other study time points (Weeks 4, 8, 12, 16, and 20) of the double-blind treatment period, were summarized descriptively (n, mean, median, standard deviation, minimum, and maximum).

Safety

The incidence of treatment-emergent AEs, discontinuations due to AEs, and drug-related, serious, and severe AEs are summarized for the double-blind treatment period. AEs were coded by body system and preferred term using the World Health Organization Adverse Reaction Thesaurus (WHO-ART). Inferential comparisons were not planned.

Changes from Baseline (last measurement prior to randomization) to the end of the double-blind treatment period for clinical chemistry, hematology, and urinalysis values were descriptively summarized. In addition, all laboratory values were classified as normal, below normal, or above normal, based on normal ranges provided by the testing laboratory. Frequencies of normal and clinically relevant abnormal values were descriptively summarized, and listings of patients with clinically relevant abnormal laboratory values were provided.

Changes from Baseline (last measurement prior to randomization) to the end of the double-blind treatment phase for physical examinations, height, weight, and vital signs were summarized descriptively. Electrocardiogram (ECG) and echocardiogram (ECHO) data, summarized as part of the efficacy data, are reported as part of the AE profile. Graphical displays were included when appropriate. Immunogenicity data were summarized over the double-blind treatment phase.

Pharmacokinetics

Pharmacokinetic assessments of plasma laronidase were made for a subset of patients (all patients at 2 investigational sites) at Weeks 1, 12, and 26. Parameters calculated included mean maximum plasma concentration (Cmax), area under the curve as a measure of total exposure (AUC), mean CL, mean volume of distribution (Vz), mean Vss, mean t½, and mean residence time.

Summary – Conclusions
Efficacy

This study demonstrates that enzyme replacement treatment with laronidase improves pulmonary function and physical functioning in patients with MPS I who were treated for 26 weeks. For the primary efficacy variables, percent of predicted normal FVC and 6-Minute Walk Test, the following were observed:

After 26 weeks of treatment, the difference from Baseline between the treatment groups in the mean percent predicted normal FVC (based on Baseline height) was 5.9 percentage points, favoring the laronidase group. The median difference from Baseline to 26 weeks between the 2 treatment groups was 3.0 percentage points (p=0.016).

After 26 weeks of treatment, the difference from Baseline between treatment groups in mean change in distance walked was 38.1 meters, favoring the laronidase group. The median difference between the 2 treatment groups was 38.5 meters (p=0.066). When an analysis of covariance (ANCOVA) was performed on these results, using treatment center, Baseline 6-minute walk, gender, Baseline height, and Baseline liver volume as covariates in the model, the resulting treatment effect achieved statistical significance (p=0.039).

Results observed in the secondary efficacy endpoints included:

The mean change from Baseline to Week 26 in AHI was –2.9 in the laronidase-treated group and +0.4 event per hour in the placebo group. The difference between the treatment groups was -3.6  events per hour (p=0.145). An additional analysis of a subset of patients with sleep apnea at Baseline (AHI >10 for children, >15 for adults) resulted in a statistically significant difference between treatments, favoring the laronidase group (p=0.037).

The percent change from Baseline to Week 26 in liver organ volume was an 18.9% decrease in the laronidase group and a 1.3% increase in the placebo group. The difference between the treatment groups was –20.0% (p=0.001), favoring the laronidase group. Of the 18 laronidase patients with abnormal liver volumes at Baseline, 13 (72%) had normalized by Week 26.

The mean changes from Baseline to Week 26 in the CHAQ/HAQ Disability Index were small in both treatment groups.

The mean change from Baseline to Week 26 in the shoulder flexion variable of the joint ROM tests was a decrease of 1.2 degrees in the laronidase group and a decrease of 4.6 in the placebo group. The difference between groups was not significant (p=0.999). An additional analysis of a subset of patients who were below the overall median at Baseline, resulted in a 9.6-degree increase in shoulder flexion in the laronidase group and a 4.3-degree decrease in the placebo group.

One tertiary efficacy endpoint showed statistical significance: The mean percent change in urinary GAG levels from Baseline to Week 26 was a 54.1% decrease in the laronidase group and a 47.3% increase in the placebo group. The difference between treatment groups (101%) was statistically significant (p<0.001).

Safety Results

None of the patients in either treatment group discontinued from the study during the Baseline period and there were no reported deaths. During double-blind treatment, 3 patients in the laronidase treatment group experienced 7 serious adverse events (SAEs). All of the placebo patients and 21 (95%) of the laronidase-treated patients experienced at least 1 AE during double-blind treatment.

The most frequent AEs reported in >30% of both the placebo and laronidase-treated groups during double-blind treatment were: headache (70% and 50%), fever (61% and 45%) and rhinitis (43% and 36%), respectively. Overall, there was a greater incidence of AEs considered related in the placebo-treated group (70%) compared to the laronidase-treated group (55%). In laronidase-treated patients, flushing (23%) and rash (14%) occurred more frequently; while in the placebo-treated patients, headache (26%), flushing (17%), arthropathy (17%) and fever (13%) occurred more frequently.

Infusion-associated reactions (IARs) occurred in both treatment groups, with 11 (48%) placebo patients experiencing 82 IARs and 7 (32%) laronidase-treated patients experiencing 66 IARs. The most frequently reported IARs in the placebo and laronidase-treated groups were: flushing (17% and 23%), fever (13% and 5%), headache (9% and 9%), and rash (9% and 5%), respectively. The majority of IARs were of mild intensity and none were reported as severe.

No patient tested positive for laronidase-specific IgE antibodies. When possible, all laronidase and placebo patients with positive ELISA samples were confirmed by RIP. Twenty of 22 patients who received laronidase treatment and 1 patient who received placebo tested positive for IgG antibodies by RIP. Since laronidase and placebo were similarly well-tolerated, it seems unlikely that the development of antibodies had any effect on safety in general.

Overall, there were few patients in either treatment group who presented with clinically significant laboratory values at Baseline or during the double-blind treatment.

A mild mean decrease in heart rate was observed for the placebo group and a mild mean increase in heart rate was observed for the laronidase-treated group. There were no patients in the laronidase-treated group who were reported as having clinically significant changes in ECG or ECHO testing.

For all patients, Baseline brain-cranio cervical junction MRI evaluations were abnormal. For all 9 placebo-treated patients, Week 26 MRI evaluations remained unchanged (abnormal) while 1 of the 6 laronidase-treated patients, abnormal at Baseline, had a normal MRI evaluation at Week 26.

The evaluation of the various safety parameters monitored during this study that included, AEs, physical exam, vital signs, ECGs, ECHOs, standard clinical laboratory and immunogenicity testing appear to indicate that laronidase is well tolerated and has an acceptable safety profile in this patient population.

Pharmacokinetics

At Baseline (Week 1), the mean Cmax was 0.197 ± 0.052 U/mL, and was reached at a median of 3.93 hours, consistent with the median infusion time of 3.98 hours. The mean CL was 1.96 ± 0.495 mL/min/kg, the mean Vz was 0.604 ± 0.172 L/kg, and Vss was 0.440 ± 0.125 L/kg. The mean t½ was 3.61 ± 0.894 hours, and the mean residence time was 3.83 ± 1.04 hours. The mean Cmax of laronidase appeared to increase, and there was a trend toward a decrease in t½ as a consequence of a decrease in Vz during the first 12 weeks of weekly intravenous infusions of approximately 100 U/kg for 26 weeks to patients with MPS I. The decrease in Vz may be related to the development of antibodies to laronidase. However, CL did not appear to be affected by the duration of the treatment period (26 weeks).

Conclusion

Based on the data collected in this study, laronidase improved physical function and endurance demonstrated by the improved 6-Minute Walk and improved pulmonary function by FVC, and reduced sleep apnea. In addition, laronidase reduced organ volumes and improved function as measured by a disability index in shoulder flexion. The data obtained in this Phase 3 double-blind, placebo-controlled study demonstrate that enzyme replacement treatment with laronidase is safe and efficacious when administered for 26 weeks to patients with MPS I.