ALID-014-02: A Phase II Open-Label Clinical Trial of Recombinant Human Alpha-l-iduronidase (Aldurazyme^®) to Evaluate the Safety and Pharmacokinetics in Mucopolysaccharidosis I (MPS I) Patients Less Than 5 Years Old

Aldurazyme^® (laronidase)

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

These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert

NAME OF SPONSOR/COMPANY

BioMarin/Genzyme LLC, 500 Kendall Street, Cambridge, Massachusetts, 02142

INVESTIGATORS AND STUDY CENTER(S)

This was a multicenter study conducted at 4 sites in the EU.

PUBLICATION (REFERENCE)

Publications

STUDIED PERIOD

23 October 2002 (first patient enrolled) to
03 May 2005 (last patient completed)

PHASE OF DEVELOPMENT

Phase 2

OBJECTIVES

Evaluation of the safety and pharmacokinetics (PK) of enzyme replacement therapy with Aldurazyme in Mucopolysaccharidosis I (MPS I) patients less than 5 years old.

Evaluation of efficacy by assessing liver size, urinary glycosaminoglycan (GAG) excretion, upper respiratory care requirements, sleep apnea, hearing, vision, growth velocity, electrocardiogram (ECG), echocardiogram, and the Investigator’s global assessment. Mental development was assessed as an exploratory measure.

METHODOLOGY

This was an open-label trial to evaluate Aldurazyme therapy in patients with MPS I who were less than 5 years of age at the time of enrollment. Following Baseline evaluation, patients were scheduled to receive weekly intravenous (IV) infusions of Aldurazyme at a dose of 100 U/kg for 52 weeks. Patients were monitored continuously during the trial, while specific evaluations were performed at 13, 26, and 52-week time points.

During the study, results for urinary GAG measurements at Baseline, Week 13, and Week 26 became available and suggested that GAG clearance was only partially achieved in some patients at the labeled dose (100 U/kg [0.58 mg/kg]). As predicted by MPS I pathophysiology and by the Phase 3 study (ALID-003-99) results, substantial GAG reduction is associated with clinical benefit. Therefore, some patients in this Phase 2 study may not have been realizing the full potential clinical benefit of Aldurazyme. Consequently, Aldurazyme doses were increased to 200 U/kg (1.2 mg/kg; starting at Week 26) for subsequently enrolled patients if urinary GAG levels remained > 200 µg/mg creatinine after 22 weeks of treatment.

NUMBER OF PATIENTS (PLANNED AND ANALYZED)

Approximately 20 patients were planned to be enrolled in the trial. Twenty patients (16 Hurler patients and 4 Hurler-Scheie patients) were enrolled and analyzed.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Patients met the following main criteria to be enrolled in this trial: written informed consent of parent(s) or legal guardian(s); age less than 5 years at the time of enrollment; confirmed iduronidase deficiency with a fibroblast or leukocyte α-l-iduronidase enzyme activity level of less than 10.0% of the lower limit of the normal range, or below the detection range of the measuring laboratory; clinical diagnosis of MPS I based on genotyping.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

Patients received Aldurazyme at a dose of 100 U laronidase per kg body weight (approximately 0.58 mg/kg). The trial medication was administered IV over approximately a 4-hour period once per week.

For some patients, the dose was increased from Week 26 onwards to 200 U/kg (1.2 mg/kg), if the urinary GAG level at Week 22 was > 200 µg/mg creatinine. (See Methodology)

DURATION OF TREATMENT

52 weeks.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

None.

CRITERIA FOR EVALUATION
Criteria for Evaluation – Safety
Safety monitoring included physical examinations, vital signs, ECG, clinical laboratory evaluations, immunogenicity testing, and adverse event (AE) monitoring.

Criteria for Evaluation – Pharmacokinetics
PK profiles were carried out at the first infusion, and at Weeks 13, 26, and 52. The following PK parameters were estimated from the plasma Aldurazyme concentration-time data at Day 0 and Weeks 13, 26, and 52: maximum plasma concentration (C_max), time to C_max (T_max), area under the (plasma concentration-time) curve (AUC_0-t), AUC_0-∞, total plasma clearance (CL), volume of distribution (V_z),volume of distribution at steady state (V_ss) λ_v, and elimination half life (t_1/2).

Criteria for Evaluation – Efficacy
Clinical evaluations consisted of GAG clearance by measuring urinary GAG excretion; liver size by measuring liver edge below right costal margin (BRCM) in the mid-clavicular line; cardiac function tests by ECG and echocardiogram; apnea/hypopnea index by polysomnography; growth velocity by tracking height and weight; cognitive function by the Griffiths Mental Development Scales; language acquisition by using the Reynell Developmental Language Scales III; and adaptive behavior by using the Vineland Adaptive Behavior Test; Investigator’s global assessment of overall changes in the patient’s condition; hearing oto-acoustic emission audiometry (OAEA), a hearing distraction test, and tympanography; tonometry and visual acuity by age appropriate eye chart testing; oxygen saturation; upper respiratory care/interventions by tracking care/interventions required to maintain adequate respiratory function.

STATISTICAL METHODS

All data collected in this trial were summarized using frequencies and percentages for categorical variables, and using descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) for continuous variables. Changes from Baseline to the various trial time points were provided for all variables where appropriate. In addition, summaries were provided by dose group.

SUMMARY / CONCLUSIONS

Summary / Conclusions – Efficacy
As in studies involving older and less severely affected patients, urinary GAG levels showed a sharp decline after initiation of therapy with Aldurazyme followed by a plateau after Week 13. The mean percentage reduction in urinary GAG level was 61.3% for all patients who completed the study, 59.1% for the patients who were treated with 100 U/kg during the whole study, and 67.7% for the 4 patients who received a double weekly dose as of Week 26.

10/10 patients with available liver edge BRCM values at Week 26 and Week 52 showed a decrease in cm liver edge BRCM from Baseline. 9/10 patients (90%) had a decrease in liver edge BRCM from > 3 cm to ≤ 3 cm. 9/18 (50%) patients normalized in liver volume (as assessed by physical examination) during the study duration of 1 year.

Left ventricular mass, an echocardiographic measure of cardiac hypertrophy, decreased by a mean of 0.9 Z-scores over the 1-year study duration. The frequency of patients with left ventricular hypertrophy decreased from 50% (9/18 patients) at Baseline to 15% (3/20 patients) at Week 52/Final Visit. There were no patients who were reported as having new clinically significant abnormalities in ECG testing at the end of the study.

Sleep studies showed a mean reduction of 5.8% in apnea/hypopnea events per hour of sleep in patients with an abnormally high frequency of apneas/hypopneas at Baseline. A more extensive expert evaluation of all sleep study results per patient indicated that approximately 33% of patients showed improvement and approximately 33% showed no change in sleep study results after 1 year of treatment with Aldurazyme.

7 study patients showed a consistent increase in height-for-age Z-score and 3 patients in weight-for-age
Z-score during the study duration of 1 year. In contrast, the best-fit regression lines of Z-score data from untreated MPS I Registry patients (Hurler and Hurler-Scheie syndromes) showed steadily declining Z-scores during the same age period.

Exploratory evaluations of mental development suggested that the attenuated MPS I patients (Hurler-Scheie syndrome) in the study derived benefit from treatment with Aldurazyme, especially in cognition and language acquisition. Cognitive function also improved in the youngest patients with severe MPS I (< 2.5 years, Hurler syndrome), whereas the older Hurler patients did not change significantly.

The Investigator global assessment showed that 17/18 patients (94%) who completed the study had improved clinical status (6 patients moderately improved and 11 patients mildly improved) after 1 year of treatment with Aldurazyme.

No obvious shifts in eye examination and hearing test results were observed among patients. However, the percentage of patients in whom middle ear fluid was present decreased from 85% (right ear) and 90% (left ear) at Baseline to 63% (right ear) and 53% (left ear) at Week 52.

During this study, no patients required the use of oxygen or positive pressure airway support such as CPAP or BiPAP. Two patients had mildly abnormal oxygen saturations at Baseline (88 and 91%), and by the end of the study, all patients had normal oxygen saturations.

Summary / Conclusions – Pharmacokinetics
At Baseline (Week 1), the mean C_max was 0.325 ± 0.669 U/mL and was reached at a median of 4.04 hours (T_max), consistent with the infusion time of 4 hours.

The mean CL was 5.73 ± 3.90 mL/min/kg, the mean V_z was 0.753 ± 0.497 L/kg and mean V_ss was 0.887 ± 0.694 L/kg.

Taking into account the sample size and variability, the AUC_∝, CL, V_ss, and t_1/2 were comparable on Weeks 1, 13, 26, and 52 of the study.

There was a statistically significant decrease in V_z with continued dosing which may have been related to an increase in antibody titer.

Summary / Conclusions - Safety Results
During this study, 15 patients experienced 54 serious adverse events (SAEs); 51/54 were assessed as unrelated to treatment with Aldurazyme. The 3 related SAEs occurred in a single patient during the 12^th infusion and were assessed as infusion-associated reactions (AEs assessed as possibly, probably, or definitely related to treatment that occurred from infusion onset up to and including the post infusion observation period.). No patient discontinued the treatment with Aldurazyme because of a drug-related AE. There were 2 deaths during the study; 1 patient died of respiratory distress and respiratory arrest and the second patient died of convulsion and cardiac failure. The events of both patients were assessed as being unrelated to treatment with Aldurazyme.

All patients experienced at least 1 AE, of which pyrexia (100%), diarrhoea (85%), cough (85%), and vomiting (70%) were most frequently reported. The majority of AEs were unrelated to Aldurazyme, mild in severity, and occurred on non-infusion days.

33 infusion-associated reactions (IARs) occurred in 7 patients (35%). The most frequently reported IARs were pyrexia (6 patients) and chills (4 patients). Overall, the majority of IARs were of mild severity and were managed with a decrease of the infusion rate, a temporary interruption of the infusion, or administration of antihistamines and/or antipyretics.

There was no clinically relevant change from Baseline for any of the serum chemistry, hematological or urinary parameters that were assessed. Changes in vital signs and physical examination parameters were either unremarkable or were attributable to complications and manifestations of underlying MPS I disease or explained by the age of the patients under study.

There was no apparent change in the tolerability of Aldurazyme in patients initially treated with 100 U/kg who had their dose increased to 200 U/kg.

All patients developed IgG antibodies against laronidase with a mean time to seroconversion of 25.8 days (median: 22.0 days). Titers were variable, and some titers began to decrease by the end of the study. One seropositive patient tolerized at Week 37. Patients with lower antibody titers showed a robust urinary GAG reduction, whereas those with higher titers showed more variable reductions. Of the patients who had higher antibody titers, those who received the 200 U/kg dose of Aldurazyme appeared to show a more robust urinary GAG reduction than those who received the 100 U/kg dose throughout the study.

The evaluation of the various safety parameters monitored during this study, which included AEs, physical examination findings, vital signs, and standard clinical laboratory and immunogenicity testing suggest that Aldurazyme is well tolerated and has an acceptable safety profile in patients less than 5 years old.

CONCLUSION

This Phase 2 study demonstrates that treatment with Aldurazyme is clinically beneficial and safe in MPS I patients less than 5 years old. Consequently, the benefit to risk ratio of Aldurazyme therapy in MPS I patients under 5 years of age is favorable.