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

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

This was a multicenter study conducted at 2 study centers in the US, 2 study centers in Europe, and 1 study center in Canada. In addition to the 5 main study centers, 34 additional regional infusion sites participated in this study.

First Patient Enrolled 29 May 2001
Last Patient Completed: 07 March 2005
Phase of Development

The objective of this Phase 3 Open-Label Extension Study was to collect additional long-term efficacy and safety data on the use of Aldurazyme (laronidase) in patients with Mucopolysaccharidosis I (MPS I) disease who were previously treated in a Phase 3 Double-Blind Study (ALID-003-99). This synopsis summarizes efficacy and safety data through 182 weeks of treatment in the Phase 3 Open-Label Extension Study (ALID-006-01).

This was a multicenter, multinational, Phase 3, Open-Label Extension Study (“Extension Study”) of patients with MPS I disease who had previously been treated in a Phase 3 Double-Blind Placebo-Controlled Study (“Double-Blind Study”). Eligible patients began treatment in the Extension Study during the 27th week following initiation of their treatment in the Double-Blind Study. Patients underwent efficacy assessments beginning at Week 12 of the Extension Study. Safety was monitored continuously throughout study participation. Patients began participation in the Extension Study at their original study center associated with the Double-Blind Study, and all efficacy evaluations were performed at this original center throughout the Extension Study. Patients may have been transferred to regional study centers for weekly Aldurazyme treatment contingent upon a full evaluation of their medical condition and all relevant safety issues by the Investigator and Sponsor’s Medical Monitor and after obtaining approval from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) at the regional study centers and regulatory agencies, if applicable.

Of 45 patients enrolled in the Double-Blind Study, all were eligible and enrolled in the Extension Study, and 40 patients completed the study. All patients received Aldurazyme. All 45 patients were analyzed for safety and efficacy.

Patients were eligible to participate in the Extension Study if they had successfully completed the previous Double-Blind Study, including having received at least 21of 26 consecutive weekly infusions and if there were no safety issues that would contraindicate 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 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.

Patients received Aldurazyme intravenously at a dose of 100 units/kg (approximately 0.58 mg/kg) over a time period of approximately 4 hours, once weekly for 182 weeks.

The total duration of treatment (including the Double-Blind phase) was 208 weeks (4 years); 182 weeks of active treatment for patients who received placebo during the Double-Blind phase, and 208 weeks of active treatment for patients who received Aldurazyme during the Double-Blind phase.

Primary efficacy variables included measurements of percent of predicted normal forced vital capacity (FVC) and the 6-minute walk test (6MWT) distance (walked in meters). Secondary efficacy variables included liver volume (hepatomegaly), sleep study measurements (apnea/hypopnea index [AHI], total respiratory event index, and oxygen saturation changes), the disability index of the Childhood Health Assessment Questionnaire (CHAQ)/Stanford Health Assessment Questionnaire (HAQ), and shoulder flexion range of motion (ROM). Tertiary efficacy variables included other joint ROM (shoulder extension, knee flexion and extension), urinary glycosaminoglycan levels (GAGs), the pain scale of CHAQ/HAQ and MPS I HAQ, the Child Health Questionnaire Parent-form 50 (CHQ-PF50) and Child-form 87 (CHQ-CF87)/Short-form 36 Health Survey (SF-36), ophthalmology testing and cardiac function tests (electrocardiograms [ECGs] and echocardiograms [ECHOs]).

In addition to the individual endpoints, a composite endpoint including the following assessments was evaluated: percent predicted normal FVC, 6MWT distance, shoulder flexion ROM, AHI, and visual acuity.

Safety was evaluated in terms of adverse events (AEs), related AEs, serious adverse events (SAEs), infusion-associated reactions (IARs), physical examinations, vital sign parameters, standard clinical laboratory evaluations (hematology, chemistry and urinalysis), ECG parameters, and immunogenicity testing.

As this Extension Study was an extension of the Double-Blind Study, the 2 treatment groups represented in the reporting of the Extension Study data were as follows:

- Aldurazyme/Aldurazyme treatment group: Patients received 26 weeks of Aldurazyme treatment in the Double-Blind Study and then received 182 weeks of Aldurazyme treatment in the Extension Study; patients have received a total of 208 weeks of Aldurazyme treatment.

- Placebo/Aldurazyme treatment group: Patients received placebo for 26 weeks in the Double-Blind Study and then received 182 weeks of Aldurazyme treatment in the Extension Study; patients have received a total of 182 weeks of Aldurazyme treatment.

Combined data from all patients were also analyzed: data from Aldurazyme treatment baseline through up to 208 weeks were combined for primary efficacy comparisons and safety evaluation of the overall Aldurazyme treatment experience.

EFFICACY: All efficacy variables were evaluated by comparing the mean change from the documented values in the Double-Blind Study at baseline (last measurement prior to randomization into Double-Blind Study) and entry (last measurement in the Double-Blind Study prior to enrollment into the Extension Study) to the values assessed at Extension Study time points through Week 182 (i.e., the end of the Extension Study). Changes in primary, secondary and tertiary variables (see Criteria for Evaluation) were calculated and were presented as descriptive statistics for the Aldurazyme/Aldurazyme and placebo/Aldurazyme treatment groups. Hypothesis testing was not performed as both treatment groups received active Aldurazyme enzyme replacement therapy in an open-label treatment format.

No rigorous sample size calculations were performed, as this was an extension study of the Double-Blind Study.

SAFETY: Clinical safety was addressed by comparing the incidence of AEs in the 2 treatment groups (Aldurazyme/Aldurazyme and placebo/Aldurazyme), evaluation of overall AEs in the combined group of all patients (up to 208 weeks of Aldurazyme treatment), and by summarizing changes from baseline (last measurement prior to randomization into the Double-Blind Study) and entry (last measurement in the Double-Blind Study prior to entry into the Extension Study) to the Extension Study time points for physical examination results, vital sign parameters, standard clinical laboratory parameters (chemistry, hematology, and urinalysis), and cardiac findings.

Summary – Conclusions
A total of 45 patients were first enrolled in the Double-Blind Study and then entered the Extension Study: 22 (49%) male and 23 (51%) female patients, the majority (82%) of which were Caucasian. The mean age for patients at enrollment was 15.5 years, with approximately half of the patients being ≤ 12 years of age. The MPS I disease syndrome for the majority of patients (82%) was Hurler-Scheie; the distribution for Hurler syndrome and Scheie syndrome was 2% and 16%, respectively. The mean time since onset of symptoms and diagnosis for all patients was 12.7 years and 9.0 years, respectively.

The increases seen in FVC as measured in liters during the 26-week Double-Blind Study in the Aldurazyme/Aldurazyme group were maintained and further improvement occurred during the 182 weeks of the Extension Study.

By Week 182, the placebo/Aldurazyme patients demonstrated an average increase in FVC of 0.16 L (15%) compared to entry. This improvement is consistent with that observed in the Aldurazyme/
Aldurazyme group (25% improvement in FVC).

Patients in the younger age groups (< 18 yr.) demonstrated markedly larger increases in FVC (L) from baseline and entry to Week 182 than those observed in the older age groups.

- There was a relative increase in lung volume in the younger Aldurazyme/Aldurazyme age group of approximately 57% between baseline and Week 182, while in the youngest placebo/Aldurazyme age group there was a relative increase of approximately 25% between entry and Week 182.

- This suggests a substantially larger increase in lung volume related to growth than would be expected in untreated MPS I patients, as the latter are severely compromised in growth rate.

Changes in mean percent predicted FVC were small in both treatment groups regardless of baseline severity.

- At Week 182, the mean change in percent predicted FVC for the Aldurazyme/Aldurazyme group was a 1.2 percentage point decrease compared to baseline and a 2.6 percentage point decrease compared to entry. These correspond to relative decreases of 1.6% from baseline and 3.2% from entry, which are not clinically significant changes (ATS, 1991, Am Rev Respir Dis).

- For the placebo/Aldurazyme group, the mean change in percent predicted normal FVC was a decrease of 3.3 percentage points compared to entry. This corresponds to a relative decrease of 6.0%, which is not a clinically significant change (ATS, 1991, Am Rev Respir Dis).

Overall, percent predicted FVC showed a linear response to Aldurazyme treatment over time; the linear coefficient from the model predicts maintenance of pulmonary function (-0.78 percentage points per year) over the course of treatment.

Overall, the mean absolute change from baseline in 6MWT distance was maintained in the Aldurazyme/Aldurazyme group during the Extension Study.

In the placebo/Aldurazyme group, the mean absolute change in 6MWT distance initially increased during the Extension Study and then decreased after Week 60 until Week 182, where the mean absolute change in distance walked increased again. The mean decreases seen in the placebo/Aldurazyme group during this time were mainly driven by 4 patients with impaired physical functioning. Thus, when excluding the 4 placebo/Aldurazyme patients with a compromised ability to perform the 6MWT, patients in the placebo/Aldurazyme group showed greater improvements in their mean performance on 6MWT after 182 weeks of treatment in the Extension Study, and the trend over time more closely resembled that of the Aldurazyme/Aldurazyme group.

Overall, patients experienced the greatest improvement in distance walked during the first year of therapy; smaller increases and decreases were seen thereafter, indicating maintenance or stabilization of the treatment effect. Patients showed a positive linear response (0.59 m per week) with a small quadratic component (-0.003 m per week²) to Aldurazyme treatment over time, with a predicted increase of 23.1 ± 5.7 m after 1 year of Aldurazyme treatment and an increase of 31.7 ± 10.2 m after 2 years of Aldurazyme treatment.

A consistent relationship between increasing age and 6MWT distance was observed in both treatment groups. These findings are consistent with data from normal populations in which taller patients with longer stride lengths walked further than shorter patients in the 6MWT (Enright, 1998, Am J Respir Crit Care Med).

In terms of baseline severity, there was a general trend seen in patients with baseline 6MWT values below the median experiencing a greater degree of change in 6MWT distance than patients with baseline 6MWT values above the median in both treatment groups.

Overall, a decrease in AHI events was observed in both treatment groups. In addition, a small decrease (improvement) in the mean total respiratory event index was observed in both treatment groups. Percent of time asleep with oxygen saturation below 90% and 80% decreased (i.e., improved) from baseline to Week 182 for patients Aldurazyme/Aldurazyme group (-7.4 and -2.7 percentage points, respectively), but increased (i.e., decline) slightly in patients in placebo/Aldurazyme group (1.9 and 0.3 percentage points, respectably).

Overall, large reductions in liver volume were observed for all patients after treatment with Aldurazyme. In the Aldurazyme/Aldurazyme group, the majority of the reduction in liver volume (18.9%) came within the first 26 weeks of treatment during the Double-Blind Study, with no further improvement seen between entry and Week 182, as most patients had normalized prior to entry into the Extension Study. After a total of 208 weeks of treatment with Aldurazyme (from baseline of the Double-Blind Study to Week 182), liver organ volume showed a mean decrease of 16.1% for this treatment group. In the placebo/Aldurazyme group, there was an initial increase (1.3%) in liver volume observed during the 26-week placebo-phase of the Double-Blind Study, followed by a 17.6% decrease from entry to Week 182 that was comparable to the reduction seen in the Aldurazyme/Aldurazyme group. To account for changes in liver volume due to patient growth, changes in mean liver organ volume as a percent of body weight (cc/g) from baseline through Week 182 were evaluated. There was a large decrease in liver volume as a percent of body weight over the first 24 to 26 weeks of Aldurazyme treatment that was followed by a smaller downward trend through the remainder of the study. Liver volumes plateaued in the later stages of the study because most had achieved a normal size by Week 24 to 26.

In both treatment groups, nearly all patients with abnormal liver volumes prior to initiation of treatment normalized their liver volumes with long-term treatment. At baseline of the Double-Blind Study, 17 Aldurazyme/Aldurazyme patients had abnormal liver volumes and also had available liver volume measurements at Week 182. After 208 weeks of treatment with Aldurazyme, 15 (88%) of the 17 patients had liver volumes in the normal range at Week 182 and 2 patients remained abnormal. All 4 patients with normal liver volume at baseline remained in the normal range at Week 182. At entry of the Extension Study, there were 5 Aldurazyme/Aldurazyme patients with abnormal liver volumes who also had available liver volume measurements at Week 182. Three (60%) of the 5 patients had liver volumes in the normal range at Week 182 and 2 patients remained abnormal. In the placebo/Aldurazyme group, 9 patients had abnormal liver volumes at entry of the Extension Study and also had available liver volume measurements at Week 182. After 182 weeks of treatment with Aldurazyme, 7 (78%) of the 9 patients had liver volumes in the normal range and 2 patients remained abnormal. Additional post-hoc analyses revealed that there was no consistent relationship between percent change in liver organ volume and absolute change in percent predicted FVC or 6MWT distance.

In terms of joint ROM, consistent improvements from baseline and entry to Week 182 were seen in both treatment groups. Patients whose baseline ROM was below the median experienced greater improvements from baseline and entry to Week 182 as compared to patients whose baseline ROM was greater than or equal to the median in both treatment groups.

At Week 182 in the Aldurazyme/Aldurazyme group, a substantial improvement in shoulder flexion was observed, that amounted to 13.1 degrees from baseline and 17.6 degrees from entry. Comparably, patients in the placebo/Aldurazyme group demonstrated an improvement of 18.3 degrees between entry and Week 182. In the Aldurazyme/Aldurazyme group, the mean improvements in degrees of shoulder extension, knee flexion, and knee extension that were observed during the Double-Blind Study (3.7, 8.5, and 2.9 degrees, respectively) had further increased to 8.6, 13.5, and 7.9 degrees, respectively, from baseline to Week 182. Comparably, patients in the placebo/Aldurazyme group demonstrated mean improvements in shoulder extension, knee flexion, and knee extension of 9.2, 4.2, and 4.4 degrees, respectively, from entry and Week 182.

After a large initial decrease in urinary GAG levels, patients maintained their overall change from Aldurazyme treatment baseline, with only a small additional decrease observed through the remainder of the study. In the Aldurazyme/Aldurazyme group, the mean decrease in urinary GAG levels from entry of the Extension Study to Week 182 was 25.9%; the total decrease over the 208 weeks of treatment was 66.3%. In the placebo/
Aldurazyme group, the mean decrease in urinary GAG levels from entry of the Extension Study to Week 182 was 77.0%. Overall, one-third of all patients normalized during the 182-week extension study treatment period. Additional post-hoc analyses revealed that there was no consistent relationship between percent change in urinary GAG level and absolute change in percent predicted FVC or 6MWT distance.

Mean visual acuity at Aldurazyme treatment baseline was generally comparable between the Aldurazyme/Aldurazyme and placebo/Aldurazyme groups and not significantly impaired for most patients. Mean changes in visual acuity for all patients from baseline or entry to Week 182 were very small and not clinically meaningful. When considering patients with significantly impaired vision, a trend towards improvement was seen at Week 182. At baseline, most of the evaluable patients in each group had normal eye pressures; there were very small changes throughout the course of the study, and all mean values remained within the normal range.

Mean changes in ECG parameters from baseline or entry to Week 182 were generally small and consistent between the 2 treatment groups (values either increased or decreased). Additionally, baseline, entry, and Week 182 mean values were all within normal range. In general, there was a large variability in ECHO parameters due to the different sizes and ages of the study patients. Overall, the majority of patients were stable at Aldurazyme treatment baseline and stayed that way throughout the study showing little disease change over time.

Qualitative assessment of patient disease was conducted using various patient questionnaires. Both treatment groups exceeded the minimal clinically important difference (MCID) from baseline (Aldurazyme/Aldurazyme group) or entry (placebo/Aldurazyme group) to Week 182 for the CHAQ/HAQ disability index, indicating clinically meaningful improvements in physical functioning.

Patients’ baseline severity was also seen to influence the overall treatment response in the pain scale component of the CHAQ/HAQ; a consistent trend was seen in patients who reported more severe pain at baseline showing a greater magnitude of pain reduction following Aldurazyme treatment.

Of the 31 patients with available data for the overall MPS I HAQ score, 26% showed improvement, 71% showed no change, and 3% showed decline. The changes were relatively consistent across domains.

Baseline and entry scores were generally high in the CHQ-PF50 domains in both treatment groups. Small, scattered improvements in Parent QoL scores were seen in both treatment groups from baseline and entry to Week 182.

Self-reported clinically meaningful mean improvements (changes ≥ 10 points) in physical domains of the CHQ CF-87 were reported by patients in both the Aldurazyme/Aldurazyme group (from baseline to Week 182) and placebo/Aldurazyme group (from entry to Week 182) for role/social limitations – physical and bodily pain/discomfort. These changes are consistent with the self-reported improvements observed in the CHAQ disability and pain indices.

There seemed to be a positive trend in mean SF-36 physical health and mental health scores in both Aldurazyme/Aldurazyme and placebo/Aldurazyme patients, although there were a small number of patients in each group. Patients in the Aldurazyme/Aldurazyme group exceeded the MCID from baseline to Week 182, indicating meaningful improvements in physical and mental health status. Patients in the placebo/Aldurazyme group also exceeded the MCID for improvement in physical health summary score from entry to Week 182, indicating clinically meaningful improvements in physical health status, although a significant change was not observed for mental health status.

Given the clinical variability and heterogeneity of clinical features in patients with MPS I, a composite endpoint was developed to evaluate clinically meaningful changes occurring across several endpoints on a patient-by-patient basis. An overall score was calculated for each patient according to the net number of clinically meaningful improvements (+1 each domain), declines (-1 each domain), or lack of change (0 each domain). From this overall score, patients were identified as having improved, remained stable, or declined. The composite endpoint consists of 5 efficacy variables: percent predicted normal FVC, 6MWT distance (m), shoulder flexion ROM (degrees), AHI (events/hour), and visual acuity (# lines). Clinically significant changes from baseline or entry to Extension Study time points were defined as: FVC ≥ 15% relative change; 6MWT ≥ 54 m; shoulder flexion ≥ 20 degrees; AHI ≥ 10 events/hour; and visual acuity ≥ 0.2 log₁₀ units (2 functional lines).

Overall, the majority (80%) of patients were improved (58%) or stable (22%) in their composite score at Week 182. When considering the 5 individual domains of the composite score, the 6MWT was the main driver for the composite score improvements seen in the Aldurazyme/Aldurazyme group, while the other domains contributed to composite score stabilization. In the placebo/Aldurazyme group, the 6MWT and shoulder flexion results drove the composite score improvements, while the other domains contributed to composite score stabilization.

From Aldurazyme treatment baseline to Week 182, 17 (77%) of 22 Aldurazyme/Aldurazyme patients showed improvement in at least 1 domain (mean of 1.9 improved domains per patient) and 19 (83%) of 23 placebo/
Aldurazyme patients showed improvement in at least 1 domain (mean of 1.7 improved domains per patient); no patients declined in all 5 domains. The mean (± SD) composite score for all patients from Aldurazyme treatment baseline to Week 182 was 0.80 ± 1.42, an overall net improvement. Analysis of the Double-Blind Study data using the composite clinical endpoint lends independent support for a positive treatment effect. After 26 weeks of placebo treatment, 13 (57%) placebo/Aldurazyme patients had declined, 3 (13%) were stable, and 7 (30%) showed improvement. After 182 weeks of Aldurazyme treatment in the Extension Study, however, 13 (57%) placebo/Aldurazyme patients showed improvement, 6 (26%) were stable, and 4 (17%) had declined. Additional post-hoc analysis revealed that there was no consistent relationship between percent change in urinary GAG level and overall composite score.

There was no consistent relationship seen between IgG antibody level and absolute change in percent predicted FVC or 6MWT. In terms of the interaction between IgG antibody level and percent change in urinary GAG level, however, there appeared to be a negative correlation between urinary GAG reduction and antibody level. There was no consistent relationship seen between IgG antibody level and overall composite score.

Forty of 45 patients completed the Extension Study (182 weeks of Aldurazyme treatment). In the Aldurazyme/
Aldurazyme group, a slightly greater mean number of infusions were administered (167.1) compared to the placebo/Aldurazyme group (146.1). This is due to 5 placebo/Aldurazyme patients who discontinued the study prior to Week 182; of these, 1 patient died after infusion 16 due to an upper respiratory tract infection that was judged by the Investigator to be unrelated to study drug treatment. There were no other patient deaths. The remaining 4 patients discontinued to due needle phobia (Week 24), pregnancy (Week 83), conflict with school schedule (Week 157), and following an anaphylactoid reaction (week 62). Twenty-five (56%) patients experienced a total of 102 SAEs during the Extension Study. The majority of SAEs appeared to be consistent with clinical manifestations and complications of patients’ underlying MPS I disease, were assessed as unrelated to study drug, and from which patients recovered without sequelae. The most commonly reported SAEs in the total population included dyspnoea (9%), vein disorder (9%), abdominal pain (7%), and hernia NOS (7%); all other SAEs occurred in ≤ 2 patients. Three patents experienced a total of 9 related SAEs, seven of which were infusion-associated reactions (IARs). The seven IARs were experienced by 2 patients; one patient with anaphylactoid reaction and respiratory disorder (same day), and the second patient with abdominal pain, back pain, fever, hypotension, and vomiting (all on the same day).

All 45 patients (100%) in both groups experienced at least 1 AE. Overall, the most commonly reported AEs included rhinitis (93%), headache (84%), fever (78%), coughing (76%), pharyngitis (71%), nausea (64%), pain (62%), arthralgia (62%), vomiting (58%), skeletal pain (58%), upper respiratory tract infection (53%), abdominal pain (53%), diarrhea (53%), and back pain (51%). The type and incidence of AEs were similar between the 2 groups. The largest differences in frequency of commonly occurring AEs between treatment groups were observed for influenza-like symptoms (27% versus 48%), myalgia (18% versus 39%), and ear ache (50% versus 30%) in the Aldurazyme/Aldurazyme and placebo/Aldurazyme groups, respectively. The majority of AEs experienced by patients were mild in severity (84%), assessed as unrelated to study drug (86%), and occurred on non-infusion days (71%). Twenty-five (56%) patients experienced a total of 96 severe AEs, of which the majority (93%) were assessed as unrelated to study drug.

Drug-related AEs (defined as those AEs assessed as possibly, probably or definitely related to study drug by the Investigator) were reported in 29 (64%) patients overall, and the frequency was similar between treatment groups. The most frequently reported drug-related AEs in the total population were arthralgia (18%), rash (16%), headache (13%), injection site reaction (13%), flushing (11%), back pain (11%), fever (11%), skeletal pain (11%) and nausea (11%).

The majority of drug-related AEs were characterized as IARs, which were related events occurring on the day of infusion, but excluding those AEs identified by protocol-required assessments performed that day prior to drug infusion (e.g., laboratory and physical examination abnormalities). Twenty-two (49%) patients experienced a total of 516 IARs. Nearly all (99%) IARs experienced by patients during the Extension Study were non-serious and mild or moderate in severity. Of note, most of the IARs (n = 414) were experienced by a single Aldurazyme/Aldurazyme patient; this patient experienced events such as rash, urticaria, abdominal pain, pruritus, and injection site reaction, which were all mild or moderate in severity and from which the patient fully recovered, usually after administration of antihistamines and/or antipyretics. Overall, this patient’s IARs appear idiosyncratic, and the extent and intensity of the patient’s symptoms lessened over time. The patient was able to tolerate infusions and continued to receive Aldurazyme treatment until study completion. Additionally, there was 1 report of anaphylactoid reaction (anaphylaxis-induced airway obstruction that required emergent tracheotomy) in another patient that was additionally characterized as an IAR.

Overall, the frequency of AEs (regardless of severity or relationship) decreased over time. The frequency of IARs also decreased over time.

Forty-two (93%) of 45 patients had IgG antibodies to rhIDU detected by ELISA and confirmed by RIP assay during the Double-Blind and Extension Studies; only 3 patients (1 Aldurazyme/Aldurazyme patient and 2 placebo/Aldurazyme patients) had IgG antibody levels that remained below minimum quantification (by ELISA) throughout their treatment with Aldurazyme (up to 208 weeks). The mean time to first detectable antibody level by ELISA was 50.6 days in the Aldurazyme/Aldurazyme group and 39.7 days in the placebo/Aldurazyme group; however, the median time to first detectable antibody level was similar between treatment groups. By the end of the study at Week 182 (or at time of early study withdrawal), 13 patients were seronegative by RIP assay. Because there were only 3 patients whose IgG antibody levels remained below minimum quantification (by ELISA) throughout the study, it is difficult to draw any conclusions regarding comparative AE profiles within or between treatment groups, but there does not appear to be any clinically meaningful differences.

No patients were tested for circulating immune complexes. The lack of sustained proteinuria in patients suggests that there was no clinical manifestation of immune complex disease. One patient had positive skin test (approximately at Week 43), positive IgE (Weeks 37, 50, 51, and 60), and positive complement activation (Weeks 34, 49, and 57) results during the Extension Study; the patient experienced an anaphylactoid reaction during the Week 62 infusion and was subsequently discontinued from the study at Week 101 (no infusions were administered between Week 62 and actual study withdrawal). A second patient tested positive for complement activation at Week 37. Among those tested, no patients demonstrated elevated serum tryptase levels.

Changes in safety laboratory parameters, vital signs, physical examination findings, and cardiac parameters during the Extension Study were generally consistent with the underlying disease or evolving clinical status of MPS I patients.

The safety profile observed during the Extension has not changed significantly over time. Safety data from both the Double-Blind and Extension Studies suggest that Aldurazyme infusions are well-tolerated with both short-term and long-term use. The presence of IgG antibodies does not appear to have an effect on overall safety.

The efficacy and safety data obtained from this 182-week open-label extension study demonstrate that enzyme replacement therapy with Aldurazyme^® (laronidase) is generally well-tolerated and provides continued clinical benefits when administered to patients with MPS I disease.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.

This Phase 3 Extension Study represents the longest longitudinal study of patients being treated for their underlying MPS I disease rather than palliatively for signs and symptoms. Long-term enzyme replacement therapy with Aldurazyme provided stabilization and maintenance of the initial improvements seen in patients treated with Aldurazyme during the 26-week Double-Blind Study; comparable improvements were seen in patients treated with Aldurazyme during the Extension Study after an initial 26-week placebo period. The overall results of this 182-week extension study demonstrate that Aldurazyme is generally well tolerated and exerts a broad, and positive treatment effect on patients with MPS I who are treated with Aldurazyme over a long-term period.


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