ALID01703: A Multicenter, Multinational, Randomized, Dose-Optimization Study of the Safety and Pharmacodynamic Response of Aldurazyme^® (laronidase) in Patients With Mucopolysaccharidosis I (MPS I).

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, multinational study that enrolled patients at study centers in Canada and Brazil.

PUBLICATION (REFERENCE)

Publications

STUDIED PERIOD

28 December 2004 (first patient enrolled)
11 January 2006 (last patient completed)

PHASE OF DEVELOPMENT

Phase 4

OBJECTIVES

The primary objective of this study was to evaluate differences in the pharmacodynamic response of 4 Aldurazyme dose regimens in patients with Mucopolysaccharidosis I (MPS I). The pharmacodynamic response in the Aldurazyme regimens was assessed in terms of the percentage change from baseline to Week 26 in urinary glycosaminoglycan (GAG) levels.
The secondary objective of this study was to evaluate differences in the clinical status of patients with MPS I disease in response to the 4 Aldurazyme dose regimens. The clinical status of patients was assessed by evaluating differences between the dose regimens in the percentage change from baseline to Week 26 in liver volume, and the change from baseline to Week 26 in the absolute distance traveled (in meters) during the 6-minute walk test (6MWT).
The safety of treatment with Aldurazyme in MPS I patients was monitored in terms of the incidence of adverse events (AEs), physical examination findings, vital signs, clinical laboratory (chemistry, hematology, and urinalysis) measurements, and immunogenicity testing.

METHODOLOGY

This was a randomized, open-label, multicenter, multinational, dose-optimization study of patients with MPS I. After providing signed, written informed consent, patients subsequently underwent a baseline visit to assess eligibility and establish the baseline measurements of several clinical assessments. Patients had to satisfy all inclusion/exclusion criteria to be eligible to received treatment with Aldurazyme. Eligible patients were then randomized to 1 of 4 dose regimens according to a central randomization method. Randomization was stratified based on baseline urinary GAG levels. The 4 dosing regimens were as follows:
- 0.58 mg Aldurazyme/kg of body weight (100 U/kg) administered weekly (qw labeled dose);
- 1.2 mg Aldurazyme/kg of body weight (200 U/kg) administered qw;
- 1.2 mg Aldurazyme/kg of body weight (200 U/kg) administered every 2 weeks (q2w); and
- 1.8 mg Aldurazyme/kg of body weight (300 U/kg) administered q2w.
Patients received intravenous (IV) administration of Aldurazyme on a weekly (7 ± 3 days) or every-2-week (14 ± 3 days) basis for 26 consecutive weeks. Patients were to receive their first infusion within 4 weeks of the baseline visit. A minimum of 4 days was required between consecutive qw infusions and a minimum of 11 days was required between consecutive q2w infusions.
At selected study visits during the baseline and treatment phases, patients underwent a series of clinical evaluations including collection of a first morning void urine sample for determination of the urinary GAG level, computed tomography (CT) scans for liver volume quantification, and a 6MWT. Safety was monitored continuously throughout study participation.

NUMBER OF PATIENTS (PLANNED AND ANALYZED)

Thirty-two patients were planned (8 patients per dose regimen); 33 patients were analyzed for safety; 32 patients were analyzed for efficacy.
A total of 34 patients were randomized in the study, but 1 patient withdrew from the study prior to first infusion therefore this patient’s data were not included in the safety or efficacy analyses. Another patient discontinued from the study due to death after receiving 1 infusion with no follow-up study information collected; therefore this patient’s data were included in the safety analysis but not included in efficacy analysis.

DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION

Each patient had to meet the following criteria to be eligible for the study: (1) have a documented diagnosis of MPS I, confirmed by measurable clinical signs and symptoms of MPS I, and a documented fibroblast or leukocyte α-L-iduronidase enzyme activity level of < 10% of the lower limit of the normal range of the measuring laboratory; (2) weigh at least 12.5 kg; (3) have serum creatinine and blood urea nitrogen (BUN) values within age appropriate normal ranges; and (4) provide signed, written informed consent prior to any protocol-related procedures being performed.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

The 4 dose regimens of Aldurazyme® (laronidase) were as follows:
- 0.58 mg Aldurazyme/kg of body weight (100 U/kg) administered qw (labeled dose);
- 1.2 mg Aldurazyme/kg of body weight (200 U/kg) administered qw;
- 1.2 mg Aldurazyme/kg of body weight (200 U/kg) administered q2w; and
- 1.8 mg Aldurazyme/kg of body weight (300 U/kg) administered q2w.
For administration to patients in the 0.58 mg/kg or 1.2 mg/kg dose regimens, Aldurazyme was diluted with 0.1% human serum albumin in 0.9% sodium chloride to a final volume of either 100 mL (12.5-20 kg body weight) or 250 mL (21-100 kg body weight). For administration to patients in the 1.8 mg/kg dose regimen, Aldurazyme was diluted with 0.1% human serum albumin in 0.9% sodium chloride to a final volume of either 250 mL (12.5–20 kg body weight) or 500 mL (21–100 kg weight).
IV infusions were administered according to the same infusion-rate protocol either qw or q2w over approximately a 4-hour (0.58 and 1.2 mg/kg dose groups) or 5-hour (1.8 mg/kg dose group) period for 26 consecutive weeks.
All patients who received infusions were pretreated approximately 1 hour prior to infusion with an antipyretic and antihistamine.

DURATION OF TREATMENT

Patients were treated with Aldurazyme for 26 weeks.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

No reference therapy was used in this open-label study.

CRITERIA FOR EVALUATION
EFFICACY: To assess the pharmacodynamic response to Aldurazyme treatment (the percentage change in urinary GAG levels from baseline to Week 26), first morning void urine samples were collected from patients once during the baseline visit and prior to infusion on Weeks 1, 3, 7, 11, 15, 19, and 23. A first morning void urine sample was also collected from patients 1 week after receiving the last infusion (Week 27 for patients randomized to a qw infusion regimen and Week 26 for patients randomized to a q2w infusion regimen).

Secondary endpoints included assessing percentage changes from baseline to Week 26 in liver volume and absolute changes in the distance traveled (in meters) during the 6MWT (for patients who were old enough to perform the test). These assessments were performed at baseline, Week 11, and 1 week after receiving the last infusion (Week 26 for patients randomized to a q2w regimen and Week 27 for patients randomized to a qw regimen). Centrally read quantitative assessments of digital CT images were performed to determine the liver volume. For the 6MWT, patients were instructed to walk (unassisted) as far as possible in 6 minutes and told that they may rest at any time. The test was performed once at each assessment visit. During the test, patients were notified when the 2-minute and 4-minute timepoints had been reached. The distance (in meters) the patient was able to ambulate in the 6 minute period was recorded. Heart rate (beats/minute), respiratory rate (breaths/minute), and pulse oximetry (%) were measured and recorded for each patient immediately prior to the start, immediately after completion, and 2 minutes following the completion of the 6MWT.

SAFETY: Safety of treatment with Aldurazyme in MPS I patients was monitored continuously throughout study participation and was assessed in terms of the incidence of AEs, physical examination results, vital signs, clinical laboratory measurements (chemistry, hematology, and urinalysis), and immunogenicity testing.

STATISTICAL METHODS

“Baseline” was defined as the last measurement prior to first Aldurazyme infusion. Absolute changes and percentage changes from baseline to follow-up study weeks were calculated, as appropriate, with 95% confidence intervals (CIs) around the mean changes from baseline calculated.

For the analyses of changes/percentage changes from baseline to Week 26, the Week 26 timepoint refers to the study visit that was conducted 1 week after the last infusion (i.e., Week 27 for patients randomized to a qw infusion regimen and Week 26 for patients randomized to a q2w infusion regimen). Therefore, the Week 26 timepoint has been termed the “final visit.” Note that for the vital signs (excluding 6MWT assessments) and infusion-related variables, the Week 26 timepoint refers to Week 25 for patients randomized to a q2w regimen and Week 26 for patients randomized to a qw regimen.

The intention-to-treat (ITT) approach was used for all safety and efficacy variables in this study. The intent-to-treat (ITT) population was analyzed for safety and efficacy and included all randomized patients who received at least 1 Aldurazyme infusion. In addition, for the primary pharmacodynamic variable, a per-protocol (PP) analysis was performed and included data from patients who received at least 1 Aldurazyme infusion and who did not miss more than 3 consecutive qw or 2 consecutive q2w infusions during their participation in the study. For safety data, all randomized patients who received at least 1 Aldurazyme infusion are included in the summaries.

EFFICACY: For the analysis of efficacy, percentage changes from baseline to follow-up study weeks in urinary GAG levels, liver volume, and distance walked were each assessed by fitting repeated measures mixed-effects models.

SAFETY: Safety evaluation was assessed by clinical adverse events (AEs) and infusion-associated reactions (IARs), discontinuations due to AEs, drug-related AEs, severe AEs, and serious adverse events (SAEs), as well as changes in physical examinations, vital signs, clinical laboratory measurements (chemistry, hematology, and urinalysis), and immunogenicity results from baseline to follow-up study weeks.

SUMMARY / CONCLUSIONS

EFFICACY: Overall, there were 16 (47%) male and 18 (53%) female patients randomized in the study. The majority (62%) of patients were Caucasian. The mean age at enrollment for patients was 8.7 years. The distribution of demographics across the 4 treatment groups was generally similar. The initial diagnosis of MPS I was based on enzyme assay (74%), clinical presentation (18%), other methods (6%), or unknown methods (3%). The most frequent MPS I disease syndrome seen in patients was Hurler-Scheie (44%), followed by Hurler (26%) and Scheie (18%) syndromes. Mean urinary GAG levels at baseline were similar between groups, ranging from 353.08 to 471.40 µg/mg creatinine.

Overall, there was no consistent trend in efficacy response across treatment groups in the different endpoints; all 4 treatment groups generally had the same level of response after 26 weeks of treatment. Descriptive differences between groups were small, but tended to favor the higher dose groups over the labeled dose (0.58 mg/kg qw). The mean percent reduction in urinary GAG levels from baseline to the final visit was 57.57% in the 0.58 mg/kg qw group (labeled dose), 62.66% in the 1.8 mg/kg qw group, 66.15% in the 1.2 mg/kg q2w group, and 66.63% in the 1.2 mg/kg qw group. A non-statistically significant trend towards slightly greater urinary GAG reduction was observed among the 3 alternative dose regimes compared to the labeled dose; however, the study was not powered to detect such small differences in GAG reduction between groups. One patient in the 0.58 mg/kg group experienced a severe femur fracture at Week 11 assessed as unrelated to treatment, and a subsequent rise in urinary GAG levels. Excluding this patient, post-hoc analysis revealed that the mean percent reduction in urinary GAG level for the 0.58 mg/kg qw group was 62.8%, which is within the range of reduction of the 3 alternative dose groups (62.66% to 66.63%).

For each treatment group, there was a precipitous drop (mean: 65.50%) in urinary GAG levels between baseline and Week 7 followed by a plateau with only small changes until the final visit (mean reduction: 63.13%). The small mean increases seen in urinary GAG level after Week 7 in all 4 treatment groups may be related to IgG antibody formation since 31 of 32 patients were seropositive by Week 7 and there was an overall correlation between antibody titer and urinary GAG reduction.

Two patients (1 each from the 0.58 mg/kg qw and 1.2 mg/kg qw groups) had urinary GAG levels normalize by the final visit.

Overall, mean percent reduction in liver organ volume was 26.27% in the 0.58 mg/kg qw group, 30.67% in the 1.2 mg/kg qw group, 30.74% in the 1.2 mg/kg q2w group, and 32.14% in the 1.8 mg/kg q2w group. A non-statistically significant trend towards slightly greater percent reduction in liver organ volume was observed among the 3 alternative dose regiments compared to the labeled dose. However, statistically significant correlations were seen between baseline liver organ volume as a percent of body weight and percentage change in liver organ volume (absolute, p = 0.0121; as a percent of body weight, p = 0.0026). After excluding the only 2 patients with normal liver volumes at baseline (both in the 0.58 mg/kg group), post-hoc analysis showed that the mean percent reduction in liver organ volume in the 0.58 mg/kg qw group was 30.42%, essentially the same as what was observed in the 3 alternative dose groups.

There was a steep drop (mean: 26.13%) in liver organ volume seen from baseline to Week 11 in all 4 treatment groups, with further reductions seen at the final visit, where mean values were similar among all 4 treatment groups (overall mean reduction: 30.05%).

By the final visit, 16 of the 21 patients with abnormal baseline results had liver organ volumes normalize: 2 patients in the 0.58 mg/kg qw group, 4 patients in the 1.2 mg/kg qw group, and 5 patients each in the 1.2 mg/kg q2w and 1.8 mg/kg q2w groups.

The mean absolute change in 6MWT distance (m) from baseline to the final visit was -12.2 m in the 1.2 mg/kg qw group, 7.0 m in the 0.58 mg/kg qw group, 25.4 m in the 1.2 mg/kg q2w group, and 52.1 m in the 1.8 mg/kg qw group. There was no pattern of dose-response seen among the treatment groups; patients in the highest dose group (1.8 mg/kg q2w) showed the greatest increases in 6MWT distance (mean of 52.1 m), while patients who received the most Aldurazyme over the study period (1.2 mg/kg qw group) in fact showed a mean decrease of 12.17 m in 6MWT distance. In all 4 treatment groups at both Week 11 and the final visit assessments, however, patients showed both improvements and declines. In addition, 4 patients were exempt from the 6MWT at baseline, lending to even smaller patient numbers per group than in the other efficacy parameters. The variability of the 6MWT results coupled with small numbers of patients in each treatment group makes interpretation of the data very difficult. Statistical differences between groups were not found in the 6MWT.

Post-hoc analyses revealed no significant correlation seen between baseline 6MWT distance and absolute change in 6MWT distance.

Additional post-hoc analyses conducted to evaluate the effect of IgG antibody formation (titers) on the efficacy parameters revealed a statistically significant inverse correlation between IgG antibody formation and percent reduction in urinary GAG level (p = 0.0123); as the antibody titer increased, the percent reduction in urinary GAG level decreased. Patients with lower IgG antibody titers had more robust urinary GAG reduction, while patients with higher titers had less and more variable reduction. There was no significant impact of IgG antibody titers on the percentage change in liver organ volume (absolute and as a percent of body weight) or on the absolute change in 6MWT distance.

Safety Results: Aldurazyme was well-tolerated and had an acceptable safety profile when administered at the currently approved dose (0.58 mg/kg qw) and the 3 alternative dose regimens.

Thirty-two (97%) of the 33 patients treated with Aldurazyme completed the study. There was 1 discontinuation due to an AE (respiratory failure) that resulted in the patient’s death; the event was assessed by the Investigator as remote/unlikely related to study drug treatment and by the Sponsor as possibly related to study drug treatment. There were no other deaths or patient discontinuations. Overall, 6 (18%) of 33 patients experienced 8 SAEs during the study; in most cases, SAEs were unrelated to study drug treatment and patients recovered without sequelae.

All patients (100%) experienced at least 1 AE during the study, the vast majority (98.7%) of which were either mild (69.9%) or moderate (28.8%) in severity and attributable to expected symptoms of the underlying disease. Overall, the most commonly occurring (≥ 25%) AEs for all patients were pyrexia (61%), diarrhoea (58%), vomiting (45%), cough (39%),and abdominal pain, nasal congestion , nasopharyngitis, sinusitis and rhinitis (each 33%). Regardless of relationship, a greater number of AEs occurred in patients treated with the qw dose regimens compared to the q2w dose regimens; however, there did not appear to be a trend between dose regimen and the incidence of individual AEs.

Five (15%) patients experienced a total of 8 AEs assessed as severe; of these 8 severe AEs, 2 events (abasia and groin pain) experienced by a single patient were assessed by the Investigator as possibly related to study drug treatment, while 1 event (respiratory failure) was assessed by the Investigator as unrelated to study drug treatment, but by the Sponsor as possibly related. The majority (81.8%) of AEs experienced during the study were assessed as unrelated to study drug treatment. Drug-related AEs (defined as those AEs assessed by the Investigator as possibly, probably or definitely related to study drug treatment) were experienced by 20 (61%) of 33 patients during the study: 3 patients in the 0.58 mg/kg qw group, 6 patients in the 1.2 mg/kg qw group, 5 patients in the 1.2 mg/kg q2w group, and 6 patients in the 1.8 q2w group. The most frequently reported (> 10%) drug-related AEs in the total population included pyrexia (21%), platelet count decreased (15%), rash (15%), vomiting (15%), and urticaria (12%). Overall, there appeared to be a relationship between both dose and frequency with the occurrence of drug-related events.

The majority of the related events (68%) were characterized as IARs. Overall, 13 (39%) of 33 patients experienced IARs at some point during treatment. The most commonly reported IARs in the total population included pyrexia (21%), vomiting (15%), rash (15%), and urticaria (12%); all other IARs occurred in ≤ 6% of patients (2 patients). Overall, there appeared to be a trend in patients who received higher amounts of Aldurazyme over a 2-week period (1.2 mg/kg qw and 1.8 mg/kg q2w groups) experiencing a greater number of IARs. This may be attributable to the higher overall protein load that these patients were exposed to as compared to the currently approved dose (0.58 mg/kg qw).

Thirty-two (97%) of 33 patients had IgG antibodies to rhIDU detected by ELISA and confirmed by radioimmunoprecipitation (RIP) assay during the study; the single patient who did not seroconvert was the patient who discontinued the study after only receiving 1 Aldurazyme infusion. It should be noted that 3 patients were seropositive at baseline, suggestive of pre-existing cross-reactivity. The mean time to seroconversion was 31.8 days (range 13 to 70 days) for all patients in this study. Time to seroconversion was earlier for patients treated with a qw infusion regimen, i.e., in the 0.58 mg/kg qw and 1.2 mg/kg qw groups, patients seroconverted after a mean of 28.1 and 30.9 days from first infusion, respectively, while patients in the 1.2 mg/kg q2w and 1.8 mg/kg q2w groups seroconverted after a mean of 33.1 and 34.7 days, respectively. Antibody titers generally approached peak levels by Week 7 and plateaued through the remainder of the study. The antibody profiles were similar between different dose regimens except for slightly faster seroconversion in the qw dose regimens as compared to the q2w dose regimens. This may be due to the greater number of infusions received with qw dosing versus q2w dosing. No patients tolerized during the study, which was not unexpected considering the short duration of the study. The first onset of IARs typically coincided with the formation of IgG antibodies to laronidase. Despite the fact that patients remained seropositive without reduction in antibody titers, the frequency of patients who experienced IARs decreased over time as did the number of unique IAR symptoms experienced with infusions during which IARs occurred.

Nine patients were tested for rhIDU-specific IgE antibodies, complement activation, and serum tryptase during the study. All 9 patients tested negative for IgE antibodies. Eight of the 9 patients tested positive for complement activation. Serum tryptase values were within the reference range (< 14.7 µg/L) for all but 1 patient. The slight elevation of serum tryptase was not considered clinically meaningful given that an IgE antibodies sample drawn per protocol 3 days following the reaction tested negative. None of the patients developed clinical manifestation of immune complex disease. No patients had skin testing performed.

Changes in safety laboratory parameters, vital signs, and physical examination findings during the study were generally consistent with the underlying disease or evolving clinical status of MPS I patients. There were no sustained clinically meaningful serum chemistry findings or significant shifts to abnormal in any treatment group over the course of treatment. Changes in hematology parameters were generally transient in nature.

The safety data from this study suggest that Aldurazyme infusions are well-tolerated at the currently approved dose regimen (0.58 mg/kg qw), and only slightly scattered differences in the safety profile were seen in the higher doses. The presence of IgG antibodies did not appear to have an effect on overall safety.

Conclusion: The results of this study confirm that the labeled dose regimen of Aldurazyme (0.58 mg/kg qw) is the most appropriate treatment regimen for patients with MPS I. There were no statistically significant differences in efficacy between the labeled dose regimen and the 3 alternative dose regimens. Although all dose regimens were well-tolerated, the labeled dose regimen was associated with fewer drug-related AEs and similar or fewer IARs than the alternative regimens. Antibody formation was similar between the different groups. The presence of antibodies did not appear to have an effect on overall safety, although lower antibody titers were associated with more robust urinary GAG reductions, while patients with higher titers had less and more variable reductions.

COMMENTS

The results of this dose optimization study suggest that higher dosing regimens (up to twice the currently approved dose) may be slightly better at reducing substrate in select patients, but they do not produce significantly higher overall substrate clearance. Data from the current study demonstrate that the labeled dose (0.58 mg/kg qw) provides a near maximal treatment effect. Doubling the dose (1.2 mg/kg) at half the frequency (q2w) appeared to provide similar urinary GAG reduction as in the labeled qw dose in this short-term study, and may be a possible regimen for patients who have difficulty receiving qw infusions. The safety profile for the 1.2 mg/kg q2w regimen also indicates a similar risk-benefit profile to the labeled dose (0.58 mg/kg qw).

The optimal dose should deliver adequate amounts of enzyme to as many clinically relevant tissues as possible. Since the liver and kidney are more readily exposed to saturating levels of Aldurazyme and respond more quickly than the joints, they may still show a maximal treatment effect with a lower dose. Conversely, enzyme diffusion into the joints and peripheral tissues is more difficult, leading to less enzyme exposure and a lower response; moreover, it could require months or years of enzyme replacement therapy before achieving maximal therapeutic effect for these parameters. The heterogeneity of patients in their age, phenotype, time from symptom to treatment, etc., makes any attempt to predict such a time of achieving optimal therapeutic effect almost impossible. Lowering the dose further is not likely to benefit patients as the labeled dose provides a near maximal therapeutic effect.