Protocol AGLU01702: An Open-Label, Multicenter, Multinational, Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Acid alpha-Glucosidase (rhGAA) Treatment in Patients > 6 and ≤ 36 Months Old with Infantile-Onset Pompe Disease (Glycogen Storage Disease Type II)

Myozyme^® (Alglucosidase alfa)

Drug Name	Generic Name	Studied Indications or Disease	Approved U.S. Drug Label
Myozyme®	Alglucosidase alfa	LSD Therapeutics Myozyme® (alglucosidase alfa) is indicated for use in patients with Pompe disease (GAA deficiency). Myozyme® has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to an untreated historical control, whereas use of Myozyme® in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy	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

Genzyme Corporation, 500 Kendall Street, Cambridge, MA 02142

INVESTIGATORS AND STUDY CENTER(S)

This was a multicenter trial that was initially conducted at six primary investigational study centers in the United States, Europe, and Israel. After a minimum of 26 weeks of treatment patients could be transferred, after consultation between the Sponsor and the Investigator, to regional investigational sites for continuing treatments for the remainder of the study. Eight sites were added as a result of transfers to regional investigational sites during the study period.

PUBLICATION (REFERENCE)

Publications

STUDIED PERIOD

AGLU01702 is a study conducted in 52-week modules. This report describes methods and results for the following time periods:
Safety and efficacy during the first 52 weeks of treatment for the first 15 treated patients;
Efficacy data on 6 additional treated patients to Week 12; and
Safety data to data cut-off (3 September 2004) for all patients treated during AGLU01702 (N=21).

PHASE OF DEVELOPMENT

Phase 1 / 2

OBJECTIVES

The overall objective of this study was to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of Myozyme® treatment in patients with infantile-onset Pompe disease.

The primary objectives of the study were: (1) to evaluate the safety profile of Myozyme; (2) to determine the proportion of patients who were alive over the course of treatment; (3) to determine the PK profile of Myozyme® in patients with infantile-onset Pompe disease as measured by Myozyme® concentration in plasma and acid alpha-glucosidase (GAA) activity in skeletal muscle tissue as measured by biochemical assessment; and (4) to determine the PD of Myozyme® in patients with infantile-onset Pompe disease by evaluating the effect of treatment on glycogen depletion in skeletal muscle tissue as measured by histological and biochemical assessment. PK analyses in muscle tissue were not performed.

Secondary objectives were to determine (1) the effect on respiratory function, measured as follows: (a) for patients who were ventilator-free at the onset of the study, the proportion of patients who were alive and ventilator-free over the course of treatment and the ventilator-free survival time; (b) for patients who required ventilator use at the onset of the study, the overall duration of ventilator support and the number of hours of ventilator use (in the 24 hours preceding each infusion visit measured every other week [qow]); (2) the effect of treatment on cardiac status as measured by the change in left ventricular mass index (LVMI) and any presence of signs and/or symptoms of cardiac failure; and (3) the effect of treatment on motor development from Baseline as measured by Alberta Infant Motor Scale (AIMS) and/or Peabody Developmental Motor Scale-2 (PDMS-2) scores, and the patient’s ability to achieve and maintain clinically relevant motor development milestones.

Other objectives included evaluation of the effect of treatment on (1) cognitive development from Baseline as measured by the Mental Development Index (MDI) of the Bayley Scales of Infant Development II (BSID-II) and/or the Brief Intelligence Quotient (IQ) score from the Leiter International Performance Scale – Revised (Leiter-R); (2) physical growth as measured by body length, weight, and head circumference; (3) change in functional status from Baseline as measured by the Pediatric Evaluation of Disability Inventory (PEDI); and (4) change in functional status from Baseline as measured by the Pompe PEDI.

METHODOLOGY

This is an open-label, multicenter, multinational, study of patients with infantile-onset Pompe disease. The initial protocol was amended 5 times, and the first patient was enrolled under protocol Amendment 1. At the time of this interim analysis, Amendment 5 to the protocol had not been implemented at the study sites; therefore the interim analysis was conducted and evaluated as described in Amendment 4.

Protocol AGLU01702 was designed to enroll up to 20 patients with infantile-onset Pompe disease to receive intravenous (IV) infusions of Myozyme® at doses of 20 mg/kg qow to 40 mg/kg qow for 52 weeks and included the option of continuation in repeating 52-week maintenance modules pending successful completion of the first 52 weeks of treatment. However, in order to assess preliminary efficacy, the protocol specified that interim analyses of all data be performed after the 15th patient completed 52 weeks of treatment. The date of data cut-off was, therefore, defined to be 3 September 2004. At the time of data cut-off, the first 15 patients treated had received between 52 and 76 weeks of treatment with Myozyme. An additional 6 patients had received between 14 and 28 weeks of treatment with Myozyme.

This report describes methods and results for the following time periods:
Safety and efficacy during the first 52 weeks of treatment for the first 15 treated patients;
Efficacy data on 6 additional treated patients to Week 12; and
Safety data to data cut-off for all patients treated during AGLU01702 (N=21).

A final analysis and report will describe all data from all 21 patients who were treated in the study.

Protocol AGLU01702 was designed to enroll up to 20 patients with infantile-onset Pompe disease. A total of 22 patients were enrolled. At the time of data cut-off for the 26-week interim analysis, 21 patients had been enrolled. The first patient enrolled in the study died prior to administration of study drug and was, therefore, replaced. With only 1 slot remaining for enrollment in the study, 2 patients presented over a very short period of time. Due to the severity of infantile-onset Pompe disease, and because the timing was so close, the decision was made to expand the enrollment to include both patients. This brought the total number of patients enrolled to 22 and the number of patients treated to 21.

After the first 4 enrolled patients completed their first 2 infusions of 20 mg/kg qow Myozyme, and before any additional patients received treatment, available safety data were reviewed by Genzyme Pharmacovigilance and an independent Data Safety Monitoring Board (DSMB) for any safety-related issues. A review of available safety data was also performed after the eighth patient had received a total of 2 infusions. As neither review revealed any significant safety concerns, an additional 13 patients were enrolled and treated with 20 mg/kg qow Myozyme® for 26 weeks. Following 26 weeks of treatment, dose augmentation requests were reviewed by the Genzyme Medical Monitor to determine whether criteria for dose augmentation (described below) were met. Per protocol, after 3 patients received 2 infusions at the increased dose (up to 40 mg/kg qow), all available safety data on these patients were to be reviewed by Genzyme and the DSMB for any safety-related issues. Although planned, this review did not occur.

Additional clinical studies had begun in which Myozyme® is administered at a dose of 40 mg/kg qow, and review of preliminary data by both the Sponsor and the DSMB had shown that the 40 mg/kg qow dose was also well tolerated. Any emergent safety issues related to patients who undergo dose augmentation would be reviewed by Genzyme Pharmacovigilance and forwarded to the DSMB, if deemed necessary by the Medical Affairs (Pharmacovigilance) Officer, or designee.

Safety, PK, and PD assessments and efficacy evaluations are being performed at scheduled visits throughout the study, while adverse events (AEs) and concomitant medications/therapies are monitored continuously. In addition, throughout the conduct of this study, an independent DSMB reviews safety information as outlined in the DSMB Charter. Moreover, an independent Allergic Reaction Review Board (ARRB) is consulted as needed for evaluation of moderate or severe infusion-associated reactions (IARs) as outlined in the ARRB Charter.

Patients began treatment under an initial 52-week treatment module. As patients complete the treatment module, they will be transitioned to a 52-week maintenance module. This maintenance module may be repeated (if there are no patient safety concerns) until the study is terminated or until market approval, whichever occurs first.

NUMBER OF PATIENTS (PLANNED AND ANALYZED)

Planned: Up to 20 patients with infantile-onset Pompe disease will be treated with Myozyme.

Actual: As noted above, 22 patients have been enrolled, as a result of 2 patients being screened simultaneously for the final place in the study, and 21 patients have been treated. One patient died during the Baseline period, prior to any treatment. At the time of data cut-off for the 26-week interim analysis, 21 patients had been enrolled.

Enrolled and Analyzed in this Interim Report: A cohort of 15 patients completing 52 weeks of study were analyzed as 1 population; data from a second cohort of all 21 treated patients were analyzed.

DIAGNOSIS AND MAIN ELIGIBILITY CRITERIA

Inclusion:

Patients who met all of the following inclusion criteria were eligible to participate in this study:

Patient’s legal guardian(s) provided written informed consent prior to any study-related procedures being performed;

Patient had a clinical diagnosis of infantile Pompe disease as defined by both: (a) Documented (in a medical record) onset of symptoms compatible with Pompe disease by 12 months-of-age adjusted for gestation, if necessary (gestational age of <40 weeks was adjusted to a full term gestational age of 40 weeks); AND (b) Documented GAA deficiency);

Patient was >6 and ≤ 36 months-of-age, adjusted for gestation (gestational age of <40 weeks was adjusted to a full term gestational age of 40 weeks) at the time of the first dose of Myozyme;

Patients ≤ 12 months-of-age had LVMI ≥ 65 g/m2; patients >12 months-of-age had LVMI >79 g/m2.

LVMI was determined by a study site cardiologist using 2D echocardiography. Age specific LVMIs were equivalent to mean LVMI plus 2 standard deviations (SDs) as published by Vogel (Vogel, 1991, Pediatr Cardiol);

Patient and his/her legal guardian(s) must have had the ability to comply with the clinical protocol.

Exclusion:

Patients were excluded from this study if they did not meet the specific inclusion criteria, or if the patient met any of the following criteria:

Signs and symptoms of cardiac failure and an ejection fraction <40 % as determined by a study site cardiologist;

Major congenital abnormality;

Clinically significant (CS) organic disease (with the exception of symptoms relating to Pompe disease), including CS cardiovascular, hepatic, pulmonary, neurologic, or renal disease, or other medical condition, serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, precluded participation in the trial or potentially decreased survival;

Use of any investigational product within 30 days prior to study enrollment; received enzyme replacement therapy (ERT) with GAA from any source.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

Myozyme® is administered by IV infusion at 20 mg/kg or 40 mg/kg qow.

DURATION OF TREATMENT

Interim analysis: 52 weeks planned, actual 17 March 2003 to 3 September 2004. Patients received a minimum of 1 infusion and a maximum of 76 weeks of treatment with Myozyme.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

There was no comparator treatment or placebo in this study given the universal fatality of untreated infantile-onset patients and the lack of any approved treatment.

CRITERIA FOR EVALUATION

Criteria for Evaluation – Efficacy
The primary efficacy endpoint is measured by the proportion of patients who are alive over the course of treatment.

Secondary efficacy is evaluated by (1) the effect on respiratory function, measured as follows: (a) for patients who were ventilator-free at the onset of the study, the proportion of patients who are alive and ventilator-free over the course of treatment and the ventilator-free survival time; (b) for patients who required ventilator use at the onset of the study, the overall duration of ventilator support and the number of hours of ventilator use (in the 24 hours preceding each infusion visit, measured qow); (2) the effect of treatment on cardiac status as measured by LVMI, and presence of any signs and/or symptoms of cardiac failure; (3) the effect of treatment on motor development as measured by the AIMS and/or PDMS-2, and the patient’s ability to achieve and maintain clinically relevant motor milestones.

Additional efficacy outcomes included the effect of treatment on: (1) cognitive development from Baseline as measured by the MDI of the BSID-II; (2) physical growth by body length, weight, and head circumference; (3) change in functional status from Baseline as measured by the PEDI; and (4) change in functional status from Baseline as measured by the Pompe PEDI.

Criteria for Evaluation – Pharmacokinetics and Pharmacodynamics
PK and PD evaluations are conducted in all patients. PK in plasma was evaluated by measuring GAA activity in plasma at time points before and after Myozyme® infusions at Day 0 and Week 12. PD in tissue is evaluated in muscle biopsy samples taken at Baseline and 48 hours after the infusions at Weeks 12 and 52; biochemical assessment of GAA activity, and biochemical and histological assessment of glycogen in quadriceps muscles is performed.

Criteria for Evaluation - Safety
Safety is evaluated in terms of AEs, vital sign parameters, physical examination findings, hearing testing, electrocardiogram (ECG) parameters, and routine laboratory measurements (hematology, chemistry, and urinalysis) including anti-rhGAA immunoglobulin G (IgG) antibody monitoring

STATISTICAL METHODS

To assess preliminary efficacy, this interim analysis was performed after the 15th treated patient completed 52 weeks of treatment. Some efficacy data are available for 6 additional treated patients to Week 12; safety results are presented for the first 15 treated patients and for all treated patients (N=21) until 3 September 2004. A final analysis will be conducted on all 21 treated patients.

Patient disposition and accountability, demography, background and Baseline characteristics, and efficacy and safety results were listed and summarized where appropriate. Categorical variables were summarized by frequency tables, while continuous variables were summarized using descriptive statistics including the sample size (n), median, mean, SD, minimum, and maximum. Missing or invalid observations were not estimated or replaced.

The following analyses were prospectively defined in the Statistical Analysis Plan for the overall study and have been conducted on all patients in the cohort of the first 15 patients who received Myozyme® in this study and, when possible, on any available data from more recently enrolled patients.

Statistical Methods - Safety
The incidence of AEs was summarized by severity, treatment relationship, and outcome. AEs, SAEs, vital signs, physical examination findings, hearing testing, and ECG assessments were summarized through tables and listings. The analysis of clinical laboratory measurements was based on the frequencies of abnormal values and frequencies of CS abnormal values. Changes in other safety variables, including anti-rhGAA antibody development (IgG), IgE antibody, serum tryptase activity, complement activation, and circulating immune complex detection (if applicable), were summarized using descriptive statistics.

Statistical Methods - Efficacy
Primary Efficacy: The number and proportion of patients alive over the course of treatment was summarized. Exact 95% confidence intervals were constructed around the proportion assuming a binomial distribution. The primary analysis considered noncompleters as failures. Patients who died or withdrew from the study prematurely were treated as failures. Kaplan-Meier plots of the survival time from birth, survival time from first symptoms, survival time from confirmed diagnosis, and survival time from treatment initiation have been prepared.

Secondary Efficacy: The effect of treatment on respiratory function was evaluated by:

For patients who were ventilator-free at the onset of the study, the proportion of patients alive and ventilator-free for at least 14 consecutive days bracketing the target time points – Weeks 26 and 52. If the Investigator determined the patient was ventilator-dependent due to secondary causes only (e.g., aspiration, pneumonia) at the target time points, the patient was followed for up to an additional 30 days. If the patient became ventilator-free for at least 14 consecutive days during this additional 30-day period, he/she was considered as ventilator free;

The ventilator-free survival time from birth to Weeks 26 and 52 was analyzed by evaluating the time to ventilator use or death as well as the overall time and the proportion of time that a patient was alive and not on ventilatory support throughout the study treatment.

The overall duration of ventilator support and the number of hours of ventilator use in the 24 hours preceding each infusion visit were summarized; the number of hours was collected from the time of first ventilator use and qow thereafter (if applicable) until (a) ventilator support was no longer needed; (b) patient died; or (c) for the purposes of this interim analysis, Week 52, whichever came first. The reason for ventilator use was provided through listings and summaries.

The effect of treatment on cardiac status was evaluated by changes in LVMIs and left ventricular mass (LVM) Z-scores from Baseline at Weeks 26 and 52. Measurements were also compared to values from normal peers (Colan, 2004; Colan, 1992, J Am Coll Cardiol). The presence of signs and/or symptoms of cardiac failure was also taliied. The proportion of patients who had an onset of cardiac failure signs and/or symptoms was summarized. Any presence of cardiac failure signs and/or symptoms was summarized at Baseline and at Weeks 26 and 52 through tables and listings.

The effect of treatment on motor development was evaluated by AIMS scores (for patients ≤ 18 months-of-age and for those patients who had not reached the ceiling of the AIMS if they were >18 months-of-age) or PDMS-2 (for patients >18 months-of-age), and achievement and maintenance of clinically relevant motor development milestones. Changes from Baseline to Week 26 and 52 in AIMS and PDMS-2 scores were summarized through tables, listings, and figures. The total number of clinically relevant motor development milestones achieved and/or maintained was summarized descriptively.

Other Efficacy: Other efficacy outcomes analyzed include the effect of treatment on cognitive development indices (MDI of the BSID-II and/or the Brief IQ score of the Leiter-R). Standardized age and gender-adjusted measurements (i.e., length, weight, and head circumference), with reference to the Centers for Disease Control and Prevention (CDC) growth curves, were analyzed and summarized descriptively. Changes from Baseline in functional status domain scores of the PEDI and the Pompe PEDI were evaluated. All of these endpoints were evaluated at Baseline, Week 26, and Week 52.

Statistical methods – Pharmacokinetics and Pharmacodynamics
The following PK parameters were estimated from the plasma Myozyme® concentration-time data at Day 0 and Week 12, whenever possible: observed peak drug concentration (Cmax); observed time to reach peak drug concentration (Tmax); area under the concentration versus time curve from time=0 to time of last quantifiable concentration (AUC(0-t)); area under the plasma concentration-time curve from 0 to infinity (AUC∞); clearance (CL); volume of distribution during terminal phase after IV administration (Vz); volume of distribution at steady-state (Vss); and terminal half-life (t1/2). The primary PD parameter evaluation was the difference in skeletal muscle glycogen content after Baseline, 12 weeks of treatment, and 52 weeks of treatment. Results were summarized descriptively. Changes (absolute and percent change) in glycogen content and GAA activity in muscle biopsy samples from Baseline were summarized. The number and proportion of patients with a decrease in glycogen content and those patients with increased tissue GAA activity over time was summarized.

SUMMARY / CONCLUSIONS

All enrolled patients had a confirmed diagnosis of infantile-onset Pompe disease. None of the 21 treated patients were diagnosed prenatally. The majority of patients in this international population (N=21) were Caucasian. Neither gender predominated, and the most common ages for patients to begin Myozyme® treatment were between 6 and 24 months-of-age. The median age at first symptoms was 3.0 months, and the median age at diagnosis was 6.8 months. About one-third of the patients were ventilated (invasively or noninvasively) at treatment initiation, and 3 patients were CRIM-negative. At Baseline, mean GAA activity in skin fibroblasts in all patients was <1%.

Summary / Conclusions – Efficacy
Twenty-two patients were enrolled under Protocol AGLU01702 and 21 received treatment. One patient died prior to receiving treatment. Efficacy results and conclusions reflect results from 15 patients treated for 52 weeks. After 52 weeks of treatment with Myozyme, 11 of 15 patients (73%) were alive. None of the deaths were assessed as treatment-related. One patient, who was among the 6 additional treated patients, also died. Twelve-month survival rates, stratified by age at first infusion were compared to estimated conditional survival rates for reference groups derived from an AGLU01702 Historical Reference Subgroup. In every category, survival rates for patients treated with Myozyme® were greater than the corresponding upper limit of the 95% CIs of the untreated reference groups, which suggests that treatment with Myozyme® is extending survival in these patients Eighty-seven percent of patients demonstrated a reduction in LVMI from Baseline to last evaluation.

LVMI at Baseline declined by an average of 43% at Week 26 and 48% at Week 52. Echocardiographic measurements of cardiac function (EF and SF) demonstrated a trend toward normalization through the 52-week treatment period. Mean improvements of 33% and 19% in EF and SF, respectively, were observed after 52 weeks of treatment.

Maintenance or improvement was seen in 80% of patients in weight-for-age percentiles; in 93% of patients in length-for-age percentiles; and 92% of patients in head circumference-for-age percentiles. Six of 15 patients (40%) had measurable gains in motor assessments (AIMS and/or PDMS-2 gross and fine motor skills), as determined by increases in raw scores and age-equivalent scores from Baseline to last assessment. The remaining patients did not demonstrate measurable gains across these motor assessments. All patients with repeat evaluations (n=13, 100%) had gains in BSID-II Mental Scale age-equivalent scores from Baseline to the last study assessment, indicating the continued acquisition of cognitive, language, and personal/social development skills.

In summary, in spite of the wide range of ages at initiation of treatment and the advanced stage of the disease progression at Baseline, these results from administration of Myozyme® to patients with infantile-onset Pompe disease indicate that Myozyme® treatment tended to prolong patient survival. Marked improvement in cardiomyopathy parameters occurred, and gains in growth and cognitive parameters were observed. A subgroup of 6 patients showed improvement in motor function. Initiation of Myozyme® therapy at an early age, prior to irreversible muscle tissue damage, may optimize clinical response.

Summary / Conclusions – Safety Results
Treatment with Myozyme® was generally well tolerated by the 21 patients who were treated for up to 76 weeks in this study. Five patients died during the treatment period (a sixth died during the Baseline period, prior to receiving therapy). None of the deaths were related to treatment with Myozyme. The data summarized below come from all 21 treated patients to 3 September 2004 (data cut-off).

The majority of treatment-emergent AEs were assessed as unrelated to Myozyme. Most were mild or moderate in intensity; 36 (5.7%) AEs were reported as severe. Thirty-three (5.2%) of the 636 treatment emergent events were assessed related to Myozyme® treatment. All related events occurred on the day of infusion; 28 (4.4%) AEs were assessed as IARs. IARs were generally well tolerated and were managed with infusion rate reduction or interruption, as well as with treatment with antihistamines, antipyretics, and/or steroids. In all instances, patients recovered without sequelae from the IARs. Only 1 patient received steroids as treatment for an IAR; this patient was also pre-treated with steroids before subsequent infusions. Two patients were pre-treated with antihistamines and/or antipyretics. There were no patient discontinuations due to IARs.

A total of 76 treatment-emergent SAEs were experienced by 15 of the 21 patients; 62% of these events were mild or moderate in intensity. The majority of SAEs were infectious or respiratory in nature; the most frequently occurring SAEs by Medical Dictionary for Regulatory Activities (MedDRA) preferred term were respiratory failure, respiratory distress, pneumonia, pyrexia, acute bronchitis, catheter-related infection, and upper respiratory tract infection. Pompe disease is often associated with compromised respiratory status. Therefore, it is not unexpected that these patients are frequently hospitalized for recurrent respiratory infections and associated pulmonary complications.

Seven (33%) of 21 patients had experienced at least 1 IAR by 3 September 2004. Per protocol, IgE antibodies, complement activation, and serum tryptase activity were assessed in the event of a moderate or severe IAR. Three patients who experienced moderate IARs were tested and a fourth with mild IARs was tested at the Investigator’s request. None of the patients tested IgE positive, and serum tryptase levels were within normal limits. Two patients tested positive for complement activation.

Nineteen of 20 treated patients with post-Baseline measurements developed IgG antibodies to Myozyme. One patient was seropositive at Baseline, suggestive of pre-existing cross-reactivity. Seventeen of the remaining 18 patients seroconverted between Week 4 and Week 12. The 1 remaining patient seroconverted by Week 38. As the majority of patients developed anti-Myozyme® antibodies, meaningful assessment of AEs based upon seroconversion status is not possible. No significant inhibitory antibody activity was detected in the any of the patients.

Additionally, circulating immune complexes could be assessed when evidence of immune complex disease was noted. No patients experienced clinical manifestations of immune complex disease, and laboratory data did not reveal any evidence of sustained CS abnormalities suggestive of immune complex formation. During the period covered by this interim report, no patients were assessed for circulating immune complexes.

Changes in laboratory parameters, physical examination, and 12-lead ECG findings observed during the conduct of this study were generally consistent with the evolving clinical status of the 21 treated patients. Based on OAE screening tests at Baseline, 4 of 8 patients tested had bilateral abnormal hearing, 2 patients had unilateral abnormal hearing, and 2 patients had bilateral normal hearing. Flat OAE and/or abnormal wave latencies in BAER suggested that, at least in some patients, there was inner ear and/or auditory nervous system involvement contributing to abnormal hearing test results. A review of the literature suggests that hearing loss has been commonly observed in patients with glycogen storage disorders (Galton, 1976, Acta Paediatr Scand.; Jurecka, 1985, Arch Dermatol), including Pompe disease (Kamphoven, 2004, Neurobiol Dis). A study in a knockout mouse model of Pompe disease revealed that hearing loss is most likely caused by cochlear pathology due to glycogen accumulation (Kamphoven, 2004, Neurobiol Dis). These data strongly suggest that hearing loss in patients with Pompe disease is related to the disease itself and is not a complication of therapy.

CONCLUSION

Treatment with Myozyme® was generally well tolerated by the 21 patients who were treated in this study. Five patients died during the treatment period and a sixth died during the Baseline period, prior to receiving therapy. None of the deaths were assessed as related to treatment with Myozyme. Fifteen of 21 patients experienced SAEs; the majority were mild or moderate in intensity, respiratory or infectious in nature, and assessed as unrelated to treatment. Relatively few AEs (5.2%) were assessed as related to treatment, and many (84.5%) of related AEs were classified by the Investigators as IARs. Seven (33%) of 21 patients experienced IARs, which were effectively managed with 1) infusion rate reduction or interruption and/or 2) treatment with antipyretics, antihistamines, and/or steroids. In some instances, pre-treatment was required. No patients discontinued treatment due to IARs.

In spite of the wide range of ages at initiation of treatment and the advanced stage of the disease progression at Baseline, these preliminary results from administration of Myozyme® to patients with infantile-onset Pompe disease indicate that Myozyme® treatment tended to prolong patient survival.

Marked improvement in cardiomyopathy parameters occurred and gains in growth and cognitive parameters were observed. A subgroup of 6 patients with preservation of muscle function at Baseline showed improvement in motor function. Initiation of Myozyme® therapy at an early age, prior to irreversible muscle tissue damage, or at higher doses may optimize the clinical response.