Protocol AGLU02804: A Single Center, Open-Label, Bridging Study of the Safety, Pharmacokinetics and Efficacy of Recombinant Human Acid Alpha-Glucosidase (rhGAA) Treatment in Patients with Late-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)

Dr. A. van der Ploeg
Sophia Children’s Hospital, Rotterdam, The Netherlands

PUBLICATION (REFERENCE)

Publications

STUDIED PERIOD

This report describes the first 26 weeks (14 infusions) of treatment. The first patient received the first infusion on 02 February 2005 and the last patient completed the Week 26 visit on 17 August 2005.

PHASE OF DEVELOPMENT

Phase 2

OBJECTIVES

The objectives of this study in late-onset Pompe patients are: (1) To evaluate the safety profile of rhGAA; (2) To determine the pharmacokinetic (PK) profile of rhGAA; (3) To determine the effect of treatment on pulmonary function as measured by Forced Vital Capacity (FVC) in the upright (sitting) and supine positions; (4) To determine the effect of treatment on muscle strength as measured by Manual Muscle Testing (MMT) and handheld dynamometry (HHD); (5) To determine the effect of treatment on muscle function as measured by the distance walked in either the 6-minute walk test (6MWT) or the 3-minute walk test (3MWT), the time to perform a 10-meter walk test, and the time to stand up from a supine position; (6) To determine the effect of treatment on cardiovascular endurance as measured by the energy expenditure index (EEI) during the 6MWT or 3MWT.

METHODOLOGY

This is a single center, open-label study of rhGAA in patients with late-onset Pompe disease. Eligible patients received an intravenous (IV) infusion of 20 mg/kg of rhGAA once every 2 weeks (qow) for 26 weeks. If there were no safety concerns, a 24-week treatment module was to be repeated successively according to Amendment 1 until the study is terminated or until reimbursement of rhGAA, whichever occurs first. An interim analysis was conducted after all patients completed the Week 12 assessments.

Safety, PK and efficacy assessments are performed at scheduled visits throughout the study. Adverse events (AEs), infusion associated reactions (IARs), concomitant medications and therapies including use of assistive devices are monitored continuously throughout the study.

An independent Data Safety Monitoring Board (DSMB) reviews safety information regularly and on an ad hoc basis as outlined in the DSMB charter, which is maintained separately from the study protocol.

An independent Allergic Reaction Review Board (ARRB) is consulted on an ad hoc basis as outlined in the ARRB charter, which is also maintained separately from the protocol.

NUMBER OF PATIENTS (PLANNED AND ANALYZED)

Five patients ≥ 5 and <18 years old with late-onset Pompe disease were planned, enrolled, and analyzed.

DIAGNOSIS AND MAIN ELIGIBILITY CRITERIA

Inclusion:

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

The patient’s legally authorized guardian(s) provided written informed consent prior to performing any study-related procedures. If the patient understood the written informed consent form, signature was required from both the patient and the legally authorized guardian(s);

The patient had a confirmation of diagnosis of Pompe disease by documentation of either acid α-glucosidase (GAA) gene mutation analysis or deficient endogenous GAA activity as determined by the assaying laboratory; The patient had demonstrable muscle weakness as measured by MMT;

The patient was ≥ 5 and <18 years of age;

The patient was able to provide 3 reproducible FVC measurements (values within 5% of each other) in the upright (sitting) position;

The patient was able to perform pulmonary and muscle function testing in the supine position;

The patient was able to ambulate 10 meters (use of assistive devices such as a walker, cane, crutches, was permitted);

The patient (and legal guardian) had the ability to comply with the clinical protocol.

Exclusion:

Subjects who met any of the following exclusion criteria were not eligible for participation in this study:

The patient required the use of invasive ventilatory support (invasive ventilation was defined as any form of ventilatory support applied with the use of an endotracheal tube; a decannulated sealed stoma was acceptable.);

The patient required the use of non-invasive ventilatory support whilst awake and in an upright position. (Non-invasive ventilation was defined as any form of ventilatory support applied without the use of an endotracheal tube.);

The patient had received enzyme replacement therapy (ERT) with GAA from any source;

The patient had received an investigational drug or device within 30 days prior to study enrolment, or was currently participating in another clinical or observational study;

The patient had a medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities;

For female patients of child bearing potential only, the patient was pregnant or lactating, or was unwilling to practice birth control methods during the course of the study, such as abstinence, barrier methods, hormonal methods (oral contraceptives or injectable), or use of intrauterine devices;

For male patients only, the patient was unwilling to use barrier contraceptives during the course of the study.

TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION

Investigational drug: Recombinant human acid alpha-glucosidase (rhGAA) produced in Chinese hamster ovary cells.
Dose: 20 mg/kg qow
Route: IV infusion
Regimen: The total amount of rhGAA was adjusted every 4 weeks to account for changes in body weight. Prior to each infusion, the patient was assessed by the Investigator or appropriate designee to determine if the patient was free from acute illness symptoms and sufficiently stable to receive the infusion. The therapy was administered at an initial rate of 0.2 mg/kg/hr and could be gradually increased incrementally every 30 minutes (if there were no signs of IARs) until a maximum rate of 10 mg/kg/hr was reached. No shortening of the infusion duration was permitted during the first 26-week treatment period.

DURATION OF TREATMENT

The initial treatment module had a duration of 26 weeks. Thereafter, patients entered the maintenance phase of this study and could be transferred to local sites in order to receive infusions.

REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION

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

CRITERIA FOR EVALUATION

Criteria for Evaluation – Efficacy
The following efficacy assessments were performed at Baseline, Week 12, and Week 26 during the study:

Pulmonary function testing (FVC measured in upright [sitting] and supine positions);

MMT – 34 muscle groups assessed;

Hand-held dynamometry (HHD);

Functional activities assessment (6MWT or 3MWT, time to walk 10 meters, time to stand up from the supine position);

Cardiovascular endurance as measured by EEI.

Criteria for Evaluation – Safety
Safety assessments consisted of AEs, laboratory tests (serum chemistry, hematology, and urinalysis), 12-lead electrocardiogram (ECG), hearing tests, anti-rhGAA antibody (immunoglobulin G [IgG]), vital signs, concomitant medications and therapies, physical examination, and for females of childbearing potential, urine pregnancy tests.

Criteria for Evaluation – Pharmacokinetics
Blood samples were drawn at selected time points to assess GAA activity in plasma. The following PK parameters were estimated from the plasma rhGAA concentration-time data at Day 0, Week 12, and Week 26: Cmax, Tmax, AUC0-t, AUC0-∞, CL, Vz, Vss, tv, and t1/2.

STATISTICAL METHODS

An interim analysis of the safety and PK data was performed after the last patient completed the Week 12 visit. In the interim analysis, results of the efficacy assessments FVC, functional activities, and EEI were also reported. An analysis of all data was performed after the last patient had completed the Week 26 visit and is described in this report.

All efficacy measurements and safety data were compared to Baseline and summarized descriptively. All patient data are presented in patient listings.

SUMMARY / CONCLUSIONS

Five patients (3 males, 2 females) were enrolled and treated with 20 mg/kg qow Myozyme® under Protocol AGLU02804. All 5 patients had confirmed diagnosis of late-onset Pompe disease (GAA deficiency and/or genotyping) between the ages of 13 months and 11.6 years. The patients in this study exhibited clinical features typical of patients with late-onset Pompe disease, including scoliosis, lordosis, joint contractures, abnormal gait and difficulties with climbing and running. The median age at first Myozyme® infusion was 12.7 years (range 5.9 to 15.2 years)

Summary / Conclusions – Efficacy
Three of the 5 patients showed clinically meaningful improvements in FVC in the upright position from Baseline to Week 26. Of these 3 patients, 2 had evidence of significant pulmonary involvement (i.e., FVC < 80% predicted) at Baseline. American Thoracic Society and European Respiratory Society (ATS/ERS) guidelines suggest that a change in FVC of at least 11% over several weeks represents a clinically meaningful change in pulmonary function.

Muscle function testing using MMT indicated mild muscle weakness in the majority of patients at Baseline with greater involvement of proximal muscles relative to distal muscles, and lower extremities relative to upper extremities. At Week 26, total MMT scores had increased from Baseline for 4 of the 5 patients indicating a clinically detectable improvement in overall body muscle strength after 26 weeks of Myozyme® treatment. Similarly, HHD data showed that 3 patients achieved a meaningful increase in muscle strength in various muscle groups at Week 26 compared to Baseline.

The 6MWT was performed initially at a comfortable speed and then at a fast speed in order to establish a baseline standard (i.e., at comfortable speed) and maximum (i.e., at fast speed) level of energy expenditure. The median distance covered during the 6MWT at the comfortable speed decreased from 360 meters (range 333 to 412 meters) at Baseline to 345 meters at Week 26 (range 216 to 457 meters). Only Patient 105 demonstrated an increased walk test distance (+45 meters) at Week 26 compared to Baseline, with the 4 remaining patients showing a decrease ranging from 15 to 117 meters.

The median distance walked at the fast speed increased from 468 meters at Baseline (range 344 to 546 meters) to 520 meters at Week 26 (range 368 to 664 meters). All 5 patients demonstrated an increased walk test distance from Baseline to Week 26 that ranged from 8 to 118 meters, with the increased distances achieved by Patients 102 (+52 meters), 103 (+41 meters), and 105 (+118 meters) considered to represent clinically meaningful improvements in walking distance. The difference in response between the comfortable and fast speed 6MWT may be a consequence of the fast speed test representing a more strenuous physical challenge to these patients.

Cardiovascular endurance was assessed using the EEI from the 6MWT administered at two different speeds. Interpretation of the changes from Baseline in EEI data at comfortable speed is difficult due to the decrease in distance walked at the Week 26 test. EEI values at fast speed did not show any discernible trend.

The 10-meter walk test and stand from the supine position test were performed in 6 seconds or less at Baseline by all patients. At Week 26, Patient 105 decreased the 10 meter walk time by 1 second, while all other patients showed no change from Baseline. At Week 26, 4 of the 5 patients completed the stand from supine position test in 1 second less than at Baseline, while no change was observed for the remaining patient (Patient 105).

Summary / Conclusions – Pharmacokinetics
Although assessed in only a small number of patients, the PK data from this study indicate there was no obvious change in the PK profile of Myozyme® (using Myozyme® manufactured at larger scale) over the course of the 26-week study period.

The data are consistent with the PK data observed with Myozyme® manufactured at the smaller scale.

Summary / Conclusions – Safety Results
All safety data collected up to Week 26 are included in this report. Treatment with Myozyme® at a dose of 20 mg/kg qow was well tolerated and no new safety concerns were identified. No patients died or withdrew from treatment during the 26 weeks of this study. A total of 33 treatment-emergent AEs were experienced by the 5 patients in this study. The most frequently reported AEs by preferred term were abdominal pain upper, headache, pharyngolaryngeal pain, and sinusitis. All AEs were mild in severity and considered either not related (31/33 events) or remotely/unlikely related (2/33 events) to study treatment. One serious adverse event (road traffic accident) was reported that was assessed as not related to treatment. No patient experienced an IAR.

All patients exhibited clinically significant elevated levels of aspartate transaminase (AST), alanine transaminase (ALT), creatine kinase (CK), and creatine kinase with MB fraction (CK-MB) at almost all assessments including Baseline, consistent with late-onset Pompe disease. Four of the 5 patients seroconverted, i.e., developed anti-hGAA IgG antibodies with antibody titers of 100 to 800; seroconversion was observed between Week 8 and Week 16. No patient developed inhibitory antibody activity (defined as inhibitory antibody activity of > 10%).

There were no consistent changes in vital signs over the 26-week treatment period. One patient had non-specific ECG abnormalities at Baseline and Week 26. Echocardiogram data indicated that no patient had cardiomyopathy at Baseline or at Week 26 in those patients with repeat assessments. Two patients had an abnormal hearing test at Baseline. At Week 26, hearing assessment was normal in one patient whereas another patient still had a mild hearing abnormality. Small improvements (e.g., reduced headlag and Gower’s sign) were observed in the physical examination status of 3 patients at Week 26 compared with Baseline.

CONCLUSION

Treatment with Myozyme® 20 mg/kg/qow IV for 26 weeks in patients with late-onset Pompe disease was well tolerated and no new safety concerns were identified. Although, the data presented are limited in that only 5 patients with late-onset Pompe disease were treated with Myozyme® for 26 weeks (14 infusions), some patients have already experienced clinically meaningful improvement in pulmonary function and increased muscle strength and function.