Protocol AGAL-005-99: A Multicenter, Open-Label Extension Study of the Safety and Efficacy of Recombinant Human α-Galactosidase A (r-hαGal) Replacement in Patients With Fabry Disease.

Protocol AGAL-005-99: A Multicenter, Open-Label Extension Study of the Safety and Efficacy of Recombinant Human α-Galactosidase A (r-hαGal) Replacement in Patients With Fabry Disease.

Drug Name	Generic Name	Studied Indications or Disease	Approved U.S. Drug Label
Fabrazyme®	agalsidase beta	Fabry disease	Prescribing Info

This was a multicenter study conducted at 15 sites in North America and 5 sites in Europe.

26 October 1999 (first patient enrolled) to
01 December 2004 (last patient completed)

The objectives of the study were to demonstrate the long-term safety and efficacy of Fabrazyme when used as enzyme replacement therapy (ERT) in patients with Fabry disease.

The Phase 3 Extension Study (Extension Study) was a multicenter, open-label extension study of patients diagnosed with Fabry disease who successfully completed the Phase 3 Pivotal Study (AGAL-1-002-98) (Pivotal Study) of Fabrazyme. No control group was employed, and patients, Investigators, and Genzyme personnel, were aware that all patients were receiving treatment with Fabrazyme. Initially, the Extension Study was designed as an 18-month study, but was later extended to 54 months so that robust long-term safety and efficacy data could be collected and analyzed.

Efficacy endpoints from the Pivotal Study were largely conserved, although designations of primary, secondary, and tertiary endpoints were unnecessary. Similarly, safety assessments were essentially unchanged from that study. Based on the experiences in that study, however, particular attention was paid to infusion-associated reactions (IARs), patients’ tolerization to Fabrazyme, and seroconversion in the Extension Study.

Periodically, safety and efficacy data were analyzed. Based on these periodic analyses, decisions were made to modify the study. Study modifications included pre-treatment regimens that mitigated IARs to treatment, additional collection of blood samples to assess serum tryptase and complement levels, options that permitted patients to be infused with Fabrazyme at home or at an increased infusion rate, and identification of renal disease progression criteria that would warrant a Fabrazyme dose increase to 3mg/kg, if necessary.

All 58 patients who participated in the Pivotal Study were eligible for enrollment in the Extension Study. All 58 patients enrolled in the Extension Study and were eligible for data analysis.

P atients who met all of the following inclusion criteria were eligible to participate in the Extension Study: 1) The patient provided written informed consent prior to any study-related procedures being performed. 2) The patient successfully completed the Pivotal Study. Successful completion of the Pivotal Study was defined as patients randomized to treatment, who received Clinical Trial Material infusions, and who continued to be evaluable for efficacy and safety measures. Patients who were unable to complete individual efficacy assessments were considered for enrollment into the extension protocol. These patients were assessed on a case-by-case basis by a Genzyme Medical Monitor (or designee) and the Investigator. 3) Female patients of childbearing potential had to have a negative pregnancy test (urine β-hCG) prior to dosing at each study visit. In addition, all female patients of childbearing potential were to use a medically accepted method of contraception throughout the study. Patients were not eligible for participation if they had current evidence of kidney failure or renal insufficiency, as defined by a serum creatinine > 2.2 mg/dL (194.7 μmol/L), had undergone kidney transplantation or were currently on dialysis, had a clinically significant organic disease, were pregnant or lactating, or were unwilling to comply with the study requirements.

Dose and Mode of Administration: approximately 1mg/kg (0.9 to 1.1mg/kg) intravenously every 2 weeks

Patients received treatment at the 8 original double-blind study sites; after approximately 4 months, and following discussion with and approval of the Genzyme Medical Monitor, patients could transition to a local physician to receive infusions for the remainder of the study.

Placebo/Fabrazyme Treatment Group: 54 months (total duration of treatment with Fabrazyme)
Fabrazyme/Fabrazyme Treatment Group: approximately 60 months (total duration of treatment with Fabrazyme)

- Reductions of globotriaosylceramide (GL-3) accumulation in the capillary endothelium (vasculature) of the kidney, heart, and skin as measured by light microscopy (LM)

- Plasma GL-3 (enzyme-linked immunosorbent assay [ELISA] and/or tandem mass spectrometry [MS])

- Renal function as assessed by serum creatinine, estimated glomerular filtration rate (GFR; determined by the Modification of Diet in Renal Disease Study [MDRD] equation) (Levey AS, Greene T, Kusek JW, Beck GJ, MDRD Study Group. A simplified equation to predict glomerular filtration rate from serum creatinine. Abstract. J Am Soc Nephrol. 11:2000), and 24-hour urinary protein excretion

The evaluation of safety included assessment of adverse experiences/events (AEs), vital signs, physical examinations, electrocardiograms (ECGs), echocardiograms (ECHOs), and clinical laboratory parameters.

The efficacy analysis was conducted on the As Treated population. One sample t-tests were conducted to test for significant differences from zero in mean changes within each treatment group.

GL-3 clearance histology data from the Pivotal Study and Extension Study were combined to show how scores changed from Baseline of the Pivotal Study to the final study visit of the Extension Study. For biochemical evaluation of GL-3 clearance, assessments were summarized along with their change from Baseline/Entry to Final Visit.

Serum creatinine results, GFR, and proteinuria (urine protein/urine creatinine) were summarized along with their change from Baseline/Entry to Final Visit.

The Short Form McGill Pain Questionnaire scores and SF-36 Health Survey scores were summarized along with their change from Baseline/Entry to Final Visit.

Frequency counts of AEs and serious adverse events (SAEs) and the unique number of patients who experienced the events were presented for each Body System and each Preferred Term. Also, frequency and percentage of patients who had an AE were presented, stratified by severity and by relationship to treatment. Frequency and percentage of patients who had a related AE on the same day as the infusion were summarized for each Preferred Term. Frequency and percentage of seroconverted (immunoglobulin G [IgG] positive) patients and time to seroconversion, in days, from the first infusion of Fabrazyme were presented. Also, antibody titers for the IgG positive patients were provided. Patients’ tolerization to Fabrazyme was also presented.

Clinical chemistry, hematology, and urinalysis results were summarized along with their change from Baseline/Entry to Final Visit. In addition, all laboratory values were classified as normal or abnormal based on normal ranges provided by the laboratory. Vital sign results were summarized along with their change from Baseline/Entry to Final Visit. Physical examination results were summarized.

ECGs were collected at Entry and every 6 months, thereafter. Summary statistics for rate (bpm), intervals: (PR, QRS, QT, and QTc [msec]), and axis (degrees) were summarized from the investigator reads for Baseline/Entry and Final Visit, as well as change from Baseline/Entry to Final Visit. Frequencies and percentages for the following parameters at Baseline/Entry and at Final Visit were also presented: rhythm; ventricular hypertrophy: left ventricular hypertrophy (LVH), right ventricular hypotrophy (RVH); conduction abnormalities: PR short, RBBB, LBBB, delta wave; evidence of prior myocardial infarction; non-specific ST-T wave abnormalities; and specific ST-T wave.

ECHO results were summarized from the investigator reads for Baseline/Entry and Final Visit, as well as change from Baseline/Entry to Final Visit.

In the Pivotal Study, the primary criterion for successful ERT with Fabrazyme in Fabry disease patients was clearance to near normal levels (Score = 0) of GL-3 from the interstitial capillary endothelium (vasculature) of the kidney, as the surrogate endpoint most likely to predict clinical benefit. The Extension Study was designed to investigate maintained clearance of GL-3 through long-term treatment of patients with Fabrazyme. Patients previously treated with Fabrazyme in the Pivotal Study received active treatment for a total of approximately 60 months (i.e., 5 years), while patients who received placebo in the Pivotal Study received active treatment for 54 months (i.e., 4.5 years). The initial timepoint of the Pivotal Study was designated as “Baseline,” while the initial timepoint of the Extension Study was designated as “Entry”. All changes in study endpoints were measured from these timepoints. Based on their original treatment assignments in the Pivotal Study and the fact that all patients received Fabrazyme treatment in the Extension Study, patients in the Extension Study were designated as either “Placebo/Fabrazyme” or “Fabrazyme/Fabrazyme” patients.

By Month 6 of the Extension Study, all 24 evaluable patients in the Placebo/Fabrazyme group with non-zero scores at Entry achieved clearance of GL-3 from interstitial capillary endothelial cells of the kidney (p < 0.0001). No Placebo/Fabrazyme patients had zero scores at Baseline of the Pivotal Study or Entry of the Extension Study. In the Fabrazyme/Fabrazyme treatment group, 23/25 (92%) evaluable patients achieved clearance of GL-3 from interstitial capillary endothelial cells of the kidney (p < 0.0001). Additionally all patients (n = 8) with Month 54 (optional) kidney biopsies maintained clearance.

For other cell types of the kidney, by Month 6, nearly all evaluable patients in both treatment groups who had non-zero Pre-Treatment scores achieved clearance of GL-3 from glomerular endothelial cells, mesangial cells, and non-capillary endothelial cells of the kidney (p < 0.0001). Interstitial cells were cleared among the majority of Placebo/Fabrazyme patients (19/24, 79%) and all 23 Fabrazyme/Fabrazyme patients (p < 0.0001). A reduction, but not complete clearance, in GL-3 accumulation in distal convoluted tubule/collecting duct cells was observed for the majority of patients with evaluable cells (n = 48). Similarly, podocytes also showed reduction among the overall population with evaluable cells (n = 39).

At Month 54, all evaluable patients in both treatment groups who had non-zero Pre-Treatment scores achieved clearance of GL-3 from glomerular endothelial cells (n = 5), mesangial cells (n = 5), and non-capillary endothelial cells (n = 6) of the kidney. Interstitial cells were cleared among the majority of Placebo/Fabrazyme patients (4/5) and half of Fabrazyme/Fabrazyme patients (1/2). All evaluable patients (n = 7) in both treatment groups who had non-zero Baseline scores achieved clearance (i.e., Score = 0) of GL-3 from distal convoluted tubule/collecting duct cells of the kidney. Four (4/6) patients showed a reduction of 1 point (from score = 3 to score = 2) in podocyte GL-3 from Baseline. Importantly, despite persistent GL-3 levels in podocytes among these patients, serum creatinine levels remained stable in all but 1 patient. This patient had significant glomerular scaring and high proteinuria (2.9) at baseline.

Evaluation of heart capillary endothelial cells showed that most patients with biopsies at Pre-treatment and Month 6 had nearly complete clearance of GL-3 from the capillary endothelium (score = 0). Similar results were achieved for the limited number of patients (n = 8) with optional biopsies at Month 54.

Evaluation of skin capillary endothelial cells showed that, overall, clearance of GL-3 was maintained through Month 54 of the Extension Study. Only 1 patient had accumulation (Score > 1) in skin capillary endothelial cells after being treated with Fabrazyme. However, this occurred at a single timepoint, and the patient’s GL-3 level subsequently normalized. For deep vessel endothelial cells, 29/36 (81%) patients had a zero-score at Month 54. Seven patients had non-zero scores at Month 54. Closer examination of these patients’ biopsy histories through the Extension Study showed that 5 patients’ Month 54 scores were lower than their Pre-treatment scores, 1 patient’s score was unchanged, and 1 patient’s score at Pre-treatment was unavailable. For smooth muscle and perineurial cells, there was no severe accumulation (score = 3) at Month 54, despite several patients with severe accumulation scores at Pre-treatment.

Mean plasma GL-3 levels measured by tandem MS for both treatment groups showed a similar pattern of rapid decrease and return to normal levels (i.e., ≤ 7.03 µg/mL) within 6 months (i.e., first timepoint tested) of treatment with Fabrazyme. Importantly, for both treatment groups, mean plasma GL-3 levels remained normal through Month 54.

Median serum creatinine values for the population remained stable and normal throughout the study. The rise in the mean serum creatinine levels observed late in the Extension Study was largely attributable to the renal disease progression of 6 patients who shared common Pre-treatment clinical profiles including significant proteinuria (at Baseline), scarred glomeruli, and advanced age (> 40 years).

Median estimated GFR (using the MDRD equation) showed that renal function remained normal (i.e., estimated GFR > 90 mL/min/1.73m²) through the study periods. A total of 9 patients had decreased estimated GFR (i.e., < 90 mL/min/1.73m²) prior to the start of treatment with Fabrazyme. At Month 54 of the Extension Study, 6 of the 9 patients had stabilization (i.e., ± 20%) or improvement in estimated GFR. The remaining 3 patients had a decrease in estimated GFR greater than 20%. These patients tended to be older, with 2 of the 3 patients having proteinuria greater than 2.0 at Baseline.

Most patients had low levels of proteinuria at Baseline of the Pivotal Study. Overall, proteinuria remained stable from Baseline of the Pivotal Study through 54 months of treatment in the Extension Study.

Under the Short Form McGill Pain Questionnaire, overall pain scores at Baseline and during the study were low, possibly due to the unrestricted use of pain medications by the patients. Overall, a slight improvement was observed in all pain scores. For patients with pain at their first measurement prior to treatment, changes in mean Present Pain Intensity scores through Month 54 showed statistically significant improvement (p = 0.0164). For patients with pain at their first measurement prior to treatment, changes in mean Visual Analog Scale (VAS) scores through Month 54 showed statistically significant improvement (p = 0.0065). Intermittent reduction and/or cessation of pain medication usage was observed among some patients in both treatment groups.

Under the SF-36 Health Survey, for most SF-36 components, patients experienced a mean improvement after long-term treatment with Fabrazyme. The mean changes through Month 54 for the components of Physical Functioning, Role Emotional, Body Pain, and Standardized Physical Component Scale (for patients with score < 100 at first measurement prior to treatment) were statistically significant (p = 0.0150, p = 0.0314, p = 0.0025, and p = 0.0064, respectively, for the overall population). Small changes were observed for the other components; however, none of these changes was statistically significant.

As a result of the extended duration spent on-study, patients were able to tolerate Fabrazyme infusions at higher rates. By Month 54, the mean infusion time for all patients who received full infusions (i.e., ≥ 450 mL) was approximately 2.5 hours ± 36.5 minutes. Among all patients treated, 42 (72%) patients received the majority of their infusions in ≤2.5 hours, and 28 (48%) patients received the majority of their infusions in ≤2.0 hours. Further, among all patients, 48 (83%) received at least 1 full infusion in ≤2.0 hours, and 23 (40%) received at least 1 full infusion in ≤1.5 hours. One patient in the Fabrazyme/Fabrazyme treatment group met the criteria for a dose increase to 3.0 mg/kg every 2 weeks. This patient’s dose was increased approximately 3.3 years (174 weeks) after Entry into the Extension Study. Around this timepoint, the patient’s serum creatinine level was 4.6 mg/dL, indicating advanced renal insufficiency. The patient’s AE profile remained similar to that observed while he received Fabrazyme at 1.0 mg/kg.

A total of 11 patients (5 Placebo/Fabrazyme and 6 Fabrazyme/Fabrazyme) were infused at home. One of these home-infusion patients preferentially returned to the study site after 10 successful home infusions. Generally, no complications were observed.

All 58 patients experienced at least 1 AE and, in aggregate, experienced a total of 3767 AEs since the beginning of treatment (i.e., Baseline of the Pivotal Study for Fabrazyme/Fabrazyme patients and Entry of the Extension Study for Placebo/Fabrazyme patients). Overall, patients spent an average of 52.2 months on-treatment. Most AEs were mild and not related to treatment with Fabrazyme. Of AEs that were related, most were also IARs. A total of 49/58 (84%) patients experienced a total of 735 IARs since the beginning of treatment with Fabrazyme in a total of 6226 infusions.

Two deaths occurred during the study. The first patient experienced SAEs of sepsis and urinary tract infection that led to death. This patient had a relevant medical history of multiple cerebrovascular accidents, intermittent palpitations, conduction abnormalities of PR shortening and non-specific ST wave changes, hypercholesterolaemia, headaches, hypertension, proteinuria, LVH, vestibular dysfunction, recent increase in memory loss and cognitive change. The second patient experienced SAEs of cardiac arrest and arrhythmia that led to death. This patient had a relevant medical history of a heart attack at age 30, heart failure, palpitations, irregular pulse, peripheral oedema, and ECG (non-specific ST wave abnormalities) and cardiac ultrasound abnormalities (ventricular hypertrophy and mitral valve regurgitation). Autopsy results showed that this patient’s cause of death had its basis in Fabry disease.

The majority of the SAEs were moderate in intensity and not related to treatment with Fabrazyme. A total of 14/58 (24%) patients experienced unrelated SAEs that were severe in intensity. Most patients recovered from the SAEs. Among patients with related SAEs (8 patients), the events of 3 patients were assessed as severe in intensity by the Principal Investigator. These SAEs included Chest Pain (also an IAR) and Throat Tightness for the first patient (patient recovered); Bradycardia, Cardiac Failure, Cardiac Arrest, and Arrhythmia for the second patient (patient died); and Fever, Tachycardia, and Rigors (all IARs) for the third patient (patient recovered).

The most frequently reported IARs (% of patients) were Rigors (59%), Temperature Changed Sensation (38%), Fever (34%), Nausea (24%), Headache (22%), Vomiting (21%), Flushing (19%), Chest Pain (16%), Rhinitis (16%), Pruritus (16%), Tremor (14%), Dyspnoea (14%), Somnolence (14%), and Fabry Pain (12%). Somnolence mostly captured the Verbatim Term “drowsiness during infusion” assessed by the Principal Investigator as mild in intensity. These IARs of Somnolence may have been the result of pretreatment regimens with hydroxyzine or other antihistamines. All other IARs occurred in ≤ 10% of patients (i.e., 6 patients) overall. Importantly, data demonstrate that the total number of patients experiencing IARs has decreased over time.

Overall 52/58 (90%) patients seroconverted. Review of the patients’ serology status at Month 54 indicates that 6/57 (11%) patients remained IgG seronegative, excluding 1 patient due to limited antibody data (available up to only 14 weeks). Mean time to seroconversion in 51/57 (89%) patients, excluding 1 patient due to seroconversion prior to receiving Fabrazyme treatment, was approximately 77 days after the first infusion with Fabrazyme. Of these patients who seroconverted, 1 patient was assessed a “low responder” (IgG titers not exceeding 800), 32 patients demonstrated a downward trend in titers based on a ≥ 4-fold reduction in titer from the peak measurement to the last measurement, 9 patients demonstrated a plateau in their antibody titers, and 9 patients tolerized. Of note, of 2 female patients enrolled, 1 patient tolerized, while the other patient remained seronegative throughout the study.

In comparing the 2 treatment groups, similar patterns are observed in the timing of seroconversion and the frequency of IARs. The majority of patients seroconverted within 3 months of treatment with Fabrazyme. Simultaneously, the frequency of IARs increases in parallel to the seroconversion rate, but then decreases over time.

There was no evidence that seroconversion inhibited or neutralized enzymatic activity of Fabrazyme, based on assessment of kidney capillary endothelial cell GL-3 clearance. There was no difference in the number of patients who showed clearance at Month 6 and Month 54 based on seroconversion status. Additionally, seroconversion did not appear to affect clearance of GL-3 from skin capillary endothelial cells. A total of 31/36 (86%) patients at Month 54 had clearance of GL-3 (i.e., Score = 0) from skin capillary endothelial cells. All but 2 of these patients were IgG seropositive. Of the 5 patients with mild GL-3 in skin capillary endothelial cells (i.e. Score =1) at Month 54, all had seroconverted and were seropositive.

Only a small number of patients experienced reactions suggestive of immediate (Type 1) hypersensitivity. Overall, 4/58 (7%) patients were withdrawn per protocol due to immunoglobulin E (IgE) antibody development and skin testing criteria. One patient tested positive for IgE antibodies and was withdrawn from the study per protocol; the patient went on to receive treatment with commercial product. Three patients had positive skin test results, although sera tested negative IgE antibodies; these 3 patients were enrolled in the Rechallenge Study (AGAL-019-01). Two of these patients completed the Rechallenge Study and began receiving commercial Fabrazyme, while the third patient was withdrawn by the Principal Investigator from the Rechallenge Study due to multiple IARs and went on to receive commercial Fabrazyme.

There were no clinically meaningful changes overall or trends in changes or shifts over time in any laboratory parameter for the treatment groups individually or overall. No pattern has been demonstrated in any laboratory parameter for individual patients or in group results that indicates treatment with Fabrazyme had a toxic effect. The majority of laboratory abnormalities that were additionally categorized as adverse events were mild or moderate in severity and not related to treatment with Fabrazyme. No new safety concerns were identified based on review of these AEs.

Overall, mean vital signs at all timepoints, as well as changes from Baseline and Entry, were normal for all patients regardless of treatment group. No new safety concerns were identified based upon review of these adverse events. No new safety concerns were identified from physical examination findings.

ECG results that were reported as AEs predominantly captured Verbatim Terms involving “ST wave abnormalities”, “bundle branch block”, and “conduction abnormalities”, nearly all of which were assessed as mild in intensity by the Principal Investigator. Among the AEs detected via the investigators’ review of ECGs, 8 AEs were considered related to treatment and none of these was serious. No new safety concerns were identified based upon review of these ECG abnormalities that investigators captured as AEs.

ECHO results were reported as SAEs for 2 patients. Events of Heart Murmur (Verbatim Term “pericardial rub”), Pericarditis, and Pericardial Effusion in the first patient, and Cardiac Tamponade in the second patient were all assessed by the Principal Investigator as severe in intensity and not related to treatment with Fabrazyme. No new safety concerns were identified based upon review of these ECHO abnormalities that investigators captured as AEs.

Clearance of GL-3 was maintained for 54 months in the kidney, heart, and skin, as well as normalization of plasma GL-3. Statistically significant improvements over 54 months of treatment were noted in Quality of Life and Pain assessments. Renal function remained stable and normal throughout the study for most of the patients.

Patients tolerated treatment well, including increases in infusion rates. IARs decreased over time. There was no impact of seroconversion on efficacy. A small number of patients experienced reactions suggestive of Type I hypersensitivity. However, these patients continued to be treated with Fabrazyme. There were no reports of anaphylaxis.

These results demonstrate that long-term treatment with Fabrazyme is safe and effective.

Based on Report Prepared On 21July2005
Synopsis Prepared on 03October2006


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