Long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease: aggregate data from two post-authorization safety studies

ABSTRACT

Background

Enzyme replacement therapy in Fabry disease has been available in Japan since 2004. Two post-authorization safety studies were conducted to evaluate agalsidase beta in Japanese patients with Fabry disease in real-world practice.

Research Design and Methods

The Special Drug Use Investigation monitored the long-term safety and efficacy of agalsidase beta, and the Drug Use Investigation monitored safety in patients not participating in the Special Drug Use Investigation. Safety and efficacy evaluations included adverse drug reactions (ADRs), infusion-associated reactions and hypersensitivity reactions, and change in blood GL-3 level over time.

Results

Of 396 patients in the aggregated data set, safety and efficacy analysis sets comprised 307 and 196 patients, respectively. ADRs occurred in 93 (30.3%) patients and serious ADRs occurred in 25 (8.1%) patients, with general disorders and administration site conditions (n=55, 17.9%), nervous system disorders (n=30, 9.8%) and skin and subcutaneous tissue disorders (n=23, 7.5%) the most common. Reductions in blood GL-3 levels occurred over the study, irrespective of age or disease phenotype.

Conclusions

Agalsidase beta demonstrated acceptable safety and tolerability, with sustained reductions in blood GL-3 levelsin Japanese patients with Fabry disease in real-world clinical practice

Clinical Trial Registration

NCT00233870/AGAL03004 (Special Drug Use Investigation of Agalsidase beta)

KEYWORDS:

• Agalsidase beta
• enzyme replacement therapy
• Fabry disease
• post-authorization safety study

1. Introduction

Fabry disease is a rare, X-linked, inherited lysosomal storage disorder caused by mutations in the GLA gene, which results in partial or complete deficiency of the lysosomal enzyme, α-galactosidase A (α-GAL) [1]. Deficiency of this enzyme leads to progressive accumulation of cellular glycosphingolipids, predominantly globotriaosylceramide (GL-3), in plasma and various body tissues, and severe multisystem effects [2,3]. Premature death occurs due to end-stage renal disease and cardiovascular and cerebrovascular complications [2].

Clinical manifestations of Fabry disease are variable, depending on the degree of deficiency [4], and may be used to characterize the disease into three distinct phenotypes [5]. The more severe classical phenotype, which arises due to total or near-total loss of α-GAL function [6], typically presents in childhood, and most commonly affects males [7]. Neuropathic pain in the extremities, sweating abnormalities, cornea verticillata, and angiokeratoma represent the earliest obvious manifestations of the disease [3,8,9]. However, some degree of underlying irreversible organ damage is already expected at this point [10,11]. Severe, life-threatening complications begin to emerge in adulthood, including renal failure, cardiac disorders (cardiomyopathy, arrhythmia), and cerebrovascular events (e.g. stroke) [12,13].

In contrast, patients with Fabry disease other than the classic phenotype, also referred to as late-onset or atypical variant, possess residual enzyme activity, and tend to lack the early classic symptoms of the disease [14]. Rather, symptoms typically develop later in life, with predominant cardiac and/or renal manifestations [5]. Although Fabry disease is X-linked, heterozygous females may also be affected. However, symptoms are particularly variable due to random X inactivation, and may range from asymptomatic disease to a more severe, classic disease course [5].

The number of therapies available for patients with lysosomal storage diseases has expanded considerably in the past several years [15,16]. Enzyme replacement therapy (ERT) represents the mainstay of treatment for Fabry Disease, with two different human recombinant α-GAL ERTs developed for Fabry disease. Agalsidase beta (Fabrazyme®), a recombinant form of human α-GAL, has been approved for the treatment of Fabry disease in the European Union and United States since 2001 [17] and 2003 [18], respectively, and in Japan since 2004 [19]. The other ERT, agalsidase alfa, has been available in the European Union since 2001 [20] and Japan since 2006 [21]. Administration of these agents has been shown to result in marked increases in α-GAL A activity in human Fabry cells and Fabry mouse tissues; however, enzymatic activity in cultured fibroblasts, kidneys, heart, and spleen was higher for agalsidase beta compared with agalsidase alfa [22]. More recently, pharmacological chaperone therapies have become available, and substrate reduction therapies and gene therapy approaches are also in development, which are expected to improve outcomes for patients with Fabry disease [23].

Evidence for the safety and efficacy of agalsidase beta is based on the positive results from several trials, including the multinational Phase 3 double-blind and open-label extension studies [24,25], Phase 2 Japanese bridging study [26], and Phase 4 double-blind study [27]. Results of these studies demonstrated that agalsidase beta decreased tissue deposition of GL-3, improved clinical symptoms, and reduced the frequency of, and delayed the time to, major clinical events such as renal, cardiac, and cerebrovascular events, and death [24–27]. However, only 13 patients with Fabry disease were enrolled in registration clinical trials in Japan [26]. We therefore conducted two post-authorization safety studies (the Special Drug Use Investigation of agalsidase beta, for evaluation of long-term use, and the Drug Use Investigation of agalsidase beta, as all-case surveillance for patients who were not registered in the long-term safety study) to evaluate the long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease in real-world practice.

2. Patients and Methods

2.1. Study Design, Patients, and Data Collection

Two post-authorization safety studies, comprising the Special Drug Use Investigation of agalsidase beta (Registry number: AGAL03004) and Drug Use Investigation of agalsidase beta (Registry number: AGAL02904), were conducted between June 2004 and March 2011, with safety data collected every 6 months. Japanese patients with Fabry disease, diagnosed by a physician according to deficient α-GAL activity or the identification of GLA gene mutation, were eligible for inclusion.

The Special Drug Use Investigation of agalsidase beta analyzed the safety and efficacy of long-term agalsidase beta use in Japanese patients with Fabry disease. The Drug Use Investigation of agalsidase beta was conducted using an all-case surveillance method and analyzed the safety profile in all Japanese patients with Fabry disease who were not included in the Special Drug Use Investigation of agalsidase beta.

These safety studies were conducted in accordance with the Japanese regulatory requirements of the Good Post-Marketing Study Practice, ethical principles of the Declaration of Helsinki　 and the Institutional Review Board (IRB) regulations. The need for informed consent was waived as these safety studies were mandated by the Japanese regulatory authorities in accordance with the Law for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices (Pharmaceutical and Medical Device Act). The clinical study protocol and other study-related documents were reviewed and approved by the local or central IRBs of study sites. Each investigator conducted the study according to applicable local or regional regulatory requirements and in accordance with the responsibilities listed in the protocol.

2.2. Data Collection and Assessments

Patient data were added into case report forms using patient medical records at baseline, and at 6-monthly intervals until the end of the study.

Upon entry to the study, baseline data were collected on demographics (sex, age, history of allergy), disease-related characteristics (disease phenotype, clinical symptoms, complications) and medication data (history of ERT, concomitant medication/s). Concomitant medications were defined as any medication that the patient was taking for any reason other than the treatment of adverse events during the study. Complications were defined as any disease that the investigator deemed insufficient to infer causal correlation with the primary disease. Clinical symptoms of Fabry disease included extremity pain, angiokeratoma, dyshidrosis, temperature paresthesias, corneal opacity, abdominal pain, diarrhea, and liver, kidney, and cerebrovascular disorders. Disease-related assessments and blood GL-3 level were collected at baseline and 6-monthly intervals. Details regarding agalsidase beta treatment, including the duration of treatment, total number of doses, mean dosing interval, time of administration, and average dose, were collected at 6-monthly intervals.

Blood samples were collected for antibody titer measurements and GL-3 levels at baseline and prior to study drug administration every 6 months, until the end of the study. The production of anti-agalsidase beta antibodies (IgG) was determined by the enzyme-linked immunosorbent assay (ELISA) and radioimmunoprecipitation (RIP) assay at the Genzyme Clinical Specialty Laboratory in Cambridge, MA, USA.

2.3. Safety

Safety assessment items were the incidence of adverse events (AEs), including serious AEs, adverse drug reactions (ADRs), infusion-associated reactions (IARs), and hypersensitivity reactions. AEs were defined as any untoward medical occurrence in a patient administered study treatment, including those that did not necessarily have a causal relationship with study treatment. Serious AEs were defined as those AEs that were life-threatening or resulted in death, permanent or significant disability, inpatient or prolonged hospitalization, or congenital abnormality. ADRs were defined as any AE for which a causal relationship to agalsidase beta could not be denied. IARs were defined as any adverse event occurring during any infusion or on the day reported after the infusion. The decision to discontinue treatment, as well as subsequent management of AEs (including switching to other treatments) was made by the individual treating investigator. Agalsidase beta-related hypersensitivity reactions were defined according to the investigators’ assessment, with adverse events defined as hypersensitivity reactions where the immune response was exaggerated or inappropriate against an antigen, allergen, or another substance. The time to onset of ADRs was also recorded. ADRs, IARs and hypersensitivity reactions were evaluated and categorized by system organ class (SOC) and preferred term (PT) using MedDRA/J version 16.1.

2.3.1. Efficacy

For the evaluation of efficacy, the change in blood GL-3 levels over time with agalsidase beta was assessed. Subgroup comparisons were performed for patient background factors (age, disease type, Fabry disease complications, concomitant medications and antibody production).

2.4. Statistical Analysis

The safety analysis sets comprised all patients who were eligible for these two studies. The efficacy analysis set included all patients in the Special Drug Use Investigation of agalsidase beta who had at least one GL-3 measurement available before and after treatment with agalsidase beta.

Baseline demographics were summarized using descriptive statistics. The mean (standard deviation [SD] and 95% CI), and median (range) were calculated for continuous variables, and the frequency number and proportion were calculated for categorical variables.

The frequency of adverse events, including ADRs, were summarized descriptively overall, and for each individual event (by SOC and PT).

The Kaplan–Meier method was used to estimate the cumulative ADR event rate throughout the study overall, and by age and phenotype subgroups.

3. Results

3.1. Patient Disposition

Details regarding patient disposition are presented in Figure 1. A total of 332 patients in the Special Drug Use Investigation and 64 patients in the Drug Use Investigation were enrolled, comprising 396 patients in the aggregated data set (Figure 1). After removal of duplicate entries at different study sites (n = 15), a total of 381 patients were enrolled. Of these, 307 patients provided permission for publication and were included in the safety analysis set (261 patients in the Special Drug Use Investigation and 46 patients in the Drug Use Investigation).

Figure 1. Disposition of patients in the (a) special drug use investigation of agalsidase beta for evaluation of long-term use and (b) drug use investigation of agalsidase beta as all-case surveillance

Abbreviation: GL-3, globotriaosylceramide.

For the efficacy analysis set, a total of 65 patients in the Special Drug Use Investigation safety analysis set did not have blood GL-3 measurements available and were excluded; therefore, 196 patients were included.

Across the safety analysis sets, a total of 171 patients discontinued treatment with agalsidase beta. Reasons for discontinuation included: insufficient effect (n = 6), adverse events (n = 8), death (n = 26), transfer to a different hospital (n = 32), and other reasons (n = 103), including switching to other drugs due to the supply shortage of agalsidase beta that occurred in 2009 [28].

3.2. Patient Characteristics

Baseline demographic and clinical characteristics of patients included in the safety analysis set, overall, in the Special Drug Investigation and Drug Investigation, and in specific subgroups (defined by age category and phenotype) are presented in Table 1.

Table 1. Demographic and baseline clinical characteristics

	Overall	Special drug use investigation	Drug use investigation	Subgroup
				Age, years		Phenotype
				≤15	>15	Classic	Cardiac	Renal	Heterozygous
Patients, n (%)	307 (100.0)	261 (85.1)	46 (15.0)	21 (6.9)	285 (93.1)	171 (56.1)	12 (3.9)	17 (5.6)	105 (34.4)
Male, n (%)	201 (65.5)	177 (67.8)	24 (52.2)	19 (90.5)	182 (63.9)	171 (100.0)	12 (100.0)	17 (100.0)	0 (0.0)
Age at initiation of ERT, years, mean (95% CI)	39.5 (37.7 − 41.3)	39.0 (37.0 − 40.9)	42.3 (37.8 − 46.8)	11.0 (9.6 − 12.5)	41.6 (39.9 − 43.2)	32.5 (30.5 − 34.5)	57.1 (45.6 − 68.6)	45.0 (38.5 − 51.5)	48.0 (45.4 − 50.7)
Age at initiation of ERT, years, category, n (%)
≤15	21 (6.8)	19 (7.3)	2 (4.3)	21 (100.0)	0 (0.0)	19 (11.1)	0 (0.0)	0 (0.0)	2 (1.9)
16─20	22 (7.2)	19 (7.3)	3 (6.5)	0 (0.0)	22 (7.7)	17 (9.9)	1 (8.3)	1 (5.9)	3 (2.9)
21─30	52 (16.9)	48 (18.4)	4 (8.7)	0 (0.0)	52 (18.2)	41 (24.0)	0 (0.0)	2 (11.8)	8 (7.6)
31─40	69 (22.5)	57 (21.8)	12 (26.1)	0 (0.0)	69 (24.2)	51 (29.8)	0 (0.0)	4 (23.5)	14 (13.3)
41─50	55 (17.9)	47 (18.0)	8 (17.4)	0 (0.0)	55 (19.3)	23 (13.5)	3 (25.0)	3 (17.6)	26 (24.8)
51─60	58 (18.9)	46 (17.6)	12 (26.1)	0 (0.0)	58 (20.4)	14 (8.2)	4 (33.3)	4 (23.5)	36 (34.3)
61─70	25 (8.1)	20 (7.7)	5 (10.9)	0 (0.0)	25 (8.8)	6 (3.5)	1 (8.3)	3 (17.6)	15 (14.3)
≥71	4 (1.3)	4 (1.5)	0 (0.0)	0 (0.0)	4 (1.4)	0 (0.0)	3 (25.0)	0 (0.0)	1 (1.0)
Data not reported	1 (0.3)	1 (0.4)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Previous ERT use, n (%)
No	234 (76.2)	200 (76.6)	34 (73.9)	16 (76.2)	218 (76.5)	116 (67.8)	9 (75.0)	15 (88.2)	93 (88.6)
Yes	71 (23.1)	60 (23.0)	11 (23.9)	5 (23.8)	66 (23.2)	55 (32.2)	3 (25.0)	1 (5.9)	12 (11.4)
Data not reported	2 (0.7)	1 (0.4)	1 (2.2)	0 (0.0)	1 (0.4)	0 (0.0)	0 (0.0)	1 (5.9)	0 (0.0)
History of allergy, n (%)
No	252 (82.1)	211 (80.8)	41 (89.1)	14 (66.7)	238 (83.5)	144 (84.2)	11 (91.7)	12 (70.6)	84 (80.0)
Yes	45 (14.7)	43 (16.5)	2 (4.3)	7 (33.3)	38 (13.3)	24 (14.0)	1 (8.3)	2 (11.8)	18 (17.1)
Data not reported	10 (3.3)	7 (2.7)	3 (6.5)	0 (0.0)	9 (3.2)	3 (1.8)	0 (0.0)	3 (17.6)	3 (2.9)
Previous concomitant medication use, n (%)
No	27 (8.8)	17 (6.5)	10 (21.7)	1 (4.8)	25 (8.8)	9 (5.3)	0 (0.0)	3 (17.6)	14 (13.3)
Yes	280 (91.2)	244 (93.5)	36 (78.3)	20 (95.2)	260 (91.2)	162 (94.7)	12 (100.0)	14 (82.4)	91 (86.7)
Presence of complications, n (%)
No	96 (31.3)	71 (27.2)	25 (54.3)	18 (85.7)	77 (27.0)	67 (39.2)	3 (25.0)	2 (11.8)	23 (21.9)
Yes	210 (68.4)	189 (72.4)	21 (45.7)	3 (14.3)	207 (72.6)	103 (60.2)	9 (75.0)	15 (88.2)	82 (78.1)
Unknown	1 (0.3)	1 (0.4)	0 (0.0)	0 (0.0)	1 (0.4)	1 (0.6)	0 (0.0)	0 (0.0)	0 (0.0)
Clinical symptoms at baseline, n (%)
Pain in extremities	174 (56.7)	148 (56.7)	26 (56.5)	18 (85.7)	156 (54.7)	128 (74.9)	0 (0.0)	1 (5.9)	44 (41.9)
Angiokeratoma	95 (30.9)	86 (33.0)	9 (19.6)	3 (14.3)	92 (32.3)	81 (47.4)	0 (0.0)	1 (5.9)	12 (11.4)
Dyshidrosis	137 (44.6)	119 (45.6)	18 (39.1)	11 (52.4)	126 (44.2)	113 (66.1)	1 (8.3)	0 (0.0)	22 (21.0)
Dysthermesthesia	68 (22.1)	55 (21.1)	13 (28.3)	2 (9.5)	66 (23.2)	57 (33.3)	0 (0.0)	0 (0.0)	11 (10.5)
Corneal opacity	90 (29.3)	80 (30.7)	10 (21.7)	9 (42.9)	81 (28.4)	47 (27.5)	0 (0.0)	1 (5.9)	41 (39.0)
Abdominal pain	45 (14.7)	42 (16.1)	3 (6.5)	2 (9.5)	43 (15.1)	32 (18.7)	0 (0.0)	0 (0.0)	13 (12.4)
Diarrhea	54 (17.6)	47 (18.0)	7 (15.2)	1 (4.8)	53 (18.6)	39 (22.8)	1 (8.3)	0 (0.0)	14 (13.3)
Functional disorder, n (%)
Renal impairment	115 (37.5)	97 (37.2)	18 (39.1)	0 (0.0)	115 (40.4)	69 (40.4)	2 (16.7)	14 (82.4)	29 (27.6)
Cardiac dysfunction	124 (40.4)	97 (37.2)	27 (58.7)	0 (0.0)	124 (43.5)	52 (30.4)	10 (83.3)	4 (23.5)	58 (55.2)
Cerebrovascular disorder	48 (15.6)	39 (14.9)	9 (19.6)	0 (0.0)	48 (16.8)	26 (15.2)	0 (0.0)	2 (11.8)	19 (18.1)
Blood GL-3 level, μg/mL, mean (95% CI), [n]	8.5 (7.7 − 9.4) [152]	8.7 (7.9 − 9.6) [139]	6.3 (4.5 − 8.1) [13]	10.0 (6.5 − 13.5) [10]	8.4 (7.6 − 9.3) [142]	10.3 (9.2 − 11.5) [88]	9.4 (3.2 − 15.7) [6]	5.9 (3.6 − 8.1) [11]	5.4 (4.8 − 6.0) [46]
Blood GL-3 level category, μg/mL, n (%)
<4.7	38 (12.4)	33 (12.6)	5 (10.9)	0 (0.0)	38 (13.3)	15 (8.8)	0 (0.0)	5 (29.4)	18 (17.1)
4.7─<7.2	42 (13.7)	38 (14.6)	4 (8.7)	5 (23.8)	37 (13.0)	15 (8.8)	3 (25.0)	3 (17.6)	21 (20.0)
7.2─<11.3	36 (11.7)	33 (12.6)	3 (6.5)	1 (4.8)	35 (12.3)	26 (15.2)	2 (16.7)	2 (11.8)	6 (5.7)
≥11.3	36 (11.7)	35 (13.4)	1 (2.2)	4 (19.0)	32 (11.2)	32 (18.7)	1 (8.3)	1 (5.9)	1 (1.0)
Data not reported	155 (50.5)	122 (46.7)	33 (71.7)	11 (52.4)	143 (50.2)	83 (48.5)	6 (50.0)	6 (35.3)	59 (56.2)

Abbreviations: ERT, enzyme replacement therapy; GL-3, globotriaosylceramide.

The majority of patients had a classic phenotype (56.1%), and a smaller proportion were heterozygous females (34.4%), or had renal (5.6%) and cardiac (3.9%) variants. The mean (95% CI) age was 39.5 (37.7 − 41.3) years, and more than half (65.5%) of patients were male. Most patients had not received prior enzyme replacement therapy (76.2%), nor had a history of allergy to medications in general or atopic conditions (82.1%). Renal impairment was present in 37.5% of patients at baseline, and 40.4% had cardiac dysfunction. Cardiac dysfunction was more common in patients enrolled in the Drug Use Investigation population compared with the Special Drug Use Investigation population (58.7% vs 37.2%, respectively). Over half (55.2%) of heterozygous females had cardiac dysfunction at baseline. Pain in the extremities was the most common symptom (56.7%) followed by dyshidrosis (44.6%), and angiokeratoma (30.9%). The mean (95% CI) blood GL-3 level at baseline was 8.5 (7.7 − 9.4) μg/mL (the upper limit of normal: 7.03 μg/mL). A higher proportion of patients aged ≤15 years (19.0%) had a blood GL-3 level ≥11.3 at baseline compared with those aged >15 years (11.2%). A similar finding was also observed in patients with classic disease (18.7%) compared with patients with cardiac (8.3%) or renal (5.9%) variants and heterozygous females (1.0%).

3.3. Treatment

In the Safety Analysis Set, the mean (SD) total duration of study drug administration was 1363.7 (772.4) days, the mean (SD) total number of doses was 83.6 (50.4), and the mean dose was 0.93 mg/kg.

3.4. Safety

3.4.1. Incidence of Adverse Events

The incidence of AEs (with a PT incidence of ≥n = 3) in the safety analysis set, overall and by subgroup are presented in Table S1.

Overall, AEs occurred in 171 (55.7%) patients, including 155 (59.4%) patients in the Special Drug Use Investigation and 16 (34.8%) patients in the Drug Use Investigation. A slightly higher proportion of patients aged ≤15 years experienced AEs compared with those aged >15 years. Similarly, a higher proportion of patients with cardiac and classic disease experienced AEs compared with patients with renal variants and heterozygous females.

The most common AEs were general disorders and administration site conditions (n = 63, 20.5%), nervous system disorders (n = 62, 20.2%), and infections and infestations (n = 52, 16.9%).

3.4.2. Incidence of Adverse Drug Reactions

The incidence of ADRs (with a PT incidence of ≥n = 3) in the safety analysis set, overall and by subgroup are presented in Table 2, and the incidence of ADRs classified by SOC and PT, overall and by subgroup are presented in Table S2.

Table 2. Occurrence of adverse drug reactions (with a PT Incidence ≥n = 3^a) overall and by subgroup

	Total, n (%)	Special drug use results, n (%)	Drug use results, n (%)	Subgroup
				Age, years		Phenotype
				≤15	>15	Classic	Cardiac	Renal	Heterozygous
No. of evaluable cases	307	261	46	21	285	171	12	17	105
No. of ADRs	288	267	21	31	254	248	7	9	19
No. of patients with ADRs	93 (30.3)	85 (32.6)	8 (17.4)	11 (52.4)	81 (28.4)	72 (42.1)	3 (25.0)	4 (23.5)	12 (11.4)
No. of deaths for which causality could not be denied	8 (2.6)	6 (2.3)	2 (4.3)	0	8 (2.8)	7 (4.1)	0	0	0
No. of serious ADRs	25 (8.1)	23 (8.8)	2 (4.3)	1 (4.8)	24 (8.4)	18 (10.5)	0	0	6 (5.7)
No. of discontinuations due to ADRs	27 (8.8)	25 (9.6)	2 (4.3)	2 (9.5)	25 (8.8)	23 (13.5)	0	0	3 (2.9)
Occurrence of ADRs, SOC (PT)
Blood and lymphatic system disorders	6 (2.0)	5 (1.9)	1 (2.2)	─	6 (2.1)	5 (2.9)	─	1 (5.9)	─
Anemia	3 (1.0)	3 (1.1)	─	─	3 (1.1)	2 (1.2)	─	1 (5.9)	─
Nervous system disorders	30 (9.8)	28 (10.7)	2 (4.3)	4 (19.0)	25 (8.8)	21 (12.3)	─	1 (5.9)	7 (6.7)
Cerebral infarction	3 (1.0)	3 (1.1)	─	─	3 (1.1)	─	─	─	3 (2.9)
Dizziness	3 (1.0)	2 (0.8)	1 (2.2)	─	3 (1.1)	2 (1.2)	─	─	1 (1.0)
Headache	12 (3.9)	11 (4.2)	1 (2.2)	4 (19.0)	8 (2.8)	10 (5.8)	─	1 (5.9)	1 (1.0)
Hypoesthesia	4 (1.3)	4 (1.5)	─	─	4 (1.4)	4 (2.3)	─	─	─
Vascular disorders	12 (3.9)	10 (3.8)	2 (4.3)	2 (9.5)	10 (3.5)	9 (5.3)	2 (16.7)	─	1 (1.0)
Flushing	5 (1.6)	5 (1.9)	─	1 (4.8)	4 (1.4)	3 (1.8)	2 (16.7)	─	─
Respiratory, thoracic and mediastinal disorders	17 (5.5)	15 (5.7)	2 (4.3)	4 (19.0)	13 (4.6)	16 (9.4)	─	─	1 (1.0)
Dyspnea	7 (2.3)	6 (2.3)	1 (2.2)	1 (4.8)	6 (2.1)	7 (4.1)	─	─	─
Nasal congestion	7 (2.3)	7 (2.7)	─	2 (9.5)	5 (1.8)	7 (4.1)	─	─	─
Gastrointestinal disorders	12 (3.9)	12 (4.6)	─	3 (14.3)	9 (3.2)	12 (7.0)	─	─	─
Abdominal pain	4 (1.3)	4 (1.5)	─	─	4 (1.4)	4 (2.3)	─	─	─
Abdominal pain upper	4 (1.3)	4 (1.5)	─	─	4 (1.4)	4 (2.3)	─	─	─
Nausea	5 (1.6)	5 (1.9)	─	2 (9.5)	3 (1.1)	5 (2.9)	─	─	─
Vomiting	5 (1.6)	5 (1.9)	─	1 (4.8)	4 (1.4)	5 (2.9)	─	─	─
Hepatobiliary disorders	3 (1.0)	2 (0.8)	1 (2.2)	─	3 (1.1)	3 (1.8)	─	─	─
Hepatic function abnormal	3 (1.0)	2 (0.8)	1 (2.2)	─	3 (1.1)	3 (1.8)	─	─	─
Skin and subcutaneous tissue disorders	23 (7.5)	20 (7.7)	3 (6.5)	2 (9.5)	21 (7.4)	17 (9.9)	1 (8.3)	2 (11.8)	2 (1.9)
Erythema	3 (1.0)	3 (1.1)	─	─	3 (1.1)	1 (0.6)	1 (8.3)	─	─
Pruritus	6 (2.0)	6 (2.3)	─	─	6 (2.1)	5 (2.9)	─	1 (5.9)	─
Rash	10 (3.3)	9 (3.4)	1 (2.2)	1 (4.8)	9 (3.2)	8 (4.7)	1 (8.3)	─	1 (1.0)
Urticaria	8 (2.6)	8 (3.1)	─	1 (4.8)	7 (2.5)	7 (4.1)	1 (8.3)	─	─
Musculoskeletal and connective tissue disorders	9 (2.9)	7 (2.7)	2 (4.3)	1 (4.8)	8 (2.8)	9 (5.3)	─	─	─
Back pain	3 (1.0)	2 (0.8)	1 (2.2)	─	3 (1.1)	3 (1.8)	─	─	─
Pain in extremity	4 (1.3)	3 (1.1)	1 (2.2)	1 (4.8)	3 (1.1)	4 (2.3)	─	─	─
General disorders and administration site conditions	55 (17.9)	50 (19.2)	5 (10.9)	7 (33.3)	47 (16.5)	47 (27.5)	1 (8.3)	2 (11.8)	4 (3.8)
Chills	27 (8.8)	26 (10.0)	1 (2.2)	4 (19.0)	23 (8.1)	25 (14.6)	─	1 (5.9)	1 (1.0)
Feeling hot	3 (1.0)	3 (1.1)	─	─	3 (1.1)	2 (1.2)	─	─	1 (1.0)
Malaise	5 (1.6)	4 (1.5)	1 (2.2)	─	5 (1.8)	4 (2.3)	─	─	1 (1.0)
Pyrexia	33 (10.7)	31 (11.9)	2 (4.3)	5 (23.8)	27 (9.5)	30 (17.5)	─	2 (11.8)	─
Investigations	10 (3.3)	9 (3.4)	1 (2.2)	1 (4.8)	9 (3.2)	9 (5.3)	─	─	1 (1.0)
Blood pressure decreased	3 (1.0)	3 (1.1)	─	─	3 (1.1)	3 (1.8)	─	─	─

Notes: No. of patients (%) are shown. ^aRows that contain any event with a frequency of ≥n = 3 are presented. Coded using MedDRA/J version 16.1.

Abbreviations: ADR, adverse drug reaction; AE, adverse event; PT, preferred term; SAE, serious adverse event; SOC, system organ class.

Overall, ADRs occurred in 93 (30.3%) patients, including 85 (32.6%) patients in the Special Drug Use Investigation and 8 (17.4%) patients in the Drug Use Investigation. A higher proportion of patients aged ≤15 years experienced ADRs compared with those aged >15 years. Similarly, a higher proportion of patients with classic disease experienced ADRs compared with patients with cardiac or renal variants and heterozygous females.

Serious ADRs were experienced in 25 (8.1%) patients, and 8 deaths (2.6%) occurred during the study where the causality to agalsidase beta or ERT could not be denied by the investigator. The causes of these deaths were completed suicide (n = 1), cachexia (n = 1), pulmonary edema (n = 1), disseminated intravascular coagulation with pneumonia (n = 1), cardio-respiratory arrest (n = 1), sudden death (n = 1), and unexplained death (n = 2).

A total of 27 (8.8%) patients discontinued treatment due to ADRs, 25 (92.6%) of whom were older than 15 years and 2 (7.4%) of whom were pediatric patients. Common ADR events (occurring with an incidence of ≥2 events) which led to treatment discontinuation included chills (7 events), pyrexia (2 events), dyspnea (5 events), rash (3 events), urticaria (3 events), tremor (2 events), cardiac failure (2 events), rhinorrhea (2 events), wheezing (2 events), abdominal pain (2 events), abdominal pain upper (2 events), and pruritus (2 events).

The most common ADRs were general disorders and administration site conditions (n = 55, 17.9%), nervous system disorders (n = 30, 9.8%) and skin and subcutaneous tissue disorders (n = 23, 7.5%).

ADR occurrence, stratified by patient background characteristics, is presented in Table S3. A higher proportion of patients with a classic phenotype experienced ADRs compared with cardiac or renal variants and heterozygous females. No difference in the incidence of ADR was observed between patients with a presence of complications, including hepatic dysfunction and renal impairment, compared with patients without these complications. There was a numerically higher incidence of ADRs in patients with a blood GL-3 level ≥7.2 μg/mL.

3.4.3. Incidence of Adverse Drug Reactions Throughout the Course of the Study Period

The incidence of ADRs occurring throughout the course of the study period overall and by age and phenotype subgroups is presented in Figure 2.

Figure 2. Incidence of adverse drug reactions throughout the course of the study period A) Overall and by age and B) Phenotype subgroup

The incidence of ADRs was 22.3% within the first year of ERT and the cumulative incidence for the 7 years was 40.0%. When examined by disease phenotype, 33.7% of patients with classic disease experienced ADRs in the first year of ERT. In contrast, the incidence of ADRs in patients with cardiac variants was 9.1% in the first year and 22.1% in the first 2 years. The incidence of ADRs in patients with renal variants was 17.6% and 25.1% in the corresponding time periods, respectively. The incidence of ADRs was lower in heterozygous females compared with other phenotypes.

3.4.4. Timing of the Occurrence of Infusion-Associated Reactions Throughout the Course of the Study Period

The majority of infusion-associated reactions (92.5%) occurred within 2 h after administration of agalsidase beta. Infusion-associated reactions occurred within the first 15 min after administration in 22.6% of patients, and within 1 h after infusion in 71.7% of patients (Figure 3).

Figure 3. Timing of infusion-related reactions following initiation of agalsidase beta

3.4.5. Correlation Between Antibody Production and the incidence of Adverse Drug Reactions and Infusion-Associated Reactions

The correlation between antibody production and the incidence of adverse drug reactions and infusion-associated reactions is presented in Table 3. Overall, a significantly higher proportion of patients who were antibody-positive experienced ADRs and IARs compared with those who were antibody-negative.

Table 3. Correlation between antibody production and adverse drug reactions and infusion-associated reactions

	No. of patients with antibody testing data available			No. of ADRs			No. of IARs
	Total	Antibody-positive	Antibody-negative	With antibody	Without antibody	P value	With antibody	Without antibody	P value
Total No.	188	95	93	53	20		47	10
Phenotype
Classic	117	85	32	50	8	<0.001	46	4	<0.001
Cardiac	4	1	3	1	0		0	0
Renal	12	5	7	2	2		1	2
Heterozygous females	55	4	51	0	10		0	4
Previous ERT use
No	142	68	74	36	18	0.055	31	8	0.386
Yes	46	27	19	17	2		16	2
Blood GL-3 level category, μg/mL
<4.7	32	10	22	7	3	0.049	5	1	0.145
4.7─<7.2	36	10	26	3	4		3	2
7.2─<11.3	32	21	11	8	3		7	2
≥11.3	29	25	4	17	1		14	0
Data not reported	59	29	30	18	9		18	5
Maximum antibody titer				N = 53	N = 20		N = 47	N = 10
<800	22	22	0	5	0		4	0
800─<3,200	24	24	0	13	0		11	0
3,200─<6,400	14	14	0	11	0		10	0
≥6,400	34	34	0	24	0		22	0
Data not reported	94	1	93	0	20		0	10

Notes: No. of patients are shown.

Abbreviations: AE, adverse event; ERT, enzyme replacement therapy; GL-3, globotriaosylceramide; IAR, infusion-associated reactions.

A significantly higher proportion of patients with a classic phenotype who experienced ADRs and IARs were antibody-positive (ADRs: 58.8%; IARs: 54.1%) compared with patients who were antibody-negative (ADRs: 25.0%; IARs: 12.5%). However, it is difficult to compare antibody-positive patients with cardiac or renal variants and heterozygous females who experienced ADRs and IARs against antibody-positive patients who experienced ADRs and IARs in the overall population due to the limited number of patients in these subgroups.

Regarding prior exposure to ERT, there was a greater incidence of ADRs and IARs in the antibody-positive population with previous ERT use (ADRs: 63.0%; IARs: 59.3%) compared with the antibody-positive population without previous ERT use (ADRs: 53.0%; IARs: 45.6%). Of those who were antibody-positive, patients with a maximum antibody titer of <800 experienced ADRs and IARs with a lower incidence (ADRs: 22.7%; IARs: 18.2%) than patients with a maximum antibody titer of 800─<3,200 (ADRs: 54.2%; IARs: 45.8%), and a substantially lower incidence than those with a maximum antibody titer of 3,200-<6,400 (ADRs: 78.6%; IARs: 71.4%).

The relationship between AEs and ADR incidence and antibody status, including maximum IgG antibody titer value, was also examined separately throughout the course of the studies (Table 4). Compared with patients who were antibody-negative, a significantly higher proportion of patients who were antibody-positive experienced AEs (P = 0.015), SAEs (P = 0.021), ADRs (P < 0.001), IARs with and without a causal relationship (P = 0.006), IARs with a causal relationship (P < 0.001), serious IARs with and without a causal relationship (P = 0.033) and hypersensitivity reactions with and without a causal relationship (P < 0.001), including severe hypersensitivity reactions (P = 0.025). In contrast, no significant difference was observed between antibody-positive and antibody-negative patients experiencing serious ADRs (P = 0.498) and serious IARs with a causal relationship (P = 0.102).

Table 4. Relationship between adverse events and IgG antibody titer

		IgG antibody titer				Antibody status
	Overall	<800	800─<3200	3200─<6400	≥6400	Positive	Negative	P value
No. of patients with IgG results available	188	22 (23.4)	24 (25.5)	14 (14.9)	34 (36.2)	95 (50.5)	93 (49.5)	−
No. of patients with AEs	127	10 (13.9)	20 (27.8)	12 (16.7)	30 (41.7)	72 (75.8)	55 (59.1)	0.015
No. of patients with SAEs	70	8 (18.6)	13 (30.2)	8 (18.6)	14 (32.6)	43 (45.3)	27 (29.0)	0.021
No. of patients with ADRs	73	5 (9.4)	13 (24.5)	11 (20.8)	24 (45.3)	53 (55.8)	20 (21.5)	<0.001
No. of patients with serious ADRs	19	1 (9.1)	3 (27.3)	3 (27.3)	4 (36.4)	11 (11.6)	8 (8.6)	0.498
No. of patients with hypersensitivity reactions	47	2 (4.8)	9 (21.4)	9 (21.4)	22 (52.4)	42 (44.2)	5 (5.4)	<0.001
No. of patients with severe hypersensitivity reactions	5	0	2 (40.0)	0	3 (60.0)	5 (5.3)	0	0.025
No. of patients with IARs	92	6 (10.7)	14 (25.0)	10 (17.9)	26 (46.4)	56 (58.9)	36 (38.7)	0.006
No. of patients with serious IARs	19	2 (14.3)	5 (35.7)	0	7 (50.0)	14 (14.7)	5 (5.4)	0.033
No. of patients with IARs with causal relationship	57	4 (8.5)	11 (23.4)	10 (21.3)	26 (46.4)	47 (49.5)	10 (10.8)	<0.001
No. of patients with serious IARs with causal relationship	6	0	2 (40.0)	0	3 (60.0)	5 (5.3)	1 (1.1)	0.102

Abbreviations: AE, adverse event; ADR, adverse drug reactions, IAR, infusion-associated reactions; IgG, immunoglobulin G; SAE, serious adverse event.

3.5. Efficacy

3.5.1. Change in Blood GL-3 Level Throughout the Course of the Study Period

The change in mean blood GL-3 level throughout of the course of the study period in the 196 patients in the efficacy analysis set is presented in Figure 4. In the overall population, reductions in blood GL-3 levels were observed over the course of the study, from 8.7 ± 5.3 μg/mL at treatment initiation, to 5.7 ± 2.5 μg/mL at 6 months, and remained below 6.0 μg/mL at all subsequent time points. Similar findings were observed when examined by age-group (≤15 years versus >15 years) (Figure 4 and Table 5). Patients with a classic phenotype experienced a comparable reduction in the first 6 months, which was maintained throughout the study period. Reductions in blood GL-3 levels were also observed in patients with the cardiac variant in the first 6 months, and values were lower in heterozygous females during the study compared with baseline. Patient background factors associated with a greater mean reduction in blood GL-3 levels were male sex (P < 0.001), concomitant medications (P < 0.001), age >15 years (P < 0.001), and classic phenotype (P < 0.001). Similarly, large reductions in blood GL-3 were observed in patients irrespective of concomitant therapy use or the presence or absence of complications.

Figure 4. Change in blood GL-3 Level by (a) age subgroups, (b) disease phenotype, and (c) antibody status

Table 5. Change from baseline in blood GL-3 level by patient background factors

	No. of patients	Mean (SD) change from baseline in blood GL-3 level	P value
Concomitant medications
No	4	−4.3 (5.1)	0.191
Yes	117	−3.2 (4.2)	<0.001
Concomitant therapies
No	76	−3.3 (4.4)	<0.001
Yes	45	−3.3 (3.8)	<0.001
Gender
Male	90	−4.2 (4.4)	<0.001
Female	31	−0.6 (1.3)	0.020
Age category at initiation of ERT, years
≤15	9	−4.1 (3.9)	0.012
>15	112	−3.2 (4.2)	<0.001
Phenotype
Classic	75	−4.4 (4.2)	<0.001
Cardiac	4	−6.4 (7.8)	0.196
Renal	10	−0.8 (2.1)	0.275
Heterozygous	31	−0.6 (1.3)	0.020
Data not reported	1	−12.5	─
Complications
No	28	−4.8 (4.9)	<0.001
Yes	92	−2.8 (3.9)	<0.001
Data not reported	1	−4.6	─

Abbreviations: ERT, enzyme replacement therapy; GL-3; GL-3, globotriaosylceramide.

4. Discussion

The aggregated data from these two post-authorization safety studies, comprising a large cohort of over 300 patients with Fabry disease, demonstrate the long-term safety and efficacy of agalsidase beta in Japanese patients with Fabry disease in real-world practice. Overall, adverse drug reactions occurred in 30.3% of patients in the safety analysis population. Importantly, no unexpected safety signals or concerns were identified, indicating that the safety profile of agalsidase beta was consistent with the established profile of this drug [18].

The most common ADRs in the aggregated data set were general disorders and administration site conditions, nervous system disorders, and skin and subcutaneous tissue disorders. Respiratory, thoracic and mediastinal disorders, and gastrointestinal disorders were reported less frequently, but occurred more frequently in pediatric patients aged ≤15 years compared with the older population, and in those with classic disease compared with other phenotypes. By preferred term, the most common ADRs were pyrexia, chills, headache, rash, and urticaria. Common ADRs reported during our study were broadly consistent with AEs reported in previous clinical trials [24,25,29,30], including the Phase 2 registration clinical trial in Japan [26], as well as the known safety profile of agalsidase beta [18]. Rigors and fever were among the most frequently reported AEs associated with agalsidase beta in the Phase 3 study (48% and 24%, respectively) [24], 54-month extension study (59% and 36%, respectively) [25], and Phase 2 Japanese Bridging study (15─23% and 15%, respectively), with headache, chills, and hypertension less frequently reported [26]. However, differences in the methods of reporting of adverse events and the small sample size in some of the clinical trials precluded meaningful comparisons from being drawn.

When examined the time to onset of ADRs over the course of the studies (Figure 2), ADRs were predominantly reported within the first year after ERT initiation, with subsequent declines to year six. A similar but slightly more pronounced pattern was observed in the phase 3 and long-term extension studies, in which an increase in ADRs was observed in the first 2 years of ERT treatment, suggesting that only a small proportion of patients may newly experience ADRs after 1 year from ERT initiation [25,30].

IgG antibodies developed in 50.5% of patients overall, which is substantially lower than the rate of IgG seroconversion reported in the product information for agalsidase beta in adult (79%) and pediatric (69%) patients [18], and the rate reported in the Japanese Phase 2 study (85%) [26]. Overall, the incidence of ADRs and IARs was higher in patients who were antibody-positive compared with those who were antibody-negative, and generally increased with increasing antibody titer level. There was no statistically significant difference in serious ADR incidence (P = 0.498) between patients with either the presence or absence of anti-drug antibodies (ADAs). However, these results should be interpreted with caution due to the relatively small number of antibody-positive (n = 11) and antibody-negative (n = 8) patients, and warrant confirmation in larger, well-designed trials.

Although no clear guidelines exist regarding the management of antibodies in Fabry disease patients treated with agalsidase beta [18], routine antibody testing in patients undergoing ERT [31,32], and close monitoring of patients with elevated antibody titers [33], particularly during the infusion process, are recommended. More recently, the application of immune tolerance induction protocols used in other lysosomal storage diseases for Fabry disease have been suggested as a possible means of preventing ADA formation in ERT-naïve patients and decreasing or saturating existing antibody titers in antibody-positive patients, although the benefit remains to be established [31,34].

Compared with other studies conducted globally and in Japan, a higher proportion of patients in our study had classic disease [35–37]. As agalsidase beta was the first approved medication for Fabry disease in Japan, it is likely that patients with relatively severe disease preferentially received agalsidase beta due to its high dosage (1 mg/kg of body weight). There was no substantial difference in the incidence of specific clinical symptoms of Fabry disease in our studies when compared against the existing literature [12,38]. Pain in the extremities was the most common symptom, and was particularly common in children aged ≤15 years and those with classic disease, followed by dyshidrosis, and angiokeratoma. Predictably, cardiac dysfunction was present in over 80% of patients with the cardiac variant at baseline. Cardiac hypertrophy is a frequent observation in patients with cardiac variants of Fabry disease and is associated with lysosomal accumulation of GL-3 [39]. Notably, over half of heterozygous females had cardiac dysfunction at baseline, consistent with the findings by MacDermot et al. (2001), who reported a high prevalence of cardiac manifestations in female patients, including chest pain, heart valve abnormalities, and arrhythmia [38]. Although ‘carrier’ females were once thought to be clinically unaffected [40], it is now recognized that heterozygous females with Fabry disease should be monitored for signs and symptoms of cardiovascular manifestations and renal impairment and considered for enzyme replacement therapy [41].

The mean age of patients with Fabry disease was 39.5 years, and most patients (76.2%) had no prior exposure to enzyme replacement therapy. By this stage, 40.4% of patients had cardiac dysfunction and 37.5% had renal impairment. It is well recognized that patients who initiate enzyme replacement therapy early in the disease experience greatest benefit, including delays in kidney and cardiac involvement [25,42]. In contrast, patients who initiate treatment at an older age, once substantial organ damage had already likely occurred, may experience continued disease progression despite therapy [42,43]. Nevertheless, efficacy was demonstrated in the overall population, irrespective of age (including elderly patients) or antibody status, with patients experiencing a substantial decline in GL-3 levels throughout the course of ERT treatment.

All recombinant protein products, including agalsidase beta, have the potential to trigger immunogenicity reactions, particularly with long-term use [44]. The presence of ADAs during enzyme replacement therapy has been previously reported, with concerns over loss of drug efficacy and disease progression, including increased cellular Gb-3 deposition [45] and plasma lyso-Gb3 concentrations [46,47]. Interestingly, Lenders et al. (2016) demonstrated that, in patients who seroconverted, saturation of ADA-binding sites during agalsidase beta treatment resulted in a stable interventricular septum thickness and a significant decrease in plasma lyso-Gb3 levels over time compared with non-saturated patients, presumably as a result of free enzyme activity [47]. These findings suggest that, in patients with ADAs, a saturated status may be preferential during infusion in terms of clinical outcome and management of progressive deterioration.

Monitoring of blood GL-3 levels is a clinically important tool to assess disease progression [48]. However, results of our current study and others suggest that blood GL-3 may not be a sensitive enough marker [49,50], including in patients with cardiac and renal variants and heterozygous females, most of whom do not exhibit a high plasma GL-3 concentration [51,52]. Recently, lyso-Gb3 has been suggested as a more sensitive biomarker for diagnosis and monitoring of response to enzyme replacement therapy [49,50]. Although not specifically measured in the post-authorization safety studies, elevated levels of lyso-Gb3 correctly identified both classic and late-onset mutations in males and females in a study of 2,360 Japanese patients with suspected Fabry disease [53].

Limitations were inherent to post-marketing safety studies, and included the noninterventional, observational study design, with the lack of an independent control arm, and incomplete or missing data. This included missing information regarding the normalized ratio of α-GAL activity to the standard reference value. Further, the correlation between phenotype and genotype information regarding GLA gene mutations in each patient was also not available for these studies, which precluded any associations between genotype and phenotype from being investigated. Nevertheless, the diagnosis of Fabry disease and management of ERT in all Fabry disease patients was performed in accordance with the guidance document of Fabry Disease-Diagnosis and Management Handbook for Japanese [54]. Further, the study populations represent a particularly large cohort of patients when taking into consideration the relative rarity of Fabry disease, and also reflect the type of patients seen in clinical practice with a relative lack of selection bias compared with randomized controlled design types.

5. Conclusions

Results of this analysis of aggregated data from these two post-authorization safety studies, conducted in over 300 Japanese patients with Fabry Disease, demonstrate the long-term safety and efficacy of agalsidase beta over a period of up to 7 years. Overall, agalsidase beta was well tolerated, and the safety profile of adverse drug reactions, including hypersensitivity reactions and infusion-related reactions, was broadly consistent with that reported in previous global clinical trials [24,25], and the Phase 2 study in Japan [26]. Further, no unexpected safety signals and concerns were identified. These findings add to the wealth of data supporting the long-term safety and efficacy of agalsidase beta in the treatment of Fabry disease [27,42].

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Declaration of interest

All authors are employees of Sanofi K.K. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data sharing statement

Data supporting the findings of this study are available in the supplementary material of this article.

Acknowledgments

The authors thank all clinicians for their involvement and contribution to the study. The authors also thank Jordana Campbell, BSc, CMPP of inScience Communications, Springer Healthcare, for writing the outline and the first draft of the manuscript. This medical writing assistance was funded by Sanofi K.K.

Supplemental material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was funded by Sanofi Genzyme.