Updated literature review of agalsidase alfa (Replagal®) and agalsidase beta (Fabrazyme®) for the treatment of Fabry disease
Page last updated: 01 August 2011
Public Summary Document
Topic: Updated literature review of agalsidase
alfa (Replagal®) and agalsidase beta
(Fabrazyme®) for the treatment of Fabry
disease
Sponsor: Shire Australia Pty Ltd and Genzyme
Australasia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Item
The PBAC was to consider a report on the updated literature review
of the comparative efficacy and safety of agalsidase alfa
(Replagal®) versus agalsidase beta
(Fabrazyme®) supplied under the Life Saving Drugs
Program (LSDP) for the treatment of Fabry disease, to determine
whether the pricing disparity in the average yearly patient
treatment cost at the registered doses between these agents was
justified.
2. Background
Agalsidase alfa and agalsidase beta were added to the LSDP in
2004.
In January 2009, the Access and Systems Branch of the Department of
Health and Ageing requested the PBAC’s advice on the current
drugs (agalsidase alfa and agalsidase beta) used to treat Fabry
disease under the LSDP. A literature review was conducted in
February 2009 to update the evidence base for both agalsidase alfa
and beta (previously reviewed by the PBAC in 2002-2003) as well as
to evaluate the comparative efficacy and safety of the two
treatments. Both sponsors were given the opportunity to prepare
detailed submissions for the November 2009 PBAC meeting. The
purpose of this current review was to evaluate the new data
presented in these submissions and to identify any issues related
to the comparative efficacy and safety of the two treatments. This
current review was supplementary to the original review conducted
in February 2009.
3. Registration Status
Agalsidase alfa (ghu) was registered with the Therapeutic Goods
Administration (TGA) on 17 May 2002 for long-term enzyme
replacement therapy of patients with Fabry disease
(alpha-galactosidase A deficiency).
Agalsidase beta-rch was TGA registered on 30 May 2002 for long-term
enzyme replacement therapy in patients with a confirmed diagnosis
of Fabry disease (alpha-galactosidase deficiency).
4. Clinical Place for the Proposed Therapy
Fabry disease is a rare (incidence generally estimated at 1 in
40,000 to 1 in 117,000), X-linked genetic disorder caused by a
deficiency of the enzyme alpha-galactosidase A, which is required
for the degradation of globotriaosylceramide (GB3 or GL-3) and
other related glycosphingolipids. Accumulation of
glycosphingolipids in various tissues (particularly the kidneys,
heart and brain) of patients with Fabry disease can disrupt
cellular function and lead to the development of serious
complications and reduced life expectancy. Treatment with either
agalsidase alfa or agalsidase beta provides an exogenous source of
the alpha-galactosidase A enzyme.
5. Clinical Trials
The scientific basis of the February 2009 report was one
head-to-head trial of agalsidase alfa versus agalsidase beta
(Vedder et al 2007), two trials of agalsidase alfa versus placebo
(Schiffmann et al 2001, Hajioff et al 2003) and two trials of
agalsidase beta versus placebo (Eng et al 2001, Banikazemi et al
2007). These studies are shown below. Various extensions of these
trials provided data beyond the initial trial periods.
| Trial ID/First author | Protocol title | Publication citation |
| Dose ranging studies & studies using non-approved doses | ||
| Clarke et al. (2007) | The pharmacology of multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease. | Genetics in Medicine 9: 504-509 |
| Eng et al. (2001b) | A phase 1/2 clinical trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance and safety studies. | The American Journal of Human Genetics 68: 711-722 |
| Lubanda et al. (2009) | Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease. | Genetics in Medicine 11: 256-264 |
| Schiffmann et al. (2007) | Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing. | Journal of the American Society of Nephrology 18: 1576-1583 |
| Renal outcome studies | ||
| Cybulla et al. (2009) | Kidney transplantation in patients with Fabry disease. | Transplant International 22: 475-481 |
| Feriozzi et al. (2009) | Agalsidase alfa slows the decline in renal function in patients with Fabry disease. | American Journal of Nephrology 29: 353-361 |
| West et al. (2009) | Agalsidase alfa and kidney dysfunction in Fabry disease. | Journal of the American Society of Nephrology 20: 1132-1139 |
| Cardiovascular outcome studies | ||
| Beer et al. (2006) | Impact of enzyme replacement therapy on cardiac morphology and function and late enhancement in Fabry’s cardiomyopathy. | The American Journal of Cardiology 97: 1515-1518 |
| Imbriaco et al. (2009) | Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long term cardiac magnetic resonance imaging study. | Heart 95: 1103-1107 |
| Weidemann et al. (2003) | Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: A prospective strain rate imaging study. | Circulation 108: 1299-1301 |
| Weidemann et al. (2009) | Long-term effects of enzyme replacement therapy on Fabry cardiomyopathy: Evidence for a better outcome with early treatment. | Circulation 119: 524-529 |
| Women and children studies | ||
| Baehner et al. (2003) | Enzyme replacement therapy in heterozygous females with Fabry disease: Results of a phase IIIB study. | Journal of Inherited Metabolic Disease 26: 617-627 |
| Schiffmann et al. (2009) | Agalsidase alfa in children with Fabry disease – A 4-year prospective study. | Abstract presented at American College of Medical Genetics Annual Meeting in March 2009 . |
| Whybra et al. (2009) | A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. | Genetics in Medicine 11: 441-449 |
| Immunogenicity studies | ||
| Benichou et al. (2009) | A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. | Molecular Genetics and Metabolism 96:4-12 |
| Linthorst et al. (2004) | Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta. | Kidney International 66: 1589-1595 |
| Vedder et al. (2008) | Treatment of Fabry disease with different dosing regimens of agalsidase: Effects on antibody formation and GL-3. | Molecular Genetics and Metabolism 94: 319-325 |
At the time of the February 2009 literature review there were no
published randomised trials that directly compared the efficacy of
agalsidase alfa and agalsidase beta at currently approved doses
(alfa 0.2 mg/kg every other week; beta 1.0 mg/kg every other
week).
6. Results of Trials
In general, the published trials and their long-term extensions appeared to support
the efficacy of agalsidase alfa and agalsidase beta (in terms of both a reduction
in clinical symptoms as well as an improvement/stabilisation of surrogate endpoints).
In the only head-to-head trial, agalsidase alfa and beta appeared to have similar
short-term efficacy (24 months) at an equal dose of 0.2 mg/kg every other week (no
differences in reported clinical or surrogate endpoints with neither product achieving
the primary endpoint at 0.2 mg/kg). However it was difficult to make comparisons between
agalsidase alfa and beta in the placebo controlled trials due to the differences in
patient populations and outcome measures.
Biochemical / pharmacokinetic evidence:
The PBAC noted that the amino acid sequences of both products are identical. In terms
of glycosylation, the oligosaccharide side chains are similar in both products, however
there are some slight differences, namely that agalsidase beta (which is produced
from cultured CHO cell lines) has a higher proportion of mannose-6-p (which is required
for binding to target cells and delivery to the lysosome) compared to agalsidase alfa
which carries the same glycosylation profile as the native human enzyme. The differences
in glycosylation are summarised in the table below, taken from Lee et al (2003).
Table III: Monosaccharide composition
| Monosaccharide mol/mol protein | ||
| Monosaccharide | Fabrazyme | Replagal |
| Fucose | 1.8 ± 0.1 | 3.0 ± 0.3 |
| Galactose | 8.0 ± 0.4 | 12.2 ± 1.0 |
| N-acetylglucosamine | 18.4 ± 0.8 | 22.5 ± 2.3 |
| Mannose | 25.7 ± 1.8 | 27.6 ± 0.5 |
| Mannose-6-phosphate | 3.1 ± 0.1 | 1.8 ± 0.0 |
| N-acetylneuraminic acid | 7.0 ± 1.0 | 6.9 ± 0.6 |
| Sialic acid: galactose | 0.88 | 0.56 |
Source: Lee et al, Glycobiology 2003; 13 305
The PBAC noted that the pharmacokinetic characteristics of the products are also similar,
with receptor binding improved in agalsidase beta compared to agalsidase alfa, but
no difference in fibroblast uptake at 10 hours after dosing. It was also noted that
Blom et al (2003) showed that functional correction of Fabry fibroblasts in vitro
for both products was also identical at identical molar exposure (0.1 mmol per hour
for 3 hours).
The registered doses of the agalsidase treatments reflected the dosage used in the
trials.
Overall, the PBAC agreed that there is neither biochemical nor pharmacokinetic evidence
to explain the five-fold difference in dose (alfa 0.2 mg/kg every other week versus
beta 1.0 mg/kg every other week) between the products.
Dose-ranging studies
The PBAC considered that overall, many of the dose-ranging studies included in the
submissions were inadequate to determine the optimal dose, since they were all short
term studies. All studies used plasma GB3 levels as their primary endpoint. Eng et
al (2001b) suggested faster plasma GB3 clearance at higher doses and GB3 was effectively
cleared from endothelium of the liver, skin, heart and kidney with agalsidase beta.
For agalsidase alfa, no differences were shown between 0.2 mg/kg biweekly and higher
doses (including 0.4 mg/kg biweekly, 0.2 mg/kg weekly and 0.4 mg/kg weekly) in a 10
week study to evaluate the effect of dose and dosing frequency on plasma GB3 levels
(Clarke et al (2007).
Two longer term (24 months) studies investigating non-approved dosage regimens were
also presented. The PBAC noted Shiffmann et al (2007) compared agalsidase alfa 0.2
mg/kg at dosing frequencies of biweekly (2-4 years) then weekly (further 2 years)
and found no changes in plasma or urine GB3 beyond the significantly reduced levels
already observed with biweekly dosing. A reduced rate of decline in estimated glomerular
filtration rate (eGFR) was observed, with increased dose frequency in this group of
patients. The PBAC also noted Lubanda et al (2009) reported that the majority of patients
switched to a lower maintenance dose of agalsidase beta (0.3 mg/kg every other week)
after being treated with the standard dose of agalsidase beta (1.0 mg/kg every other
week for 6 months) maintained similar levels of GB3 clearance, thereby noting that
a lower maintenance dose may be sufficient for some patients after stabilisation with
the standard dosing. However Lubanda et al (2009) note that the long term clinical
effects of transitioning to the lower dose have not been evaluated.
Clinical outcome studies
The PBAC noted that there were no published randomised controlled trials comparing
agalsidase alfa and agalsidase beta at their approved doses. The only published head-to-head
trial of agalsidase treatments compared both treatments at the same dose of 0.2 mg/kg
every other week (Vedder et al 2007). The recommended dose of agalsidase beta is 1.0
mg/kg every other week.
Vedder et al (2007) showed no significant differences between treatments when agalsidase
alfa and agalsidase beta were compared at identical doses of 0.2 mg/kg biweekly, as
shown in the table below. High rates of treatment failure were noted by the authors
in both treatment groups dosed at 0.2 mg/kg biweekly however it was also noted that
treatment failure occurred predominantly in patients with more extensive pre-treatment
manifestations based on the Mainz Severity Score Index scores and were generally older
than non treatment failures.
Summary of results of the direct comparison between agalsidase alfa and agalsidase
beta (Vedder et al 2007)
| Outcome | n | Agalsidase alfa (0.2 mg/kg) [N = 20] | n | Agalsidase beta (0.2 mg/kg) [N = 16] |
| Primary outcome | ||||
| LV mass | 13 | Baseline median 288g (range 177, 479) | 13 | Baseline median 316g (range 213, 517) |
| 10 | Median change at 12 months -23g (range -167, 136) p = 0.51 | 10 | Median change at 12 months -46g (range -226, 131) p = 0.17 | |
| No significant change was observed in either treatment group at 12 months or 24 months (data not reported) | ||||
| Key secondary outcomes | ||||
| Treatment failure a | 18 | 5 (28%) patients failed treatment within 24 months | 16 | 3 (19%) patients failed treatment within 24 months |
| The time to occurrence of treatment failure did not differ between treatment groups ( p = 0.54) | ||||
| Urinary GL-3 | NR | Median change at 12 months -284 nmol/24hr (range -4939, 1350), p = 0.04 | NR | Median change at 12 months -265 nmol/24hr (range -1216, 1450, p = 0.66 |
| Agalsidase alfa significantly reduced urinary GL-3 compared to baseline. There was no significant difference in the median change at 12 months between alfa and beta ( p = 0.65) | ||||
| Plasma GL-3 | 10 | Median change at 12 months -2.56 umol/L (range -5.81, 0.32), p = 0.009 | 8 | Median change at 12 months -1.84 umol/L (range -5.17, -0.23), p = 0.012 |
| Both treatments significantly reduced plasma GL-3 compared to baseline. There was no significant difference in the median change at 12 months between alfa and beta ( p = 0.46) | ||||
Abbreviations: LV, left ventricular
a Treatment failure was defined as progression of renal disease (33% increase in serum
creatinine, need for dialysis or transplantation); cardiac disease (new infarction,
need for cardioversion, or anti-arrhythmic drugs, heart-failure necessitating hospitalization),
or occurrence of a new cerebrovascular accident as diagnosed by a neurologist or new
lacunar infarctions on magnetic resonance imaging as assessed by an experienced neuro-radiologist.
For the primary outcome of change in left ventricular mass, no significant change
was observed in either treatment group at 12 months or 24 months. The PBAC considered
that the results of this trial were uncertain due to the small sample size, open label
design and possible differences in patient discontinuations between the treatment
arms.
Summary of clinical events in agalsidase beta trials
| Trial ID | Outcome | Agalsidase | Placebo | Hazard ratio (95% CI) |
| Agalsidase beta vs. placebo | ||||
| Banikazemi (2007) | Time to first clinical event | Patients with clinical events 14/51 (27%) | Patients with clinical events 13/31 (42%) | 0.47 (0.21, 1.03) ( p = 0.06) a |
| Time to first renal event | Patients with renal events 10/51 (20%) | Patients with renal events 7/31 (23%) | 0.49 (0.17, 1.4) ( p = 0.18) | |
| Time to first cardiac event | Patients with cardiac events 3/51 (6%) | Patients with cardiac events 4/31 (13%) | 0.42 (0.058, 2.7) ( p = 0.42) | |
| Time to first cerebrovascular event | Patients with cerebrovascular events 0/51 (0%) | Patients with cerebrovascular events 2/31 (6%) | 0.0 (0.0, 3.2) ( p = 0.14) | |
Note: Clinical event = renal or cardiac or cerebrovascular event
Renal event (33% increase in serum creatinine on two consecutive occasions or ESRD
requiring long-term dialysis or transplantation); cardiac event (infarction, new symptomatic
arrhythmia requiring antiarrhythmic medication, pacemaker or cardioversion or defibrillator
implantation, unstable angina with EKG changes requiring hospitalisation, heart failure
requiring hospitalisation); cerebrovascular event (stroke or transient ischemic attack
document by physician).
a Post-hoc secondary analyses: protocol adherent patients – hazard ratio 0.39 (95%
CI: 0.16, 0.93, p = 0.034); patients with GFR > 55 ml/min – hazard ratio 0.19 (95% CI: 0.05, 0.82,
p = 0.025); patients with GFR < 55 ml/min – hazard ratio 0.85 (95% CI: 0.32, 2.3, p = 0.75)
The 18 month study by Banikazemi et al (2007) identified a statistically significant
reduction in risk of clinical events (based on post-hoc analyses of protocol adherent
patients) and a non-significant trend towards agalsidase beta delaying time to first
event (renal, cardiac, cerebrovascular event or death) compared to placebo. Clinical
events have not been reported as outcomes in agalsidase alfa trials.
An indirect comparison of Fabry patients treated with agalsidase alfa at 0.2 mg/kg
biweekly or agalsidase beta at 1.0 mg/kg biweekly provided no clear conclusion in
the comparative rate of change of eGFR in patients. A comparison of results from Schiffmann
et al (2001) and Eng et al (2001) suggested more responders for both renal and cardiac
GB3 clearance in patients treated with agalsidase beta compared to agalsidase alfa.
However, the PBAC agreed that there was methodological confounding around these results,
particularly related to the methods of detection of GB3.
With respect to the impact of either product on cardiac outcomes, Vedder et al (2007)
showed no effect when both products were dosed at 0.2 mg/kg biweekly, however Beer
et al (2006), Imbriaco et al (2009) and Weidemann et al (2003, 2009) reported that
left ventricular mass and measures of myocardial function were improved with agalsidase
beta (1.0mg/kg biweekly) treatment. Hughes et al (2008) and Baehner et al (2003) reported
improved left ventricular mass in patients treated with agalsidase alfa. However,
it was noted that the clinical relevance of left ventricular mass as an outcome in
Fabry patients was uncertain as these patients tend to suffer poor diastolic function.
The results for renal and cardiac GB3 clearance are presented in the table below.
Renal and cardiac GB3 clearance in agalsidase alfa and agalsidase beta trials
| Trial ID | Outcome | Agalsidase | Placebo | p-value |
| Agalsidase alfa vs placebo | ||||
| Schiffmann et al (2001) | Kidney GB3 (nmol/mg tissue) | Mean baseline 19.5 (SE 1.68), mean final 15.6 (SE 1.60) | Mean baseline 19.0 (SE 3.59), mean final 18.1 (SE 3.18) | Change from baseline (p = 0.27) |
| Hughes et al (2008) | MRI change in LV mass (g) | -11.5 | 21.8 | 0.041 |
| ECG change in LV mass (g) | -6.2% | 6.3% | > 0.05 | |
| QRS duration (ms) | -12.9 | 4 | 0.8 | |
| Schiffmann (2001) | Mean change in QRS complex duration (ms) | -2.4 | 3.6 | 0.047 |
| Agalsidase beta vs placebo | ||||
| Eng et al (2001) | Proportion kidney GB3 free a | 20/29 free of kidney GB3 (69%) | 0/29 free of kidney GB3 (0%) | Chi-square test (p < 0.001) |
| Kidney GB3 score a | Mean baseline 1.9 (SD 0.8), mean final 0.4 (SD 0.7) | Mean baseline 2.2 (SD 0.7), mean final 2.1 (SD 0.8) | Change from baseline (p < 0.001) | |
Abbreviations: SD, standard deviation; SE, standard error
a Pathologist histology score for GB3 clearance, scale 0-3 with 0 score indicating
only trace amounts of GB3 and 3 score indicating large accumulations of GB3 ECG, electrocardiogram;
LV, left ventricular; MRI, magnetic resonance imaging.
Both treatments appeared to have similar safety profiles however agalsidase beta may
have a less favourable immunogenicity profile. IgE antibodies as well as a higher
frequency of IgG antibodies have been reported with agalsidase beta compared to agalsidase
alfa. The implication of these antibody responses is unclear.
7. Clinical Claim
Agalsidase alfa
The submission from the sponsor of agalsidase alfadescribed
agalsidase alfa as equivalent in terms of comparative efficacy to
agalsidase beta. The submission claimed that the current evidence
(direct and indirect) for both products could not distinguish any
clear advantage of either product at the approved dose. The
submission suggested that it is reasonable to assume that the
agalsidase treatments are equi-effective in the absence of any
direct comparison between treatments at their approved doses.
Agalsidase beta
The submission from the sponsor of agalsidase beta described
agalsidase beta as superior in terms of comparative efficacy over
agalsidase alfa. The submission claimed that the current body of
evidence demonstrated that agalsidase beta treatment at the TGA
approved dose of 1 mg/kg biweekly improves clinical outcomes, renal
outcomes and cardiovascular outcomes in Fabry disease patients. The
submission appeared to suggest that equivalence between agalsidase
treatments could not be assumed without sufficient evidence that
agalsidase alfa can improve outcomes similarly to agalsidase beta
(e.g. clinical, renal, cardiovascular) in Fabry disease
patients.
The PBAC considered that there are significant areas of uncertainty
regarding the evidence of comparative effectiveness of agalsidase
alfa versus agalsidase beta. The PBAC noted that against most of
the surrogate outcomes there appears to be no significant
difference between the two agents, although there seems to be a
trend which favours higher doses used in agalsidase beta. The
clinical outcomes reported for agalsidase beta have not been
reported for the alfa form but the PBAC regarded that this is not
evidence of superiority for agalsidase beta. The PBAC also noted
that switching between the products in Australia rarely occurs
which suggests that they may have similar patient-relevant
outcomes.
The PBAC concluded that the optimal doses for agalsidase alfa and
agalsidase beta are uncertain and that there was an insufficient
scientific basis at the time of the review for the dose difference
between these agents based on clinical or physiochemical endpoints.
The PBAC noted that while the beta form may stimulate the greater
production of antibodies (of the small number of patients analysed
for anti-agalsidase antibodies in Vedder et al (2007), anti-bodies
were found in 4 out of 8 agalsidase alfa patients versus 6 out of 8
agalsidase beta patients) which may result in a greater dose
requirement, the data to support this hypothesis are
uncertain.
8. Recommendation and Reasons
The PBAC recommended that the price of agalsidase beta (Fabrazyme)
be reduced to meet the cost on a per patient basis of agalsidase
alfa (Replagal) on the basis that there is insufficient evidence at
this stage to support a finding that there is any clinical
difference between the alfa and beta forms at the registered
doses.
The PBAC noted that the amino-acid sequences of both products are
identical. In terms of glycosylation, the oligosaccharide side
chains are similar in both products, however there are some slight
differences, namely that agalsidase beta (which is produced from
cultured CHO cell lines) has a higher proportion of mannose-6-p
(which is required for binding to target cells and delivery to the
lysosome) compared to agalsidase alfa which is carries the same
glycosylation profile as the native human enzyme. The
pharmacokinetic characteristics of the products are also similar,
with receptor binding improved in agalsidase beta compared to
agalsidase alfa, but no difference in fibroblast uptake at 10 hours
after dosing. The study Blom et al (2003) showed that functional
correction of Fabry fibroblasts in vitro for both products is also
identical at identical molar exposure (0.1 mmol per hour for 3
hours).
The PBAC agreed that overall there is neither biochemical nor
pharmacokinetic evidence to explain the five-fold dose difference
(alfa 0.2 mg/kg every other week versus beta 1.0 mg/kg every other
week) between agalsidase alfa and agalsidase beta.
There are no published randomised controlled trials comparing
agalsidase alfa and agalsidase beta at their approved doses. The
only published head-to-head trial of agalsidase treatments compared
both treatments at the same dose of 0.2 mg/kg every other week
(Vedder et al 2007). The dose of agalsidase beta used in this study
was lower than currently recommended (1.0 mg/kg every other week)
with high rates of treatment failure noted by the authors in both
treatment groups at a dose of 0.2 mg/kg biweekly.
Vedder et al (2007), the head-to-head study which forms part of the
scientific basis of comparison in the literature review, showed no
significant differences between treatments when agalsidase alfa and
agalsidase beta were compared at identical doses of 0.2 mg.
The PBAC considered that overall many of the dose-ranging studies
included in the submissions were inadequate to determine the
optimal dose, since they are all short term studies (i.e. 10
weeks). All studies used plasma GB3 levels as their primary
endpoint, with no differences shown between 0.2 mg/kg biweekly and
higher doses for agalsidase alfa (including 0.4 mg/kg biweekly, 0.2
mg/kg weekly and 0.4 mg/kg weekly). One study, Eng et al (2001b),
suggested faster GB3 clearance at higher doses for agalsidase beta,
however the clinical relevance of these outcomes remains unclear,
given the chronicity of the condition. Two longer term (24 months)
studies, of poor design, investigating non-approved dosage regimens
compared agalsidase alfa 0.2 mg/kg at dosing frequencies of weekly
and biweekly (Shiffmann et al (2007) and found no changes in plasma
or urine GB3, but a reduced rate of decline in eGFR, with increased
dose frequency). Lubanda et al (2009) found no significant
difference in tissue, plasma or urine GB3 when agalsidase beta
patients had their doses reduced from 1.0 mg/kg biweekly to 0.3
mg/kg biweekly.
In terms of clinical outcomes, an indirect comparison of Fabry
patients treated with agalsidase alfa at 0.2 mg/kg biweekly or
agalsidase beta at 1.0 mg/kg biweekly provided no clear conclusion
in the comparative rate of change of eGFR in patients. A comparison
of results from Schiffmann et al (2001) and Eng et al (2001)
suggest more responders for both renal and cardiac GB3 clearance in
patients treated with agalsidase beta compared to agalsidase alfa,
however, it was noted there was methodological confounding around
these results, particularly related to the methods of detection of
GB3.
Vedder et al (2007) showed no effect of either product on cardiac
outcomes when both products were dosed at 0.2 mg/kg biweekly,
however Beer et al (2006), Imbriaco et al (2009) and Weidemann et
al (2003, 2009) reported that left ventricular mass and measures of
myocardial function were improved with agalsidase beta (1.0 mg/kg
biweekly) treatment. Hughes et al (2008) reported improved left
ventricular mass in patients treated with agalsidase alfa. However,
the clinical relevance of left ventricular mass as an outcome in
Fabry patients, who tend to suffer poor diastolic function, was
questioned.
The PBAC considered that there are significant areas of uncertainty
regarding the evidence of comparative effectiveness of agalsidase
alfa versus agalsidase beta. The PBAC noted that against most of
the surrogate outcomes there appears to be no significant
difference between the two agents, although there seems to be a
trend which favours higher doses used in agalsidase beta. The
clinical outcomes reported for agalsidase beta have not been
reported for the alfa form but the PBAC regarded that this is not
evidence of superiority for agalsidase beta. The PBAC also noted
that switching between the products in Australia rarely occurs
which suggests that they may have similar patient-relevant
outcomes.
The PBAC concluded that the optimal doses for agalsidase alfa and
agalsidase beta are uncertain and that there was an insufficient
scientific basis at the time of the review for the dose difference
between these agents based on clinical or physicochemical
endpoints. The PBAC noted that while the beta form may stimulate
the greater production of antibodies which may result in a greater
dose requirement, the data to support this hypothesis are
uncertain.
The PBAC indicated its willingness to reconsider the situation when
more definitive data become available. The PBAC noted that the
Canadian Fabry Disease Initiative Study of enzyme replacement
therapy for Fabry disease is in progress which is the first
head-to-head comparison of the agalsidase treatments at their
approved doses.
9. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
10. Sponsors’ Comment
Genzyme reaffirms its views on the clinical evidence, comparative
effectiveness and dosing of agalsidase beta as outlined under
‘7. Clinical Claim Agalsidase beta’.
Shire maintains its position regarding agalsidase alfa as described
under ‘7. Clinical Claim Agalsidase alfa’.
