Alglucosidase Alfa, powder for I.V. infusion, 50 mg, Myozyme® - July 2011
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Public Summary Document
Product: Alglucosidase Alfa, powder for I.V.
infusion, 50 mg, Myozyme®
Sponsor: Genzyme Australasia Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The re-submission sought a recommendation for inclusion on the Life
Saving Drugs Program (LSDP) for the treatment of late onset Pompe
disease.
Life Saving Drugs Program:
Through the Life Saving Drugs Program (LSDP), the Australian
Government provides subsidised access, for eligible patients, to
expensive and potentially life saving drugs for very rare
life-threatening conditions.
Before a drug is made available on the LSDP it must generally be
accepted by the Pharmaceutical Benefits Advisory Committee as
clinically necessary and effective, but not recommended for
inclusion on the Pharmaceutical Benefits Scheme due to unacceptable
cost-effectiveness.
2. Background
Alglucosidase alfa has been considered by the PBAC on four previous occasions for
the treatment of patients with late onset Pompe disease, at its meetings in July 2008,
March 2009, November 2009 and November 2010. Details of these considerations are in
the relevant Public Summary Documents (PSD).
At the July 2008 meeting, the PBAC rejected a submission to list alglucosidase alfa
as a Section 100 Highly Specialised Drug for the treatment of patients with Pompe
disease with a documented deficiency of alfa-glucosidase enzyme activity on the basis
of unacceptably high cost effectiveness.
3. Registration Status
Alglucosidase alfa was TGA registered on 14 March 2008 for the
long-term treatment of patients with a confirmed diagnosis of Pompe
disease (acid alfa-glucosidase deficiency).
4. Listing Requested and PBAC’s View
The re-submission sought a recommendation from the PBAC that
alglucosidase should be included in the LSDP for the treatment of
late onset Pompe disease. The sponsor did not propose wording for a
PBS listing.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Pompe disease is an inherited disorder caused by a lack of the
enzyme acid alfa-glucosidase. This results in an accumulation of
glycogen, impairing the function of muscle tissues. Clinically,
Pompe patients experience progressive muscle weakness and often
death from respiratory and/or cardiac failure secondary to glycogen
accumulation in cardiac, respiratory and skeletal muscle
tissue.
Pompe disease encompasses a single disease continuum and presents
in a spectrum of patients characterised by the amount of enzyme
activity present. On one end, patients with low or absent enzyme
activity (Infantile-onset) present within a few months of birth
with rapidly progressive disease. On the other end, patients with
some residual enzyme activity (Late-onset) present later in life
with less rapid but steadily progressive disease.
Alglucosidase alfa is an enzyme-replacement therapy for patients
with Pompe disease.
6. Comparator
The submission nominated standard (palliative) therapy including
intensive respiratory support, cardiac care, dietary therapy and
rehabilitative services, as the main comparator. The PBAC has
previously considered this appropriate.
7. Clinical Trials
The key study in the re-submission remained the LOTS trial, a
randomised comparison of alglucosidase versus placebo in patients
with late-onset Pompe disease. The details of the LOTS (AGLU002704)
trial are presented in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Randomised trials | ||
| AGLU0027 | Late-Onset Treatment Study (LOTS) | |
| Van der Ploeg et al | Lysosomal storage disease II: Pompe disease. | The Lancet, 2008; 372:1342-1353. |
| Van der Ploeg et al | A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe’s Disease; | New England Journal of Medicine, 2010; 362:1396-1406. |
The re-submission also presented new survival data based on
unpublished reports from the Erasmus Medical Centre (EMC) – a
research organisation independent to the sponsor/International
Pompe Association (IPA) Pompe survey, an 8-year prospective
observational study. The main analysis was based on a
non-randomised comparison of survival between treated and untreated
patients (EMC research report 2011). The re-submission also
presented three small case series as supportive evidence.
Publication details are presented in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Case series | ||
| Bembi et al | Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II. | J Inherit Metab Dis: 2010; 1-9 |
| Papadimas et al | Adult Pompe disease: Clinical manifestations and outcome of the first Greek patients receiving enzyme replacement therapy. | Clin Neurol Neurosurg: 2011 |
| van Capelle et al | Effect of enzyme therapy in juvenile patients with Pompe disease: A three-year open-label study | Neuromuscular Disord; 2010: 20(12):775-82. |
8. Results of Trials
The key results of the LOTS trial (previously reported) were a 3.4%
improvement in forced vital capacity (FVC) and a 28.1 m gain in the
six-minute walk test (6MWT) associated with alglucosidase treatment
compared to placebo after 18 months. However, the PBAC had
expressed concern about the relevance of these surrogate outcomes
for patient survival.
The non-randomised comparison of survival between treated and
untreated patients in the EMC research report divided the EMC/IPA
survey population into two groups; those who were never treated
with alglucosidase and those who received at least one dose of
alglucosidase (referred to as the ever treated group).
The re-submission presented the results for deaths in the EMC/IPA
survey which showed that between 2002 and February 2011, there were
more deaths in the never treated group compared to the ever treated
group.
The re-submission presented logistic regression analyses and an
adjusted Cox Proportional Hazards regression analyses to examine
the influence of various factors on patient survival.
The EMC report claimed that alglucosidase treatment has a strong
positive influence on survival in patients with late-onset Pompe
disease.
The PBAC considered the improvements in FVC and 6MWT values seen in
the LOTS trial after 18 months of treatment (3% improvement in FVC
and a 28 m gain in the 6MWT) to be relatively modest and appeared
inconsistent with the substantial survival benefit claimed on the
basis of the observational EMC/IPA survey population.
The EMC research report plotted unadjusted Kaplan-Meier survival
curves for the ever treated and never treated patient groups.
No new safety issues were identified.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission claimed that the results of the EMC research report
show a strong and statistically significant relationship between
alglucosidase use and survival in patients with late-onset Pompe
disease.
For PBAC’s view, see Recommendation and
Reasons.
The PBAC considered that, in spite of the new Erasmus data, and the
multiple analyses thereof, significant uncertainty remains as to
whether alglucosidase therapy as proposed substantially prolongs
life.
10. Economic Analysis
The re-submission did not present an economic evaluation. The PBAC
has previously accepted that alglucosidase alfa is not
cost-effective.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated in the
re-submission to be less than 10,000 in Year 5, at an estimated net
cost per year to the Government of between $10-30 million in Year
5.
12. Recommendation and Reasons
As previously, the key study in the re-submission remained the LOTS
trial, a randomised comparison of alglucosidase versus placebo in
patients with late-onset Pompe disease. The key results were a 3%
improvement in FVC and a 28m gain in the 6MWT associated with
alglucosidase treatment compared to placebo after 18 months.
However, the PBAC had expressed concern about the relevance of
these surrogate outcomes for patient survival.
The resubmission presented new survival data based on unpublished
reports from the Erasmus Medical Centre (EMC)/International Pompe
Association (IPA) Pompe survey, an 8-year prospective observational
study. The PBAC agreed that the Erasmus study was probably more
relevant to the Australian population than the trial population but
acknowledged that the information was typical of that seen with
rare diseases – low quality, uncontrolled data with major
inherent and unknown biases. Varying analytical choices have been
performed to try and overcome the resulting confounders.
Between 2002 and February 2011 there were statistically
significantly more deaths in the in the never treated group than in
the ever treated group in the EMC/IPA survey population. These
results were based on a non-randomised comparison and the PBAC
considered that any differences in death between treatment groups
cannot necessarily simply be attributed to alglucosidase treatment
due to potential confounding factors that may mean that there are
systematic differences between the ever-treated and the
never-treated groups. No deaths were recorded in either arm over 18
months in the LOTS trial.
The re-submission extrapolated the results of the EMC research
report using various survival models and claimed that alglucosidase
treatment may be associated with a mean survival benefit of between
4.58 years and 12 years compared to no treatment. The PBAC
considered that this estimate was highly uncertain due to the
limitations of the EMC research report. Additionally, there was
sufficient uncertainty associated with the long-term survival of
patients with late-onset Pompe disease to make it difficult to
reliably extrapolate the results.
The PBAC noted that the proposed price of alglucosidase per vial
had been reduced in the re-submission and was now claimed to be
comparable to other LSDP drugs. The PBAC considered that, while the
revised Australian price was comparable to idursulfase (for the
treatment of MPS Type 2); it was still substantially more expensive
than other drugs listed on the LSDP and the international prices
quoted were not accepted at face value as it seemed that the only
negotiated price was with the Department of Veterans Affairs in the
US (based on local regulations).
The PBAC considered that decision making around the type of patient
in whom to initiate therapy and when this should start in Australia
was critical, particularly as it involved starting a patient on
long term therapy at a very high cost per annum. Better definition
around what level of functional incapacity and the discontinuation
rules were also needed before the PBAC could identify which
patients would be treated with alglucosidase under the LSDP. The
possibility of dose titration based on residual activity instead of
using a fixed dose of regimen was raised, but the sponsor’s
clinical expert at the Hearing stated that it was not possible to
do so at this stage.
The PBAC considered that, in spite of the new Erasmus data, and the
multiple analyses thereof, significant uncertainty remains as to
whether alglucosidase therapy as proposed substantially prolongs
life. It was accepted that the dataset was the best that is likely
to be obtained and that the study provided some new information
that contributed to the discussion. However, the paucity of the
data and the difficulty in interpreting it did not allow committee
to have confidence that it was prolonging life.
PBAC therefore deferred its decision on the submission for
alglucosidase to seek further analysis of observational data
provided to see if it.will allow PBAC to have confidence that
criterion 4 of LSDP guidelines has been met.
The PBAC also acknowledged and noted the consumer comments received
in its consideration of alglucosidase.
Recommendation
Defer
13. 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.
14. Sponsor’s Comment
Genzyme is disappointed at the PBAC deferring its recommendation on
Myozyme for late-onset Pompe disease, given the new evidence
provided in the submission. Genzyme Australasia continues to be
committed to working with the PBAC and the LSDP to demonstrate the
life-saving benefit of Myozyme experienced by 1500 patients
worldwide and ensure that people with late-onset Pompe disease have
funded access to treatment.
