Alglucosidase alfa, powder for I.V. infusion, 50 mg, Myozyme®, March 2009
Public summary document for Alglucosidase alfa, powder for I.V. infusion, 50 mg, Myozyme®, March 2009
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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: March 2009
1. Purpose of Application
The submission sought a Section 100 Highly Specialised Drug PBS
listing or a recommendation for inclusion on the Life Saving Drugs
Program (LSDP) for the treatment of late-onset Pompe disease.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
Life Saving Drugs Program
The Commonwealth Government provides funds under an appropriation
item established for the specific purpose of assisting access to
expensive and lifesaving drugs accepted by the PBAC as clinically
effective, but not available as pharmaceutical benefits because of
a failure to meet cost effectiveness criteria. Financial assistance
for such drugs is approved in accordance with specified eligibility
criteria and subject to certain conditions as agreed by the
Ministers for Health and Finance.
2. Background
At the July 2008 meeting, the PBAC rejected the 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 acid alfa-glucosidase (GAA) enzyme activity on the
basis of unacceptably high cost effectiveness. However, the
Committee concluded that alglucosidase alfa met the criteria for
the Life Saving Drugs Program (LSDP) for infantile-onset Pompe
disease only.
A copy of the Public Summary Document from that meeting is
available from http://www.health.gov.au/internet/main/publishing.nsf/Content/104DDB6DAE2F4AEECA2574EE008351FE/$File/Alglucosidase%20Final%20PSD%20Genzyme.pdf
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
Section 100 Highly Specialised Drug
Authority Required
Patients with a confirmed clinical diagnosis of Pompe disease who
have had their diagnosis confirmed by a documented deficiency of
acid alfa-glucosidase enzyme activity in either skin fibroblasts,
muscle tissue, lymphocytes, mixed leukocytes or dried blood spots
(< 40% of normal levels) or through identification of a mutation
in the GAA gene.
The prescription should allow for sufficient vials for the patients
to obtain 20 mg/kg (i.e., one treatment) every two weeks. The
original prescription and one repeat may be authorised per
authority, providing 4 weeks of treatment. Treatment would be
ongoing, requiring an intravenous infusion once every two
weeks.
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 called acid alpha-glucosidase (commonly called GAA or acid
maltase). 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 phenotypes 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 as it provides a source of GAA.
6. Comparator
The submission nominated standard (palliative) therapy including
intensive respiratory support, cardiac care, dietary therapy and
rehabilitative services, as the main comparator, which the PBAC
considered appropriate.
7. Clinical Trials
The submission presented one randomised trial (LOTS trial) comparing alglucosidase alfa 20 mg/kg with placebo (supportive care) in 90 patients with late-onset Pompe disease over a treatment period of 18 months. Trial details are shown below.
| Trial | Protocol title |
| AGLU02704 Late-Onset Treatment Study (LOTS) | A Randomized, Double-Blind, Multicenter, Multinational, Placebo-Controlled Study of the Safety, Efficacy, and Pharmacokinetics of Myozyme, Recombinant Human Acid alpha-Glucosidase (rhGAA), Treatment in Patients with Late-Onset Pompe disease. |
8. Results of Trials
Alglucosidase alfa met both co-primary endpoints. The results
showed that, at 18 months, patients treated with alglucosidase alfa
increased their distance walked in six minutes by an average of
approximately 30 meters as compared with the placebo group
(P=0.0283; Wilcoxon test). The placebo group did not show any
improvement from baseline. The average baseline distance walked in
six minutes in both groups was approximately 325 metres.
Percent predicted forced vital capacity in the group of patients
treated with alglucosidase alfa increased by 1 percent at 18
months. In contrast, it declined by approximately 3 percent in the
placebo group (P=0.0026; Wilcoxon test). The average baseline
percent predicted forced vital capacity in both groups was
approximately 53 percent. The results for both efficacy endpoints
were consistent across various prospectively defined
subgroups.
The safety of alglucosidase alfa was similar to placebo in the LOTS
study. The number of patients with serious and treatment-emergent
non-serious adverse events was similar in the alglucosidase alfa
and placebo groups. Approximately 25 percent of patients in each
group experienced infusion-associated reactions. There was one
death in the alglucosidase alfa group unrelated to treatment.
9. Clinical Claim
The submission claimed that alglucosidase alfa was associated with
greater efficacy than placebo (supportive care) and would be
expected to stop disease progression but was associated with
greater toxicity. (For details of toxicity/safety see
“Results of Trials”).
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a trial-based economic evaluation
(cost-effectiveness analysis) using data from the LOTS trial. The
analysis used a time horizon of 52 weeks (based on the first
52-weeks of the 78-week LOTS trial).
The PBAC noted that the incremental cost per additional metre
walked at 52 weeks was within the range $15,000-$45,000.
The results of the sensitivity analyses indicated that the economic
evaluation was sensitive to assumptions regarding: patients’
weight, the size of the treatment effect, the time horizon chosen
and the outcome measure used.
11. Estimated PBS Usage and Financial Implications
The submission advised an estimate of Australian birth prevalence
(i.e. annual incidence) of 1:70,000 has been calculated and
estimated the financial cost per year to the PBS to be $10-18
million in Year 4 of listing.
The PBAC considered this estimate to be uncertain due to the high
drug cost per patient per year and sensitivity to assumptions
regarding the number of treated patients and the weight of
patients.
12. Recommendation and Reasons
The pivotal clinical evidence presented was the LOTS trial, a
randomised trial of 90 patients with late-onset Pompe disease (aged
8 years or older) comparing alglucosidase alfa with placebo over 18
months. The PBAC also noted the clinical study reports of the two
non-randomised trials, provided in the sponsor’s
Pre-Sub-Committee Response, which provided data on patients with
more severe Pompe disease. The PBAC accepted that alglucosidase
alfa therapy is associated with an improvement in the 6-minute walk
test (6MWT) and a stabilisation of forced vital capacity (upright)
compared with placebo. However, the PBAC remained concerned about
the uncertainty associated with assuming that these short-term
surrogate outcomes can be extrapolated to improvements in patient
morbidity and mortality in a chronic disorder and that this
uncertainty remained unaddressed. The PBAC agreed that there was
still considerable uncertainty remaining around the magnitude of
benefit gained through treatment with this product, and the extent
to which alglucosidase alfa can be reasonably expected to prolong
life in late-onset Pompe patients. The PBAC therefore did not
consider that it was appropriate to include alglucosidase alfa in
the LSDP as criterion 2 was not satisfied – ie a
patient’s lifespan will be extended as a direct consequence
of the use of the drug.
The PBAC also expressed concern that Australian patients currently
on the alglucosidase alfa compassionate access programme have more
advanced disease when compared with the patients in the LOTS trial,
as they seem to require higher ventilator support and have less
ability to walk 10 metres. Therefore, the results of the LOTS trial
may not be applicable to the requested population as the LOTS trial
excluded patients with advanced disease (ie patients requiring
invasive ventilation, patients requiring non-invasive ventilation
while awake or patients with severe ambulatory impairment) and also
may have excluded patients with asymptomatic/mildly symptomatic
disease (ie patients with forced vital capacity (FVC) >
80%).
A trial-based economic analysis using a time horizon of 52 weeks
(based on the first 52 weeks of the 78 week LOTS trial) was
presented in the submission. The PBAC noted that the incremental
cost per additional metre walked at 52 weeks was in the range
$15,000-$45,000.
The PBAC rejected the submission to list alglucosidase alfa as a
Section 100 Highly Specialised Drug for the treatment of patients
with late-onset Pompe disease with a documented deficiency of
alfa-glycosidase enzyme activity on the basis of unacceptably high
cost effectiveness.
The PBAC concluded that alglucosidase alfa for treatment of
late-onset Pompe disease does not fulfil criterion 2 of the LSDP
criteria as there is no evidence to expect that a patient’s
lifespan will be extended as a direct consequence of the use of
alglucosidase alfa and therefore did not recommend inclusion of
alglucosidase alfa on the LSDP for late-onset Pompe disease.
The PBAC reaffirmed its previous recommendation for inclusion of
alglucosidase alfa on the LSDP for infantile-onset Pompe disease
only with the formation of a reference group to establish treatment
initiation and continuation guidelines and to develop specific
criteria for the cessation of alglucosidase alfa treatment.
The PBAC noted that the submission meets the criteria for an
Independent Review.
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 Australia continues to work with the PBAC and LSDP to
ensure that all appropriate Pompe disease patients have funded
access to Myozyme by addressing the uncertainties raised by the
PBAC.
