Alglucosidase alfa, powder for I.V. infusion, 50 mg, Myozyme®, November 2009
Public Summary Document for Alglucosidase alfa, powder for I.V. infusion, 50 mg, Myozyme®, November 2009
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Public Summary Document
Product: Alglucosidase alfa, powder for I.V.
infusion, 50 mg, Myozyme®
Product: Genzyme Australasia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought a Section 100 (Highly Specialised Drug)
listing or 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 alfa-glycosidase 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
disease only.
At the March 2009 meeting, 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 did 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.
A copy of the Public Summary Document from that meeting is available.
3. Registration Status
Alglucosidase alfa was granted orphan drug status by the TGA on 8
September 2003.
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)
Private hospital authority required
Patients with a confirmed clinical diagnosis of Pompe disease who
have had their diagnosis confirmed by a documented deficiency of
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 and who meet the criteria below:
- Inclusion criteria:
- Patients with significant deterioration in either: or
- Lung function: FVC in upright position of < 80% predicted;
- Muscle function: clinically significant muscle weakness.
Exclusion criteria:
- Patients with chronic invasive ventilation of >12 months duration.
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.
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.
The PBAC had previously considered this appropriate.
7. Clinical Trials
The key study in the re-submission remained the LOTS trial
(ALGLU02704), a randomised trial comparing alglucosidase 20 mg/kg
with supportive care in late-onset Pompe disease.
The main clinical outcome in the re-submission was ventilator use
in the LOTS study, rather than forced vital capacity (FVC) and 6
minute walk test (6MWT) as in previous submissions. This was in
order to address the PBAC’s concern in the previous
submission regarding the uncertainty in assuming FVC and 6MWT
outcomes can be extrapolated to improvements in patient morbidity
and mortality.
Three additional non-randomised studies (AGLU02804, Hartung 2007
and Angelini 2009) were included as supportive evidence.
The key trials presented in the submission are shown in the table
below:
| Trial ID/First author | Protocol title / Publication title | Publication citation |
| Randomised trials | ||
| 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. | |
| Non-randomised studies | ||
| AGLU02804 | A Single Center, Open-Label, Bridging Study of the Safety, Pharmacokinetics and Efficacy of Recombinant Human Acid Alpha-Glucosidase (rhGAA) Treatment in Patients with Late-Onset Pompe disease (Glycogen Storage Disease Type II). | |
| Hartung et al (2007) | Initial therapy response of 6 months of enzyme replacement therapy in 11 juvenile/adult M. Pompe patients. | Clinical Therapeutics, Vol 29 p S86 |
| Supportive non-randomised trial | ||
| Angelini et al (2009) | Progress in enzyme replacement therapy in glycogen storage disease type II. | Therapeutic Advances in Neurological Disorders 2009; 2; 143 |
To support the correlation between FVC and ventilator use, the
resubmission presented two published studies as shown below:
| Trial ID/First author | Protocol title / Publication title | Publication citation |
| Pellegrini et al (2005) | Respiratory insufficiency and limb muscle weakness in adults with Pompe’s disease | Eur Respir J 2005; 26: 1024–1031 |
| Van der Beek (2009) | Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease | Neuromuscular Disorders 19 (2009) 113–117 |
8. Results of Trials
The re-submission aimed to address the PBAC’s previous
uncertainty from the March 2009 submission around the survival
benefits of alglucosidase alfa treatment in late-onset Pompe
disease patients by demonstrating a link between forced vital
capacity (FVC) and survival, via another surrogate outcome:
ventilator use.
Two patients in the alglucosidase alfa treatment group did not
require ventilatory support at the time of treatment initiation,
despite having indicated in the Pompe Disease Questionnaire that
they used ventilatory support. The re-submission included these
patients as not utilising ventilatory support at baseline,
resulting in 3 patients initiating ventilator use in the duration
of the study in the alglucosidase arm, and 4 in the placebo arm: a
risk difference of 8.3%. If these patients were classified as
ventilator users at baseline, then only one patient in the
alglucosidase alfa treatment arm would have initiated ventilator
use during the trial, for a risk difference of 11.6%.
An updated Periodic Safety Update Report (PSUR) for alglucosidase
was presented in the re-submission for the period of December 2008
– March 2009. This report included patients with both
infantile-onset and late-onset Pompe disease. The PSUR stated that
the majority of adverse reactions observed during the current
reporting period were consistent with the manifestation of the
underlying disease, and notes that reports of significant allergic
and anaphylactic reactions, immune mediated reactions and clinical
decline, as well as reports of cardiac, respiratory and muscular
nature will be closely monitored by the Sponsor, and followed for
further evaluation.
For PBAC’s comments see Recommendation and Reasons.
9. Clinical Claim
The submission described alglucosidase alfa as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over placebo (standard management).
The PBAC recalled that at the March 2009 meeting it accepted that
alglucosidase alfa therapy was associated with an improvement in
the 6-minute walk test (6MWT) and a stabilisation of forced vital
capacity (upright) compared with placebo.
The PBAC noted the re-submission presented data from two
retrospective reviews of the medical records of patients with late
onset Pompe disease, Pellegrini et al (2005) and Van der Beek
(2009), to support the proposed correlation between ventilator use
and FVC. Data from these studies showed that patients requiring
respiratory support tended to have worse vital capacity than
patients not requiring any respiratory support, however the PBAC
noted that there was no indication that one is the cause or effect
of the other. The studies also showed there was considerable
variation in the rate of disease progression in patients with late
onset Pompe disease. The PBAC considered there was uncertainty in
the assumption of correlation between FVC scores and ventilator
use, and the extrapolation of the surrogate of ventilator use with
survival gain, and hence the re-submission’s claim that FVC
is a surrogate for survival in late onset Pompe disease.
10. Economic Analysis
The submission presented a trial based economic evaluation using
the data from the LOTS study with a time horizon of 52 weeks (based
on the first 52 weeks of the 78 week LOTS trial). This approach was
unchanged compared to the previous submission. The economic
evaluation was updated to reflect updated characteristics of the
overall population with a reduction in the average number of vials
required per treatment however the incremental cost per additional
metre walked at 52 weeks remained in the same range as previously,
$15,000 – $45,000.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated to be slightly
lower than the March 2009 submission but in the range of $10
– $23 million per year in Year 5. Due to the high drug cost
per patient per year the estimated financial impact of
alglucosidase is sensitive to any assumptions regarding the number
of treated patients, and the weight of patients.
12. Recommendation and Reasons
The PBAC noted the clinical evidence presented in the re-submission
of the LOTS trial (ALGLU02704) was unchanged, however the main
outcome in the current re-submission was ventilator use in the LOTS
trial, to address the PBAC’s previous concerns, rather than
forced vital capacity (FVC) and six minute walk test (6MWT) in
previous submissions. The re-submission presented one open-label
study with unspecified doses of alglucosidase alfa (Angelini 2009)
as supportive evidence. The re-submission stated that there are
currently no studies available illustrating a statistically
significant correlation between ventilator use and death in
patients with late onset Pompe disease, hence no data were
presented in the re-submission directly supporting the proposed
correlation of survival increase and ventilator use.
The re-submission presented data from two retrospective reviews of
the medical records of patients with late onset Pompe disease,
Pellegrini et al (2005) and Van der Beek (2009), to support the
proposed correlation between ventilator use and FVC. Data from
these studies showed that patients requiring respiratory support
tended to have worse vital capacity than patients not requiring any
respiratory support, however the PBAC noted that there was no
indication that one is the cause or effect of the other. The
studies also showed there was considerable variation in the rate of
disease progression in patients with late onset Pompe disease. The
PBAC considered there was uncertainty in the assumption of
correlation between FVC scores and ventilator use, and the
extrapolation of the surrogate of ventilator use with survival
gain, and hence the re-submission’s claim that FVC is a
surrogate for survival in late onset Pompe disease. The PBAC hence
considered that criterion 2 of the LSDP was not satisfied, that is
uncertainty remained as to whether a patient’s lifespan would
be extended as a direct consequence of treatment with alglucosidase
alfa in late onset Pompe disease.
The PBAC noted the periodic safety update in the re-submission
raised no new safety issues with the treatment of Pompe disease
(infantile-onset and late onset) with alglucosidase alfa. The PBAC
however noted that patients develop antibodies to alglucosidase
alfa and that patients with sustained high anti-alglucosidase alfa
IgG antibodies titres may have a poorer clinical response to
alglucosidase, and that the effect of the development of antibodies
on the long term efficacy of alglucosidase alfa is uncertain.
The submission presented a trial based economic evaluation using
the data from the LOTS study with a time horizon of 52 weeks (based
on the first 52 weeks of the 78 week LOTS trial). This approach was
unchanged compared to the previous submission. The economic
evaluation was updated to reflect updated characteristics of the
overall population with a change to the average number of vials
required per treatment.
The PBAC rejected the re-submission to list alglucosidase alfa on
the PBS as a Section 100 Highly Specialised Drug for the treatment
of patients with late onset Pompe disease on the basis of
unacceptably high cost effectiveness compared to standard
(palliative) therapy. The PBAC noted that the cost of alglucosidase
alfa in late onset Pompe disease, was substantially unchanged from
the previous submission, was very high and the cost-effectiveness
was far outside that which would be considered acceptable for
listing on the PBS.
The PBAC did not recommend inclusion in the LSDP of alglucosidase
alfa for the treatment late onset Pompe disease considering that
insufficient evidence was provided to demonstrate that a
patient’s lifespan will be extended as a direct consequence
of treatment with alglucosidase alfa, and hence that criterion two
of the LSDP had not been met. The PBAC also noted that the cost per
patient per year in the re-submission was again higher than other
enzyme replacement therapies recommended for inclusion on the
LSDP.
Recommendation:
Reject
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 Australasia remains committed to working with the PBAC and the LSDP to ensure that people with late-onset Pompe disease have funded access to Myozyme.
