Velaglucerase alfa, powder for IV infusion, 400 units in 4 mL, VPRIV® - November 2011
Page last updated: 16 March 2012
Public Summary Document
Product: Velaglucerase alfa, powder for IV
infusion, 400 units in 4 mL, VPRIV®
Sponsor: Shire Australia Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
To request inclusion on the Life Saving Drugs Program (LSDP) for
the treatment of type 1 Gaucher disease in a patient who meets
certain criteria.
Through the 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
This drug had not previously been considered by the PBAC.
3. Registration Status
On 29 February 2012, velaglucerase was registered by the TGA for the following indication:
long-term enzyme replacement therapy (ERT) for paediatric and adult patients with Type 1 Gaucher disease associated with at least one of the following clinical manifestations: anaemia, thrombocytopaenia, hepato-splenomegaly.
4. Listing Requested and PBAC’s View
The submission sought a recommendation from the PBAC that
velaglucerase be included in the LSDP for the treatment of type 1
Gaucher disease, under the same conditions as imiglucerase.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Gaucher disease is a rare condition caused by the inherited
deficiency of an enzyme, glucocerebrosidase, which is required for
the breakdown of a specialised lipid, called glucocerebroside.
Glucocerebroside accumulates in the lysosomes of predominantly
monocyte and macrophage cells particularly in the liver, spleen and
bone marrow. This accumulation of undegraded glucocerebroside can
result in a spectrum of symptoms, from mild to severe. Clinical
manifestations of the disease include spleen and liver enlargement,
bone marrow infiltration causing anaemia, and skeletal involvement
causing bone pain and fracture.
There are three forms of Gaucher disease, characterised by the
absence (Type 1) or presence (Types 2 and 3) of central nervous
system (CNS) involvement. These three forms have also been labelled
as adult (Type 1), infantile (Type 2) and juvenile (Type 3), based
on the usual age of presentation of the disease.
The submission proposed that the place in therapy of velaglucerase
was an alternative enzyme replacement therapy to imiglucerase for
the treatment of paediatric and adults patients with type 1 Gaucher
disease.
6. Comparator
The submission nominated imiglucerase as the comparator.
The PBAC agreed that imiglucerase was the appropriate comparator as
it is the product most likely to be replaced in clinical
practice.
7. Clinical Trials
The key study included in the submission was a head-to-head trial
of velaglucerase 60 U vs. imiglucerase 60 U (HGT-039).
The submission also included three supportive studies: a randomised
trial of velaglucerase 60 U vs. velaglucerase 45 U (TKT-032), a
non-randomised study of patients switching from imiglucerase to
velaglucerase (TKT-034), and a non-randomised study of the
long-term safety and efficacy of velaglucerase treatment
(TKT-025).
The following trials had been published at the time of
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Randomised trials | ||
| Non-randomised studies | ||
| HGT-039 | A multicenter, randomized, double-blind, parallel-group study of Gene-Activated ® Human Glucocerebrosidase (GA-GCB) enzyme replacement therapy compared with Imiglucerase in patients with Type I Gaucher disease. | Shire clinical study report (October 2009) a . |
| TKT-032 | A multicenter, randomized, double-blind, parallel group, two-dose study of Gene-Activated ® Human Glucocerebrosidase (GA-GCB) enzyme replacement therapy in patients with Type 1 Gaucher disease. | Shire clinical study report (July 2009) a . |
| TKT-034 | A multicenter open-label study of Gene-Activated® Human Glucocerebrosidase (GA-GCB) enzyme replacement therapy in patients with Type 1 Gaucher disease previously treated with Imiglucerase | Shire clinical study report (August 2009) a . |
| TKT-025 | ||
| Zimran et al (2007) | A pharmacokinetic analysis of a novel enzyme replacement therapy with Gene- Activated® Human Glucocerebrosidase (GA-GCB) in patients with Type 1 Gaucher disease | Blood Cells, Molecules, and Diseases 39(1): 115-118 |
| Zimran et al (2010) | Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with Type 1 Gaucher disease: 48-month experience | Blood 115(23): 4651-4656 |
| Elstein et al (2011a) | Significant and continuous improvement in bone mineral density among type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, including dose reduction | Blood Cells, Molecules, and Diseases 47(1): 56-61 |
| Elstein et al (2011b). | Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in Type 1 Gaucher disease | Blood Cells, Molecules, and Diseases 46(1): 119-23. |
a Study results are publicly available on the
ClinicalTrials.gov website
8. Results of Trials
The HGT-039 trial was designed to demonstrate that velaglucerase
alfa is non-inferior to imiglucerase in terms of maintaining
haemoglobin concentration.
The key results for the primary outcome of the HGT-039 trial are
summarised in the table below.
Primary outcome (change in haemoglobin concentration) of
the HGT-039 trial
| Outcome | Velaglucerase (N = 17) | Imiglucerase (N = 17) |
|---|---|---|
| Mean change in Hb concentration from baseline | ||
| Baseline Hb concentration (g/dL) [mean, SE] | 11.51 (0.30) | 10.46 (0.33) |
| Final Hb concentration (g/dL) [mean, SE] | 13.14 (0.36) | 11.95 (0.28) |
| Change for baseline (g/dL) [mean, SE] | 1.62 (0.22) | 1.49 (0.28) |
| Treatment difference (g/dL) [mean, 97.5% CI] | 0.135 (-0.596, inf) | |
Abbreviations: Hb, haemoglobin; inf, infinity; SE, standard
error
Note: Difference in Hb concentration treatment effect > 0
favours velaglucerase
There was no statistically significant difference between treatment
arms in the mean change in haemoglobin concentration from baseline.
The lower bound of the treatment effect confidence interval (-0.596
g/dL) met the pre-defined non-inferiority criterion (lower 97.5% CI
should not exceed -1g/dL).
Key secondary outcomes of the HGT-039 trial included a responder
analysis based on the minimum clinically meaningful change in
haemoglobin concentration, platelet count, liver volume, and spleen
volume.
Velaglucerase and imiglucerase appear to be associated with similar
improvements in measures of disease burden.
Study TKT-032 was a randomised, controlled trial evaluating the
efficacy and safety of two different doses of velaglucerase (45
U/kg and 60 U/kg) in Type 1 Gaucher disease. Both doses were
associated with improvements in disease burden measures
(particularly haemoglobin concentration and spleen volume) with the
results generally favouring the 60 U/kg dose. However, the lack of
statistical comparisons between treatment groups limited any formal
assessment of a dose response relationship.
Study TKT-034 was a non-randomised study evaluating the efficacy
and safety of patients switching from imiglucerase to
velaglucerase. All patients were required to have received
consistent treatment with imiglucerase for a minimum of 30
consecutive months. Patients were switched to a velaglucerase
maintenance dose that was the same as previous imiglucerase
maintenance dose.
Patients switching from imiglucerase to velaglucerase appeared to
maintain constant haemoglobin concentrations over time. Similar
results were also observed in terms of platelet counts, liver
volumes and spleen volumes. Maintenance of treatment effect was
observed in all dose cohorts (15, 30, 45 and 60 U/kg).
Study TKT-025 was a non-randomised study evaluating the long-term
efficacy and safety of velaglucerase alfa treatment. Patients
treated in the TKT-025 study (and extension) received up to five
years of therapy. The majority of patients enrolled in the TKT-025
extension study had their velaglucerase dose titrated down from 60
U/kg to 30 U/kg every two weeks after successfully meeting
therapeutic goals. Results from the study show that patients were
able to maintain initial improvements in disease burden measures
for up to five years.
Velaglucerase and imiglucerase appear to have similar safety
profiles when used at a dose of 60 U/kg every two weeks. The most
frequently reported adverse events in the HGT-039 trial were
influenza, arthralgia, pyrexia, nasopharyngitis, headache,
rhinitis, diarrhoea, peripheral oedema, bone pain and upper
abdominal pain.
Drug-related adverse events were reported by eight (47.1%) patients
in the velaglucerase treatment group. Two of these events were
classified as severe (allergic skin reaction, prolonged activated
partial thromboplastin time (aPTT)). Drug-related adverse events
experienced by more than one patient in the velaglucerase treatment
arm included headache and urticaria.
Drug-related adverse events were also reported by 6 (35.3%)
patients in the imiglucerase treatment group. One of these events
was classified as severe (chills/rigours). Headache was the only
drug-related adverse events experienced by more than one patient in
the imiglucerase treatment arm.
Drug-related adverse events associated with velaglucerase treatment
in the supportive TKT-032, TKT-034 and TKT-025 studies included:
arthralgia, back pain, dizziness, fatigue, headache, hypertension,
hypotension, malaise, nausea, pain in the extremity, petechiae and
tremor.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission described velaglucerase (60 U/kg every two weeks) as
non-inferior in terms of comparative effectiveness and equivalent
in terms of comparative safety to imiglucerase (60 U/kg every two
weeks).
Based on the surrogate measure of disease burden outcomes presented
in the submission, the PBAC concluded that velaglucerase may be
non-inferior to imiglucerase in terms of comparative effectiveness
and equivalent in terms of comparative safety, pending a final
decision from the TGA.
10. Economic Analysis
The submission presented a cost-minimisation analysis of
velaglucerase compared to imiglucerase.
The submission claimed that the dose relativity of velaglucerase to
imiglucerase is 1 U/kg to 1 U/kg.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year was estimated by the submission to be less than 100
patients in
Year 5. The estimate is uncertain.
The financial cost/year to the PBS was estimated by the submission
to be nil. The submission claimed that the listing of velaglucerase
is not expected to increase the cost of treating Type 1 Gaucher
disease under the LSDP based on the assumption that all patients
who will be treated with velaglucerase would have otherwise
received imiglucerase. The submission therefore assumed that the
costs of listing velaglucerase are completely offset by the reduced
usage of imiglucerase.
12. Recommendation and Reasons
The PBAC agreed that imiglucerase was the appropriate comparator as
it is the product most likely to be replaced in clinical
practice.
The PBAC noted that the key study (HGT-039 trial) presented in the
submission was designed to demonstrate that velaglucerase alfa is
non-inferior to imiglucerase in terms of maintaining haemoglobin
concentration. The PBAC noted that there was no statistically
significant difference between treatment arms in the mean change in
haemoglobin concentration from baseline, the primary outcome. The
lower bound of the treatment effect confidence interval
(-0.596g/dL) met the pre-defined non-inferiority criterion (lower
97.5% CI should not exceed -1g/dL). The PBAC agreed that the chosen
non-inferiority margin is reasonable.
The PBAC noted that the key secondary outcomes of the HGT-039 trial
included a responder analysis based on the minimum clinically
meaningful change in haemoglobin concentration, platelet count,
liver volume, and spleen volume. The PBAC considered that
velaglucerase and imiglucerase appear to be associated with similar
improvements in measures of disease burden.
The PBAC noted that velaglucerase had not
yet been approved by the TGA and therefore could not make a
decision on its place in therapy.
Based on the surrogate measure of disease burden outcomes presented
in the submission, the PBAC concluded that velaglucerase may be
non-inferior to imiglucerase in terms of comparative effectiveness
and equivalent in terms of comparative safety, pending a final
decision from the TGA. The Committee considered that velaglucerase
and imiglucerase appear clinically equi-effective at a 1:1 dose
ratio, although data investigating the comparative effectiveness of
velaglucerase and imiglucerase at other relative doses in this
patient population are not available.
The PBAC noted that due to the probable high cost of velaglucerase
(even if at a significant discount to imiglucerase), it would not
be considered cost effective for listing on the PBS and hence
proceeded to consider the possible inclusion of velaglucerase on
the LSDP. The PBAC noted that this was a necessary prerequisite
under the LSDP criterion 5.
The PBAC considered that if the TGA recommends velaglucerase as an
alternative first line ERT, and non-inferiority versus imiglucerase
is accepted, there is an inherent acceptance, based on equivalence
with imiglucerase, that velaglucerase meets the criteria for the
funding of a drug through the LSDP, in particular criterion 4:
“There is evidence acceptable to the PBAC to predict that a
patient’s lifespan will be substantially extended as a direct
consequence of the use of the drug.” This would not be the
case if velaglucerase was approved for second line therapy.
Given that is unclear whether velaglucerase will be used in the
first or second-line setting, pending finalisation of the TGA
recommendation, the PBAC considered that it is difficult to make a
recommendation whether a cost-minimisation approach might be
acceptable for listing on the LSDP. If velaglucerase is approved by
the TGA for use in the first-line setting then a cost-minimisation
approach might be acceptable. However, given that
cost-effectiveness is not a criterion for the LSDP, the PBAC noted
that the implementation of a cost-minimisation approach might be
different than applies for the PBS and a net cost saving as offered
by the sponsor would be more appropriate. Further, the PBAC
considered that, if approved for use as a second-line agent, then a
different approach might be necessary.
The PBAC therefore deferred its decision on the submission for
velaglucerase on the LSDP pending the finalisation of the
TGA’s evaluation which will determine the place in therapy of
velaglucerase.
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
Shire looks forward to working positively with the PBAC to allow
patients access to this treatment in Australia.
