MIGLUSTAT, capsule, 100 mg, Zavesca®, July 2010
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Public Summary Document
Product: MIGLUSTAT, capsule, 100 mg,
Zavesca®
Sponsor: Actelion Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission requested inclusion in the Life Savings Drugs
Program (LSDP) for patients with Niemann-Pick Type C (NP-C)
disease.
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 for this
indication.
3. Registration Status
Miglustat was TGA registered on 3 February 2010 for the treatment
of progressive neurological manifestations in adult and paediatric
patients with Niemann-Pick Type C disease.
4. Listing Requested and PBAC’s View
Inclusion on the LSDP for treatment of progressive neurological
manifestations in adult and paediatric patients with Niemann-Pick
disease TypeC.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Niemann-Pick Type C disease is a very rare inherited disorder that
is progressive, debilitating, degenerative and ultimately fatal,
affecting the liver, lungs, bone marrow and brain. The neurological
manifestations are caused by the accumulation of lipids primarily
in the brain.
Treatment for Niemann-Pick Type C disease is currently palliative
only and depends on the needs of the individual, the symptoms and
the clinical manifestations. It is proposed that miglustat will
provide a pharmacologic intervention that may interrupt disease
progression.
6. Comparator
The submission nominated standard medical management (standard
care) comprising of palliative care as the comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented the following studies in support of the comparative effectiveness of miglustat in patients with NP-C:
- One open-label randomised trial comparing miglustat with standard care in combined adult and juvenile NP-C patients (referred to as the juvenile/adult patient population) over a 12 month period (Study 007a), with a 12 month single arm extension study (Study 007a (ext));
- One single arm study in paediatric NP-C patients over 12 month period (Study 007p), with a 12 month extension study (Study 007p (ext));
- Two surveys, one regarding NP-C patients receiving standard care (Stage II survey), and one concerning NP-C patients initially receiving standard care and subsequently treated with miglustat (Stage I survey).
- Two case-series and 19 case reports.
The trials published at the time of submission are shown in the
table below:
| Trial ID/ First author | Protocol title/ Publication title | Publication citation |
| Direct randomised trial | ||
| Study 007a | ||
| Patterson MC et al 2007 | Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. | Lancet Neurology 2007; 6(9):765-772. |
| Studies presented in the submission | ||
| Miglustat | ||
| Study 007p | ||
| Patterson MC et al 2007 | Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. | Lancet Neurology 2007; 6(9):765-772. |
| Study 007a (ext) | ||
| Wraith JE et al 2009 | Miglustat in adult and juvenile patients with Niemann-Pick disease type C: Long-term data from a clinical trial. | Molecular Genetics and Metabolism, epub 30 December 2009. |
| Study 007p (ext) | ||
| Patterson MC et al 2010 | Long-term miglustat therapy in children with Niemann-pick disease Type C. | Journal of Child Neurology 2010; 25:300-305. |
| Stage I survey | ||
| Pineda M et al 2009 | Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study. | Molecular Genetics and Metabolism 2009; 98:243-249. |
| Pineda M et al 2009 | Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. | Molecular Genetics and Metabolism, 2010; 99(4):358-66 |
| Fecarotta et al 2009 | Efficacy of miglustat on the neurological involvement in Italian patients with Niemann-Pick disease type C. | Molecular Genetics and Metabolism 2009; 98:70 (Abstract). |
| Main comparator – standard care | ||
| Stage II survey | ||
| Wraith JE et al 2009 | Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study. | Molecular Genetics and Metabolism 2009; 98:250-254. |
8. Results of Trials
Study 007a and Study 007a (ext)
The results for the primary endpoint, horizontal saccade eye movement α (HSEM-α),
are presented in the following table. HSEM-α is a metric, estimated as the slope of
the linear regression line of peak duration (amplitude/peak velocity, ms) vs. amplitude
(degree) of horizontal saccadic eye movement. The submission claimed that this endpoint
reflects brainstem involvement in patients with NP-C.
Analysis of changes in HSEM-α from baseline in adults and juveniles in the randomised
trial and its extension study
| Study | Time point | Adjusted mean change from baseline (ms/deg) a (no of patients) | Estimated treatment difference (ms/deg) a | 95% CI (ms/deg) a | p-value | |
|---|---|---|---|---|---|---|
| Study 007a | 12-month miglustat (N=20) | 12-month standard care (N=9) | ||||
| Month 12 | -0.329 (n=17) | -0.055 (n=8) | -0.274 | (-0.959, 0.411) | 0.414 | |
| Last value | -0.376 (n=18) | -0.050 (n=8) | -0.326 | (-1.000, 0.458) | 0.327 | |
| Study 007a (ext) | 24-month miglustat (N=17) | 12-month standard care, followed by 12-month miglustat (N=8) | ||||
| Month 24 | 0.155 (n=15) | 1.150 (n=4) | -0.994 | (-2.796, 0.808) | 0.258 | |
| Last value | 0.166 (n=15) | 0.761 (n=6) | -0.594 | (-2.078, 0.889) | 0.410 | |
CI = confidence interval
a ms/deg = amplitude/peak velocity (ms) per amplitude (degree)
The analysis of HSEM-α using an analysis of covariance (ANCOVA) model, which involved
terms for baseline, age and treatment group, indicated that HSEM-α was improved in
both of the treatment groups. Although the decrease in the miglustat group was greater
than that in the standard care group (adjusted mean change = -0.329ms/deg vs. -0.055ms/deg),
the difference did not approach statistical significance (p=0.414). Results from the
extension study showed that HSEM-α deteriorated after 24 months of miglustat treatment.
Although the patients in the 24-month miglustat group had less worsening of HSEM-α
than those who received miglustat treatment for 12 months (adjusted mean change =
0.155ms/deg vs. 1.150ms/deg), the difference was not statistically significant (p
= 0.258).
Evaluation of the HSEM-α assessment results was difficult due to the small sample
size in the study, the unmatched baseline patient characteristics between the two
treatment groups, and the lack of patient and investigator blinding.
The SF-36 Quality of Life Questionnaire, in patients older than 13 years in Study
007a, did not indicate any statistically significant difference in changes from baseline
to the last assessment of quality of life between the miglustat group and the standard
care group. Additionally, the results of the quality of life assessment are prone
to information and observer bias due to the lack of patient and investigator blinding.
Study 007p and Study 007p(ext)
The following table presents an analysis of changes in HSEM-α in the paediatric sub-study
of Study 007 and its extension study (all patients received miglustat treatment).
| Study | Time point | n | Baseline (ms/deg) a (SD) | Actual value (ms/deg) a (SD) | Change from baseline (ms/deg) a (SD) | 95% CI (ms/deg) |
| Study 007p | Baseline | 10 | 2.201 (1.217) | |||
| Month 12 | 9 | 2.181 (1.289) | 1.692 (1.077) | -0.489 (0.139) | (-0.810, -0.167) | |
| Last value | 10 | 2.201 (1.217) | 1.736 (1.025) | -0.465 (0.127) | NR | |
| Study 007p (ext) | Month 24 | 9 | 2.181 (1.289) | 2.106 (1.213) | -0.075 (1.235) | (-1.024, 0.874) |
| Last value | 10 | 2.201 (1.217) | 2.109 (1.144) | -0.093 (1.165) | (-0.926, 0.741) |
CI = confidence interval; NR = not reported; SD = standard deviation
a ms/deg = amplitude/peak velocity (ms) per amplitude (degree)
A statistically significant improvement in HSEM-α from baseline to month 12 was reported
in Study 007p, with a decrease of 0.489ms/deg (95%CI=(-0.810ms/deg, -0.167ms/deg))
in paediatric patients with NP-C. However, this beneficial effect of miglustat could
not be demonstrated after 24 months’ treatment.
In Study 007a, adverse events (AEs) considered to be treatment related were reported
for all 20 patients in the miglustat treatment group. Three cases of severe diarrhoea
and one case of severe weight loss were considered treatment-related. Two patients
experienced an AE that led to withdrawal of miglustat. The most common individual
AEs in the miglustat treatment group were diarrhoea (85%), flatulence (70%), weight
decrease (65%) and abdominal pain (50%). Neurological system disorders, such as tremor
and gait spasticity, were also common. In the paediatric sub-study, adverse events
that were considered to be treatment related were reported in 8 of the 12 patients.
One patient withdrew from the study due to lethargy, memory impairment and depression.
The most common adverse events in paediatric patients were diarrhoea and fatigue.
For PBAC’s view, see Recommendation and Reasons.
9. Clinical Claim
The submission presented Stage I and Stage II surveys to support
the claim that treatment with miglustat improves composite
disability score, which the submission presented as an appropriate
surrogate for survival in NP-C patients.
The submission claimed that the data from the surveys consistently
indicated that stabilisation of the disease and, in some cases,
improvement, can be achieved with miglustat treatment in the
majority of NP-C patients with progressive neurological
disease.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a trial-based cost-utility analysis, based
on the outcomes of the direct randomised trial, Study 007a, for
juvenile and adult NP-C patients. The time horizon was 12 months.
An economic analysis for paediatric patients was not
included.
The incremental cost per quality adjusted life-year was greater
than $10 million.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The drug cost per patient per year was estimated by the submission,
for juvenile and adult patients, assuming a daily dose of 600 mg
miglustat and for paediatric patients, assuming an average daily
dose of 400 mg miglustat.
The requested cost per pack of miglustat was consistent with the
cost in the current LSDP listing, however the recommended dose for
treating NP-C is double that for the treatment of Gaucher.
Therefore, the drug cost per patient per year for miglustat for the
treatment of NP-C is double the cost per patient per year for
treating Gaucher disease.
The net financial cost/year to the PBS was estimated by the
submission to be less than $10 million in Year 5. The estimate was
uncertain, as there was a substantial degree of uncertainty in the
prevalence of NP-C disease in Australia. As variations in the
number of eligible patients are likely to have considerable impact
on the financial implications, any estimate of the net cost to the
PBS was equally uncertain.
12. Recommendation and Reasons
The PBAC considered that placebo plus standard medical management
(standard care) was the appropriate comparator for miglustat in the
treatment of Niemann-Pick Type C (NP-C) disease, rather than
standard care alone as nominated in the submission. The PBAC noted
the submission stated that miglustat would be used in addition,
rather than replacing, standard care.
The PBAC noted the requested restriction for miglustat was
consistent with the TGA approved indication.
The PBAC noted that the difference in the change of horizontal
saccade eye movement α (HSEM-α) from baseline, the
primary endpoint of Study 007a and Study 007a (ext), was not
significantly different between the miglustat group and the
standard care group. The PBAC also noted that the analysis of
changes in quality of life scores from baseline on various SF-36
domains in Study 007a did not indicate any statistically
significant difference between the miglustat group and the standard
care group.
The PBAC noted there was some suggestion of a small improvement in
HSEM-α from baseline in paediatric patients with NP-C who
were treated with miglustat for 12 months (mean change =
-0.489ms/deg (95% CI, -0.810ms/deg, -0.167ms/deg)) in the single
arm study 007p, however no statistically significant difference was
reported after 24 months in 007p (ext).
The PBAC hence considered that the clinical efficacy of miglustat
in the treatment of NP-C was uncertain. The PBAC considered that
the relationship between HSEM-α as a primary endpoint for the
assessment of miglustat in the treatment of NP-C and survival was
uncertain, and considered that the submission did not provide
sufficient evidence to indicate a direct relationship between trial
outcomes (HSEM-α) and survival.
The PBAC noted the submission also presented two surveys, one
regarding NP-C patients receiving standard care (Stage II survey),
and one concerning NP-C patients initially receiving standard care
and subsequently treated with miglustat (Stage I survey). The PBAC
noted that the composite disability score was a surrogate outcome
derived retrospectively from a non-blinded assessment of subjective
data, using a non-validated disability scale and that the data were
based on a small number of patients with large variability in
intra- and inter-individual rates of progression. The PBAC also
noted that the utility of the results was further limited by the
potential for bias and large degree of uncertainty in the
estimates. The PBAC did not consider that the survey results
provided sufficient evidence to support the submission’s
claim of an increased survival in NP-C patients treated with
miglustat. The PBAC also considered the use of the composite
disability score as a surrogate for survival was uncertain.
The PBAC considered there is limited information on the long-term
safety of miglustat treatment, especially at the relatively high
dose recommended for NP-C disease; however, the evidence presented
indicated that miglustat is not as safe as standard care
alone.
The PBAC considered there were a number of translation issues,
including the extrapolation of the survey results. The PBAC noted
that the submission assumed that the rate of progression in the
composite disability score, for both patients receiving standard
care and patients receiving miglustat, would remain constant over
time, up to 10 years after diagnosis. The PBAC considered this
assumption is not justified as the evidence suggested that there
can be variation in the rate of disease progression over the course
of the disease. The PBAC also noted that the outcome used in the
extrapolation (composite disability score) is not the outcome used
in the economic evaluation.
The submission presented a trial-based cost-utility analysis, based
on the outcomes of the direct randomised trial, Study 007a, for
juvenile and adult NP-C patients. An economic analysis for
paediatric patients was not included. The PBAC considered that the
time horizon of 12 months was not realistic and noted that only the
cost of treatment and the costs associated with treating the most
common adverse event, as determined from the trial, were included.
The health outcome used in the evaluation was quality adjusted
life-years, derived from quality of life data recorded during the
trial. The PBAC noted the cost per adult or juvenile patient per
year, and that the incremental cost per quality adjusted life-year
was greater than $10 million.
The PBAC hence rejected the application to list miglustat on the
PBS for the treatment of NP-C disease on the basis of uncertain
clinical efficacy and a very high and uncertain cost effectiveness
ratio.
The PBAC considered that miglustat for the treatment of NP-C
disease meets criterion one of the Life Saving Drug Program (LSDP),
as miglustat is TGA registered for the treatment of progressive
neurological manifestations in adult and paediatric patients with
NP-C disease. The PBAC however noted that in making the
recommendation for registration the TGA, the ADEC noted the limited
evidence of efficacy. The PBAC also considered that criteria two,
three, six, seven and eight of the LSDP are met.
The PBAC did not consider that there was acceptable evidence to
predict that a patient’s lifespan will be substantially
extended as a direct consequence of the use miglustat in NP-C
disease and hence considered that criterion four of the LSDP was
not met. The PBAC considered that there was uncertainty in the
relationship between the surrogate measure of HESM-α and
survival and the use of the composite disability score derived from
the survey results as a surrogate for survival, and considered that
no evidence was presented to conclude that the lifespan of NP-C
patients is substantially extended by receiving treatment with
miglustat.
The PBAC considered that as there is considerable uncertainty
regarding the clinical efficacy of miglustat in the treatment of
NP-C disease, it is uncertain whether miglustat meets criterion
five of the LSDP.
The PBAC hence recommended that miglustat for the treatment of
Niemann-Pick Type C disease does not meet the criteria for the
LSDP, and hence is not suitable for consideration of inclusion in
the LSDP.
The PBAC welcomed and noted the consumer comments provided in
relation to the miglustat submission.
The PBAC noted that the submission meets the criteria for an
independent review.
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
The sponsor, Actelion Pharmaceuticals, acknowledges the
recommendations of the PBAC. Actelion recognises the significant
challenges faced in the clinical study of such rare diseases, but
remains committed to working cooperatively with the PBAC in seeking
a favorable outcome in the future.
