Fingolimod, capsule, 0.5 mg (as hydrochloride), Gilenya® - March 2011
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Public Summary Document
Product: Fingolimod, capsule, 0.5 mg (as
hydrochloride), Gilenya®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought an Authority Required listing for the initial
and continuing treatment of clinically relapsing-remitting multiple
sclerosis (RRMS) in an ambulatory patient who has experienced at
least two documented attacks of neurological dysfunction, believed
to be due to multiple sclerosis in the preceding two years who
meets certain criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Fingolimod was TGA registered on 1 February 2011 for the treatment
of relapsing remitting multiple sclerosis and secondary progressive
multiple sclerosis with superimposed relapses to delay the
progression of physical disability and reduce the frequency of
relapse. Safety and efficacy of fingolimod beyond 2 years are
unknown.
4. Listing Requested and PBAC’s View
Authority required
Initial treatment of clinically definite relapsing-remitting
multiple sclerosis in ambulatory (without assistance or support)
patients who have experienced at least 2 documented attacks of
neurological dysfunction, believed to be due to the multiple
sclerosis, in the preceding 2 years. The diagnosis must be
confirmed by magnetic resonance imaging of the brain and/or spinal
cord and the date of the scan included in the authority
application, unless the authority application is accompanied by
written certification provided by a radiologist that an MRI scan is
contraindicated because of the risk of physical (not psychological)
injury to the patient. The authority will be limited to the maximum
quantity and number of repeats indicated in the schedule;
Continuing treatment of clinically definite relapsing-remitting
multiple sclerosis in patients previously issued with an authority
prescription for this drug who do not show continuing progression
of disability while on treatment with this drug and who have
demonstrated compliance with, and an ability to tolerate, this
therapy. Authorities will be limited to the maximum quantity and
number of repeats indicated in the schedule.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Multiple sclerosis (MS) is a chronic-progressive autoimmune
disorder of uncertain cause. MS causes inflammation and
neurodegeneration, characterised by demyelination, axonal loss,
gliosis and failure of effective repair. The vast majority of
patients (between 65 % and 85%) show a relapsing-remitting form of
MS (RRMS), which is characterised by recurrent and unpredictable
acute episodes of neurological dysfunction (relapses), followed by
a full or partial recovery and periods of clinical stability. The
repeated damage to the myelin sheaths and other parts of nerves can
lead to the accumulation of serious disability over time.
The submission proposed that the place in therapy of fingolimod 0.5
mg capsules is to provide an additional treatment option for
patients with relapsed remitting multiple sclerosis. There are
currently five treatment options listed on the PBS.
6. Comparator
The submission nominated intramuscular interferon beta-1a (Avonex)
as the main comparator. The submission also nominated interferon
beta-1b (Betaferon) and natalizumab as secondary comparators.
The PBAC considered that the main comparator, intramuscular (IM)
interferon beta-1a, was appropriate, and that the comparison
presented with natalizumab as a secondary comparator, was
informative.
7. Clinical Trials
The submission presented one direct randomised comparative trial
(plus its extension study) comparing fingolimod and interferon
beta-1a (TRANSFORMS) and one direct randomised comparative trial
(plus its extension study) comparing fingolimod and placebo
(FREEDOMS).
The results of the FREEDOMS trial were used in indirect comparisons
of fingolimod versus interferon beta-1b and natalizumab as a
supportive analysis.
The trials and associated reports presented in the submission are
summarised in the table below:
| Trial ID/First author | Protocol title / Publication title | Publication citation |
| Direct randomised trials of fingolimod | ||
| 2302 (TRANSFORMS) Cohen JA, et al. | Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. | N Engl J Med 2010;362(5):402-415. Published online on 20 January at NEJM.org |
| 2302E1 (TRANSFORMS extension) Khatri B et al. | 24-month efficacy and safety outcomes from the TRANSFORMS extension study of oral fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis. | Neurology 2010; 74(9 Suppl 2): A239. [Conference Paper]. |
| 2301 (FREEDOMS) Kappos L et al | A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. | N Engl J Med. 2010;362(5):387-401. Published online on 20 January 2010 at NEJM.org |
| Kappos L et al | Oral fingolimod (FTY720) vs placebo in relapsing-remitting multiple sclerosis: 24-month clinical efficacy results from a randomized, double-blind, placebo-controlled, multicenter phase III study (FREEDOMS). | Neurology 2010; 74(9 Suppl 2): A194 [Conference Paper]. |
| Radue EW et al. | Oral fingolimod (FTY720) reduces inflammatory activity vs placebo in relapsing-remitting multiple sclerosis: 24-month MRI results from a randomized, double-blind, placebo-controlled, multicenter phase III study (FREEDOMS). | Neurology 2010; 74(9 Suppl 2): A194. [Conference Paper]. |
| 2309 (FREEDOMS II) Calabresi PA et al | Oral fingolimod (FTY720) in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a 2-year phase III trial (FREEDOMS II). | Neurology 2010; 74 (9 Suppl 2): A416-A417 [Conference Paper]. |
| Direct randomised trials of interferon beta-1b | ||
| IFNB MSSG | Pooled results from two identically designed 2-year trial comparing interferon beta-1b 1.6 MIU, beta-1b 8MIU and placebo | |
| Duquette P et al. | Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. | Neurology 1993;43:655-661. |
| Paty DW et al | Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. | Neurology 1993;43:662-667. |
| Sibley WA et al. | Interferon beta treatment of multiple sclerosis | Neurology 1994;44:188-190. |
| Duquette P et al | Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. | Neurology 1995;45:1277-1285 |
| Direct randomised trials of natalizumab | ||
| AFFIRM | 2-year randomised trial comparing natalizumab vs. placebo | |
| Polman CH et al. | A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. | N Engl J Med 2006;354:899-910 |
8. Results of Trials
DIRECT RANDOMISED EVIDENCE: FINGOLIMOD VERSUS INTERFERON BETA-1A
(TRANSFORMS)
Aggregate annualised relapse rate (ARR)
The results of the primary outcome of aggregate annualised relapse
rate (ARR) of fingolimod 0.5 mg daily and IFN beta-1a 30 g IM once
weekly from the TRANSFORMS trial at 12 months showed are shown in
the table below:
| Fingolimod 0.5mg po daily N=429 | IFN beta-1a I.M. 30g weekly N=431 | Rate Ratio Fingolimod 0.5mg vs. INFB-1a | |
| Modified ITT population^ (Primary outcome) | |||
| Number of relapses | 75 | 129 | - |
| Adjusted ARR (95% CI) p-value | 0.16 (0.122-0.212) | 0.33 (0.262-0.417) | P<0.001 |
For the primary study outcome of aggregate annualised relapse rate
(ARR), the PBAC noted that the post-hoc sub-group analysis of
patients with at least two relapses in the two years prior to
randomisation showed that treatment with fingolimod was associated
with a statistically significantly lower ARR than interferon
beta-1a which was comparable to the results of the modified
intention to treat (mITT) population.
The sub-group of patients in the TRANSFORMS study of fingolimod
versus interferon beta-1a who had at least 2 relapses in the 2
years prior to randomisation is representative of the population
eligible for fingolimod treatment according to the proposed PBS
restriction.
3 Months confirmed disability progression
For the study outcome of proportion of patients free of 3-months
confirmed disability progression at month 12, the PBAC noted a
trend favouring fingolimod in both the mITT population and the
sub-group of patients with at least 2 relapses in the 2 years prior
to randomisation, however, the differences did not reach
statistical significance. However, the PBAC acknowledged that the
TRANSFORMS study was not powered to detect a difference in
disability progression at 12 months.
The submission also presented an indirect comparison of fingolimod
versus natalizumab using trial outcomes from FREEDOMS and
AFFIRM.
For PBAC’s view of these results, see Recommendation and
Reasons.
The incidence of any adverse event was lower in patients treated
with fingolimod 0.5mg versus IFN beta-1a (86% vs 91.6%), however
more patients in the fingolimod 0.5 mg treatment group had
interrupted drug therapy due to AE (10.5% vs 4.6%).
There were 2 deaths in the fingolimod 1.25 mg treatment arm, but no
death was observed with fingolimod 0.5 mg and IFN beta-1a
treatments.
The incidence of AEs in the system organ classes of investigations
was statistical significantly higher in the fingolimod 0.5 mg than
the interferon beta-1a group (20.0% vs 8.6%), neoplasms benign,
malignant and unspecified (14.5% vs. 9.7%). Number of patients
experiencing ALT raises was higher in the fingolimod treatment
group compared to IFN beta-1a (6.5% vs 1.9%).
The incidence of organ class AE of general disorders and
administration site conditions was lower in the fingolimod 0.5 mg
versus IFN beta-1a group (25.2% vs 62.6%) and influenza-like
illness (3.5% vs 36%). Similarly, the incidence of pyrexia was
lower in the fingolimod versus interferon beta-1a group (4.2% vs
17.9%), as was myalgia (3.3% vs 10.2%) and arthralgia (2.8% vs
5.6%).
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission claimed fingolimod as superior in terms of
comparative effectiveness and with a similar safety profile to
interferon beta-1a (Avonex) its main comparator, as well as
interferon beta 1b, (Betaferon), interferon beta-1a SC (Rebif) and
glatiramer acetate (Copaxone) based on the cost minimisation
recommendations of these currently listed treatments with
interferon beta-1a (Avonex).
The PBAC accepted that fingolimod was superior in terms of
comparative effectiveness and with a similar safety profile to
interferon beta-1a.
10. Economic Analysis
A stepped economic evaluation was presented.
The time horizon in the modelled economic evaluation was life time.
The model followed patients until death.
The stepped economic evaluation produced a base case incremental
cost per extra quality adjusted life year (QALY) gained in the
range of $45,000 – $75,000. Sensitivity analyses showed the
results are most sensitive to changes in model time horizon. When
the model duration was reduced from an average of 62 years to 5
years, the incremental cost per QALY increased and was estimated to
be in the range of $105,000 – $200,000. The results are also
very sensitive to changes in discontinuation rates and utility
values applied in the modelled economic evaluation.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less
than 10,000 in Year 5.
The financial cost per year to the PBS was estimated to be in the
range of $30 – $60 million in Year 5.
12. Recommendation and Reasons
The PBAC agreed that the restriction should stipulate that
fingolimod be used as monotherapy as it was not intended for use as
add-on therapy and should not be limited to neurologists because of
issues with access. The PBAC did not consider switching criteria to
be necessary as the requested restriction for initial treatment
allows switching provided the initiation criteria are met.
The PBAC considered the submission’s main comparator,
intramuscular (IM) interferon beta-1a, was appropriate, and that
the comparison presented with natalizumab as a secondary
comparator, was informative.
The PBAC noted that the sub-group of patients in the TRANSFORMS
study of fingolimod versus interferon beta-1a who had at least 2
relapses in the 2 years prior to randomisation is representative of
the population eligible for fingolimod treatment according to the
proposed PBS restriction. For the primary study outcome of
aggregate annualised relapse rate (ARR), the PBAC noted that the
post-hoc sub-group analysis showed that treatment with fingolimod
was associated with a statistically significantly lower ARR than
interferon beta-1a. This was comparable to the results of the
modified intention to treat (mITT) population.
For the study outcome of proportion of patients free of 3-months
confirmed disability progression at month 12, the PBAC noted a
trend favouring fingolimod in both the mITT population and the
sub-group of patients with at least 2 relapses in the 2 years prior
to randomisation, however, the differences did not reach
statistical significance. However, the PBAC acknowledged that the
TRANSFORMS study was not powered to detect a difference in
disability progression at 12 months.
Overall, the PBAC accepted that fingolimod was superior in terms of
comparative effectiveness and with a similar safety profile to
interferon beta-1a.
The PBAC noted that the submission did not explicitly claim that
fingolimod is non-inferior to natalizumab, however, natalizumab is
assumed to have the same treatment benefit as fingolimod when
included in a sensitivity analysis of the economic model. The PBAC
noted the results of the simple/unadjusted indirect comparison of
fingolimod versus natalizumab using placebo as the common
comparator from the FREEDOMS and AFFIRM studies (which did not
account for differences in patient characteristics of the two
trials) suggested a lower ARR for natalizumab. The PBAC did not
accept the argument in the submission’s Pre-Sub-Committee
Response that between-trial differences in trial population
characteristics influenced the results of the indirect comparison.
However, in the absence of direct head-to-head evidence comparing
natalizumab and fingolimod, the result of this indirect comparison
is uncertain/inconclusive.
The PBAC noted the stepped economic evaluation produced a base case
incremental cost per extra quality adjusted life year (QALY) gained
in the range of $45,000 – $75,000. Sensitivity analyses
showed the results are most sensitive to changes in model time
horizon. When the model duration was reduced from an average of 62
years to 5 years, the incremental cost per QALY increased and was
estimated to be in the range of $105,000 – $200,000. The
results are also very sensitive to changes in discontinuation rates
and utility values applied in the modelled economic evaluation. The
high treatment discontinuation rates used in the model may not be
appropriate. When all patients are assumed to be on first line
treatment until SPMS (or beyond EDSS 5), the ICER increased and was
estimated to be in the range of $75,000 – $105,000. When
utility values from Fisk et al (2005) are used the ICER increased
and was estimated to be in the range of $45,000 – $75,000.
The model is also sensitive to disutility associated with
injectable DMTs, which if removed altogether increase the ICER to
be in the range of $75,000 – $105,000.
The PBAC noted the submission claimed that the ICER was likely to
be overestimated based on a number of conservative assumptions,
such as:
- Indirect costs (e.g., lost productivity, short-term absenteeism, and forced early retirement) or value of informal community care (e.g., care by family members etc) are not considered. (However, it is noted that these are generally not taken into account in the base case ICER by PBAC but may be taken into account in terms of other relevant factors).
- Emotional/physical/health related quality of life burden experienced by families or carers of the patients are not considered (although, including costs and utilities for carers would have been double counting.)
- The model largely disregards the disutility directly attributable to the necessity for frequent injections associated with the existing DMTs itself.
- Administration/monitoring costs are largely ignored. In particular, the model does not include potential economic benefits associated with orally administered fingolimod over self-injected drugs, for example, avoided home nursing services.
- Cost of corticosteroid use for the treatment of relapse is not included.
- Relapse rates are as observed in the clinical trial environment. The MSBase Registry data indicate the presence of considerably higher relapse rates in practice.
- Relapses do not contribute to a permanent change in health state
- MS management costs (i.e., health state costs) for RRMS are applied to SPMS.
However, as was discussed in the evaluation, there were also a number of assumptions used in the model that may not be appropriate and would potentially lead to underestimation of the ICER.The PBAC agreed with the main issues of economic uncertainty as identified by the ESC:
- whether the MSBase registry ABCR drug cohort is representative of the patients likely to be accessing fingolimod on the PBS, given the differences in Expanded Disability Status Scale (EDSS) scores at baseline;
- whether the derivation and application of trial based transition probabilities to the modelled economic evaluation is appropriate, considering whether the use of whole point EDSS transitions, disease modifying treatment (DMT) stopping rule of EDSS > 5 and no more than one transition per year appropriately reflects MS progressions in real life and DMT treatment on the PBS;
- the application of discontinuation rates, given that it is likely that patients who discontinue from treatment will try other DMTs;
- the use of similar relapse rates for RMSS and secondary progressive multiple sclerosis (SPMS);
- whether the submission’s assumption of identical relapse rates for natalizumab and fingolimod is appropriate.
The PBAC considered that in the context of these uncertainties, the
base case ICER was unacceptably high to recommend listing. The PBAC
considered that the uncertainties in the model could be managed
with a lower price offer and that an acceptable ICER for fingolimod
based on the current model would need to be in the range of
$15,000- $45,000 per QALY.
The PBAC therefore deferred its decision on the submission for
fingolimod pending further negotiation with the sponsor. The PBAC
acknowledged and noted the consumer comments on this item.
Subsequent to the meeting, the sponsor offered a further price
reduction. The PBAC therefore recommended out-of-session listing
fingolimod on the PBS as an Authority Required benefit for the
initial and continuing treatment of clinically relapsing-remitting
multiple sclerosis (RRMS) in a patient who meets certain criteria
on the basis of an acceptable cost-effectiveness ratio compared
with interferon beta-1a.
Recommendation:
FINGOLIMOD, capsule, 0.5 mg (as hydrochloride)
Restriction:
Authority required
Initial treatment, as monotherapy, of clinically definite relapsing-remitting multiple sclerosis in an ambulatory (without assistance or support) patient who has experienced at least 2 documented attacks of neurological dysfunction, believed to be due to the multiple sclerosis, in the preceding 2 years. The diagnosis must be confirmed by magnetic resonance imaging of the brain and/or spinal cord and the date of the scan included in the authority application, unless the authority application is accompanied by written certification provided by a radiologist that an MRI scan is contraindicated because of the risk of physical (not psychological) injury to the patient. The authority will be limited to the maximum quantity and number of repeats indicated in the schedule;Continuing treatment, as monotherapy, of clinically definite relapsing-remitting multiple sclerosis in a patient previously issued with an authority prescription for this drug who does not show continuing progression of disability while on treatment with this drug and who has demonstrated compliance with, and an ability to tolerate, this therapy. Authorities will be limited to the maximum quantity and number of repeats indicated in the schedule.
Max qty: 28
Repeats: 5
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
Novartis welcomes the PBAC’s positive recommendation for fingolimod (Gilenya). Gilenya is the first oral treatment and was recommended by the PBAC on the basis of superiority to interferon beta-1a with acceptable cost-effectiveness for treatment in patients with relapsing-remitting forms of MS who meet certain criteria. Novartis is working closely with the Department of Health to ensure timely listing of Gilenya on the PBS.
