ICATIBANT, injection, 30 mg in 3 mL (as acetate), single use pre-filled syringe, Firazyr®, July 2010
Page last updated: 03 November 2010
Public Summary Document
Product: ICATIBANT, injection, 30 mg in 3 mL (as
acetate), single use pre-filled syringe, Firazyr®
Sponsor: Shire Australia Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission sought an Authority Required listing for treatment
of laryngeal/oro-pharyngeal and severe abdominal attacks of acute
hereditary angioedema (HAE) for patients with confirmed diagnosis
of C1-esterase inhibitor deficiency.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Icatibant was TGA registered on 3 September 2010 for symptomatic
treatment of acute attacks of hereditary angioedema (HAE) in adults
(with C1-esterase-inhibitor deficiency).
4. Listing Requested and PBAC’s View
Authority required
Supply for anticipated emergency treatment of
laryngeal/oro-pharyngeal and severe abdominal attacks of acute
hereditary angioedema (HAE) for patients with confirmed diagnosis
of C1-esterase inhibitor deficiency with treatment initiated by a
specialist immunologist or other relevant specialist.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Hereditary angioedema is a rare, potentially fatal, autosomal
dominant disease caused by deficiency of C1 esterase inhibitor
(C1-INH) due to mutations of the C1-INH gene. HAE is characterised
by spontaneous, unpredictable and recurrent attacks of oedema of
the extremities, face, trunk abdominal viscera and upper airways
that can be painful and debilitating.
Icatibant is proposed as an alternative treatment, administered
subcutaneously, of potentially life-threatening acute episodes of
hereditary angioedema.
6. Comparator
The submission nominated C1-INH (Berinert®) as the
comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
Five randomised double-blind controlled trials were included in the submission – FAST-1,
FAST-2, IMPACT.1, Kunschak and Zuraw. The submission presented an indirect comparison
of icatibant and C1-INH with placebo as the common reference, using the icatibant
study (FAST-1) and the C1-INH studies (Zuraw, Kunschak, IMPACT.1).
The PBAC noted that none of the studies presented in the submission included self
administered icatibant.
The table below details the published trials presented in the submission.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Icatibant vs Placebo (Icatibant vs Tranexamic acid) | ||
| FAST-1 (FAST-2) Reidl M (2008) | Icatibant, a selective bradykinin B2 receptor antagonist, proves effective and safe in treating the symptoms of hereditary angioedema (HAE) attacks. | J Allergy Clin Immunol, 2008;21:S103 |
| C1-INH vs Placebo | ||
|
IMPACT.1 Craig TJ et al Bernstein JA et al. Kiessling P et al. |
Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. Treatment of acute abdominal and facial attacks of hereditary angioedema (HAE) with human C1 esterase inhibitor (C1-INH): Results of a global, multicenter, randomized, placebo-controlled, Phase II/III Study (IMPACT.1). Treatment of hereditary angioedema with human C1 esterase inhibitor: results of a global, multicentre, randomised, placebo-controlled, phase II/III dose-finding study of acute abdominal and facial attacks (IMPACT.). |
J Allergy Clin Immunol: (available online Sept 2009 as an epublication) J Allergy Clin Immunol, 2008; 121 (3): 795. Abstract LB16. Clin Experimental Immunol , 2008; 154 (Suppl. 1):143-144, Abstract P220B. |
|
Kunschak M et al. (1998) Waytes AT et al. (1996) |
A randomized, controlled trial to study the efficacy and safety of C1-Iinhibitor concentrate in treating hereditary angioedema. Treatment of hereditary angioedema with a vapour-heated C1-Iinhibitor concentrate. |
Transfusion, 1998;38:540-9. NEJM, 1996;334 (25):1630-1634 |
| Zuraw BL et al. (2008) | Results of a randomized double-blind controlled study of nanofiltered C1-inhibitor for the treatment of HAE attacks. | Annals of Allergy, Asthma & Immunology, 2008;1 (Suppl 1):A7 (abstract 16). |
8. Results of Trials
FAST-1: Efficacy of icatibant vs placebo.
ATTACKS RANDOMISED (NON-LARYNGEAL)
The results for time to onset of symptom relief-based on composite
visual analogue scale (VAS) score showed that there was a
statistically significant difference, between icatibant and
placebo, in time to onset of symptom relief (using the composite
VAS score) after censoring of patients before the onset of relief
at 120 hours (1.5 hrs vs 9.0 hrs; p = 0.01) and at time rescue
medication was taken (1.5 hrs vs 8.0 hrs; p = 0.024).
ATTACKS NOT RANDOMISED (SINGLE OPEN-LABEL ICATIBANT) –
LARYNGEAL
The median time to observable regression of visual symptoms (as
measured by the investigator) appeared to vary between the
non-randomised icatibant treatment arms (laryngeal vs non-laryngeal
attacks). These outcomes were not the primary outcomes of the
FAST-1 trial and the icatibant laryngeal arm data represented
evidence from a single treatment arm.
IMPACT.1, Kunschak and Zuraw: Efficacy of C1-INH vs placebo.
Data from the IMPACT.1 trial demonstrated evidence for the efficacy
of C1-INH 20U/kg in the absence of any new attack occurring in this
treatment group before complete resolution of the previous attack,
indicating an absence of rebound angioedema. This endpoint was not
examined in the icatibant trial, FAST-1.
Patients in the Kunschak trial appeared to experience a longer time
to symptom relief compared to the other trials. However, only the
symptoms with the longest time-to relief were included in the
analysis.
Zuraw reported that the time to onset of unequivocal relief from
the angioedema symptom was reduced in the treated arm (2 hours)
compared to the placebo arm (>4 hours).
Indirect comparison of effectiveness (FAST-1, Kunschack, IMPACT.1. and Zuraw)
The clinical assessment of symptom relief varied across the trials
included in the indirect comparison. This and other differing
characteristics among the trials may reflect the apparent
heterogeneity in treatment effect observed, among the placebo arms
across the trials and among the C1-INH active treatments across the
trials. These differences made it difficult to conduct a robust
assessment of comparative effectiveness between icatibant and
C1-INH concentrate.
The results for time to complete resolution (Kunschak and
IMPACT.1.) or “almost complete” resolution (FAST-1) of
symptoms are summarised below. No data were provided for
Zuraw.
Time to complete or almost complete resolution of attack
symptoms
| Trial ID | Treatment arm | N | Time to (almost) complete resolution | p value vs placebo | |
|---|---|---|---|---|---|
| FAST-1 | Icatibant | 27 | Median hrs (25%, 75% IQR) | 8.5 (2.5, 31.5) | p=0.08 |
| PBO | 29 | 19.4 (10.2, 55.7) | |||
| IMPACT. 1 | C1-INH 20U/kg | 39 | Median hrs (range) | 4.92 (0.47-1486) | p=0.02 |
| C1-INH 10U/kg | 43 | 20.00 (0.47-1486) | NS | ||
| PBO | 42 | 7.79 (0.33 - 1486) | |||
| Kunschak | C1-INH 25U/kg | 11 | Median hrs (25%, 75% IQR) | 14.08 (3.00, 29.08) | NR |
| PBO | 12 | 26.00 (25.00, 50.83) | NR | ||
NS = Not statistically significant; IQR = Inter quartile range; NR
= Not reported; PBO = placebo
The results were difficult to interpret given that the time
estimates may be substantially affected by the use of rescue
medication which could have varied among the trials – both in
timing and extent of use. Furthermore, the endpoints vary in terms
of degree of resolution and the times for complete resolution in
the icatibant FAST-1 trials may be longer than those observed for
“almost complete resolution”.
In an informal indirect comparison, the results of use of rescue
medications (C1-INH and symptomatic therapy) and response rate at 4
hours post treatment favour C1-INH 25U/kg over icatibant. It is
unclear how many patients had multiple attacks within either
study.
Overall, compared with placebo, C1-INH demonstrated a statistically
significant difference in time to complete resolution whereas time
to “almost complete resolution” favoured icatibant
although this difference was not statistically significant.
For PBAC’s comments on these results, see Recommendation
and Reasons.
The PBAC noted there were no available data from direct trials
comparing icatibant with C1-INH concentrate and given the
heterogeneity among the trials considered for the indirect
comparison, a robust comparative assessment of their toxicity
profiles was difficult.
A summary of the safety data from the FAST-1 and FAST-2 trials showed:
-Nearly all patients (>96%) receiving icatibant experienced
injection site reactions, compared to approximately 25% of patients
in the comparator groups;
-In FAST-1, all (100%) icatibant treated patients experienced
erythema; 23 patients (85.2%) experienced swelling; 18 patients
(66.7%) experienced warm sensation, 6 patients (22.2%) experienced
burning and 5 patients (18.5%) experienced both itching and
cutaneous pain. In patients with laryngeal symptoms at baseline,
there were 8 severe injection site reactions of erythema (100.0%)
and 6 events of swelling (75.0%);
-In FAST-2, more patients in the icatibant arm experienced adverse
events (excluding injection site reactions) than did patients in
the tranexamic acid arm (50.0% versus 36.8%). A total of 4 patients
(5.4 %) experienced 6 severe adverse events, all of which were
considered ‘unrelated’ to the study treatment.
No safety issues associated with C1-INH concentrate were identified
in IMPACT.1 or Kunschak and Zuraw provided inadequate data on
safety. The submission noted that C1-INH concentrate has been used
extensively and is considered to have a good safety profile.
9. Clinical Claim
The submission described icatibant as non-inferior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over C1-INH concentrate, noting the limitations of the
indirect evidence.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented two economic analyses.
1) A modelled evaluation of the cost-effectiveness of C1-INH
concentrate vs best supportive care (without C1-INH concentrate
being available). The model replicated an HAE attack (of both
laryngeal and severe abdominal types, respectively) for each
treatment arm, and assigned probabilities of hospitalisation and
death.
The incremental cost per life year gained (LYG) for both sites
pooled (laryngeal and abdominal) was calculated to be less than
$15,000.
2) A cost-minimisation analysis of icatibant vs C1-INH concentrate.
Two alternative calculations of equi-effective doses were
presented, determined on the basis of total dose used per attack.
These were: that 1.12 (x30 mg) injections of icatibant (av.
requirement per attack) would replace 2.31 or 3.97 (x500 U)
vials of C1-INH concentrate, depending on whether trial-based or
practice-based dosing was used.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the financial cost per year to the PBS to
be less than $10 million in Year 5. The PBAC considered the
financial implications were underestimated.
12. Recommendation and Reasons
The PBAC considered that there is a clinical need for an effective treatment for hereditary
angioedema (HAE) for administration outside the emergency setting. However, the appropriate
setting for icatibant on the PBS is uncertain, given the recommendation for registration
by the Advisory Committee on Prescription Medicines (ACPM) that “it was clinically
appropriate in view of the supporting safety data to allow patient self administration.”
The sponsor’s Pre-PBAC Response noted that the ACPM recommendation for home administration
was unexpected and that the submission had been prepared in the context of treatment
under medical supervision only.
The PBAC noted that the requested restriction was narrower than the ACPM recommended
indication and the Australian Society of Clinical Immunology and Allergy (ASCIA) guidelines.
These guidelines recommend the use of icatibant for mild abdominal pain, as well as
for peripheral attacks. The clinician representative from ASCIA at the hearing stated
that ASCIA recommends the use of icatibant in the following situations:
- patients with a history of laryngeal or severe abdominal attacks;
- patients in remote locations;
- families where there are multiple HAE sufferers where it is necessary to have one injection on hand due to the higher probability of an attack
- ASCIA recommend individual and specific care plans for each patient which will include the option for the patient to call the treating physician or immunologist at the onset of an attack and discuss if self administering Firazyr is suitable
- ASCIA recommends a follow up visit with the physician in person or over the phone soon after an attack where Firazyr has been self administered
The clinician assured the Committee in the hearing that ASCIA would be willing to
work with the PBAC to ensure that PBS usage complied with the PBS restriction.
The PBAC noted that it is not possible to construct a PBS restriction around a patient’s
location. Members were also concerned that it was impractical to suggest that patients
be required to experience severe abdominal pain before administering icatibant. It
places the responsibility on the patient to have to make clinical decisions as to
whether they were experiencing an attack serious enough to warrant its use. Furthermore,
the term ‘severe’ abdominal attacks’ requires a subjective assessment by the patient
and also partially defeats the purpose of early intervention by self-administration,
which is to stop an attack progressing to such a point. The PBAC thus considered there
was considerable potential for utilisation outside the intended restriction.
The PBAC noted that the appropriate comparator can no longer be simply defined as
C1-INH concentrate, but more might be accurately described in this setting as “delayed
treatment with C1-INH concentrate, where necessary”. Further there is no evidence
demonstrating the effectiveness or safety of icatibant actually undertaken in the
self-administration setting ie. effectiveness and safety are assumed to be applicable
from trials undertaken in the hospital setting, where icatibant is administered under
medical supervision and patient conditions are monitored.
In addition, the PBAC considered that there is limited evidence and high uncertainty
surrounding the evidence presented in the submission to support use of icatibant in
the hospital/emergency setting. The PBAC noted that there are no studies directly
comparing icatibant and C1-INH, and the indirect studies were not sufficiently exchangeable
to be useful for an indirect comparison. The claim of non-inferiority between icatibant
and C1-INH concentrate is made on the basis of an informal comparison and the submission
did not conduct a formal indirect comparison between icatibant and C1-INH due to the
apparent heterogeneity between the trials. The PBAC considered the individual results
suggested that icatibant may not be as effective as C1-INH in preventing rebound oedema,
as in the FAST-1 trial occasional post icatibant angioedema attacks required treatment
with C1-INH. In contrast, results from the IMPACT.1 study indicated that acute treatment
with C1-INH protects patients with HAE from rebound angioedema attacks. The sponsor’s
pre-sub-committee response notes that whilst there were no reports of rebound oedema
in the IMPACT.1 study, worsening of symptoms after initiation of C1-INH was reported
in 2/27 patients. In the FAST 1 study, HAE reported as an AE included inadequate initial
treatment, worsening or recurrence of a treated attack or the emergence of a new attack,
and was also observed in 2/27 patients. Given the differences in definitions between
the trials, the pre-sub-committee response concludes that it is difficult to compare
the incidence of rebound across the studies. The PBAC noted that the half-life of
C1-INH is considerably longer than icatibant (icatibant t1/2 =1-1.5 hrs, C1-INH concentrate t1/2 = 32 hrs).
The PBAC concluded that the data presented in the submission were insufficient to
support a claim of non-inferiority against C1-INH, and that the cost-minimisation
approach was therefore not adequately supported.
The appropriate dose of C1-INH is also unclear. The submission stated that the dosing
regimen that would be expected to be used in clinical practice is: 500 U for patients
<50kg, 1000 U for patients 50-100kg, 1500 U for patients ≥100kg. This represents a
range of doses between 10U/kg and 20U/kg, depending on the patient’s actual weight.
Further, the submission presented two alternative calculations of equi-effective doses,
determined on the basis of total dose used per attack. These are: that 1.12 (x30mg)
injections of icatibant (av. requirement per attack) will replace 2.31 or 3.97 (x500U) vials of C1-INH concentrate, depending on whether trial-based or practice-based
dosing is used. Additionally, the cost-minimisation assumes no leakage or wastage
of PBS-funded icatibant which is unrealistic.
The ESC advised that the FAST trials (used to calculate the average dose requirement
per attack for icatibant) included the treatment of less severe attacks (including
cutaneous and mild abdominal attacks), which might reasonably be expected to require
fewer doses than the more severe attacks specified in the proposed PBS restriction.
This concern is supported by the fact that when only laryngeal attacks in the FAST
trials are considered, the average number of doses required per attack was 1.17.
Further, the cost-minimisation approach against C1-INH assumed that all use of icatibant
would be in a hospital setting and is therefore not appropriate given the potential
for self-administration. Thus in addition to the uncertainty about the claim of non-inferiority,
there was also considerable uncertainty about the submission’s calculation of equi-effective
doses for icatibant and C1-INH concentrate.
The PBAC noted further that the validity of the cost-minimisation approach would also
require acceptance of the cost effectiveness analysis presented in the submission
for C1-INH concentrate. The PBAC agreed with ESC advice that the results of this cost
effectiveness analysis, including the calculation of the cost per life year gained,
are not valid given the concerns with the model structure and inputs, and are highly
uncertain.
The PBAC considered the submission’s estimate of utilisation to be highly uncertain
and a likely underestimate because of the high likelihood of usage outside the intended
population. Further, this estimate did not include the initial distribution of icatibant
injections (prior to an attack but in anticipation of a severe attack).
The PBAC therefore rejected the submission because of insufficient evidence in the
proposed setting to support the clinical place of the therapy and uncertain cost-effectiveness.
The PBAC indicated a willingness to meet with the sponsor, ASCIA and patient groups
to determine the appropriate clinical setting for icatibant on the PBS.
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
Shire Australia appreciate the PBAC’s view that there is a clinical need for an effective treatment like icatibant outside the emergency setting. Shire thank the PBAC for a constructive stakeholder meeting held in September and is committed to working with the PBAC, ASCIA and patient groups to determine the appropriate clinical setting for icatibant on the PBS.
