Abatacept, powder for I.V. infusion, 250 mg, Orencia® - July 2011
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Public Summary Document
Product: Abatacept, powder for I.V. infusion, 250
mg, Orencia®
Sponsor: Bristol-Myers Squibb Australia Pty
Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an extension to the current Section 100
(Highly Specialised Drugs Program) listing to include treatment of
severe active juvenile idiopathic arthritis (JIA) in patients who
have severe intolerance of, or toxicity due to methotrexate or who
have failed to achieve an adequate response to methotrexate.
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.
2. Background
Abatacept had not previously been considered by the PBAC for this
indication.
Abatacept is currently listed on the PBS in the Section 100 (Highly
Specialised Drugs Program) for the treatment of severe active
rheumatoid arthritis.
3. Registration Status
The TGA registration of abatacept was amended on 4 March 2010 to
include the following:
“For reducing signs and symptoms in paediatric patients 6
years of age and older with moderately to severely active
polyarticular juvenile idiopathic arthritis who have had an
inadequate response to one or more disease-modifying anti-rheumatic
drugs (DMARDS). Abatacept may be used as monotherapy or
concomitantly with methotrexate (MTX).”
Abatacept is also currently TGA registered for the following
indications in adults:
Treatment, in combination with methotrexate, of moderate to severe
active rheumatoid arthritis in patients who have had an
insufficient response or intolerance to other DMARDs (e.g.
methotrexate or TNF blocking agents).
Treatment, in combination with methotrexate, of severe, active and
progressive rheumatoid arthritis in patients not previously treated
with methotrexate.
4. Listing Requested and PBAC’s View
The submission proposed that the restriction for abatacept for
treatment of JIA should be the same as that currently applied to
etanercept and adalimumab. The current JIA listings for etanercept
and adalimumab are within Section 100 for patients under the age of
18 at initiation of the treatment cycle, and in Section 85 for
adult patients diagnosed with JIA prior to age 18, but who are 18
years or older at initiation of the treatment cycle. Due to the
intravenous administration of abatacept, the submission requested a
Section 100 listing for both children and adults.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Juvenile idiopathic arthritis is a rheumatic disease experienced by
children which may continue into adulthood and often results in
severe limitation of activity. The aim of management of JIA is to
control inflammation, reduce symptoms and associated disability.
Patients with JIA commence treatment with non-steroidal
anti-inflammatory drugs, and progress to one of the disease
modifying anti-rheumatic drugs (DMARDs) if pain and symptoms
persist. Patients who fail to respond to first-line DMARDs may then
use biological DMARDs (bDMARDs). Current PBS-listed bDMARDs for JIA
are the TNF-inhibitors, etanercept and adalimumab.
The submission proposed that the place in therapy of abatacept is
as an alternative treatment for JIA to etanercept and adalimumab,
with a different mechanism of action.
The PBAC acknowledged there was a clinical need for abatacept for
the treatment of juvenile idiopathic arthritis in a small group of
patients, as it provided an alternative bDMARD treatment option
with a different mechanism of action (T-cell co-stimulation
modulator). However, the PBAC was concerned that it may not be as
effective as the two other TNF-alfa bDMARDS currently PBS listed
for this condition, particularly when used in the second or
third-line setting, the most likely clinical place of
abatacept.
6. Comparator
The submission nominated etanercept as the main comparator and
provided a supplementary comparison with adalimumab.
The PBAC agreed that the appropriate main comparator was
etanercept, with adalimumab as a secondary comparator.
7. Clinical Trials
The basis of the submission was an indirect comparison of one
randomised trial (IM101-033) comparing abatacept (10 mg/kg
intravenously (IV) monthly) with placebo and one randomised trial
(Lovell 2000) comparing etanercept (0.4 mg/kg up to 25 mg
subcutaneously (SC) twice weekly) with placebo in patients with
JIA.
The submission also presented a supplementary indirect comparison
of abatacept (10mg/kg IV monthly) with placebo (IM101-033) and
adalimumab (24 mg/m2 SC every other week) with placebo
(DE038) in patients with JIA. The adalimumab trial had two strata,
one receiving adalimumab or placebo with MTX and the other strata
not receiving concomitant MTX.
The published trials presented in the submission are shown in the
table below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Abatacept | ||
| Study IM101-033 Ruperto et al. (2008) | Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. | The Lancet 372(9636): 383-391 |
| Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. | Arthritis and Rheumatism 62(6): 1792-1802 | |
| Giannini et al. (2006) | Conference Abstract: Efficacy and safety of abatacept in children and adolescents with active juvenile idiopathic arthritis (JIA): Results of double-blind withdrawal phase | Abstract presented at the American College of Rheumatology and the Association of Rheumatology Health Professionals Annual Scientific Meeting. 2006, presentation L2/482. |
| Lovell et al. (2006b) | Conference Abstract: Assessment of open label co-stimulation blockade with abatacept in children and adolescents with active juvenile idiopathic arthritis (JIA). | Abstract presented at the American College of Rheumatology and the Association of Rheumatology Health Professionals Annual Scientific Meeting. 2006, presentation 719. |
| Ruperto et al. (2010b) | Additional publication: Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis. | Arthritis Care Res (Hoboken) 62(11): 1542-51 |
| Etanercept | ||
| Lovell et al. (2000) | Etanercept in children with polyarticular juvenile rheumatoid arthritis. | New England Journal of Medicine 342(11): 763-769 |
| Lovell et al. (2003) | Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: Interim results from an ongoing multicenter, open-label, extended-treatment trial. | Arthritis and Rheumatism 48(1): 218-226 |
| Lovell et al. (2006a) | Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis. | Arthritis and Rheumatism 54(6): 1987-1994 |
| Lovell et al. (2008a) | Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis. | Arthritis and Rheumatism 58(5): 1496-1504 |
| Brunner et al. (2002) | Preliminary definition of disease flare in juvenile rheumatoid arthritis. | Journal of Rheumatology 29(5): 1058-1064 |
| Adalimumab | ||
| DE038 study Lovell et al. (2008b) | Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. | New England Journal of Medicine 359(8): 810-820 |
| Lovell et al. (2004) | Preliminary data from a study of adalimumab in children with JIA. | Arthritis Rheum 50:S436 (Suppl) |
| Ruperto et al. (2006) | 48-week data from the study of adalimumab in children with juvenile rheumatoid arthritis (JRA). Oral Presentation (OP0007). | Annals of the Rheumatic Diseases 65(Suppl 2): 56 |
8. Results of Trials
From study IM101-033, the submission presented a primary analysis of the double-blind
phase of abatacept over placebo using the primary outcome of disease flare, defined
as a worsening of 30% or more in at least 3 of 6 Paediatric American College of Rheumatology
(PedACR) core response variables and at least 30% improvement in no more than one
of the other variables. Overall, patients randomised to receive continued treatment
with abatacept after the open-label lead-in phase were more likely to have a longer
time to disease flare compared with placebo, [HR = 0.31 (95%CI: 016 to 0.59), p =
0.0002].
PedACR responses (improvement) were also analysed, measured from baseline (start of
the open-label lead in phase) to the end of the double blind phase. The response rates
for the PedACR 50, 70 and 90 were all statistically significantly higher in the abatacept
group compared with the placebo group, but the PedACR 30 response rates were not.
The response rates of patients in the abatacept trial with and without previous bDMARD
therapy are shown in the table below.
Response Rates at the end of the Open-Label Lead-In Period for Study IM101-033 by prior bDMARD therapy
| Response | No prior bDMARD therapy (N=133) | Prior bDMARD therapy (N=57) |
| PedACR30 | n=101; 76% (95% CI: 69%, 83%) | n=22; 39% (95% CI: 26%, 51%) |
| PedACR50 | n=80; 60% (95% CI: 52%, 69%) | n=14; 25% (95% CI: 13%, 36%) |
| PedACR70 | n=48; 36% (95% CI: 28%, 44%) | n=6; 11% (95% CI: 3%, 19%) |
Abbreviations: bDMARD, biological disease modifying anti-rheumatic drug; CI, confidence interval;
PedACR, American College of Rheumatology Paediatric.
An indirect comparison using the proportion of patients experiencing a disease flare
at the end of the double-blind phase of the trials was conducted for both etanercept
and adalimumab. Results are presented in the tables below. The maximum length of the
double-blind phase of the trials was 6 months in abatacept trial, 4 months in the
etanercept trial and 32 weeks in the adalimumab trial. An indirect comparison using
a common time period was not conducted in the submission. The disease flare rates
in the common comparator (placebo) groups differed between all three trials with 53%
in the abatacept trial, 81% in the etanercept trial and 68% in the adalimumab trials.
The response rates (improvements) using the PedACR 30/50/70/90 were also different
between the placebo groups of the trials, with those in the abatacept trial having
a higher percentage than etanercept or adalimumab for PedACR 30, 50 and 70.
Indirect Comparison of abatacept and etanercept (proportion with disease flare – double blind period)
| Trial ID | Treatment effect a RR (95% CI) | Abatacept n with event/N (%) | Placebo n with event/N (%) | Etanercept n with event/N (%) | Treatment effect b RR (95% CI) | Indirect estimate of effect c Indirect RR (95%CI) |
| Study IM101-033 | 0.376 (0.215, 0.656) | 12/60 (20.0%) | 33/62 (53.2%) | 1.08 (0.458, 2.56) | ||
| Lovell 2000 | 21/26 (80.8%) | 7/25 (28.0%) | 0.347 (0.180, 0.668) |
aAbatacept over placebo (pooled using Bucher method)
bEtanercept over placebo (pooled using Bucher method)
cInferred as abatacept over etanercept
Abbreviations: CI: confidence interval, n: number with event, N: number in group,
RR: relative risk
Indirect Comparison of abatacept and adalimumab (proportion with disease flare – double blind period)
| Trial ID | Treatment effect a RR (95% CI) | Abatacept n with event/N (%) | Placebo n with event/N (%) | Adalimumab n with event/N (%) | Treatment effect b RR (95% CI) | Indirect estimate of effect c Indirect RR (95%CI) |
| Study IM101-033 | 0.376 (0.215, 0.656) | 12/60 (20.0%) | 33/62 (53.2%) | 0.641 (0.334, 1.23) | ||
| Study DE038 | 44/65 (67.7%) | 27/68 (39.7%) | 0.587 (0.418, 0.822) |
aAbatacept over placebo (pooled using Bucher method)
bAdalimumab over placebo (pooled using Bucher method)
cInferred as abatacept over adalimumab
Overall numbers of patients responding in the DE038 study and percentages were calculated
from the strata specific results (No MTX and MTX) and shown in italics.
Abbreviations: CI: confidence interval, n: number with event, N: number in group,
RR: relative risk
The most common adverse events experienced during the open-label lead-in phase of
the abatacept trial were injection-site reactions, upper respiratory tract infections
and headaches. There were no significant differences in the frequency of adverse events
experienced in the two treatment groups in the double-blind phase. No subjects discontinued
treatment of either abatacept or placebo during the double-blind phase.
The trials for both etanercept and adalimumab also reported no statistically significant
differences in the rates of adverse events in the treatment arms versus the placebo
arms during the double-blind phases of the trials.
For PBAC’s comments on these results, see Recommendations and Reasons.
9. Clinical Claim
The submission claimed that abatacept is non-inferior to both
etanercept and adalimumab in terms of comparative effectiveness and
comparative safety.
The PBAC considered that the data presented indicate that abatacept
may not be as clinically effective as etanercept or adalimumab as
first -line treatment and is inferior in patients who had prior
exposure to bDMARD therapy compared to patients naïve to
bDMARD therapy.
10. Economic Analysis
The submission presented a cost minimisation analysis based on the
indirect comparison of treatment with abatacept versus etanercept
using placebo as a common comparator.
The equi-effective doses were: abatacept approximately10 mg/kg for
patients weighing less than 75 kg, 750 mg for patients weighing 75
to 100 kg and 1,000 mg for patients weighing over 100 kg,
administered by 30 minute IV infusion and etanercept 0.4 mg/kg up
to 25 mg administered subcutaneously twice weekly.
The price of abatacept was determined by equating the etanercept
annual treatment cost to abatacept (i.e. the submission worked
backwards from the annual treatment cost of etanercept to determine
the price per vial of abatacept). The number of infusions per year
(weighted by responders and non-responders) was applied to an
average number of vials per infusion for each weight category. The
weighted average was then applied to the overall price per vial of
abatacept.
The submission assumed a standard consultation fee ($41.35) from a
specialist rheumatologist (MBS item 105) for abatacept and no costs
for administration of etanercept.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of prescriptions/packs dispensed was estimated in
the submission to be less than 10,000 in year 5.
The submission estimated net financial savings to the PBS of less
than $10 million in year 5, and a total net cost to the MBS of less
than $10 million in year 5. The additional cost to the MBS was
based on the cost of IV administration over 5 years.
The financial implications were still to be further verified by the
Department.
12. Recommendation and Reasons
The PBAC acknowledged there was a clinical need for abatacept for
the treatment of juvenile idiopathic arthritis in a small group of
patients, as it provided an alternative bDMARD treatment option
with a different mechanism of action (T-cell co-stimulation
modulator). However, the PBAC was concerned that it may not be as
effective as the two other TNF-alfa bDMARDS currently PBS listed
for this condition, particularly when used in the second or
third-line setting, the most likely clinical place of
abatacept.
The PBAC agreed that the appropriate main comparator is etanercept,
with adalimumab as a secondary comparator.
The basis of the submission was an indirect comparison of one
randomised trial (IM101-033) comparing abatacept (10 mg/kg IV
monthly) with placebo and one randomised trial (Lovell 2000)
comparing etanercept (0.4mg/kg up to 25 mg SC twice weekly) with
placebo in patients with JIA. The PBAC was concerned about the
exchangeability of the trials used in the indirect comparison
particularly differences in the use of methotrexate (MTX) and
disease severity between the abatacept and etanercept trials. The
PBAC noted that use of MTX was not permitted in the etanercept
trial compared with 74% of the patients who received MTX in the
abatacept trial. The etanercept trial also had a greater median
number of active joints (28 vs. 12) and longer duration of disease
(5.9 years vs. 4.4 years) than the abatacept trial, which indicates
that the etanercept trial recruited subjects with greater disease
severity.
The submission also presented a supplementary indirect comparison
of abatacept (10mg/kg IV monthly) with placebo (IM101-033) and
adalimumab (24 mg/m2 SC every other week) with placebo
(DE038) in patients with JIA. The adalimumab trial had two strata,
one receiving adalimumab or placebo with MTX and the other strata
not receiving concomitant MTX. Again, the PBAC was concerned about
the exchangeability of the trials for use in the indirect
comparison particularly differences between the inclusion/
exclusion criteria and previous MTX therapy. The PBAC noted that
patients with previous bDMARD therapy were excluded from the
adalimumab trial but permitted in the abatacept trial (30% of those
in the abatacept trial had previous bDMARD usage); patients in the
adalimumab trial were not required to have demonstrated intolerance
to, or an inadequate response to a DMARD previously, compared with
the abatacept trial; patients were excluded if recently treated
prior to enrolment with a DMARD other than MTX in the adalimumab
trial; and patients must have failed to respond to treatment with
NSAIDs in the adalimumab trial. In the abatacept trial 94.2% of
patients had previous MTX therapy compared with only 65% of
patients in the adalimumab trial.
The PBAC also expressed concerns over the design of the trials,
which included an open-label lead-in phase followed by a
double-blind phase. Only patients who had an initial response were
randomised to continue study treatment which may bias the results
in favour of responders. The PBAC acknowledged that similar trial
exchangeability and applicability issues were identified during the
recent consideration of adalimumab for JIA.
The PBAC considered that the claim of improved efficacy of
abatacept over placebo (IM101-033) was reasonable as patients
randomised to receive continued treatment with abatacept after the
open-label lead-in phase were more likely to have a longer time to
disease flare compared with placebo, [HR = 0.31 (95%CI: 016 to
0.59)]. However, while response rates for the PedACR 50, 70 and 90
were all statistically significantly higher in the abatacept group
compared with the placebo group, the PedACR 30 response rates,
which are a clinically important outcome for patients, were
not.
The PBAC was concerned about the low response rates of patients in
the abatacept trial who had previous bDMARD therapy, particularly
as the interchangeability rules in the restriction would allow its
use as second or third line treatment. The PBAC noted that the
lower response rates in the abatacept trial in patients previously
treated with bDMARD therapy may indicate that it might be difficult
to elicit a response in these patients.
The PBAC considered that non-inferiority had not been shown for the
indirect comparison with etanercept and adalimumab due to the poor
exchangeability of the trials, with differences identified in the
inclusion/exclusion criteria, patient characteristics, response
rates of the common comparator (placebo) arms, duration of the
studies and concomitant therapies. The PBAC concluded that the data
presented indicate that abatacept may not be as clinically
effective as etanercept or adalimumab as first -line treatment and
is inferior in patients who had prior exposure to bDMARD therapy
compared to patients naïve to bDMARD therapy.
The PBAC noted that a revised unit price had been calculated in the
evaluation via a simplified model (based on the initial treatment
phase of 16 weeks and assuming all patients have the same duration
of treatment). The PBAC considered that IV administration of
abatacept compared to SC injection of etanercept and adalimumab
would limit the uptake of abatacept treatment in the juvenile
population. However, this would impact significantly on the drug
administration costs associated with abatacept treatment as most
juvenile patients would require a day ward admission for each IV
infusion. The Committee noted that this cost was not accounted for
in the assumptions used to determine price equivalence. The PBAC
therefore considered IV drug administration cost for abatacept
infusions were underestimated.
The PBAC noted that the current PBS listing for bDMARDs for the
treatment of severe active JIA allows three attempts within a
treatment cycle: two attempts with one TNF alfa inhibitor and one
attempt with the second TNF alfa inhibitor. The PBAC was concerned
that with the addition of abatacept under the proposed restriction
and interchangeability rules it would not be possible for patients
to trial and fail the same bDMARD more than once in a treatment
cycle. The PBAC considered that if a patient was to trial all 3
bDMARDs in a treatment cycle it may be inappropriate to make them
cycle through each available bDMARD, particularly as there is
concern that prior bDMARD therapy indicates a worse outcome for
patients receiving abatacept as second or third line therapy.
The PBAC therefore deferred its decision on the submission pending
further discussion with the Sponsor regarding the clinical trial
data, administration costs and price.
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
The sponsor has no comment.
