Tocilizumab, solution for I.V. infusion, 80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL, Actemra®, July 2009
Public Summary Document for Tocilizumab, solution for I.V. infusion, 80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL, Actemra®, July 2009
Page last updated: 30 October 2009
Public Summary Document
Product:Tocilizumab, solution for I.V. infusion,
80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL,
Actemra®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request a Section 100 (Highly Specialised Drugs Program) listing
for treatment of severe, active rheumatoid arthritis, in
combination with methotrexate or other disease modifying
anti-rheumatic drugs (DMARDs).
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
This drug had not previously been considered by the PBAC.
3. Registration Status
Tocilizumab (Actemra) was registered by the TGA on 21 May 2009 for
the treatment of moderate to severe active rheumatoid arthritis
(RA) in adult patients: in combination with methotrexate (MTX) or
other non-biological disease-modifying anti-rheumatic drugs
(DMARDs) in case of either an inadequate response or intolerance to
previous therapy
with one or more DMARDs; or as monotherapy in case of intolerance
to MTX or where continued treatment with MTX is
inappropriate.
4. Listing Requested and PBAC’s View
The submission requested a Section 100 (Highly Specialised Drugs
Program) listing with a restriction for tocilizumab in combination
with methotrexate similar to the current restrictions for other
biological DMARD (bDMARD) therapies in rheumatoid arthritis i.e.
first line use. Following the ADEC recommendation in April 2009,
the sponsor requested an amendment to the listing requested in the
major submission, to include use in combination with other
non-biological DMARDs.
An abbreviated version of the requested listing is shown
below:
Section 100 (Highly Specialised Drugs Program)
Public and Private Hospital Authority
Required
Initial treatment would be restricted to use of tocilizumab in
combination with methotrexate at a dose of at least 7.5 mg weekly
or other non-biological disease-modifying anti-rheumatic drugs
(DMARDs), by a rheumatologist or clinical immunologist with
expertise in the management of rheumatoid arthritis, of adults who:
- have severe active rheumatoid arthritis; and
- have received no prior PBS-subsidised treatment with a bDMARD for this condition in this treatment cycle; and
- have failed to achieve an adequate response to the following treatments:
a. methotrexate at a dose of at least 20 mg weekly; and
b. methotrexate (at a minimum dose of 7.5 mg weekly), in
combination with 2 other non-biological disease modifying
anti-rheumatic drugs (DMARDs), for a minimum of 3 months; and a
minimum of 3 months’ treatment with leflunomide alone; or
leflunomide in combination with methotrexate, or
cyclosporine.
The submission proposed that the initial treatment authorisation
for tocilizumab be limited to provide a maximum of 16 weeks of
therapy. Patients would need to demonstrate an adequate response to
treatment, using the same criteria that were currently in place for
continuing treatment with other bDMARDs in RA, to qualify for this
continuing treatment. A maximum of 24 weeks of continuing treatment
would be approved under this restriction.
An initial PBS-subsidised treatment restriction for
‘grandfather’ patients was also requested.
The PBAC agreed that the basis of the restriction wording would be
that for rituximab in rheumatoid arthritis, where rituximab is
available second-line to those meeting certain criteria and who
have not adequately responded to a TNF-alfa antagonist.
5. Clinical place for the proposed therapy
Tocilizumab would provide another treatment option for adult
patients with severe active rheumatoid arthritis.
6. Comparator
The submission nominated abatacept and infliximab as the main
comparators for the clinical evaluation, and abatacept as the main
comparator for the economic evaluation.
The PBAC agreed that the choice of abatacept and inflixmab as the
main comparators was appropriate.
7. Clinical Trials
The submission presented indirect comparisons of tocilizumab and
abatacept and tocilizumab and infliximab based on three tocilizumab
trials, two abatacept trials, two infliximab trials and one trial
including both abatacept and infliximab, using placebo +
methotrexate as the common comparator. All trials included patients
with moderate to severe rheumatoid arthritis (RA) and the key
outcomes assessed were ACR response (a measure of treatment
response in rheumatoid arthritis, proposed by the American College
of Rheumatology) and DAS28 response (Disease Activity Score
involving 28 joints – another measure of the activity of RA)
at six months.
The mean methotrexate dose used in the trials was 15 mg weekly,
which was lower than the methotrexate dose stipulated by the PBS
eligibility criteria for prior therapy, which was for a
methotrexate dose of at least 20 mg weekly.
Details of the published trials presented are shown in the
following table.
| Trial ID | Protocol title/ Publication title | Publication citation |
| Direct randomised trials | ||
| Tocilizumab | ||
| WA17822 (OPTION) | Smolen JS, Beaulieu A, Rubbert-Roth A et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with RA (OPTION study): a double-blind, placebo-controlled, randomised trial. | Lancet 2008; 371(9617):987-997. |
| WA17823 (LITHE) | Kremer JM, Fleischmann RM, Halland A-M et al. (2008). Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with an inadequate response to methotrexate: The LITHE study. L11. | American College of Rheumatology abstract/presentation number |
| WA18063 (TOWARD) | Genovese M, McKay J, Nasonov E et al. (2008). Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs. | Arthritis and Rheumatism 58 (10): 2968-2980. |
| Abatacept | ||
| AIM | Kremer J, Genant H, Moreland L et al. (2006). Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis. Russell A, Wallenstein G, Li T et al. (2007). Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. Li T, Gignac M, Wells G et al. (2008). Decreased external home help use with improved clinical status in rheumatoid arthritis: An exploratory analysis of the Abatacept in Inadequate Responders to Methotrexate (AIM) trial. | Annals of Internal Medicine 144: 865-876. Annals of the Rheumatic Diseases 66: 189-194. Clinical Therapeutics 30 (4): 734-748. |
| Kremer et al. 2003 | Kremer J, Westhovens R, Leon M et al. (2003). Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. Kremer J, Dougados M, Emery P et al. (2005). Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept. Emery P, Kosinski M, Li T et al. (2006). Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. Weisman M, Durez P, Hallegua D et al. (2006). Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. | New England Journal of Medicine 349: 1907-1915. Arthritis and Rheumatism 52 (8): 2263-2271. Journal of Rheumatology 33 (4): 681-689. Journal of Rheumatology 33 (11): 2162-2166. |
| Infliximab | ||
| ATTRACT | Maini R, St Clair E, Breedveld F et al. (1999). Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lipsky P, van der Heijde D, St Clair E et al. (2000). Infliximab and methotrexate in the treatment of rheumatoid arthritis. Maini RN, Breedveld FC, Kalden JR et al. (2004). Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis and Rheumatism 50: 1051-65. | Lancet 354: 1932-1939. New England Journal of Medicine 343: 1594-1602. |
| Smolen J, Han C, Bala M et al. (2005). Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Breedveld F, Han C, Bala M et al. (2005). Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis. St Clair E, Wagner C, Fasanmade A et al. (2002). The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. | Arthritis and Rheumatism 52 (4): 1020-30. Annals of the Rheumatic Diseases 64 (1): 52-5. Arthritis and Rheumatism 46 (6): 1451-1459. | |
| START | Westhovens R, Yocum D, Han J et al. (2006). The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities. | Arthritis and Rheumatism 54: 1075-1086. |
| Abatacept and infliximab | ||
| ATTEST | Schiff M, Keiserman M, Codding C et al. (2008). Efficacy and safety of abatacept or infliximab versus placebo in ATTEST: a phase III, multicenter, randomized, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. | Annals of the Rheumatic Diseases , published on November 29, 2007 as 10.1136/ard.2007.080002. |
The submission also
included results of a published trial assessing the use of
tocilizumab following failure of other bDMARDs:
Emery P, Keystone E, Tony HP et al. (2008). IL-6 receptor
inhibition with tocilizumab improves treatment outcomes in patients
with rheumatoid arthritis refractory to anti-tumor necrosis factor
biologicals: results from a 24-week multicentre randomised
placebo-controlled trial. Annals of the Rheumatic Diseases
67: 1516-1523
8. Results of Trials
The primary efficacy endpoint for the tocilizumab studies was a
comparison of the proportion of patients in each treatment with an
ACR20 response at week 24.
The following table provides the results of the indirect
comparisons of tocilizumab and abatacept and infliximab for
proportion of patients achieving ACR response and DAS28 response at
six months.
Results of the indirect comparisons of tocilizumab and
abatacept and tocilizumab and infliximab for ACR response and DAS28
response at 6 months
| Outcome | Tocilizumab versus abatacept RR (95% CI) | Tocilizumab versus infliximab RR (95% CI ) |
| ACR response | ||
| ACR20 | 1.35 (1.14, 1.61) | 1.16 (0.79, 1.69) |
| ACR50 | 1.62 (1.19, 2.20) | 1.33 (0.75, 2.35) |
| ACR70 | 2.31 (1.13, 4.71) | 2.48 (1.38, 4.45) |
| DAS28 response | ||
| DAS remission (DAS28 <2.6) | 3.34 (1.70, 6.54) | 4.76 (2.19, 10.36 |
| Low disease activity (DAS28 ≤3.2) | 3.54 (2.29, 5.49) | 3.60 (1.84, 7.06) |
RR=relative risk.
The results of the indirect comparisons showed that tocilizumab
had a statistically significant advantage over abatacept for all
ACR outcomes and DAS remission and low disease activity.
Tocilizumab also demonstrated a statistically significant advantage
compared to infliximab in proportion of patients achieving ACR70
response as well as DAS remission and low disease activity. The
submission removed the ATTEST trial (comparing abatacept and
infliximab) from all analyses due to heterogeneity. When the ATTEST
trial was excluded the advantage remained for tocilizumab, except
for ACR70 versus both abatacept and infliximab, as no statistically
significant differences were observed.
There was a statistically significant advantage for tocilizumab,
abatacept and infliximab versus placebo + methotrexate across all
trials in achievement of greater than or equal to 0.3 point
decrease in Health Assessment Questionnaire Disability Index
(HAQ-DI) score. There were a greater proportion of patients
achieving a HAQ-DI decrease for abatacept and infliximab compared
to tocilizumab (e.g. proportions ranged from 58.3 % to 63.7 % for
abatacept compared to 36.2 % to 54.4 % for tocilizumab). The
pre-sub-committee response noted that although a numerical
comparison of the HAQ scores shows higher absolute improvements for
abatacept and infliximab, compared with tocilizumab, this
difference does not take into account the HAQ scores in the common
reference MTX arms of the studies. The incremental improvement in
HAQ scores for tocilizumab compared with MTX is similar to the
incremental improvement in HAQ scores for abatacept. In addition,
the incremental improvement in HAQ scores for tocilizumab compared
with MTX was greater than the incremental improvement in HAQ scores
for infliximab. The pre-sub-committee response also provided an
indirect comparison of HAQ scores, which demonstrated a
statistically significant advantage for tocilizumab compared to
both abatacept and infliximab with respect to achieving at least a
0.22 to 0.3 point decrease from baseline at week 24.
The submission also provided the results of a trial in which
patients who had failed treatment with one or more TNF inhibitors
were randomised to treatment with tocilizumab + methotrexate or
placebo + methotrexate. A comparison of this trial with the three
other trials in the first-line setting indicated that the
proportion of patients with an ACR response was lower in
second-line treatment compared to first-line therapy. For example,
28.8 % of patients in the trial achieved an ACR50 response, whereas
in the pivotal trials the proportion achieving ACR response ranged
from 32.2 % to 43.9 %. The proportion of placebo-treated responders
was also lower in Emery et al. 2008. Therefore, overall the
incremental improvement in efficacy associated with use of
tocilizumab in the second-line setting is consistent with the
incremental improvement in efficacy in the first-line
setting.
The pre-sub-committee response provided an indirect comparison in
second-line settings between tocilizumab and abatacept which
suggested that, with the exception of ACR20, there were no
statistically significant differences for ACR50, ACR70, DAS
outcomes or HAQ between the two drugs.
With respect to the requested listing for use in combination with
DMARDs other than methotrexate, the submission stated that the use
of DMARDs other than methotrexate in combination with tocilizumab
did not modify the treatment effect (i.e. in terms of adverse
events and measures of efficacy) associated with tocilizumab.
The submission noted that despite the differences in the regimens
for tocilizumab in combination with methotrexate and other DMARDs
used in Trials WA17822, WA17823 and WA18063, the findings in terms
of the absolute risk differences and relative risks were similar
for the ACR50 response rates and for the DAS28 scores. In trials
WA17822 and 17823, all patients were using methotrexate. In trial
WA18063, 75.8 % of patients used methotrexate and only a small
proportion of patients used tocilizumab in combination with another
DMARD.
The submission referred to a test for interaction analysis
presented in the major submission, reporting that the results of
this test found that the choice of background DMARD did not
influence the treatment effect associated with tocilizumab.
Tocilizumab appeared to be associated with a lower incidence of
upper respiratory tract infection, headache, nausea and fatigue
than abatacept and infliximab. Tocilizumab was also associated with
a lower incidence of infection than infliximab, but higher than
abatacept and also a higher incidence of musculoskeletal and
connective tissue disorders than abatacept. However, the results of
the indirect comparison presented in the pre-subcommittee response
indicated no statistically significant difference in any of the
adverse events known to be associated with bDMARDs at 24
weeks.
On the basis of the evidence presented regarding extended
assessment of comparative harms the submission concluded that no
additional adverse events or safety concerns had been identified.
During evaluation it was identified the submission did not
adequately address a number of issues, including a greater rate of
occurrence of infusion reactions and infection based on long-term
data; more than doubling of incidence of malignancy in the
long-term data compared to trial data; impact of lipid parameters,
particularly in terms of need for additional treatment; and deaths
reported (n=15) in a post-marketing surveillance study of Japanese
patients.
The pre-sub-committee response argued that these long term safety
outcomes had already been assessed by the TGA. Infection rates did
not increase beyond the rates in the six month safety population,
infusion reactions were uncommon and there was no data to suggest
an increased risk of malignancy
Increases in mean fasting lipid level were observed in all
tocilizumab groups at 6 months, however only mean triglyceride
levels rose above the normal range. Elevations in lipid levels
appeared to stabilise in the long term safety population and only
139 of 2,439 patients receiving tocilizumab (5.7 %) commenced lipid
lowering therapy. However, the PI stated that ‘approximately
24 % of patients receiving tocilizumab in clinical trials
experienced sustained elevations in total cholesterol greater than
6.2 mmol/L (240 mg/dL), with 15 % experiencing a sustained increase
in LDL greater than or equal to 4.1 mmol/L (160 mg/dL). Elevations
in lipid parameters responded to treatment with lipid-lowering
agents.’
Based on the results of a pooled meta-analysis of the ACR20, ACR50
and ACR70 response rates for trials WA18063, WA17822 and WA17823
presented in the major submission, which found no significant
differences in the overall incidence of adverse events, the
submission considered that the safety profile of different DMARDs
used in combination with tocilizumab was similar.
9. Clinical Claim
The submission claimed that tocilizumab was no worse than abatacept
and infliximab in terms of comparative efficacy and safety.
For PBAC’s views see Recommendation and
Reasons.
10. Economic Anaylsis
The submission presented a cost-minimisation analysis using
abatacept as the comparator.
The equi-effective doses were tocilizumab 8 mg/kg administered on
days 1 and 29 and then every 28 days, and abatacept at
approximately 10 mg/kg administered on days 1, 15, 29 and then
every 28 days.
The results of the cost-minimisation analyses presented by the
submission across a number of timepoints showed the cost of
tocilizumab was less than that for abatacept. However, following
one year of treatment when both drugs were administered every four
weeks the cost difference was negligible.
11. Estimated PBS Usage and Financial Implications:
The likely number of patients per year was less than 1000 patients
in Year 5 of listing. The financial cost per year to the PBS was
less than $10 million.
12. Recommendation and Reasons
The PBAC recommended that tocilizumab solution for infusion 80 mg
in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL be listed for the
treatment of severe, active rheumatoid arthritis in combination
with methotrexate in patients who have failed to demonstrate a
response to at least one TNF-alfa antagonist treatment on a
cost-minimisation basis compared to abatacept. In the context of
cost-minimisation the equi-effective doses were tocilizumab 8 mg/kg
administered on days 1 and 29 and then every 28 days and abatacept
10 mg/kg administered on days 1, 15, 29 and then every 28
days.
The PBAC agreed that the basis of the restriction wording would be
that for rituximab in rheumatoid arthritis, where rituximab was
available second-line to those meeting certain criteria and who had
not adequately responded to a TNF-alfa antagonist.
The PBAC agreed that the choice of abatacept and infliximab as the
main comparators was appropriate.
The PBAC considered that tocilizumab was no worse that abatacept
and infliximab in terms of comparative efficacy. The results of the
indirect comparisons showed that tocilizumab had a statistically
significant advantage over abatacept for all ACR outcomes, and DAS
(Disease Activity Score) remission and low disease activity.
Tocilizumab also demonstrated a statistically significant advantage
compared to infliximab in proportion of patients achieving ACR70
response as well as DAS remission and low disease activity. There
was a statistically significant advantage for tocilizumab,
abatacept and infliximab versus placebo plus methotrexate across
all trials in achievement of greater than or equal to 0.3 point
decrease in Health Assessment Questionnaire Disability Index
(HAQ-DI) score. The Pre-Sub-Committee response provided an indirect
comparison of HAQ scores, which demonstrated a statistically
significant advantage for tocilizumab compared to both abatacept
and infliximab with respect to achieving at least a 0.22 to 0.3
point decrease from baseline at week 24.
The PBAC noted that results of a published trial in patients
who had failed treatment with one or more TNF inhibitors (Emery et
al. 2008), a comparison with use in the first-line setting
indicated that the proportion of patients with an ACR response was
lower in the second-line setting compared to first-line
therapy
The PBAC was concerned with respect to comparative safety, in
particular long-term safety. Tocilizumab was associated with a
higher incidence of infection than abatacept, more than doubling of
incidence of malignancy in the long-term data compared to trial
data, sustained elevations in total cholesterol requiring
additional treatment, and recently, 15 deaths had been reported in
a post-marketing surveillance study of Japanese patients.
The PBAC noted that tocilizumab belonged to a new class of
biological DMARDS, being an interleukin-6 monoclonal antibody with
a place in the treatment of severe active rheumatoid
arthritis.
Therefore, given the toxicity concerns of the increased risks of
infection and raised lipid profile the PBAC considered that a
second-line listing on a cost-minimisation basis with abatacept
appropriate.
The PBAC noted listing was also requested for the treatment of
severe active rheumatoid arthritis with tocilizumab in combination
with a non-biological DMARD.
The PBAC noted in the pivotal trial WA18063 (published as Genovese
et al, 2008) in support of the extension, 75.8 % of patients in the
tocilizumab plus DMARD arm received methotrexate, and only a
relatively small proportion of patients in this arm were treated
with other DMARDs.
The submission claimed that the results of an interaction analysis
demonstrated that the choice of background DMARD did not alter the
treatment effect associated with tocilizumab. However, the PBAC
questioned the validity of this analysis due to the small
proportion of patients who used non-MTX DMARDs.
Further, the plausibility that, for example, hydroxychloroquine was
equivalent to leflunomide was clinically questionable.
The PBAC considered there was uncertainty associated with the
costings for the use of DMARDs in combination with tociliziumab.
The submission claimed, based on the Genovese study and Chan and
Tett et al (2006) that the majority of use will be in methotrexate,
however the Chan and Tett data suggested that a substantial
proportion (43 %) of DMARDs other than methotrexate were used in
combination with tocilizumab.
The PBAC decided not accept listing in combination with other
DMARDs on the basis of uncertain equivalent efficacy of tocilizumab
in combination with non-MTX DMARDs and the uncertain costs of
non-MTX DMARDs in the cost minimisation equation.
Recommendation
TOCILIZUMAB, solution for IV infusion, 80 mg in 4 mL, 200 mg in 10
mL and 400 mg in 20 mL
Restriction:
Section 100 (Highly Specialised Drugs Program)
Public and private hospital authority
required
To be finalised
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 further comment.
