Etanercept, injection set containing 4 vials powder for injection, 25 mg and 4 pre-filled syringes solvent 1 mL, injection set containing 4 vials powder for injection, 50 mg and 4 pre-filled syringes solvent 1 mL, injections, 50 mg in 1 mL single use pre-filled syringes, Enbrel®, March 2009
Public summary document for Etanercept, injection set containing 4 vials powder for injection, 25 mg and 4 pre-filled syringes solvent 1 mL, injection set containing 4 vials powder for injection, 50 mg and 4 pre-filled syringes solvent 1 mL, injections, 50 mg in 1 mL single use pre-filled syringes, Enbrel®, March 2009
Page last updated: 03 July 2009
Public Summary Document
Product: Etanercept, injection set containing 4
vials powder for injection, 25 mg and 4 pre-filled syringes solvent
1 mL, injection set containing 4 vials powder for injection, 50 mg
and 4 pre-filled syringes solvent 1 mL, injections, 50 mg in 1 mL
single use pre-filled syringes, Enbrel®
Sponsor: Wyeth Australia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The re-submission requested an amendment to the treatment regimen
for etanercept in chronic plaque psoriasis to allow etanercept 50
mg/week for 12 weeks of initial treatment to be followed by
continuous treatment of 50 mg/week, or, a flexible intermittent
dosing regimen, for those patients who meet the continuation
criteria.
2. Background
At the March 2006 meeting, the PBAC recommended listing of
etanercept for patients with severe chronic plaque psoriasis on a
cost-minimisation basis concluding that, based on an indirect
comparison, etanercept was no worse than efalizumab for the
treatment of severe refractory chronic plaque psoriasis.
Etanercept for chronic plaque psoriasis was listed on the PBS from
1 August 2006.
At the March 2007 meeting, the PBAC rejected a submission to change
the restriction for etanercept for psoriasis which would allow a
proportion of ‘high needs’ patients access to
continuous treatment and also allow an initial treatment period of
24 weeks for all patients instead of the currently approved 12
weeks because of uncertainty about the clinical evidence for the
proposed model of treatment and inadequate evidence supporting the
role of continuous versus intermittent treatment, and because of a
high and uncertain cost effectiveness ratio.
At the July 2008 meeting, the PBAC rejected a submission for
etanercept to extend the initial treatment period for psoriasis to
24 weeks for patients who achieve a Psoriasis Area and Severity
Index (PASI) 50 at week 12, and to allow continuing treatment to be
a continuous regimen or a flexible intermittent regimen on the
basis of uncertainty in the clinical data and economic model,
resulting in a high and uncertain cost-effectiveness ratio.
3. Registration Status
Etanercept is TGA registered for:
- rheumatoid arthritis (RA)
- active polyarticular course juvenile chronic arthritis
- psoriatic arthritis
- ankylosing spondylitis
- treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for phototherapy or systemic therapy. Safety and efficacy beyond 12 months have not been demonstrated.
4. Listing Requested and PBAC’s View
The following are the requested changes to the restriction.
Requested change to continuing treatment regimen
- Patients who achieve a PASI 75 response after initial therapy be treated with either continuous etanercept 50 mg/week or a flexible intermittent dosing regimen which allows treatment breaks, at the discretion of the clinician and patient (a minimum of 12-weeks re-treatment with etanercept 50 mg/week is required before a subsequent break can be taken).
Current continuing treatment regimen
- Patients who achieve a PASI 75 response after 12 weeks initial therapy (and subsequently undergo an initial 12 week biological treatment-free period) can begin continuing treatment with etanercept 50 mg/week on a cyclical basis consisting of 12 weeks on-treatment followed by a minimum 12-week biological treatment-free period.
- Patients who have a break in therapy may recommence treatment with etanercept under Initial 2 providing they have not failed treatment with etanercept.
Proposed assessment of response
- Initial assessment of treatment response at week 12.
- For patients prescribed the continuous dosing regimen, continuing treatment response assessment every 24 weeks.
- For patients prescribed the flexible intermittent dosing regimen, continuing treatment response assessment completed at the end of each active treatment cycle (minimum 12 weeks with maximum 24 weeks of etanercept treatment), and no later than 4 weeks after treatment cessation.
Current assessment of response
- Initial assessment of treatment response at week 12.
- Continuing treatment response assessment after 12 weeks of etanercept treatment and no later than 4 weeks from cessation of that treatment course.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The requested change to the listing alters the current treatment
algorithm (12 weeks initial treatment followed by 12 week treatment
break then further 12 week treatment for responders) to 12 week
initial treatment followed by either continuous treatment or
intermittent treatment for responders, and would continue to
provide a PBS listed treated option for chronic plaque
psoriasis.
6. Comparator
The submission nominated efalizumab as the main comparator, rather
than the current treatment regimen with etanercept. This was
accepted by the PBAC.
7. Clinical Trials
The re-submission included four previously presented etanercept
trials, and five previously presented efalizumab trials (Dubertret
2006 Dubertret et al, Group CMS. Clinical experience acquired
with the efalizumab (Raptiva) (CLEAR) trial in patients with
moderate-to-severe plaque psoriasis: results from a phase III
international randomized, placebo-controlled trial, The British
Journal of Dermatology 2006;155:170-81.; Gordon 2003
Gordon et al, Efalizumab Study G. Efalizumab for patients with
moderate to severe plaque psoriasis: a randomized controlled trial.
JAMA : the Journal of the American Medical Association
2003;290:3073-80.; Lebwohl 2003 Lebwohl et al, Efalizumab
Study G. A novel targeted T-cell modulator, efalizumab, for plaque
psoriasis, The New England Journal of Medicine
2003;349:2004-13.; Leonardi 2005 Leonardi CL, Papp KA,
Gordon KB, Menter A, Feldman SR, Caro I, Walicke PA, Compton PG,
Gottlieb AB. Extended efalizumab therapy improves chronic plaque
psoriasis: Results from a randomized phase III trial. J Am Acad
Dermatol 2005;52:425-433.; Papp 2006 Papp et al,
Efalizumab Study G. Safety of efalizumab in adults with chronic
moderate to severe plaque psoriasis: a phase IIIb, randomized,
controlled trial, International Journal of Dermatology
2006;45:605-14.); were used to provide an indirect comparison
of initial treatment response using placebo the common
comparator.
Publication details of the two cohort studies follow:
- Berends M.A.M., Driessen R.J.B., Langewouters A.M.G., Boezeman J.B., van de Kerkhof P.C.M., de Jong E.M.G.J, Etanercept and efalizumab treatment for high-need psoriasis: Effects and side effects in a prospective cohort study in outpatient clinical practice, Journal of Dermatological Treatment, 2007;18:76-83.
- Driessen, R.J.B., Berends M.A.M., Boezeman J.B., van de Kerkhof P.C.M., de Jong E.M.G.J, Psoriasis treatment with etanercept and efalizumab: clinical strategies influencing treatment outcome, British Journal of Dermatology, 2008;158:1098-106.
8. Results of Trials
The table below provides the results of the indirect comparisons presented by the
re-submission comparing etanercept and efalizumab for achievement of initial PASI
75 response at 12 weeks. The re-submission provided analyses using 95% and 75% confidence
intervals.
Results of the indirect comparisons of etanercept and efalizumab for initial response
| Outcome | Pooled treatment effect RR (95% CI) | Indirect estimate RR | ||
| Etanercept | Efalizumab | RR (95% CI) | RR (75% CI) | |
| PASI 75 response | 10.9 (6.4, 18.6) | 7.5 (5.2, 10.3) | 1.5 (0.8, 2.8) | 1.5 (1.0, 2.2) |
| Adverse event withdrawals | 0.71 (0.33, 1.56) | 1.41 (0.86, 2.30) | 0.50 (0.20, 1.25) | 0.50 (0.29, 0.86) |
| Serious adverse events | 0.62 (0.20, 1.85) | 1.25 (0.64, 2.45) | 0.50 (0.13, 1.85) | 0.50 (0.13, 1.07) |
| Pooled treatment effect RD (95% CI) | Indirect estimate RD | |||
| Etanercept | Efalizumab | RD (95% CI) | RD (75% CI) | |
| PASI 75 response | 31% (27%, 36%) | 24% (19%, 30%) | 7% (1%, 13%) a | 7% (3%, 11%) |
| Adverse event withdrawals | -1% (-3%, 2%) | 1% (0%, 3%) | -2% (-4%, 0%) | -2% (-3%, -1%) |
| Serious adverse events | -1% (-4%, 2%) | 1% (0%, 2%) | -2% (-5%, 1%) | -2% (-4%, 0%) |
a p=0.004
The re-submission claimed that the indirect comparisons indicate etanercept is at
least as safe and effective as efalizumab and shows trends toward superiority over
efalizumab, the latter claim based on the analyses using 75% confidence intervals.
The assessment of response during continuing treatment was done by reviewing: two
prospective cohort studies assessing use of etanercept and efalizumab (Berends et
al., 2007; Driessen et al., 2008); the CRYSTEL study (a randomised trial comparing
intermittent and continuous etanercept) and an open-label etanercept follow-up study
to a previously presented randomised trial of etanercept.
The re-submission claimed that the PASI 75 response for both etanercept and efalizumab
is maintained over the longer term. The evidence in support of continuing treatment
presented by the re-submission was as follows:
Efalizumab evidence: The re-submission presented a figure from the Leonardi et al
(2008) Leonardi et al. Efalizumab: results of a 3-year continuous dosing study for the long-term
control of psoriasis. British Journal of Dermatology 2008;158:1107-16. efalizumab trial and claimed no significant difference between the proportion of
PASI 75 responders at week 12 and week 24. Etanercept evidence: The re-submission
did not provide any analysis of longer-term etanercept response but claimed that there
is no observable decline in response and thus response will be maintained.
- The re-submission stated that the number of PASI 75 responders increased over time in the continuous treatment arm of the CRYSTEL trial (127/352 at week 12 and 196/352 at week 54). The re-submission also stated that there was a small decline in PASI 75 responder rates in the intermittent treatment arm in CRYSTEL.
The mean Physicians Global assessment of Psoriasis (PGA) score over 54 weeks was significantly
better for subjects in the continuous therapy group compared to those in the intermittent
group (1.98 versus. 2.51, P<0.001). The mean PGA score from week 12 to week 54 was
also significantly better for those in the continuous therapy group compared to subjects
in the intermittent group (1.80 versus. 2.46, p<0.001).
- Based on the Driessen et al (2008) cohort study, the re-submission claimed that eight patients with PASI 75 response at week 24 were the same patients with PASI 75 response at week 18.
- The re-submission, and Pre-Sub-Committee response, stated that in the open labelled etanercept follow-up study there were one hundred and forty (140) PASI 75 responders at baseline and one hundred and eighty five (185) PASI 75 responders at week 72, which demonstrated that PASI 75 responders increased over time.
Analysis of toxicity data following initial treatment was provided by the re-submission
and it was concluded there are no statistically significant differences between etanercept
and efalizumab in the occurrence of serious adverse events or withdrawals due to adverse
events. The re-submission provided no assessment of comparative toxicity during continuing
treatment and provided no extended assessment of comparative harms.
9. Clinical Claim
The re-submission claimed the indirect comparison showed that
etanercept is at least as safe and effective as efalizumab, and on
the basis of 75% CI analysis, showed a trend towards superiority
over efalizumab in proportion of patients with initial PASI 75
response.
The re-submission claimed that etanercept 50mg/week continuous
therapy, or a flexible intermittent regimen that allows treatment
breaks, is equi-effective to efalizumab 1mg/kg/week for maintenance
treatment.
For PBAC’s view see Recommendation and
Reasons.
10. Economic Analysis
The re-submission presented a cost-minimisation analysis. The
equi-effective doses were estimated as etanercept 50 mg/week and
efalizumab 1 mg/kg/week during both the initial and maintenance
treatment periods.
Three cost-minimisation analyses were presented, a base case
analysis including trial-based and ‘real-life’
analyses, and two alternate analyses, one assuming both etanercept
and efalizumab have 24 weeks initial treatment and the second
comparing the current etanercept treatment regimen to efalizumab
and to the requested etanercept regimen for a treatment duration of
48 weeks.
11. Estimated PBS Usage and Financial Implications
The submission estimated the number of one-month treatment courses
per year to be less than 10,000 at a likely cost of < $10
million in Year 4. However, the PBAC noted that the assumptions and
values used by the re-submission to arrive at the estimated cost
have not been completely justified, and therefore these values are
uncertain and should be interpreted with caution.
12. Recommendation and Reasons
The PBAC recommended amending the listing of etanercept to allow
for continuous treatment in the management of chronic plaque
psoriasis on the basis of cost-minimisation against efalizumab
continuous treatment at the requested price. The equi-effective
doses are etanercept 50 mg/week and efalizumab 1 mg/kg/week during
both initial and maintenance treatment periods. The submission had
sought an amended listing for either continuous or flexible
intermittent use, or continuous use only.
The PBAC noted that after 12 weeks of therapy the indirect
comparisons showed the effectiveness of etanercept based on a PASI
75 response is no worse than efalizumab.
The assessment of response during continuing treatment was done by
reviewing: two prospective cohort studies assessing use of
etanercept and efalizumab (Berends et al., 2007; Driessen et al.,
2008); the CRYSTEL study (a randomised trial comparing intermittent
and continuous etanercept) and an open-label etanercept follow-up
study to a previously presented randomised trial of
etanercept.
The 54 week results from CRYSTEL showed the mean Physician Global
assessment of Psoriasis (PGA) score over 54 weeks was significantly
better for subjects in the continuous therapy group compared to
those in the intermittent group (1.98 versus. 2.51, P<0.001).
The mean PGA score from week 12 to week 54 was also significantly
better for those in the continuous therapy group compared to
subjects in the intermittent group (1.80 versus. 2.46, p<0.001).
The 54 week results also showed 55.7% of patients on continuous
treatment compared to 34% on intermittent achieved a PASI 75
improvement from baseline.
The PBAC concluded from the data presented overall that efalizumab
and etanercept are equally effective in patients with severe plaque
psoriasis after 12 weeks of therapy and it is likely that
continuous etanercept is as effective as efalizumab over 48 weeks
of treatment. However, it was less clear that intermittent
etanercept is as least as effective as efalizumab over 48 weeks of
treatment. Therefore, the PBAC recommended etanercept be made for
available for continuous treatment, noting that patients can have a
break from treatment and later re-commence under the current
listing criteria (initial 2), provided evidence of a response to
etanercept within that treatment cycle is supplied to Medicare
Australia.
As a general comment with respect to the biological
Disease-Modifying Antirheumatic Drugs (bDMARDs) for the treatment
of chronic plaque psoriasis, the PBAC noted that the different
drugs have different patterns of effectiveness over time. The PBAC
agreed the sponsor Wyeth should be offered the opportunity to
request an amendment to the listing of etanercept such that a
patient who achieved a PASI 50 response at three months be allowed
to continue treatment for a further 3 months to achieve a PASI 75
response. However, the PASI 50 response at three months would be
deemed a failure.
Recommendation
The PBS listing restriction can be found in the Schedule of
Pharmaceutical Benefits at www.pbs.gov.au.
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
Wyeth is pleased that etanercept will be available on the PBS for
continuous use in chronic plaque psoriasis. It should be noted that
since this submission was considered by the PBAC, efalizumab, the
nominated comparator, has been withdrawn from the Australian market
due to long term safety concerns. The long term safety of
etanercept, which has been on the PBS since 2003, is well
established with over 16 years and an estimated 1.8 million
patient-years of collective clinical experience.
