Exenatide, pre-filled injection pen, 5 micrograms per dose, 10 micrograms per dose, Byetta®, November 2008
Public summary document for Exenatide, pre-filled injection pen, 5 microgram per dose, 10 microgram per dose, Byetta®, November 2008
Page last updated: 06 March 2009
Public Summary Document
Product: Exenatide, pre-filled injection pen, 5
micrograms per dose, 10 micrograms per dose,
Byetta®,
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission sought an Authority Required listing for use in
combination with metformin and/or a sulfonylurea, in patients with
type 2 diabetes who no longer achieve glycaemic control despite
optimal therapy with metformin and/or a sulfonylurea, or in whom a
combination of metformin and a sulfonylurea is contraindicated or
not tolerated.
2. Background
The PBAC has considered exenatide on two previous occasions for the
indication mentioned above. On the first occasion in July 2007, the
PBAC rejected the submission on the grounds of high and uncertain
cost-effectiveness against the comparators in the absence of any
evidence of clinical benefit other than the observational finding
of weight loss which had not been shown to be durable or to
translate into morbidity or mortality benefits, and because of
unresolved safety concerns. (See also Public Summary Document for
July 2007).
At its March 2008 meeting, the PBAC noted that the re-submission
provided no additional data to address its previous concern that
the claim of non-inferiority to rosiglitazone was inadequately
demonstrated. In terms of weight changes, the Committee agreed that
the exenatide versus insulin glargine trials showed a statistically
significant difference, favouring exenatide. However, as before the
weight loss benefit associated with exenatide had not been verified
in a properly designed weight loss or quality of life study. The
PBAC thus considered there was no basis for it to change its view
that the weight loss benefit associated with exenatide has not been
shown to be durable in the longer term.
The Committee further noted at its March 2008 meeting that no new
data had been provided to alter its previous conclusion that
exenatide was associated with a higher incidence of adverse events
versus insulin glargine. A difference in hypoglycaemic events
between exenatide and insulin glargine was also not convincingly
demonstrated. Again, no indirect estimates of the comparative
safety of exenatide and rosiglitazone were presented to allow
assessment of the comparative safety of exenatide and
rosiglitazone. Therefore, like the July 2007 application,
the Committee rejected the March 2008 application on the grounds of
a high and uncertain cost-effectiveness ratio against the
comparator, insulin glargine, in the absence of evidence of
clinical benefit other than the observational finding of weight
loss. (See also Public Summary Document for March 2008).
3. Registration Status
Exenatide was TGA registered on 28 June 2007 for ‘adjunctive
therapy to improve glycaemic control in patients with type 2
diabetes mellitus who are taking metformin, a sulfonylurea or a
combination of metformin and a sulfonylurea but are not achieving
adequate glycaemic control’.
4. Listing Requested and PBAC’s View
Authority required
Combination therapy with metformin and a
sulfonylurea
Initiation of therapy, in combination with metformin and a
sulfonylurea, in type 2 diabetes mellitus patients who have an
HbA1c greater than 7% despite maximally tolerated doses of
metformin and a sulfonylurea.
The date of the HbA1c measurement, which must be no greater than 4
months old at the time of application, must be provided.
Continuation of therapy, in combination with metformin and a
sulfonylurea, in type 2 diabetes mellitus patients where the
patient has previously been issued with an authority prescription
for exenatide.
Authority required
Combination therapy with metformin or a
sulfonylurea
Initiation of therapy, in combination with either metformin or a
sulfonylurea, in type 2 diabetes mellitus patients who have an
HbA1c greater than 7% and in whom a combination of metformin and a
sulfonylurea is contraindicated or not tolerated.
The date of the HbA1c measurement, which must be no greater than 4
months old at the time of application, must be provided.
Continuation of therapy, in combination with either metformin or a
sulfonylurea, in type 2 diabetes mellitus patients where the
patient has previously been issued with an authority prescription
for exenatide.
The PBAC agreed with the Secretariat’s suggestion that the
restriction wording be consistent with the Restrictions Working
Group’s (RWG) advice arising from the March 2008 meeting but
updated to account for the listing of sitagliptin.
5. Clinical Place for the Proposed Therapy
The submission stated that exenatide provides clinicians with an
alternative class of drug for adjunctive third line therapy in
adults with type 2 diabetes who are taking metformin, a
sulfonylurea, or a combination of metformin and a sulfonylurea but
are not achieving adequate glycaemic control, or in whom the
addition of metformin or a sulfonylurea is contra-indicated or not
tolerated when used in combination.
6. Comparator
The submission nominated insulin glargine as the main comparator.
This was considered reasonable. The PBAC noted that the dose of
insulin glargine (75 IU/day) selected in the cost-minimisation
analysis was the single biggest source of uncertainty within the
submission.
7. Clinical Trials
No new trials were presented in the current re-submission. The
re-submission presented a direct comparison in one RCT (GWAA) and
one randomised cross-over trial (GWAO). Three placebo-controlled
randomised trials (112, 113 and 115) and one RCT (GWAD) comparing
exenatide with insulin aspart are included as supportive
evidence.
At the time of the submission the published studies were:
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| Direct randomised trials (exenatide versus insulin glargine) | ||
| GWAA Heine RJ | Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. | Heine RJ. Ann Intern Med 2005; 143:559-569. |
| GWAO Barnett AH | Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: A multinational, randomized, open-label, two-period, crossover noninferiority trial. | Barnett AH. Clin Ther 2007; 29(11):2333-2348. |
| Supplementary randomised trials (exenatide versus placebo) | ||
| 112 DeFronzo RA | Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. | DeFronzo RA. Diabetes Care 2005; 28:1092-1100. |
| 113 Buse JB | Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. | Buse JB. Diabetes Care 2004 ; 27 :2628-2653. |
| 115 Kendall DM | Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. | Kendall DM. Diabetes Care 2005; 28:1083-1091. |
| Supplementary randomised trials (exenatide versus insulin aspart) | ||
| GWAD Nauck MA | A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. | Nauck MA. Diabetologia 2007; 50:259-267. |
8. Results of Trials
No new efficacy data were presented in the current re-submission.
The PBAC has previously accepted that exenatide is non-inferior to
insulin glargine in terms of its effects on HbA1c and
concluded that neither the long-term benefits associated with
weight change nor its durability are adequately established.
No new toxicity data was presented except the results of
re-analysis of hypoglycaemia event rates and a summary of Periodic
Safety Update Report (PSUR06). The PBAC has previously concluded
that exenatide was associated with a higher incidence of adverse
events versus insulin glargine and that a difference in
hypoglycaemic events between exenatide and insulin glargine was not
convincingly demonstrated. Based on the new supporting data
presented in the current re-submission, exenatide appeared to be
associated with statistically significant reductions in rates of
overall and nocturnal hypoglycaemic episodes compared to insulin
glargine. However, the PBAC noted that:
- Conclusions were based on rates of hypoglycaemic events, not patients with hypoglycaemic events;
- It was unclear that the claimed statistically significant differences represented clinically important differences given the low event rates;
- There were insufficient data to conclude differences between use of exenatide in dual and triple therapy regimens, or differences between concomitant use of metformin or a sulfonylurea.
9. Clinical Claim
The re-submission described exenatide as superior in terms of
comparative effectiveness (equivalent glycaemic control but
superior in weight management) and equivalent in terms of
comparative safety over insulin glargine. The PBAC had previously
accepted the non-inferiority of exenatide in glycaemic control. As
no new evidence regarding the long-term durability of weight
benefits and transformability of weight benefits into long-term
morbidity and mortality benefits were presented in the
re-submission, the claim of superiority of exenatide in weight
management was not established. The PBAC had previously concluded
that exenatide was associated with higher incidences of adverse
events.
Claims of statistically significant benefits of exenatide over
insulin glargine in overall rates and rates of nocturnal
hypoglycaemia were new to this submission and were based on numbers
of events, not numbers of patients with events. The clinical
importance of these differences between exenatide and insulin
glargine was unclear.
10. Economic Analysis
In contrast to a modelled economic evaluation considered at the
March 2008 PBAC meeting, the current re-submission presented a
cost-minimisation analysis (CMA). It was noted that the
cost-minimisation analysis presented was not trial-based.
The dosage of drugs used for comparison in the CMA is: exenatide 20
micrograms/day compared with insulin glargine 75 IU/day. Based on
an analysis (Mean average daily dose (ADD) = 101.2 IU for 1,330
patients; ADD = 67.8 IU after 5% of top outliers are removed from
the sample. of a random sample) of glargine scripts processed
by Medicare Australia from October 2006 to September 2007, the
re-submission considered it “reasonable to assume that the
average dose per day of insulin glargine dispensed through the PBS
is between 60IUs and 100IUs per day” and therefore it was
reasonable to use a daily glargine dose of 75 IU in CMA. This is
much higher than the mean final glargine dose in the head-to-head
randomised trials used in the re-submission to establish
non-inferiority.
Based on results from the GWAA trial, i.e. when used in triple
combination with metformin and a sulfonylurea, the equi-effective
doses are estimated as exenatide 9.07 μg twice daily and insulin
glargine 24.93 IU/day over 26 weeks. Based on results from the GWAO
trial, i.e. when used in dual combination with either metformin or
a sulfonylurea, the equi-effective doses are estimated as exenatide
9.35 μg twice daily and insulin glargine 27.30 IU/day over 16
weeks. These estimated equi-effective doses may change as trial
results of GWBG become available. Trial GWBG is a phase 3 trial
designed to compare the effects of twice daily exenatide plus oral
antidiabetic agents (OADs) and once-daily insulin glargine plus
OADs with respect to glycaemic control, as measured by hemoglobin
A1c, with minimum weight gain, in patients with uncontrolled type 2
diabetes on OADs.
11. Estimated PBS Usage and Financial Implications
The likely number of treated patients per year was estimated to be
between 10,000 – 50,000 per year, while the financial cost
per year to the PBS (excluding savings on patient co-payments)
minus savings in use of insulin glargine and insulin aspart was
estimated to be < $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of exenatide on the Pharmaceutical
Benefits Scheme on a cost-minimisation basis with insulin glargine
taking into account the higher costs associated with the initiation
and titration of the dose of insulin glargine. The equi-effective
doses were exenatide 9.07 micrograms twice daily and insulin
glargine 24.93 international units (IU) per day when these agents
were in used in triple combination therapy with metformin and a
sulfonylurea; and 9.35 exenatide micrograms twice daily and insulin
glargine 27.30 IU per day when these agents were used as part of
dual combination therapy with either metformin or a
sulfonylurea.
The Committee agreed that the clinical trials GWAA and GWAO
provided the best available evidence upon which to calculate the
equi-effective doses of exenatide and insulin glargine, as these
two randomised trials formed the basis for the PBAC’s earlier
acceptance of the non-inferiority of exenatide compared to insulin
glargine in terms of its effects of HbA1c, and as in both trials
the dose of insulin glargine could be titrated according to
response. The PBAC did not accept the sponsor’s claim that it
was not valid to calculate equi-effective doses based on these two
trials, noting that no substantive arguments invalidating the trial
results were made in either the submission or the hearing.
The submission’s choice of insulin glargine dose of 75 IU/day
to establish equi-effective doses was in contrast not derived from
clinical trials and was much higher than the mean final glargine
dose (less than 30 IU/day) in the direct randomised trials.
Although the PBAC had indicated in March 2008 that a daily dose of
75 IU insulin might be able to be justified, it did not accept that
the current submission provided adequate justification for
accepting a dose based on a random sample of Medicare Australia
prescriptions, which is subject to well known confounders, over the
consistent results generated in two rigorous, randomised
trials.
The Committee also considered that, as previously, the long term
benefits and durability of weight change with exenatide have not
been adequately established. PBAC also did not accept the
submission’s claim that exenatide was equivalent in terms of
comparative safety over insulin glargine. The difference in overall
hypoglycaemic event rates in study GWAA, although statistically
significant in favour of exenatide over insulin glargine were
considered clinically immaterial and unlikely to be discernible in
practice. On the other hand, treatment with exenatide was
associated with more treatment emergent adverse events than insulin
glargine. Overall, however, the Committee’s safety concerns
with exenatide were not sufficient to overturn its
cost-minimisation recommendation.
The Committee did not accept the validity of all the claimed
cost-offsets for exenatide compared to insulin glargine.
Specifically the PBAC considered it only reasonable to offset, on a
single occasion, the cost of one diabetes nurse educator visit
during treatment initiation as patients would still require
training in how to administer exenatide, and of the higher costs
associated with treatment titration for glargine. The Committee did
not accept that there would be any difference in monitoring
costs.
Recommendation
EXENATIDE, injection, 5 micrograms in 20 microlitres, 10 micrograms
in 40 microlitres, Byetta®, Eli Lilly Pty Ltd.
(7.2)
Restriction:
Authority Required
Dual combination therapy with metformin
or
a
sulfonylurea
Initiation of therapy, in combination with either metformin or a
sulfonylurea, in a patient with type 2 diabetes mellitus who has an
HbA1c greater than 7% and in whom a combination of metformin and a
sulfonylurea is contraindicated or not tolerated.
The date of the HbA1c measurement, which must be no greater than 4
months old at the time of application, must be
provided.Continuation of therapy, in combination with either
metformin or a sulfonylurea, in a patient with type 2 diabetes
mellitus where the patient has previously been issued with an
authority prescription for exenatide.NOTE: Exenatide is not
PBS-subsidised as monotherapy or in combination with an insulin, a
thiazolidinedione (glitazone), or sitagliptin.Blood glucose
monitoring as an alternative assessment to HbA1c levels will be
accepted in the following circumstances:
(a) clinical conditions with reduced red blood cell survival,
including haemolytic anaemias and haemoglobinopathies
and/or
(b) red cell transfusion within the previous 3 months.
Patients in these circumstances will be eligible for treatment
where blood glucose monitoring over a 2 week period shows blood
glucose levels greater than 10 mmol per L in more than 20% of
tests. The date of measurement of the most recent blood glucose
level, which must be no greater than 4 months old at the time of
application, must be provided. Authority
Required
Triple combination therapy with metformin
and
a
sulfonylurea
Initiation of therapy, in combination with metformin and a
sulfonylurea, in a patient with type 2 diabetes mellitus who has an
HbA1c greater than 7% despite maximally tolerated doses of
metformin and a sulfonylurea.The date of the HbA1c measurement,
which must be no greater than 4 months old at the time of
application, must be provided.Continuation of therapy, in
combination with metformin and a sulfonylurea, in a patient with
type 2 diabetes mellitus where the patient has previously been
issued with an authority prescription for exenatide.NOTE: Exenatide
is not PBS-subsidised as monotherapy or in combination with an
insulin, a thiazolidinedione (glitazone) or sitagliptin.Blood
glucose monitoring as an alternative assessment to HbA1c levels
will be accepted in the following circumstances:
(a) clinical conditions with reduced red blood cell survival,
including haemolytic anaemias and haemoglobinopathies
and/or
(b) red cell transfusion within the previous 3 months.
Patients in these circumstances will be eligible for treatment
where blood glucose monitoring over a 2 week period shows blood
glucose levels greater than 10 mmol per L in more than 20% of
tests. The date of measurement of the most recent blood glucose
level, which must be no greater than 4 months old at the time of
application, must be provided.Maximum quantity: 1
Number of 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
Eli Lilly welcomes the positive recommendation from the PBAC to
recommend listing of exenatide on the PBS. Eli Lilly is
disappointed that the Committee did not accept the Medicare
Australia data used in the submission to determine the insulin
glargine dose to establish equi-effective doses. The costs,
resources implications, outcomes and increased reporting of adverse
events associated with higher dosages of insulin used in the cost
minimisation analysis, were supported by observational studies and
database analyses but were not considered valid in the current
submission.
