Exenatide, powder for injection, 2 mg, Bydureon®
Public summary document on Exenatide relating to the July 2011 PBAC meeting
Page last updated: 20 May 2013
PDF printable version of Exenatide, powder for injection, 2 mg, Bydureon® (PDF 206
KB)
Public Summary Document
Product: Exenatide, powder for injection, 2 mg,
Bydureon®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required listing for the
treatment of type 2 diabetes mellitus in combination with metformin
or a sulfonylurea and triple combination therapy with metformin and
a sulfonylurea.
2. Background
This presentation of exenatide had not previously been considered by the PBAC.
At its November 2008 meeting, the PBAC recommended listing exenatide injection solution,
5 micrograms and 10 micrograms per dose in a pre-filled pen (Byetta®, administered
twice daily) as an Authority required benefit 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, 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 exenatide 9.35 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.
Details of the PBAC consideration are available in the Exenatide, Byetta®, November 2008 Public Summary Document.
Exenatide twice daily was PBS listed from 1 August 2010.
3. Registration Status
Exenatide powder for injection, 2 mg was TGA registered on 20 December 2012 for the treatment of type 2 diabetes mellitus in combination with:
- metformin;
- sulfonylureas;
- metformin and a sulfonylurea;
in patients who have not achieved adequate glycaemic control.
4. Listing Requested and PBAC’s View
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 who has an HbA1c
greater than 7% prior to initiation of a dipeptidyl peptidase 4
inhibitor (gliptin), a thiazolidinedione (glitazone) or a
glucagon-like peptide-1 and in whom a combination of metformin and
a sulfonylurea is contraindicated or not tolerated.
The date and level of the HbA1c must be documented in the patient's
medical records at the time therapy with a gliptin, a glitazone or
a glucagon-like peptide-1 is initiated. The HbA1c must be no more
than 4 months old at the time treatment with a gliptin, a glitazone
or a glucagon-like peptide-1 is initiated;
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 results of this blood glucose monitoring, which must be
no more than 4 months old at the time of initiation of treatment
with a gliptin, a glitazone or a glucagon-like peptide-1, must be
documented in the patient's medical record;
Continuation of therapy, in combination with either metformin or a
sulfonylurea, in a patient with type 2 diabetes 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 a dipeptidyl
peptidase 4 inhibitor (gliptin) or another glucagon-like
peptide-1.
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 who has an HbA1c
greater than 7% prior to initiation of a dipeptidyl peptidase 4
inhibitor (gliptin), a thiazolidinedione (glitazone) or a
glucagon-like peptide-1 despite maximally tolerated doses of
metformin and a sulfonylurea.
The date and level of the HbA1c must be documented in the patient's
medical records at the time therapy with a gliptin, a glitazone or
a glucagon-like peptide-1 is initiated. The HbA1c must be no more
than 4 months old at the time treatment with a gliptin, a glitazone
or a glucagon-like peptide-1 is initiated;
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 results of this blood glucose monitoring, which must be
no more than 4 months old at the time of initiation of treatment
with a gliptin, a glitazone or a glucagon-like peptide-1, must be
documented in the patient's medical record.
Continuation of therapy, in combination with metformin and a
sulfonylurea, in a patient with type 2 diabetes 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 a dipeptidyl
peptidase 4 inhibitor (gliptin) or another glucagon-like
peptide-1.
Special Pricing Arrangements apply.
The PBAC accepted the requested restriction as appropriate and it
is consistent with the PBS restriction for exenatide twice
daily.
5. Clinical Place for the Proposed Therapy
Type 2 diabetes is a metabolic disorder characterised by
hyperglycaemia resulting from resistance to the action of insulin,
insufficient insulin secretion or both. Diet and exercise are the
first steps in managing the disease, followed by the addition of
drug therapy with metformin. When diet and exercise modifications
and metformin monotherapy is inadequate in controlling blood
glucose, current treatment guidelines recommend adding a
sulfonylurea. If dual therapy with metformin and a sulfonylurea is
unsuccessful, insulin should preferably be added. Instead of adding
insulin, other options include the addition of a glucagon like
peptide 1 (GLP-1) receptor agonist, a dipeptidyl peptidase-4
(DPP-4) inhibitor, a thiazolidinedione (e.g. rosiglitazone,
pioglitazone), an alpha-glucosidase inhibitor (e.g. acarbose), or a
meglitinide (e.g. repaglinide).
Exenatide is a treatment option for adults with type 2 diabetes not
achieving adequate glycaemic control when treated with diet and
exercise and maximally tolerated doses of either a combination of
metformin and a sulfonylurea; or metformin or a sulphonylurea and
combination treatment with metformin and a sulfonylurea is
contra-indicated or not tolerated.
The submission proposed that exenatide once weekly would substitute
for exenatide twice daily. The submission expected the clinical
management algorithm for patients with type 2 diabetes mellitus to
remain unchanged with the introduction of exenatide once
weekly.
6. Comparator
The submission nominated exenatide administered twice daily as the
main comparator. Liraglutide was nominated as a secondary
comparator. This was accepted by the PBAC.
7. Clinical Trials
The basis of the submission was two pivotal head-to-head trials
comparing exenatide 2 mg weekly with exenatide 10 micrograms twice
daily (BD) (Studies 105 and 108), and two supportive trials
comparing exenatide 2 mg weekly with sitagliptin 100 mg daily or
pioglitazone 45 mg daily (Study 106) and insulin glargine (Study
GWBR) in patients with type 2 diabetes.
The submission presented an indirect comparison of exenatide 2 mg
weekly with the supplementary comparator liraglutide 1.8 mg daily,
using exenatide 10 micrograms BD as the common comparator. The
indirect comparison was based on two trials comparing exenatide 2
mg weekly with exenatide 10 micrograms BD (Studies 105 and 108) and
one trial comparing exenatide 10 micrograms BD with liraglutide 1.8
mg daily (LEAD-6).
Studies 105 and 106 included extension phases where all patients
received exenatide weekly. For Study GWBR extension phase (84 week
interim analysis of a 130 week study), all patients remain on
randomised therapy.
Publication details of the trials presented in the submission are
in the table below.
Trials and associated reports presented in the
submission
Exenatide weekly versus exenatide BD (pivotal)
| Trial ID | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Study 105 (includes extension study) | A randomized, open-label, multicenter comparator-controlled study to examine the effects of exenatide long-acting release on glucose control (HbA1c) and safety in subjects with type 2 diabetes mellitus managed with diet modification and exercise and/or oral anti-diabetic medications. | |
| Drucker et al. | Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. | Lancet 2008; 372: 1240-50 |
| Buse et al. | DURATION 1: Exenatide one weekly produces sustained glycaemic control and weight loss over 52 weeks. | Diabetes Care. published online ahead of print, 9 March 2010 |
| Trautmann et al. | Exenatide once weekly treatment elicits sustained glycaemic control and weight loss over 2 years. | European Association for the Study of Diabetes 2009 [abstract]. |
| Study 108 | A randomized, open-label, parallel-group, comparator controlled, multicenter study to evaluate the glycaemic effects, safety and tolerability of exenatide once weekly in subjects with type 2 diabetes mellitus. | |
| Blevins et al. | DURATION 5: Exenatide once weekly resulted in greater improvements in glycaemic control compared to exenatide twice daily in patients with type 2 diabetes. | Journal of Clinical Endocrinology and Metabolism 2011; 96(5): 1-10 (to be published) |
Exenatide weekly versus other comparators (supportive)
| Trial ID | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Study 106 (includes extension study) | A randomized, double-blind, parallel-group, multicenter study to compare the glycaemic effects, safety and tolerability of exenatide once weekly to those of sitagliptin and pioglitazone in subjects with type 2 diabetes mellitus treated with metformin. | |
| Bergenstal et al. | Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION 2): a randomised trial. | Lancet 2010; 376:9739: 431-439 |
| Wysham C et al. | DURATION 2: Effect of switching to once-weekly exenatide from maximum daily doses of sitagliptin or pioglitazone. | American Diabetes Association 2010 [abstract] |
| Study GWBR (includes extension study) | Efficacy of once-weekly exenatide long-acting release and once-daily insulin glargine in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylurea. | |
| Diamant et al. | Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION 3): an open-label randomised trial. | Lancet 2010; 375: 2234-43 |
| GWBR Clinical Study Report 84 week extension | Publication in press |
Exenatide BD versus liraglutide (used in indirect comparison)
| Trial ID | Protocol title/ Publication title | Publication citation |
|---|---|---|
| LEAD-6 Buse et al. | Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26 week randomised, parallel-group, multinational, open-label trial (LEAD 6). | Lancet 2009; 374: 39-47 |
Abbreviations: BD, twice daily; met, metformin; QD, once daily;
QW, once weekly; SC, subcutaneously; SU, sulfonylurea
8. Results of Trials
The results for the primary outcome of mean change in HbA1c from baseline to endpoint
of Studies 105 and 108 are shown in the tables below.
Mean change in HbA1c from baseline to endpoint for Studies 105 (30 weeks)
| Exenatide 2mg weekly N=148 | Exenatide 10µg BD N=147 | |
|---|---|---|
| Baseline mean (SE) | 8.3 (0.08) | 8.3 (0.08) |
| Mean change in HbA1c (SE) | -1.6 (0.09) | -1.3 (0.08) |
| LS mean change in HbA1c (SE) | -1.9 (0.08) | -1.5 (0.08) |
| LS mean difference (95% CI) | -0.33 (-0.54, -0.12) p=0.0023 |
Mean change in HbA1c from baseline to endpoint for Studies 108 (24 weeks)
| Exenatide 2mg weekly N=129 | Exenatide 10µg BD N=123 | |
|---|---|---|
| Baseline mean (SE) | 8.5 (0.10) | 8.4 (0.10) |
| Mean change in HbA1c (SE) | -1.4 (0.10) | -0.7 (0.10) |
| LS mean change in HbA1c (SE) | -1.6 (0.10) | -0.9 (0.10) |
| LS mean difference (95% CI) | -0.7 (-0.90, -0.40) p<0.0001 |
Abbreviations: BD, twice daily; CI, confidence interval; HbA1c, glycosylated haemoglobin;
LS, least squares; SE, standard error
Note: Treatment group difference (exenatide weekly minus comparator).
There were statistically significant larger reductions in HbA1c from baseline to endpoint
for exenatide weekly compared to exenatide BD in Studies 105 and 108. The difference
was statistically significant from week 10 onwards for Study 105 and from week 8 onwards
for Study 108.
There was no evidence to suggest that the magnitude of the reduction of HbA1c varied
with baseline treatment of diabetes based on the subgroup analyses (dual therapy with
metformin, triple therapy with metformin and a sulfonylurea and sulfonylurea at baseline).
Most of the patients in the two studies were taking a combination of metformin and
sulfonylurea (triple therapy); only seven patients in the exenatide weekly arm and
18 patients in the exenatide BD arm were on sulfonylurea alone at baseline.
The results from the pivotal trials were pooled for analysis, using data collected
at Week 26 for Study 105 and Week 24 for Study 108. The results are presented in the
table below.
Pooled analysis of Study 105 (Week 26) and Study 108 (Week 24) for mean change in HbA1c from baseline
| Exenatide 2mg weekly N=277 | Exenatide 10µg BD N=270 | |
|---|---|---|
| Baseline LS mean (SE) | 8.37 (0.06) | 8.35 (0.07) |
| Mean change in HbA1c (SD) | -1.51 (1.11) | -0.98 (1.08) |
| LS mean change in HbA1c (SE) | -1.71 (0.07) | -1.18 (0.07) |
| Without treatment*study interaction term | With treatment*study interaction term | |
|---|---|---|
| LS mean difference (95%CI) | -0.53 (-0.70, -0.36); p<0.001 a | -0.54 (-0.71, -0.37); p<0.001 a |
Abbreviations: BD, twice daily; CI, confidence interval; HbA1c, glycosylated haemoglobin;
LS, least squares; SD, standard deviation; SE, standard error
a p-value is based on an ANCOVA model with effects for treatment, study, sulfonylurea
usage and HbA1c stratum.
There were statistically significant larger reductions in HbA1c in the exenatide weekly
group compared to the exenatide BD group for the pooled results (-0.53% [95% CI -0.70,
-0.36] p<0.001). Applying a margin of 0.3%, the additional reductions in HbA1c with
exenatide weekly dosing would be considered clinically important, and of borderline
clinical importance applying a margin of 0.4%. There were some concerns with pooling
the results of Studies 105 and 108 due to the differences in the treatment effect
in the two trials.
In the extension arm of Study 105, all patients received exenatide weekly following
30 weeks of randomised treatment. The mean reduction in HbA1c from baseline was maintained
with exenatide weekly treatment at 52 and 100 weeks.
The table below summarises the proportions of patients achieving the HbA1c target
of ≤7%, <7% or ≤6.5% for Studies 105 and 108, as well as the pooled results of these
trials.
Individual trial and pooled results of the proportion of patients achieving target HbA1c of ≤7%, <7% or 6.5% for Studies 105 and 108
| Type of Study | HbA1c target | Exen QW n/N (%) [% achieving target] | Exen BD n/N (%) [% achieving target] | Crude risk difference (95% CI) [Exenatide weekly vs exenatide BD] | Crude odds ratio (95% CI) [Exenatide weekly vs exenatide BD] | Adjusted odds ratio a (95% CI) [Exenatide weekly vs exenatide BD] |
|---|---|---|---|---|---|---|
| Study 105 (Week 30) | ≤7.0% b | 104/142 (73.2) | 80/140 (57.1) | 0.16 (0.05, 0.27) | 2.05 (1.25, 3.38) | 2.17 (1.27, 3.72) |
| Study 105 (Week 30) | ≤6.5% | 67/148 (45.3) | 56/147 (38.1) | 0.07 (-0.04, 0.18) | 1.34 (0.84, 2.14) | 1.34 (0.82, 2.20) p=0.2042 |
| Study 108 (Week 24) | <7.0% | 75/129 (58.1) | 37/123 (30.1) | 0.28 (0.16, 0.40) | 3.23 (1.92, 5.43) | 3.68 (2.10, 6.45) |
| Study 108 (Week 24) | ≤6.5% | 53/129 (41.1) | 20/123 (16.3) | 0.25 (0.14, 0.36) | 3.59 (1.98, 6.50) | NR |
| Pooled results (Study 105 at Week 26 and Study 108 at Week 24 week) | <7.0% | 170/267 (63.7) | 109/250 (43.6) | 0.20 (0.12, 0.29) | 2.27 (1.59, 3.23) | 2.65 (1.80, 3.90) |
Abbreviation: BD, twice daily; Exen, exenatide; CI, confidence interval; HbA1c, glycosylated
haemoglobin; NR, not reported; QW, weekly
a Adjusted for baseline HbA1c stratum and concomitant sulfonylurea use at screening
b only patients with a baseline HbA1c >7% included
Bolded results are statistically significantly different.
Individual trial and pooled results of the proportion of patients achieving target
HbA1c of ≤7%, <7% or ≤6.5% for studies 105 and 108 showed that statistically significantly
higher proportions of patients achieved HbA1c targets of <7% or ≤7% with exenatide
weekly compared to exenatide BD for study 105 (adjusted odds ratio (OR) 2.17 [95%
CI: 1.27, 3.72]), study 108 (adjusted OR 3.68 [95% CI: 2.10, 6.45]) and the pooled
results (adjusted OR 2.65 [95% CI 1.80, 3.90]).
There were statistically significant larger reductions in fasting blood glucose (FPG)
for exenatide weekly compared to exenatide BD in Studies 105 and 108 and the pooled
results.
There were no statistically significant differences between exenatide weekly and exenatide
BD in quality of life measures.
The results for the mean change in HbA1c from baseline to endpoint of Studies 106
and GWBR are shown in the table below.
Mean change in HbA1c from baseline to endpoint Study 106
| Study 106 (26 wks) | Exenatide 2mg QW N=160 | Sitagliptin 100mg N=166 | Pioglitazone 45mg N=165 |
|---|---|---|---|
| Baseline mean (SE) | 8.6 (0.09) | 8.5 (0.09) | 8.5 (0.08) |
| Mean change in HbA1c (SE) | -1.4 (0.11) | -0.8 (0.09) | -1.1 (0.09) |
| LSM change in HbA1c (SE) | -1.6 (0.10) | -0.9 (0.10) | -1.2 (0.10) |
| LSM difference (95% CI) | -0.63 (-0.89, -0.37) p<0.0001 | -0.32 (-0.57, -0.06) p=0.0165 |
Mean change in HbA1c from baseline to endpoint Study GWBR
| Study GWBR (26 wks) | Exenatide QW N=233 | Insulin glargine N=223 |
|---|---|---|
| Baseline mean (SE) | 8.3 (1.10) a | 8.3 (1.02) a |
| Mean change in HbA1c (SE) | -1.4 (1.02) a | -1.3 (0.92) a |
| LSM change in HbA1c (SE) | -1.4 (0.06) | -1.3 (0.06) |
| LSM difference (95% CI) | -0.16 (-0.31,-0.02) p=0.027 |
Abbreviations: BD, twice daily; CI, confidence interval; HbA1c, glycosylated haemoglobin;
LSM, least squares mean; QW, once weekly; SE, standard error; wks, weeks
Note: Treatment group difference (exenatide weekly minus comparator), results from
Study 106 appropriately adjusted to reflect this.
a mean and SD reported
There were statistically significant greater reductions in HbA1c for exenatide weekly
compared to sitagliptin, pioglitazone and insulin glargine. The results suggest that
exenatide weekly may be clinically superior to sitagliptin, as the additional reductions
in HbA1c with exenatide weekly would be considered clinically important applying a
margin of 0.3 %, and of borderline clinical importance applying a margin of 0.4 %.
However, the difference between exenatide weekly and pioglitazone is of uncertain
clinical importance as the 95 % CI include values that are not clinically important.
The difference between exenatide weekly and insulin glargine is unlikely to be clinically
important.
The submission concluded that there was no difference between exenatide weekly and
liraglutide daily based on an indirect comparison using exenatide BD as the common
comparator. However, the preliminary results of the head-to-head trial of exenatide
weekly versus liraglutide (DURATION-6) available in the public domain indicate that
exenatide weekly did not meet the pre-specified primary endpoint of non-inferiority
to liraglutide. In light of the availability of the preliminary results from DURATION-6
(see table below), the sponsor stated that as exenatide once weekly did not meet the
pre-specified primary endpoint of non-inferiority to liraglutide, the clinical claim
of non-inferiority of exenatide once weekly with liraglutide 1.8mg presented in the
submission was no longer supported.
LS mean change in HbA1c from baseline to endpoint: DURATION 6
| Exenatide 2mg QW | Liraglutide 1.8 mg QD | |
|---|---|---|
| LS Mean change from baseline in HbA1c(SE) | -1.28 (0.05) | -1.48 (0.05) |
| pvalue | <0.001 | |
| LS Mean difference (SE) | 0.21 (0.07) | |
| 95%CI (for difference) | (0.08,0.34) | |
| p value | 0.002 |
The most frequent adverse events reported with exenatide weekly were gastrointestinal
events (mainly nausea, vomiting, and diarrhoea), injection site reactions, nasopharyngitis,
hypoglycaemia and headache. When compared to exenatide BD (pooled results of Studies
105 and 108), there were statistically significantly more patients treated with exenatide
weekly reporting injection site reactions (pruritus, erythema, induration, and nodule);
whereas there were statistically significantly more exenatide BD patients reporting
nausea, and vomiting. Differences in the rates of nausea and injection site reactions
are carried into the economic model.
The submission presented additional data beyond the duration of the trials discussing
pancreatitis, acute renal failure, rapid weight loss, anti-exenatide antibodies (anaphylactic-type
reactions), cardiovascular events and malignant neoplasm (particularly pancreatic
and thyroid cancers). The PBAC noted that the FDA has requested a thorough QT study
with exposures of exenatide higher than typical therapeutic levels of exenatide weekly.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission described exenatide weekly as superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety over exenatide BD.
The submission described exenatide weekly as superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety to sitagliptin, pioglitazone, and insulin glargine.
For PBAC’s view, see recommendation and
reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The type of economic
evaluation presented was a cost-utility analysis. The
individual-patient simulation model compared treatment with
exenatide weekly and treatment with exenatide BD in patients with
type 2 diabetic patients who have failed first line therapy
(metformin/and or sulfonylurea therapy). The model had three health
states: ‘alive, no complications,’ ‘alive,
complications,’ and dead. The complications included in the
model were ischaemic heart disease (IHD), congestive heart failure
(CHF), myocardial infarction (MI), stroke, amputation and
blindness. The time horizon in the modelled economic evaluation was
a patient’s lifetime (until death or aged 100 years). The
model’s cycle length was one year. HbA1c was the only
clinical parameter that differed significantly between patients
receiving exenatide weekly and exenatide BD, and was updated
annually in the model.
It was assumed that patients switch to insulin glargine after a
period of time on treatment with exenatide (weekly or BD) and
remain on insulin glargine for the remainder of the model. It was
also assumed that the difference in HbA1c observed at the end of
the trial was maintained for the duration of the model in patients
who were initially treated with exenatide compared with those
initially treated with insulin glargine.
The incremental cost per quality adjusted life year (QALY) gained
was less than $15,000 in the base case.
The model was sensitive to disutilities associated with differing
administration schedule (weekly versus daily), the time horizon,
and the difference between treatment arms in HbA1c after switching
from exenatide (weekly and BD) to insulin glargine.
During the evaluation, a multi-variate sensitivity analysis testing
all three assumptions resulted in an incremental cost per QALY
gained of between $105,000 and $200,000.
The PBAC considered there were several uncertainties with the
economic model.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The submission’s estimate of the net cost per year to the
PBS/RPBS was less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC accepted the requested restriction as appropriate and it
is consistent with the PBS restriction for exenatide twice
daily.
The PBAC noted the comparator nominated for this submission was
exenatide twice daily (BD) injection with a higher price requested
for the exenatide once weekly (QW) injection than that of the
comparator.
The basis of the higher price was an overall 0.53 % reduction in
HbA1c based on the pooled results from studies 105 and 108. This
difference in HbA1c was statistically significant and the PBAC
agreed it would represent a clinically meaningful difference.
However, there was some uncertainty about this pooled result. The
clinical importance of the HbA1c reduction in Study 105 is
uncertain as the 95 % CI includes values that are not clinically
important (0.12 %). In Study 108, the difference between treatment
arms exceeded the non-inferiority margin of 0.4 %, consistent with
exenatide weekly being clinically superior to exenatide BD with
respect to diabetes control. There were substantially larger
reductions in HbA1c in the exenatide BD arm of Study 105 than Study
108 (LS mean reduction of -1.5 % versus -0.9 %). The reasons for
these differences between trials are unclear.
The claim of non-inferior safety to the BD injection is uncertain,
as the long-term safety of exenatide QW is unknown. This is of
particular concern given the dose of the weekly injection (2000
microgram) is over tenfold higher than the dose of the BD
injections over an equivalent period (140 microgram/week).
The PBAC considered there were several uncertainties with the
economic model.
The PBAC considered that the assumed continuation of a treatment
effect (i.e. 0.53% difference in HbA1c) unchanged for a lifetime,
regardless of subsequent treatment, is inappropriate. HbA1c is
unlikely to be different once patients are switched to insulin and
the progression of HbA1c over 10 years in the model was considered
implausible.
The PBAC recognised there were statistically significantly more
exenatide BD patients reporting nausea, and vomiting than exenatide
QW patients. However, the inclusion of disutilities for these
events in the model may have lead to double counting, as patients
would discontinue treatment if these events are of concern, given
there are other treatment options available. The disutilities for
fewer injections were notably not supported in the quality of life
data collected during Study 105. The PBAC considered that these
disutilities are likely to be overestimated. The PBAC noted that
injection site reactions are more common with exenatide QW.
The use of some of the risk equations from the UKPDS Outcomes model
may not be valid. An Australian study found that the UKPDS risk
equations overestimated the number of coronary heart disease (CHD)
events in Australian type 2 diabetics (Davis et al, 2009). The
authors concluded that UKPDS CHD equations are not suitable for
predicting the risk in Australians with type 2 diabetes. The model
is therefore likely to significantly overestimate the reductions in
CHD events associated with exenatide weekly versus exenatide
BD.
The PBAC therefore rejected the submission on the basis of
uncertain cost-effectiveness, with particular concern over the
model assumptions regarding duration of treatment benefit, timing
of the switch to insulin, disutilities associated with GI events
and injections, and overestimation of cardiovascular
benefits.
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
The sponsor has no comment.
