Saxagliptin, tablets, 5 mg, Onglyza® - March 2010
Public Summary Document for Saxagliptin, tablets, 5 mg, Onglyza® - March 2010
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Public Summary Documents
Product: SAXAGLIPTIN, tablets, 5 mg,
Onglyza®
Sponsor: Bristol-Myers Squibb
Pharmaceuticals
Date of PBAC Consideration: March 2010
1. Purpose of Application.
The submission sought an Authority required (Streamlined) listing
for the treatment of type 2 diabetes in combination with metformin
or a sulfonylurea in patients who meet certain criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
At the time of consideration, saxagliptin was not registered with
the Therapeutic Goods Administration (TGA).
Listing on the PBS is contingent upon successful TGA
registration.
4. Listing Requested and PBAC’s View.
Authority required (STREAMLINED)
Dual oral combination therapy with metformin or a
sulfonylurea.
Type 2 diabetes mellitus, in combination with metformin or a
sulfonylurea, in a patient whose HbA1c is greater than 7 % prior to
initiation of saxagliptin despite treatment with either metformin
or a sulfonylurea and where a combination of metformin and a
sulfonylurea is contraindicated or not tolerated.
The date and level of the qualifying HbA1c must be documented in
the patient's medical records at the time saxagliptin treatment is
initiated. The HbA1c must be no more than 4 months old at the time
saxagliptin treatment is initiated.
Blood glucose monitoring may be used as an alternative assessment
to HbA1c levels 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.
A patient 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 saxagliptin
therapy, must be documented in the patient's medical records.
Note:
Saxagliptin is not PBS-subsidised for use in combination with
metformin and a sulfonylurea (triple oral therapy), as monotherapy
or in combination with a thiazolidinedione (glitazone).
The PBAC recommended the restriction wording for saxagliptin and
all currently PBS subsidised dipeptidyl peptidase 4 inhibitors
(gliptins) and thiazolidinediones (glitazones) be modified to allow
patients to switch between agents in these two classes without
having to requalify with respect to glycosylated haemoglobin levels
(HbA1c). Although the evidence to support switches from a gliptin
to a glitazone, and vice versa, is limited, the Committee
considered it unreasonable to require a loss of diabetic control
prior to switching.
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 lifestyle
modifications are the first steps in managing the disease, followed
by the addition of drug therapy with metformin. When diet,
lifestyle modifications and metformin monotherapy is inadequate in
controlling blood sugar levels, current treatment guidelines
recommend adding a sulfonylurea. If dual therapy with metformin and
a sulfonylurea is unsuccessful, insulin can be added. Other options
include thiazolidinediones, acarbose, incretins, glitinides and
gliptins. Saxagliptin would provide another gliptin option.
6. Comparator
The submission nominated sitagliptin as the main comparator. The
PBAC considered this appropriate.
7. Clinical Trials
The submission presented one unpublished randomised head-to-head
trial comparing saxagliptin 5 mg/day with sitagliptin 100 mg/day
each in combination with metformin 1,500 mg to 3,000 mg daily in
patients with type 2 diabetes mellitus (T2DM) not adequately
controlled by metformin alone over an 18-week study period.
The submission also presented an indirect comparison of saxagliptin
and sitagliptin in combination with a sulfonylurea (glyburide or
glimepiride) based on the results of two 24-week duration,
multi-centre, randomised double-blind, placebo-controlled phase III
trials (Hermansen et al. 2007 and an unpublished trial) using
placebo as the common reference. The unpublished trial compared
saxagliptin (2.5 mg/day or 5 mg/day plus glyburide 7.5 mg) to
placebo (plus glyburide 7.5 mg). Hermansen et al. (2007) compared
sitagliptin (100 mg/day plus glimepiride 4 – 8 mg/day) to
placebo (plus glimepiride 4 – 8 mg/day).
One trial had been published at the time of the submission, as
follows:
| Trial ID / First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Indirect comparison – saxagliptin as add-on to a sulfonylurea versus a sulfonylurea | ||
| Hermansen et al. (2007) | Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. | Diabetes, Obesity and Metabolism 2007; 9 (5): 733-745. |
In addition, an indirect comparison of sitagliptin plus metformin
(Charbonnel et al. 2006) versus saxagliptin plus metformin (an
unpublished trial) using metformin (placebo) as the common
comparator was presented in the submission.
The PBAC noted concerns about whether the patients included in the
clinical trials were representative of those for whom PBS listing
was sought, and whether the results of the indirect comparison were
sufficient to support a listing for use in combination with a
sulfonylurea. Despite this the PBAC accepted that the data
supported the clinical claim.
8. Results of Trials
In the unpublished, direct head-to-head comparison of saxagliptin
versus sitagliptin (either agent added to metformin), the change in
HbA1c % from baseline at week 18 was the primary outcome.
Based on the upper limit of the 95 % confidence interval (i.e. 0.2
%), the mean difference in HbA1c was below the pre-defined
non-inferiority margin of less than 0.3 %, indicating saxagliptin 5
mg/day was non-inferior to sitagliptin 100 mg/day when added to
metformin, in reducing HbA1c from baseline.
The results of the indirect comparison of saxagliptin to
sitagliptin (either agent added to a sulfonylurea) showed that
there was no statistically significant difference between
saxagliptin 5 mg and sitagliptin 100 mg for the reduction in HbA1c
from baseline at Week 24.
The PBAC accepted that saxagliptin is no worse in terms of efficacy
than sitagliptin when either agent is used in combination with
metformin or a sulfonylurea. However, the Committee noted concerns
about the limited data on the long term durability of effect of
saxagliptin.
In the unpublished, direct head-to-head trial of saxagliptin versus
sitagliptin (both agents added to metformin), there were no
statistically significant differences between the two treatments in
the number of adverse events reported, the proportion of subjects
experiencing serious adverse events, drug related adverse events,
or serious drug-related adverse events. The numbers of
hypoglycaemic events with saxagliptin and sitagliptin were low and
there was no statistically significant difference in the number of
hypoglycaemic events experienced between the two treatment
arms.
With the exception of ‘Any adverse event’, the indirect
comparison of safety outcomes from the unpublished indirect
comparison of saxagliptin versus sitagliptin (either agent added to
a sulfonylurea) and Hermansen et al. (2007) showed that there were
no statistically significant differences between saxagliptin 5
mg/day and sitagliptin 100 mg/day in the occurrence of adverse
events or safety related outcomes. The relative risk (RR) for the
occurrence of ‘any adverse event’ was statistically
significantly lower for saxagliptin 5 mg/day than sitagliptin 100
mg/day. However, the adverse event rates (i.e. for ‘any
adverse event’) in the placebo arms across trials were
significantly different. A similarly large difference in the
placebo arms for ‘drug-related adverse events’ was also
observed.
There appeared to be no statistically significant differences
between treatment (saxagliptin 5 mg/sitagliptin 100 mg) and placebo
for any of the other reported adverse events across the randomised
controlled trials including; all hypoglycaemic events, confirmed
hypoglycaemic events, gastrointestinal adverse events, abdominal
pain, diarrhoea, nausea, and vomiting.
The extended assessment of comparative harms suggested that there
was no evidence of dependence or abuse developing for saxagliptin.
Further, there was no evidence that saxagliptin increased cardio
vascular risk.
The PBAC accepted that saxagliptin is no worse in terms of safety
than sitagliptin when either agent is used in combination with
metformin or a sulfonylurea. However, the Committee noted concerns
about the long term safety of the dipeptidyl peptidase inhibitors
(gliptins) in general.
9. Clinical Claim
The submission described saxagliptin (5 mg/day) as non-inferior in
terms of comparative effectiveness and non-inferior in terms of
comparative safety to sitagliptin (100 mg/day) as dual oral
combination therapy with metformin, for the treatment of patients
with type 2 diabetes mellitus where a combination of metformin and
a sulfonylurea is contraindicated or not tolerated.
The submission also described saxagliptin (5 mg/day) as
non-inferior in terms of comparative effectiveness and non-inferior
in terms of comparative safety to sitagliptin (100 mg/day) as dual
oral combination therapy with sulfonylurea, for the treatment of
patients with type 2 diabetes mellitus where a combination of
metformin and a sulfonylurea is contraindicated or not
tolerated.
The PBAC accepted that saxagliptin is no worse in terms of efficacy
and safety than sitagliptin when either agent is used in
combination with metformin or a sulfonylurea.
10 Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as saxagliptin 5 mg/day and
sitagliptin 100 mg/day.
11. Estimated PBS Usage and Financial Implications
The likely number of packs dispensed/year was estimated by the
submission to be in the range of 100,000 – 200,000
prescriptions in Year 5.
The financial cost/year to the PBS of listing saxagliptin on the
BPS was predicted by the submission to be less than $15,000 in Year
1 to Year 5. The submission anticipated the listing of saxagliptin
on the PBS will be cost-neutral to the Government as it will
directly substitute for sitagliptin, pioglitazone or
rosiglitazone.
12. Recommendation and Reasons
The PBAC recommended the listing of saxagliptin as an Authority
required (Streamlined) benefit for the treatment of type 2 diabetes
mellitus, in combination with metformin or a sulfonylurea, in a
patient whose HbA1c is greater than 7 % despite treatment with
either metformin or a sulfonylurea and where a combination of
metformin and a sulfonylurea is contraindicated or not tolerated.
Listing was recommended on a cost-minimisation basis with
sitagliptin with the equi-effective doses of saxagliptin 5 mg/day
and sitagliptin
100 mg/day.
Despite concerns about whether the patients included in the
clinical trials were representative of those for whom PBS listing
is sought, and whether the results of the indirect comparison were
sufficient to support a listing for use combination with a
sulfonylurea, the PBAC accepted that saxagliptin is no worse in
terms of efficacy and safety than sitagliptin when either agent is
used in combination with metformin or a sulfonylurea. However, the
Committee noted concerns about the limited data on the long term
durability of effect of saxagliptin, and about the long term safety
of the dipeptidyl peptidase inhibitors (gliptins) in general.
The PBAC recommended the restriction wording for saxagliptin and
all currently PBS subsidised dipeptidyl peptidase 4 inhibitors
(gliptins) and thiazolidinediones (glitazones) be modified to allow
patients to switch between agents in these two classes without
having to requalify with respect to glycosylated haemoglobin levels
(HbA1c). Although the evidence to support switches from a gliptin
to a glitazone, and vice versa, is limited, the Committee
considered it unreasonable to require a loss of diabetic control
prior to switching.
The PBAC also noted that the listing of saxagliptin is contingent
upon successful TGA registration.
Recommendation:
SAXAGLIPTIN, tablet, 5 mg
Restriction:
NOTE:
Saxagliptin is not PBS-subsidised for use in combination with metformin and a sulfonylurea (triple oral therapy), as monotherapy or in combination with a thiazolidinedione (glitazone).
Authority required (STREAMLINED)
Dual oral combination therapy with metformin or a sulfonylurea.Type 2 diabetes mellitus, in combination with metformin or a sulfonylurea, in a patient whose HbA1c is greater than 7 % prior to initiation of a dipeptidyl peptidase 4 inhibitor (gliptin) or a thiozolidinedione (glitazone) despite treatment with either metformin or a sulfonylurea and where a combination of metformin and a sulfonylurea is contraindicated or not tolerated.The date and level of the qualifying HbA1c must be documented in the patient's medical records at the time treatment with a gliptin or glitazone is initiated. The HbA1c must be no more than 4 months old at the time treatment with a gliptin or glitazone is initiated.Blood glucose monitoring may be used as an alternative assessment to HbA1c levels 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.A patient 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 or glitazone, must be documented in the patient's medical records.
Maximum quantity: 28
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
The sponsor has no comment.
