DENOSUMAB, injection, 60 mg in 1 mL, single use pre-filled syringe, Prolia®
Page last updated: 19 October 2010
Public Summary Document
Product: DENOSUMAB, injection, 60 mg in 1 mL,
single use pre-filled syringe, Prolia®
Sponsor: Amgen Australia Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission sought an Authority required (STREAMLINED) listing
for:
1. the treatment of osteoporosis in women aged 70 years of age or
older with a bone mineral density (BMD) T-score of -3.0 or less,
and
2. the treatment of established post-menopausal osteoporosis in
patients with fracture due to minimal trauma.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Denosumab was TGA registered on 22 June 2010 for the treatment of
osteoporosis in postmenopausal women. Denosumab significantly
reduces the risk of vertebral, non-vertebral and hip
fractures.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
osteoporosis in a woman aged 70 years of age or older with a Bone
Mineral Density (BMD) T-score of -3.0 or less.
The date, site (femoral neck or lumbar spine) and score of the
qualifying BMD measurement must be documented in the
patient’s medical records when treatment is initiated.
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
established post-menopausal osteoporosis in patients with fracture
due to minimal trauma. The fracture must have been demonstrated
radiologically and the year of plain x-ray or CT-scan or MRI scan
must be documented in the patient’s medical records when
treatment is initiated.
A vertebral fracture is defined as a 20% or greater reduction in
height of the anterior or mid portion of a vertebral body relative
to the posterior height of that body, or, a 20% or greater
reduction in any of these heights compared to the vertebral body
above or below the affected vertebral body.
Note:
Anti-resorptive agents in established osteoporosis include
alendronate sodium, risedronate sodium, disodium etidronate,
raloxifene hydrochloride, strontium ranelate, zoledronic acid and
denosumab.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Osteoporosis affects the skeleton and is characterised by low bone
mass and micro-architectural deterioration of bone tissue with a
subsequent increase in bone fragility and susceptibility to
fracture.
Denosumab is a subcutaneous injection given every 6 months and has
a different mechanism of action to other PBS-listed drugs for
osteoporosis treatment. It would provide an alternative treatment
option for women with post-menopausal osteoporosis.
6. Comparator
The submission nominated a mixed comparator comprising of
alendronate, risedronate, strontium and zoledronic acid based on
post-menopausal women initiating therapy.
The submission nominated alendronate as the main clinical
comparator as it is the efficacy benchmark against which the other
treatments in the nominated mixed comparator were assessed for PBS
listing.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The basis of the submission was a direct comparison of BMD
outcomes, patient satisfaction and treatment adherence, using four
head-to-head trials of denosumab and alendronate in post-menopausal
osteoporosis (DECIDE, STAND, Study 179 and Study 232) as well as an
indirect comparison of fracture outcomes with denosumab (FREEDOM),
alendronate (FIT-VFA, FIT-CFA), risedronate (VERT-MN, VERT-NA,
HIP), zoledronic acid (HORIZON-PFT, HORIZON-RFT) and strontium
ranelate (TROPOS, SOTI).
Fracture outcomes from two additional risedronate trials (BMD-MN
and BMD-NA) were presented in a secondary pooled analysis of
risedronate trials.
The key trials published at the time of submission are shown in the
tables below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Denosumab vs. Alendronate trials | ||
| Study 141 (DECIDE) | ||
| Brown JP et al. (2009) | Comparison of the effect of denosumab and alendronate on bone mineral density and biochemical markers of bone turnover in postmenopausal women with low bone mass: A randomised, blinded, phase 3 trial. | J Bone Miner Res (JBMR) 2009; 24:153–161. |
| Study 234 (STAND ) | ||
| Kendler et al. | Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women Transitioning from Alendronate Therapy. | JBMR 2010;25(1):72-81 |
| Study 179 | ||
| Seeman E et al | Baseline Remodelling Intensity and Greater Suppression by Denosumab Than Alendronate: Effects on HR-pQCT Parameters at the Radius. | ASBMR 31st Annual meeting 2009, Abstract A09001600. |
| Seeman E et al. | Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate. | JBMR 2010; 25(8);1886-94 |
Placebo-controlled trials included in the submission
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Denosumab vs. Placebo trials | ||
| Study 216 (FREEDOM) | ||
| Cummings S et al. | Denosumab for prevention of fractures in postmenopausal women with osteoporosis. | NEJM 2009; 361:756-765 |
| Alendronate vs. Placebo trials | ||
| FIT-VFA Black et al. | Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. | Lancet 1996; 348:1535-41. |
| FIT-CFA Cummings et al. | Effect of Alendronate on Risk of Fracture in Women With Low Bone Density but Without Vertebral Fractures. | JAMA 1998; 280:2077-2082. |
| Risedronate vs. Placebo trials | ||
| BMD-MN Fogelman I et al. | Risedronate Reverses Bone Loss in Postmenopausal Women with Low Bone Mass: Results From a Multinational, Double-Blind, Placebo-Controlled Trial. | Journal of Clinical Endocrinology & Metabolism 2000; 85: 1895-1900 |
| BMD-NA McClung MR et al. | Risedronate increases BMD at the hip, spine and radius in postmenopausal women with low bone mass [abstract]. | Journal of Bone and Mineral Research 1997; 12(Suppl 1):S169 |
| HIP McClung MR et al. | Effect of risedronate on the risk of hip fracture in elderly women. | NEJM 2001; 344:333-40 |
| Zoledronic acid vs. Placebo trials | ||
| HORIZON-PFT Black DM et al. | Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. | NEJM 2007; 356:1809-22. |
| HORIZON-RFT Lyles KW et al. | Zoledronic acid and clinical fractures and mortality after hip fracture 1049. | NEJM 2007; 357:1799-809 |
| Strontium ranelate vs. Placebo trials | ||
| TROPOS Reginster JY et al. | Strontium ranelate reduces the risk of non-vertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. | Journal of Clinical Endocrinology & Metabolism 2005; 90:2816-22. |
| SOTI Meunier PJ et al. | The Effects of Strontium Ranelate on the Risk of Vertebral Fracture in Women with Postmenopausal Osteoporosis. | NEJM 2004; 350:459-68 |
8. Results of Trials
The head-to-head trials of denosumab and alendronate [DECIDE and
STAND] showed that denosumab treatment was associated with a small
but statistically significant increase in BMD compared to
alendronate (approximately 1% in absolute terms at all measured
locations) after 12 months of treatment. Differences between
treatments in Study 179 were not formally assessed.
Patient surveys administered during these trials suggested that
most patients preferred a 6-monthly injection to receiving a weekly
oral tablet.
The primary analysis of fracture outcomes presented in the
submission was based on the total population which included results
from trials in primary and/or secondary prevention. Supportive
analyses were also presented separately for patients without prior
vertebral fracture (approximating a primary prevention population)
and for patients with a prevalent vertebral fracture (approximating
a secondary prevention population). There was doubt about whether
the included trials were sufficiently comparable to enable an
indirect comparison.
The results of the indirect meta-analysis for morphometric
vertebral fractures suggested that denosumab treatment may reduce
morphometric vertebral fractures compared to alendronate in a mixed
population of osteoporosis patients (relative risk (RR) 0.60, 95%
CI 0.44, 0.83). There were statistically significant reductions in
morphometric vertebral fractures in denosumab treated patients
compared to risedronate and strontium ranelate.
The results of the indirect meta-analysis for clinical vertebral
fractures identified no statistically significant difference
between denosumab and alendronate. However, the submission noted
that denosumab was associated with a numerically greater reduction
in clinical vertebral fractures in the total population analysis
(RR 0.60, 95% CI 0.34, 1.04) and this result is similar to that
observed for morphometric vertebral fractures. The reduction in
clinical vertebral fracture risks was numerically greater in
patients without prior fracture (RR 0.48, 95% CI 0.21, 1.07)
compared to patients with a prevalent fracture (RR 0.69, 95% CI
0.31, 1.51).
The results of the indirect meta-analyses for hip fractures or
other non-vertebral, non-hip fractures indicated there were no
statistically significant differences between denosumab and the
comparator drugs in the total osteoporosis population or the
subgroups with and without fracture at baseline. The confidence
intervals around the estimates in the indirect analyses of hip
fracture were wide, reflecting the small numbers of events in these
trials.
The PBAC noted that the indirect analyses did not demonstrate
statistically significant differences between denosumab and
zolendronic acid for any of the above outcomes.
For PBAC’s comments on these results, see Recommendation
and Reasons.
Denosumab and alendronate appeared to have similar short-term (1-2
years) safety profiles in the direct clinical trials. There are
limited data on the long-term adverse event profile of denosumab
treatment.
A review by the U.S Food and Drug Administration (FDA) also noted
that denosumab treatment appeared to be associated with a slightly
increased risk of breast cancer, pancreatic cancer,
gastrointestinal cancer and reproductive cancers compared to
placebo. However, there were more new cases of malignant
respiratory neoplasm among patients receiving placebo than
denosumab. Denosumab was also associated with a slightly increased
risk of serious infection (skin, ear, abdominal system and urinary
tract) compared to placebo. The review noted that denosumab
markedly suppressed osteoclast and osteoblast counts compared to
placebo and alendronate. Dynamic bone formation parameters were
also suppressed. The FDA review suggested that long-term denosumab
treatment may lead to delayed fracture healing, ONJ or atypical
fracture.
For PBAC’s view, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that denosumab treatment is associated with
a reduction in the incidence of vertebral fractures and an
improvement in persistence relative to a mixed comparator comprised
of alendronate, risedronate, zoledronic acid and strontium
ranelate. The PBAC did not accept this claim.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a stepped economic evaluation with the
modelled results of the primary and secondary populations presented
separately. However, the efficacy estimates used in the economic
model were based on the total population (mixed primary and
secondary) indirect analysis.
Based on the structure and assumptions used in the
submission’s model, denosumab treatment was associated with
an incremental cost of between $15,000 and $45,000 per QALY gained
in the primary prevention setting and less than $15,000 per QALY
gained in the secondary prevention setting compared to the mixed
comparator.
The PBAC considered a cost effectiveness approach was not valid.
See Recommendation and Reasons, for PBAC’s
view.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated by the
submission to be between 50,000 and 100,000 in Year 5. The
submission estimated that 56% of eligible patients receive
treatment for primary prevention while the remaining 44% receive
treatment for secondary prevention. The estimate was considered
highly uncertain and it was more likely that the majority of
patients received treatment for secondary prevention.
The financial cost per year to the PBS was estimated by the
submission to be between $10 and $30 million in Year 5. The
submission did not provide a break down of net costs in the primary
and secondary prevention settings. However, the PBAC considered
that the net cost could potentially be between $10 and $30 million
in the secondary prevention setting alone.
12. Recommendation and Reasons
The PBAC recommended listing on a cost minimisation basis compared
with zoledronic acid. The equi-effective doses are denosumab 60 mg
administered every six months and zoledronic acid 5 mg administered
once per year. Pricing should also take account of the two
doctor’s visits required for the administration of denosumab,
as well as the administration costs for zoledronic acid.
Although there were concerns about possible signals for long-term
toxicity with denosumab, in particular of an increased risk of
certain types of cancer and serious infections, the PBAC noted that
there was no difference in the overall rate of neoplasms between
denosumab and placebo. The PBAC also noted from the hearing that
any skin infections resulting from denosumab treatment are readily
treated with a single course of antibiotics. The clinician at the
hearing also indicated that experts in the field, including the
Australian Bone and Mineral Society and the Medical and Scientific
Committee of Osteoporosis Australia, believe that denosumab should
provide a further first line treatment option to the currently
listed agents, given its novel mechanism of action. The PBAC
therefore agreed that denosumab should not be listed as second line
to current therapies. However, a streamlined authority listing was
not considered appropriate for a member of this new class of
agents, which has limited clinical and safety data and that will be
subject to on-going surveillance with Risk Management Plans.
The PBAC considered that the comparator should be zoledronic acid,
as an alternative injectable agent, noting that the comparison of
denosumab with zoledronic acid showed no differences between the
two drugs. The information provided by the clinician during the
hearing was also consistent with zoledronic acid being the key
comparator.
The PBAC considered that alendronate was a relevant but secondary
comparator and noted that denosumab treatment was associated with a
small but statistically significant increase in BMD compared to
alendronate (approximately 1% in absolute terms at all measured
locations) after 12 months of treatment in the DECIDE and STAND
trials. Differences between treatments in Study 179 were not
formally assessed however BMD results at the lumbar spine and
distal 1/3 radius favoured denosumab while BMD results at the total
hip, femoral neck and trochanter favoured alendronate. The PBAC
agreed that the clinical importance of differences in BMD outcomes
between denosumab and alendronate is unclear and that there is
uncertainty regarding how changes in BMD translate into differences
in clinical fractures.
The PBAC noted there was no head-to-head trial evidence comparing
fracture outcomes for denosumab with any of the nominated
comparators. Further there was doubt about whether the included
trials were sufficiently comparable to enable an indirect
comparison, given the differences in patient populations (e.g.
fracture history including type of previous fracture, age, BMD),
treatment characteristics (e.g. use of non-approved doses, calcium
and vitamin D, concomitant therapy) and study design (e.g. trial
duration). The PBAC also noted that the results of an indirect
analysis showed a statistically significant reduction in
morphometric vertebral fractures (clinical importance unknown) with
denosumab treatment compared to alendronate, risedronate and
strontium ranelate as well as a trend towards a greater clinical
vertebral fracture reduction with denosumab. Denosumab did not
significantly reduce the risk of hip fractures compared to other
treatments. The PBAC noted that the indirect analyses did not
demonstrate statistically significant differences between denosumab
and zolendronic acid for any outcomes.
The PBAC thus did not accept the claim of superiority against oral
bisphosphonates and considered denosumab had been demonstrated to
be similar in effectiveness to zoledronic acid.
The PBAC noted the 12 month results of Study 232 (unpublished)
suggest that patients treated with denosumab are likely to be more
adherent, compliant and persistent with therapy compared to
alendronate patients. The PBAC considered that the results of this
study may not to be representative of adherence and persistence in
a PBS population. Furthermore, given that the PBAC considered
zoledronic acid to be the appropriate comparator, the issue of
compliance with oral agents was irrelevant.
Given the uncertainty about improvements in either efficacy or
compliance, a cost effectiveness approach was not considered to be
valid and the results of the modelled economic evaluation were
therefore not relevant. The PBAC did note however that there were a
number of issues of concern raised about the model by the ESC,
including the issue of double counting with the effect of
persistence, overestimate of fracture mortality and utility
estimates.
The PBAC was concerned about the long-term toxicity of denosumab.
In addition to concerns about risks of cancer and serious
infection, the PBAC noted that denosumab markedly suppressed
osteoclast and osteoblast counts compared to placebo and
alendronate. Dynamic bone formation parameters were also
suppressed. Further, the FDA review suggests that long-term
denosumab treatment may lead to delayed fracture healing, ONJ or
atypical fracture. The PBAC also noted that the Advisory Committee
on Prescription Medicines had recommended a risk management plan as
a pre-requisite for registration, including the establishment of a
patient registry. The PBAC requested that it be kept informed about
any toxicity signals that may arise from this post-marketing
surveillance.
The PBAC requested that NPS produce a RADAR for denosumab in view
of the potential for long-term toxicity.
Recommendation:
DENOSUMAB, injection, 60 mg in 1 mL, single use pre-filled
syringe
Restriction:
Authority required
Treatment as the sole PBS-subsidised anti-resorptive agent for osteoporosis in a woman aged 70 years of age or older with a Bone Mineral Density (BMD) T-score of -3.0 or less.
The date, site (femoral neck or lumbar spine) and score of the qualifying BMD measurement must be documented in the patient’s medical records when treatment is initiated.
Authority required
Treatment as the sole PBS-subsidised anti-resorptive agent for established post-menopausal osteoporosis in a woman with fracture due to minimal trauma. The fracture must have been demonstrated radiologically and the year of plain x-ray or CT-scan or MRI scan must be documented in the patient’s medical records when treatment is initiated.
A vertebral fracture is defined as a 20% or greater reduction in height of the anterior or mid portion of a vertebral body relative to the posterior height of that body, or, a 20% or greater reduction in any of these heights compared to the vertebral body above or below the affected vertebral body.
Note: Anti-resorptive agents in established osteoporosis include alendronate sodium, risedronate sodium, disodium etidronate, raloxifene hydrochloride, strontium ranelate, zoledronic acid and denosumab.
Maximum quantity: 1
Repeats: 0
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
Amgen is pleased that denosumab will be made available through the PBS for Australian women with postmenopausal osteoporosis.
