ECULIZUMAB, solution concentrate for I.V. infusion, 300 mg in 30 mL, Soliris®
Page last updated: 29 October 2010
Public Summary Document
Product: ECULIZUMAB, solution concentrate for I.V.
infusion, 300 mg in 30 mL, Soliris®
Sponsor: Alexion Pharmaceuticals Australasia Pty
Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
To request the PBAC:
- provide advice to the Minister regarding the suitability of eculizumab for inclusion on the Life Saving Drugs Program (LSDP) for treatment of paroxysmal nocturnal haemoglobinuria (PNH) under the revised LSDP funding criteria and conditions;
- consider the proposed initiation and continuation criteria for eculizumab for the LSDP which endeavours to identify those patients with PNH who would benefit most from treatment with eculizumab.
Through the LSDP, the Australian Government provides subsidised
access, for eligible patients, to expensive and potentially life
saving drugs for very rare life-threatening conditions. Before a
drug is made available on the LSDP, it must generally be accepted
by the Pharmaceutical Benefits Advisory Committee as clinically
necessary and effective, but not recommended for inclusion on the
Pharmaceutical Benefits Scheme due to unacceptable
cost-effectiveness. On 10 May 2010, the criteria for inclusion on
the LSDP were revised.
2. Background
At the July 2008 meeting, the PBAC rejected the application for
Section 100 listing of eculizumab for the treatment of patients
with PNH, on the basis of an unacceptably high and highly uncertain
estimated cost per additional death avoided over a 2-year
period.
The PBAC also rejected the July 2008 application for consideration
for the LSDP. The Committee agreed that eculizumab might meet the
criteria for the LSDP for an as yet unidentified subgroup of
patients with PNH, but that it is not possible to identify this
subgroup at the present time. The Committee noted the
sponsor’s indication that it was working on a set of
eligibility criteria to identify a population of patients that
would benefit most from treatment with eculizumab.
At the March 2009 meeting, the PBAC again rejected listing
eculizumab on the PBS, on the basis of unacceptably high and highly
uncertain cost-effectiveness.
However, the PBAC considered that eculizumab met the criteria for
inclusion on the LSDP.
For full details, see the July 2008 and March 2009 Public
Summary Documents.
3. Registration Status
Eculizumab was registered by the TGA on 17th February 2009 for the
treatment of patients with paroxysmal nocturnal haemoglobinuria
(PNH) to reduce haemolysis.
4. Listing Requested and PBAC’s View
Inclusion on the Life Saving Drugs Program for treatment of
paroxysmal nocturnal haemoglobinuria to reduce haemolysis.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Paroxysmal nocturnal haemoglobinuria is a clonal haemopoietic stem
cell disorder that is extremely rare, progressive and
life-threatening. Complement mediated intravascular haemolysis is
the central mechanism responsible for morbidities and mortality in
PNH including thromboembolism, renal dysfunction, pulmonary
hypertension, severe anaemia and disabling fatigue.
Currently, therapeutic management of PNH is supportive and mainly
addresses the treatment of anaemia and prevention of thrombotic
events, with limited evidence of efficacy of these basic standard
care methods.
Eculizumab would provide a treatment option for patients with PNH
to significantly reduce haemolysis, but it is not curative for the
underlying disease.
6. Comparator
At the July 2008 meeting, the PBAC agreed that supportive care is
the appropriate comparator.
7. Clinical Trials
The submission addressed each of the revised LSDP funding criteria
and conditions, and re-presented data from the March 2009
submission to support the claim that eculizumab satisfied each of
the revised criteria and conditions for PNH.
The submission also presented an updated literature search, which
identified two new studies not included in the March 2009
submission (Weitz et al. and Helley et al.).
Details of the published studies identified in the submission are
presented in the following table.
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| Hillmen P, et al | Natural history of paroxysmal nocturnal haemoglobinuria. | N Engl J Med 1995; 333(19): 1253-8 |
| de Latour RP, et al | Paroxysmal nocturnal haemoglobinuria: natural history of disease subcategories. | Blood 2008; 112(8): 3099-106 |
| Nishimura J, et al | Clinical course and flow cytometric analysis of paroxysmal nocturnal haemoglobinuria in the United States and Japan. | Medicine (Baltimore) 2004; 83(3): 193-207 |
| Socie G, et al | Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. | Lancet 1996; 348(9027): 573-7 |
| Parker C, et al | Diagnosis and management of paroxysmal nocturnal haemoglobinuria. | Blood 2005; 106(12): 3699-709 |
| Hillmen P, et al | Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal haemoglobinuria. | Blood 2007; 110(12): 4123-8 |
| Fowkes FJ, et al | Incidence of diagnosed deep vein thrombosis in the general population: systematic review. | Eur J Vasc Endovasc Surg 2003; 25(1): 1-5 |
| Kanakura Y, et al | Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal haemoglobinuria: AEGIS Phase II Clinical Study Results. | ASH Annual Meeting Abstracts 2008; 112(11): 3438 |
| Hill A, et al | Nitric oxide consumption and pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. | American Society of Haemotology 2005 (Abstract) |
| Machado RF, et al | N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. | JAMA 2006; 296(3): 310-8 |
| Hillmen P, et al | Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal haemoglobinuria. | American Journal of Hematology 2010; 85(8): 553-9 |
| Hill A, et al | Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. | British Journal of Hematology 2010; 149(3): 414-425 |
| Rother RP, et al | Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal haemoglobinuria. | Nat Biotechnol 2007; 25(11): 1256-64 |
| Weitz IC, et al | Thrombosis in Paroxysmal Nocturnal Haemoglobinuria – insights into the role of complement in thrombosis. | Thrombosis Res. 2010 Apr; 125 Suppl 2:S106-7. |
| Helley D, et al | Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal haemoglobinuria receiving eculizumab. | Haematologica 2010 Apr; 95(4):574-81 |
| Hillmen P, et al | The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobionuria. | N Engl J Med 2006; 355(12): 1233-43 |
| Hillmen P, et al | Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal haemoglobinuria. | N Engl J Med 2004; 350(6): 552-9 |
| Brodsky RA, et al | Multicentre phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal haemoglobinuria. | Blood 2008; 111(4): 1840-7 |
8. Results of Trials
A summary of the arguments from the submission in support of
eculizumab for PNH meeting the revised LSDP criteria is presented
below:
Criterion 3 stated:
Epidemiological and other studies provide evidence acceptable to
the PBAC that the disease causes a significant reduction in
age-specific life expectancy for those suffering from the
disease.
The submission argued that the PSD for the March 2009 submission
stated, “In relation to the criteria for inclusion on the
Life Saving Drugs Program (LSDP), the Committee accepted that PNH
may shorten the lifespan of some patients suffering from the
Disease”, and therefore considered that PNH has met
Criterion 3. The submission noted that the median age of onset of
PNH was 30-40 years, and that following diagnosis the five-year
mortality rate for patients with PNH ranged from 15% to 35% and the
ten-year mortality ranged from 24% to 48%.
Criterion 4 stated:
There is evidence acceptable to the PBAC to predict that a
patient’s lifespan will be substantially extended as a direct
consequence of the use of the drug.
The submission claimed that the following recommendation from the
March 2009 PSD supported the argument that PNH as a disease meets
this reworded criterion in the newly implemented criterion:
“…and that the submission’s proposed
link between treatment with eculizumab resulting in the reduction
of thromboembolic events and an improved lifespan of some patients
with PNH was not unreasonable (Criterion 2).”
The submission’s argument that treatment with eculizumab was
associated with an extension of life in PNH patients, was based on
the claim it reduced life-threatening complications of PNH
including thrombosis, kidney damage, pulmonary hypertension,
ischemic brain damage, liver and gastrointestinal organ damage.
This argument was consistent with those made in the previous
submissions to the PBAC.
The submission used the Weitz et al. and Helley et al. studies as
additional evidence to support eculizumab’s qualification for
criterion 4 of the revised funding criteria. The submission stated
that these studies demonstrate that complement mediated haemolysis
leads to chronic activation of both the inflammatory and
coagulation pathways, ultimately explaining why PNH patients have
an increased number of thromboembolic events, severe morbidities
and early mortality. The submission reported that both studies
demonstrated evidence that treatment with eculizumab reduced
haemolysis (P<0.001) and measures of inflammation (interleukin
(IL)-6: P=0.04) and haemostatic activation (D-dimer: P≤0.01) in
these patients.
The submission presented the same funding algorithm with initiation
and continuation requirements as in the March 2009 submission.
These were developed by experienced PNH experts and clinicians in
response to PBAC’s March 2008 recommendation that criteria
were needed to identify those PNH patients who would most benefit
from eculizumab therapy.
The submission stated its support for the prompt appointment of a
panel of independent experts to reconfirm the already developed
expert criteria, which identify those patients with PNH who would
benefit most from treatment with eculizumab.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The submission claimed that eculizumab was an effective therapy
that directly targeted the life threatening consequences of PNH and
transformed the quality of patients’ lives, with evidence
that eculizumab substantially extended the lifespan of treated
patients.
For PBAC’s view, see Recommendation and
Reasons.
10. Estimated PBS Usage and Financial Implications
The submission provided updated usage and financial costs and
estimated less than 10,000 patients in Year 5 of listing at a cost
to Government of $30 – $60 million in Year 5. The commentary
considered the submission’s financial estimates are highly
uncertain and are likely to be under-estimated because only drug
acquisition costs have been included in the estimates.
The only change in estimated financial implications between the
current submission and the March 2009 submission is the use of
revised uptake rates, which results in higher estimates of the
eligible patient population.
11. Recommendation and Reasons
The PBAC deferred the submission for eculizumab to allow the sponsor time to obtain
further data about the magnitude of the survival gain before making a decision on
whether eculizumab substantially extends a patient’s lifespan as per criterion 4 of
the Life Saving Drugs Program (LSDP).
The PBAC considered that the historical control data presented in the submission (Hillmen
1995, Socie 1996, Nashimura 2004 and de Latour 2008) may not reflect recent best supportive
care practice and that best supportive care has improved over the years. The PBAC
noted there have been many improvements in the treatment of thromboembolic events
as well as the treatment of iron overload and anaemia.
The PBAC noted that patient mortality of the historical controls at 10 years had decreased,
as reported by Hillmen (1995) as 48% and 24% by de Latour (2008). The de Latour study
included a mix of patients with classic PNH, intermediate and aplastic anaemia-PNH
(AA-PNH) who were diagnosed between 1950 and 2005. The PBAC noted that 35% of patients
were diagnosed prior to 1986, 31% between 1986 and 1995 and 33% after 1995. The Kaplan-Meier
curve plotted survival for the global population, for the three sub-categories of
PNH and for the three different time periods over which the data were collected. However,
only survival for AA-PNH was plotted for the three different time periods, and these
data demonstrated improved survival rates for patients diagnosed with AA-PNH after
1995. As a result, the PBAC was uncertain that the magnitude of the survival benefit
for eculizumab was substantial when compared with modern best supportive care. However,
the AA-PNH population may not be reflective of the group of patients for whom treatment
with eculizumab is intended under the LSDP, i.e. classic PNH. Therefore, the PBAC
considered that further information about recent historical controls (from 1995 onwards)
with similar characteristics to those now treated with eculizumab, and relevant to
the group of patients proposed for access in Australia, would provide better matched
control data for the eculizumab treated group. As more recently diagnosed patients
are also likely to be younger, it would be most informative to have the historical
control data from a source such as the de Latour study published in 2008 presented
along the following lines:
(a) confirmation that no patient in the cohort received eculizumab during the period of follow-up being reported;
(b) for the subgroup of classical PNH patients only, but further sub-categorised into three groups according to year of diagnosis:
- recent (eg since 1996)
- intermediate (eg 1986 to 1995) and
- more distant (eg 1985 or before);
(c) for each sub-category, a description of the characteristics of the included patients including the number of patients, proportion of males, age at diagnosis (mean and distribution), year of diagnosis (mean and distribution) and preferably also other characteristics which were included in the proposed eligibility and initiation criteria for the Phase III randomised trial and/or the LSDP because of their prognostic value;
(d) on a single figure, as exemplified by Figure 1(c) on page 3101 of the de Latour (2008) paper, the three Kaplan-Meier plots of overall survival representing each sub-category;
(e) and, preferably, the 3-year and/or 10-year survival rates for each sub-category (as a complement to, but not a substitute for, the requested Kaplan-Meier plots).
The PBAC was satisfied that eculizumab meets all the other new LSDP criteria. With
respect to Criterion 4, the PBAC accepted that patients with classic PNH were demonstrated
in epidemiological and other studies to have a significant reduction in age-specific
life expectancy. The PBAC also noted the data presented to address Criterion B1, showed
that the price proposed for eculizumab in Australia is less than prices paid overseas.
The PBAC also noted the comparison with other drugs funded under the LSDP (Criterion
B2) showing the price is less for adults than other drugs in the Program.
Recommendation
Defer
Further Information
Further to the PBAC’s consideration of this product at the July 2010 meeting (at which
the Committee deferred the submission to allow the sponsor time to obtain further
data about the magnitude of the survival gain), the sponsor presented a re-submission
to the PBAC Special Meeting held in August 2010.
The re-submission addressed questions from the PBAC pertaining to the de Latour manuscript,
with a focus on PNH mortality rates described in de Latour (2008).
The PBAC noted the additional data of three-year mortality rates for all paroxysmal
nocturnal haemoglobinuria patients from de Latour (2008) provided by the sponsor in
support of the request to list eculizumab on the Life Saving Drugs Progam for the
treatment of PNH. As requested by the PBAC, the data was categorised into three groups
according to year of PNH diagnosis – diagnosis in 1985 or before, between 1986 and
1995 and between 1996 and 2005. The PBAC noted that the survival rates for this three-year
period of follow-up appeared consistent across the three groups based on year of diagnosis,
however that no further disaggregation of these data had been provided for the type
of PNH (classic, intermediate and aplastic anaemia PNH). The sponsor had also confirmed
that the data from the de Latour study were not confounded to any material extent
by use of eculizumab during the follow-up period.
The PBAC considered that the additional evidence, including that presented by the
sponsor and unpublished data, acceptably supported the prediction that a patient’s
lifespan with classic PNH would be substantially extended as a direct consequence
of treatment with eculizumab compared to best supportive care and hence concluded
that criterion four of the LSDP was now met.
The PBAC considered that the history component of the proposed treatment funding algorithm
should be limited to include only patients with a history of either thrombosis or
transfusion of four or more units in the most recent 12 months. However, further advice
should be sought from the clinical advisory committee on the remaining five proposed
alternative history criteria to be justified on the basis of unambiguously identifying
patients likely to benefit most from treatment with eculizumab. For example, the PBAC
considered that inclusion of fatigue as an alternative in these criteria may not be
appropriate, as it is likely that the majority of patients with any form of PNH could
qualify under this criterion, rather than those patients with PNH who would be most
likely to gain an extension in their lifespan from treatment with eculizumab. A comparison
of corresponding funding algorithms and their rationales from other similar jurisdictions
overseas may also be informative in this regard.
The PBAC considered that patients funded under the LSDP, including those to be grandfathered,
should be required to meet the more limited qualification criteria for treatment as
modified by the PBAC from those specified by the clinical advisory committee. The
PBAC considered that PNH patients currently receiving treatment through compassionate
access schemes should continue to receive treatment through compassionate access should
they not meet the LSDP qualification criteria
12. 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.
13. Sponsor’s Comment
Alexion welcomes the PBAC’s recommendation that Soliris now meets the revised criteria, (effective May 10th 2010), for consideration of funding via the LSDP by Government. We look forward to working with the Department of Health and Ageing and Government to ensure an expedited review of possible funding arrangements and to ensure urgent funded access to Soliris therapy for PNH patients who will most benefit will be achieved expeditiously.
