Australian Public Assessment Report (AUSPAR) for Romiplostim

Australian Public Assessment Report (AUSPAR) for Romiplostim

SAMPLE AUSPAR
Australian Public Assessment Report (AUSPAR)
for
Romiplostim
Proprietary Product Name: Nplate
Submission No: 2007-3359-4
Sponsor: Amgen Australia Pty Ltd
July 2008
SAMPLE AUSPAR
Contents
I.
Introduction to Product Submission ........................................................................3
Product Details........................................................................................................................ 3
Product Background................................................................................................................ 3
Status in Other Countries at the time of Submission .............................................................. 4
II.
Quality.........................................................................................................................4
Drug Substance ....................................................................................................................... 4
Drug Product ........................................................................................................................... 5
Quality Summary and Conclusions......................................................................................... 6
III.
Non-Clinical................................................................................................................6
Introduction............................................................................................................................. 6
Pharmacology.......................................................................................................................... 6
Pharmacokinetics .................................................................................................................... 7
Toxicology .............................................................................................................................. 8
Non-Clinical Summary and Conclusions.............................................................................. 13
IV.
Clinical ......................................................................................................................13
Introduction........................................................................................................................... 13
Pharmacokinetics .................................................................................................................. 14
Pharmacodynamics ............................................................................................................... 15
Efficacy ................................................................................................................................. 16
Safety .................................................................................................................................... 22
Clinical Summary and Conclusions ...................................................................................... 27
V.
Overall Conclusion and Risk/Benefit Assessment ................................................28
Quality................................................................................................................................... 28
Non-Clinical.......................................................................................................................... 28
Clinical .................................................................................................................................. 29
Risk-Benefit Analysis ........................................................................................................... 30
Recommendation .................................................................................................................. 31
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I.
Introduction to Product Submission
Product Details
Type of Submission:
Decision:
New biological entity
Approved
Date of Decision
Active ingredient(s):
Romiplostim
Product Name(s):
Nplate
Dose form(s):
Powder for Injection
Strength(s):
375 micrograms and 625 micrograms
Container(s):
Type I glass vial (5 mL) with an elastomeric stopper and an
aluminium seal with flip-off dust cover
Pack size(s):
Single vial
Therapeutic use:
Treatment for thrombocytopenia in adult patients with chronic
immune (idiopathic) thrombocytopenic purpura (ITP):
who are non-splenectomised and have had an inadequate
response or are intolerant to corticosteroids and
immunoglobulins;
who are splenectomised and have had an inadequate response to
splenectomy.
Route(s) of administration:
Subcutaneous injection
Dosage:
Weekly administration. Starting dose 1 microgram/kg, with
weekly adjustments in 1 microgram/kg intervals until platelet
levels between 50 and 200 x 109/L. Maximum dose 10
microgram/kg.
Product Background
Immune (idiopathic) thrombocytopenic purpura (ITP) is an autoimmune disorder in which
thrombocytopenia results when platelets are destroyed more rapidly than they can be produced.
Platelet consumption is mediated by antiplatelet glycoprotein autoantibodies. The presence of
antiplatelet autoantibodies results in a decrease in platelet counts due to the clearance of platelets,
typically by the reticuloendothelial system of the bone marrow, spleen, and/or the liver.
Thrombocytopenia, when severe (i.e., < 30 × 109/L platelet count), can result in spontaneous
bruising or bleeding and occasionally can lead to death. Chronic ITP is a serious and lifethreatening condition that affects more adult women than men (approximately 2:1). The incidence
of ITP in the US is estimated as 58 to 66 new cases per million population per year, or
approximately 16,000 new cases per year (McMillan, 1997).
Current treatments for ITP target modulation of the immune system and include corticosteroids
such as prednisone, intravenous (IV) immunoglobulin infusions (IVIG), and/or anti D
immunoglobulin infusion (WinRho®), splenectomy, and various salvage treatments for the
refractory patient. Most current treatments for ITP have limited chronic efficacy, intolerable side
effects, and/or have significant convenience issues with respect to their administration, and
therefore an unmet medical need exists for patients with ITP.
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Romiplostim is a novel thrombopoiesis-stimulating protein that has been developed as a treatment
for adults with thrombocytopenia associated with ITP. Romiplostim is a recombinant protein that is
expressed in Escherichia coli (E coli). It has an Fc domain and 4 Mpl (thrombopoietin receptor)binding domains. Romiplostim stimulates platelet production by a mechanism similar to that of
endogenous thrombopoietin (eTPO). Romiplostim was known as AMG 531 during the clinical
development programme.
Status in Other Countries at the time of Submission
A similar application has been submitted in the US (23 October 2007), European Union (EU) (2
November 2007) and Canada (16 November 2007). Orphan designation has been granted in the US
and EU, and priority review has been granted in Canada and Australia. Amgen is participating in
the pilot Parallel Review Project between Health Canada’s BGTD and the TGA in this submission.
Romiplostim is not yet approved in any country.
II.
Quality
Drug Substance
Structure
The drug substance, romiplostim or AMG 531, is a recombinant non-glycosylated 59 kDa
thrombopoietic protein produced in E. coli. It is termed a peptibody comprising of two identical
subunits. Each subunit consists of a human immunoglobulin IgG1 Fc domain at the N-terminus
which is fused at the C-terminus to two thrombopoietin receptor binding domains (TRBD).
AMG 531 is non-glycosylated and has no amino acid sequence homology to endogenous
thrombopoietin.
Figure 1.
Manufacture
The drug substance is manufactured at Amgen Inc, Boulder, CO, USA. It is expressed from an
expression vector in E. coli. Cell banking processes are satisfactory.
The commercial manufacturing process uses E. coli fermentation and cell processing unit
operations to produce a process intermediate (slurry). The purification process begins with slurry
thaw followed by solubilization. Romiplostim is purified using a series of chromatography,
concentration and diafiltration steps to produce purified bulk active substance.
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All viral/prion safety issues have been addressed, including use of animal-derived excipients,
supplements in the fermentation process and in cell banking.
Manufacturing Process Development
The drug substance manufacturing process was developed to optimize the process for commercial
production. Analytical comparability studies have been executed to support the manufacturing
process changes during development.
Physical and Chemical Properties
Various techniques have been used to confirm and characterise the primary, secondary and tertiary
structure of romiplostim. The molecule is comprised of two identical subunits. Each subunit
consists of a human immunoglobulin IgG1 Fc domain at the N-terminus which is fused at the Cterminus to two thrombopoietin receptor binding domains (TRBD), with each binding domain
consisting of a 14-amino acid sequence.
Charge heterogeneity of the romiplostim molecule as a result of amino acid substitution,
deamidation, oxidation and manufacturing process conditions have been characterised. Biological
characterisation showed that romiplostim increases platelet production via interaction with the
thrombopoietin receptor (referred to as Mpl) on megakaryocytes, which activates intracellular
transcriptional pathways, and thereby, results in stimulation platelet production. Romiplostim is not
glycosylated as it is synthesised in E coli.
Assessment of product–related impurities was accomplished through forced degradation studies.
The results of these studies identified product- and process- related impurities and showed
consistency in their removal through the purification process.
Specifications
The proposed specifications, which control identity, content, potency, purity and other biological
and physical properties of the drug substance relevant to the dose form and its intended clinical use,
where provided for evaluation.
Appropriate validation data was submitted in support of the test procedures.
Stability
The stability programme, including the testing intervals and temperature storage conditions, has
been designed in accordance with the relevant guidelines. The tests chosen are a subset of tests from
the release specifications selected for stability-indicating properties.
Stability of the active substance was evaluated at the recommended storage temperature and under
other conditions. The stability program consisted of clinical lots, commercial lots and data from the
initial generation process. The stability data provided are within the specifications and the storage
period at the recommended storage temperature is accepted.
Drug Product
Formulation(s)
AMG 531 drug product is supplied as a sterile, preservative free lyophilized white powder ready for
reconstitution. It is supplied for single use in 5 mL Type I glass vials containing 375 or 625 µg of
AMG 531, 250 or 500 µg deliverable drug product, respectively.
Manufacture
The product is manufactured in Italy and sterilised by filtration.
Assessment of drug product comparability includes biochemical, biophysical, biological, and
structural comparisons, as well as stability under stressed (high temperature) and recommended
storage conditions. Process-related impurities, formulation parameters, and other drug product
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parameters were also compared. Drug product has been demonstrated to be comparable throughout
development.
Specifications
The proposed specifications for the drug product were supplied for evaluation. Appropriate
validation data have been submitted in support of the test procedures.
Stability
Stability data have been generated under stressed and real time conditions to characterise the
stability profile of the product. Photostability data showed that the product is not photostable.
The proposed shelf life of 36 month expiry period for drug product stored at the recommended
storage condition of 2-8°C is supported by real time data submitted. Additionally, an in-use shelflife of up to 24 hours when reconstituted and held at 2°C to 8°C in the vial, protected from light, is
also proposed.
The proposed shelf-life of the drug product is acceptable.
Quality Summary and Conclusions
The administrative, product usage, chemical, pharmaceutical, microbiological and biopharmaceutic
data (as applicable) submitted in support of this application have been evaluated in accordance with
the Australian legislation, pharmacopoeial standards and relevant technical guidelines adopted by
the TGA.
All Module 3 issues have been resolved. There is no objection to the registration of NPLATE on
quality grounds.
III.
Non-Clinical
Introduction
The general quality of the submitted studies was high. All safety-related studies were conducted
under GLP conditions with the exception of a study on antigenicity, which was conducted in an
established laboratory and adequately documented.
Pharmacology
Primary pharmacodynamics
In vitro, romiplostim was shown to bind to human c-Mpl with nanomolar or subnanomolar affinity,
and to also target the c-Mpl of mice, rats and monkeys. Agonism of the receptor was demonstrated
by phosphorylation of c-Mpl and its downstream effector JAK2 in human platelets following
exposure to romiplostim, and by the drug’s enhancement of the sensitivity of human and rabbit
platelets to ADP-induced aggregation. Stimulation of megakaryopoiesis was shown in cultures of
bone marrow cells (human, baboon, cynomolgus monkey and rhesus monkey) treated with
romiplostim. In vivo, administration of a single dose of romiplostim by the proposed clinical route
(SC) resulted in dose-dependent increases in platelet counts in mice, rats, rhesus monkeys and
cynomolgus monkeys. It took several days for the increase in circulating platelets to first become
apparent, reflecting the time required for megakaryocyte maturation (Hartwig and Italiano, 2003);
peak increases were observed 5–11 days post-dose. Examination of bone marrow samples taken
from monkeys 3 days after treatment with romiplostim revealed proliferation and maturation of
megakaryocytes. Romiplostim displayed efficacy in a murine model of ITP, including in
splenectomised animals.
The platelets induced by romiplostim treatment were shown to be functional in repeat-dose toxicity
studies conducted in rats and rhesus monkeys.
The in vivo data reveal that the laboratory animal species used in the toxicity studies are vastly less
sensitive to the thrombopoietic effect of romiplostim than humans. In combined
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pharmacodynamic/pharmacokinetic studies, a single SC dose of romiplostim at 2 µg/kg caused a
peak increase in platelets of 2.5-fold in healthy humans (AUC0–∞, 4.6 ng·h/mL; Study 20000109),
compared with a 2.5-times increase observed in rats at 30 µg/kg (AUC0–∞, 793 ng·h/mL;
Study 100909), a 2.3-times increase in rhesus monkeys at 500 µg/kg (AUC0–∞, 49500 ng·h/mL;
Study 100998) and a 4.6-times increase in cynomolgus monkeys at 5000 µg/kg (AUC0–∞,
56000 ng·h/mL). The basis for this is unclear, and not predicted by in vitro data, nor due to drugneutralising antibodies.
Secondary pharmacodynamics and safety pharmacology
Romiplostim displayed no significant secondary activity against a panel of 63 other targets
(comprising receptors, ion channels, transporters and enzymes). IC50 values for inhibition of ligand
binging/enzyme activity were all >2 µM (i.e., >14000-times higher than the clinical Cmax 1 ).
Examination of the potential cross-reactivity of romiplostim for selected human and cynomolgus
monkey tissues was attempted using immunohistochemical techniques but was of limited value as
no specific reactivity could be demonstrated for the drug in any of the experiments, including to
c-Mpl-expressing cells.
Specialised safety pharmacology studies examined potential effects on the CNS and cardiovascular
system. Effects on the respiratory system were examined in a 3-/6-month repeat-dose toxicity study
in monkeys. CNS function was unaffected in rats with treatment up to 100 µg/kg SC, a dose
producing a peak serum concentration of romiplostim ~4-times the clinical Cmax. There were no
changes in ECG, blood pressure or heart rate in cynomolgus monkeys after IV administration of
romiplostim at doses up to 5000 µg/kg, where serum levels of romiplostim were >5000-times the
clinical Cmax. No ECG abnormalities were observed in the repeat-dose toxicity studies conducted
with cynomolgus and rhesus monkeys but the examinations were performed days after drug
administration. There was no in vitro examination of the potential for inhibition of the hERG K+
channel current. Respiration was unaffected in cynomolgus monkeys at serum concentrations
~200-times higher than the clinical Cmax (4 h after dosing at 5000 µg/kg SC).
Pharmacokinetics
Absorption of romiplostim into the systemic circulation after SC administration was slow in all
species studied, with peak serum concentrations typically reached 12 h post-dose in rats and rabbits,
4–8 h post-dose in monkeys and 24 h post-dose in humans. Terminal elimination following SC
administration was also slow, with t½ values of 17–21 h observed in rats, 110–195 h in rhesus
monkeys, 296 h in cynomolgus monkeys and 56 h in humans. Serum AUC after SC administration
was generally seen to be greater than dose-proportional in rats and less than dose-proportional in
monkeys, but this is considered to reflect the higher and wider range of doses studied in monkeys
cf. rats rather than a species difference in the drug’s pharmacokinetics. The presence of antibodies
to romiplostim did not affect the pharmacokinetics of romiplostim in monkeys. Whether antiromiplostim antibodies affect exposure in rats could not be ascertained as different animals were
used in the antibody and pharmacokinetic analyses.
Thrombocytopenia was associated with increased systemic exposure to romiplostim in mice at
3 µg/kg IV, but not at 30 µg/kg, suggesting that binding by platelets (mediated by c-Mpl and
overwhelmed at high doses) is involved in drug clearance, just as it is for endogenous
thrombopoietin (Fielder et al., 1996). The Clinical Overview indicates that this effect was more
readily demonstrated in the clinical studies (as they involved low, therapeutic doses of
romiplostim). With repeat dosing, exposure to romiplostim declined as platelet count improved.
Volume of distribution exceeded the whole blood volume in all species (mice, rats, cynomolgus
monkeys, rhesus monkeys and humans), indicating extravascular distribution. Accordingly,
1
Based on a value of 8 ng/mL, as predicted at the maximum recommended human dose of 10 µg/kg in patients
with a baseline platelet count of 5 × 109/L
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widespread tissue distribution of radioactivity was observed in female rats after IV administration
of 125I-romiplostim. Besides the thyroid, the kidneys, bone marrow (the target tissue), liver, lung
and ovary displayed the highest peak tissue concentrations of radioactivity relative to serum.
Penetration of the blood-brain barrier was poor. Tissue levels of radioactivity declined slowly.
Protein binding by romiplostim was not examined.
No conventional metabolism studies were conducted, which is acceptable for a protein drug as
degradation to small peptides and individual amino acids is expected. The majority of radioactivity
in serum (91–95%) and selected tissues (≥ 84%) in the distribution study was observed to be TCAprecipitable, indicating that it is associated with intact romiplostim or large fragments of the
molecule. Significant loss of the thrombopoietin mimetic peptide portion of the drug was indicated
by the serum AUC0–∞ for romiplostim determined by the standard ELISA technique (involving a
secondary antibody directed against the thrombopoietin mimetic binding portion of the molecule)
being ~40% of that for total or TCA-precipitable radioactivity (the radiolabel assumed to be present
on the Fc domain of the molecule) and a similar percentage of the AUC for species detected by an
alternative ELISA technique in which a secondary antibody against the Fc domain was used.
Excretion of 125I-romiplostim-derived radioactivity following IV dosing in rats was predominantly
via the urine, principally in the form of small peptides or free iodide (88% of the dose was excreted
renally and 11% of the total radioactivity recovered in urine was TCA-precipitable). The importance
of renal excretion to the clearance of romiplostim was also demonstrated in a single-dose
pharmacokinetic study in rats (Study 101402), where AUC0–12 h for serum romiplostim was 26–
80% higher in bilaterally nephrectomised animals cf. sham-operated controls. Routes of excretion
were not examined in other laboratory animal species nor in humans.
Toxicology
Acute toxicity
One single-dose toxicity study, conducted in rats and using the proposed clinical route, was
submitted. The study established a maximum non-lethal dose for romiplostim by the SC route of ≥
1000 µg/kg in the rat. Platelets were increased at all dose levels tested (100, 300 and 1000 µg/kg; by
up to 3.2-times 9-days post-dose), as expected. Modest reductions in red blood cell counts and
indices (≤ 12%) were seen from the low- or mid-dose level and are consistent with the drug’s
pharmacological activity — the stimulation of megakaryopoiesis resulting in suppression of
erythropoiesis due to stem-cell competition (van Zant and Goldwasser, 1979). Increased splenic
extramedullary haematopoiesis and increased bodyweight-relative spleen weight, observed in highdose animals, are considered to be compensatory responses to the haematological changes. No
further studies, involving IV administration or conducted in a second species, were submitted. This
deficiency is largely overcome by data provided by the repeat-dose toxicity studies.
Repeat-dose toxicity
Studies of up to 4 weeks duration were conducted in rats, 4 weeks in rhesus monkeys and 6 months
in cynomolgus monkeys. All involved SC administration (the clinical route); additional groups of
animals were employed in the 4-week rat and rhesus monkey studies to receive the highest dose
level IV. These species are appropriate models of romiplostim-toxicity given their
pharmacodynamic responsiveness to the drug, but it must be noted that their responsiveness is
substantially less than that of humans, especially so for monkeys. Numbers of animals and the use
of both sexes (in the definitive studies) were appropriate. Suitable doses were used, with the
selection of the high-dose levels based on their production of a maximal increase in platelet counts
(rats and monkeys) and/or a substantial multiple of the anticipated clinical exposure level
(monkeys). The dosing frequency in the 3- and 6-month monkey study was the same as that to be
used in patients (once weekly); dosing in the other studies was 3-times weekly. Studies in rats
longer than 4 weeks were not feasible due to the development of drug-neutralising antibodies. At
6 months, the duration of the pivotal monkey study was consistent with the length generally
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considered appropriate under ICH guidelines for a chronically administered, biotechnology-derived
drug. However, it is considered that such a study would be unlikely to yield any further insight into
the drug’s toxicology given that no significant progression in toxicity was observed over the course
of 1 to 6 months in the species. The use of cynomolgus rather than rhesus monkeys in this chronic
study was prudent given their lesser immunological response to the drug.
Relative exposure
Exposure ratios have been calculated based on animal:human serum AUC0–168 h values for
romiplostim (see Table 1) 2 . Animal AUC0–168 h values have been calculated based on AUC values
for shorter periods (0–24 h or 0–48 h) multiplied by an appropriate factor according to the dosing
frequency. This approach is a conservative one, recognised to underestimate the actual AUC0–168 h
value (and, consequently, the relative exposure level), made necessary by the limited toxicokinetic
sampling regimen employed in the studies.
Table 1
Study
100876
Relative exposure in repeat-dose toxicity studies
Species
& strain
Rat (SD)
Treatment
duration
4 weeks
Dosing
frequency
3/week
Route
SC
IV
100877
Monkey (rhesus)
4 weeks
3/week
SC
IV
101158
Monkey
(cynomolgus)
4 weeks
3/week
SC
Monkey (rhesus)
101814
108644
Monkey
(cynomolgus)
6 months
Human (platelet count, 5 × 109/L)
1/week
1/week
SC
SC
Dose
(µg/kg)
AUC0–168 h
(ng·h/mL)
Exposure
ratio†
30
651a
0.8
100
7350
9
100
13710a
16
500
142500a
168
1000
184500a
217
5000
1023000a
1204
5000
3510000a
4129
100
717b
0.8
300
5100b
6
500
8700
5000
a
b
10
b
120600
142
5000
209400
b
246
500
1920c
2
1000
4190
5
5000
20100
24
10#
850
–
c
c
†
= calculated as animal:human AUC0–168 h ; a = estimated by multiplying AUC0–48 h by 3; b = estimated by multiplying
AUC0–24 h by 3; c = AUC0–24 h; AUC values are for the sexes combined; # = the maximum recommended clinical dose
2
The author of the Nonclinical Overview calculated relative exposure levels using a lower human AUC0–168 h value at
10 µg/kg SC than has been used here. This was extrapolated linearly from data obtained in healthy human volunteers
given romiplostim at 2 µg/kg SC (Study 20000109). Given the size of the extrapolation, the uncertainty of the dose
proportionality and the demonstration of increased exposure with thrombocytopenia, a higher, more conservative
value (derived from modelling performed by the Sponsor) has been used for calculating relative exposure levels in this
report.
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Major findings
Changes attributable to the drug’s pharmacological activity, produced either directly or indirectly,
were the predominant findings in the studies.
Stimulation of thrombopoiesis by romiplostim, indicated by significantly increased platelet count,
was apparent at every dose level in every study. With 3-times weekly administration, the highest SC
doses used in the studies produced increases in platelets of 3.6-times in rats (100 µg/kg), up to 7.4times in rhesus monkeys (5000 µg/kg) and 5.7-times in cynomolgus monkeys (5000 µg/kg); platelet
counts in cynomolgus monkeys treated with romiplostim once weekly at 5000 µg/kg SC were on
average 2.9-times higher than controls. Stimulation of megakaryopoiesis was usually evident upon
microscopic examination of the bone marrow of treated animals, and was additionally observed in
the spleen of rats. Megakaryocytes were detected in the lung and liver of rats and monkeys and the
submandibular lymph node of cynomolgus monkeys.
Alterations in mean platelet volume, with increases observed in rats and decreases in monkeys, also
indicate an effect on megakaryocyte maturation and/or platelet life-cycle. Bodyweight-relative
spleen weights were higher in treated animals cf. controls, an effect consistent with the increased
demand for clearance of platelets from the blood and also extramedullary haematopoiesis. Other
findings considered to be related to increased platelet count were enhanced platelet aggregation and
incidents of haemorrhage at the injection site in the 4-week rhesus monkey study (100877; all dose
levels), haemorrhage and eosinophilic substance in blood vessels in the lungs of rhesus and/or
cynomolgus monkeys treated at 5000 µg/kg SC × 3/week for 4 weeks (Study 101158), increased
serum inorganic phosphorous and potassium in the 4-week rat study (100876; at all dose levels; as
previously observed in the single-dose study in rats and consistent with ex vivo release), and
increased serum lactate dehydrogenase in both 4-week monkey studies (100877 and 101158; at
5000 µg/kg × 3/week, SC or IV; also reflecting release from platelets ex vivo in blood samples
taken for clinical chemistry [Rothwell et al., 1976]). Mortality in rats, observed at all dose levels
and without prior clinical signs, might have been due to stroke or other thromboembolic events,
caused by increased blood viscosity owing to the elevation in platelets (histological evidence for
this was, however, lacking). There were no deaths in the monkey studies.
Treatment with romiplostim produced dose-dependent hyperostosis of trabecular bone (at ≥
30 µg/kg × 3/week) and myelofibrosis (at all dose levels 3 ) in rats. The effect on bone growth is
consistent with the increase in megakaryocytes induced by the drug, with the cells recognised to
influence skeletal homeostasis by stimulating the proliferation and activity of osteoblasts and
inhibiting that of osteoclasts (Kacena et al., 2004, 2006; Beeton et al., 2006). Myelofibrosis has
been observed in rats treated with pegylated recombinant human thrombopoietin (Yanagida et al.,
1997) and mice that overexpress thrombopoietin (Yan et al., 1996) and is attributed to the increased
release of cytokines such as transforming growth factor-β and platelet-derived growth factor from
the elevated number of megakaryocytes. These changes were absent in monkeys, even in animals
showing marked megakaryocytic hyperplasia in bone marrow.
A generalised increase in leukocytes was observed in rats at ≥ 30 µg/kg × 3/week and cynomolgus
and rhesus monkeys treated at 5000 µg/kg × 3/week. This is consistent with the drug’s activation of
c-Mpl on pluripotent haematopoietic stem cells. Reductions in red blood cell counts and/or indices
were apparent at all dose levels in the rat study and at 5000 µg/kg × 3/week (SC or IV) in rhesus
monkeys, mirroring findings in the single-dose rat study. Erythroid hypoplasia, minimally severe,
was observed in rhesus monkey bone marrow. The likely basis for these findings is inhibition of
erythropoiesis due to the diversion of stem cells to the megakaryocytic pathway. Findings of
extramedullary haematopoiesis in the spleen, liver and/or lymph nodes of treated animals are likely
3
The incidence among low-dose animals was 1/20, and this single case was of minimal severity.
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to be compensatory responses to anaemia. No effects on white or red blood cell counts/indices were
observed in the 6-month monkey study.
Ovarian cysts were observed at an incidence and level of severity considered by the Sponsor to be
above background levels at doses ≥ 1000 µg/kg × 3/week in the first monkey study, conducted in
rhesus animals. This finding was not reproduced in a subsequent study, and no ovarian changes
were observed in cynomolgus monkeys, nor rats. The findings of the initial study are therefore
considered to be incidental and no effect of romiplostim on the ovaries is indicated.
Inflammatory changes at the SC injection site were more frequent and/or more severe in treated
monkeys cf. controls. They were, at most, of moderate severity, and more usually slight or very
slight. The most severe findings were in rhesus monkeys, in which romiplostim was more
immunogenic than in cynomolgus monkeys. Chronic inflammation was observed at the SC
injection site in rats, but its relationship to treatment was unclear.
All haematological, clinical chemistry and histopathological changes were shown to be reversible
upon withdrawal of treatment. In most instances they were fully resolved within 4 weeks.
Genotoxicity
In line with ICH guidelines, no genotoxicity studies were conducted with romiplostim. Given its
size and composition, the drug is not expected to interact directly with DNA or other chromosomal
material.
Carcinogenicity
No carcinogenicity studies were conducted. While such studies are generally inappropriate for
biotechnology-derived products, romiplostim’s activity as a growth factor mimetic poses cause for
concern regarding its carcinogenic potential. Lifetime studies in rodents would not be feasible,
though, because of the development of drug-neutralising antibodies; the absence of carcinogenicity
studies is therefore acceptable. Thrombopoietin has been shown to stimulate the proliferation of a
subset of acute myeloblastic leukaemia cells in vitro (Matsumura et al., 1995; Fontenay-Roupie et
al., 1998; Corazza et al., 2006). Accordingly, stimulation of existing myeloid leukaemias in patients
treated with romiplostim is possible. A statement to this effect appears in the draft Product
Information document. No expression of c-Mpl was detected by Graf et al. (1996) in cell lines
derived from 21 different solid tumour types or by Columbyova et al. (1995) in 11 primary
malignant human tissues, indicating stimulation of other tumour types is unlikely.
Reproductive toxicity
Reproductive toxicity studies submitted by the Sponsor covered all stages (fertility, early embryonic
development and pre- and post-natal development). Numbers of animals in the definitive studies
and the timing and duration of treatment were appropriate. Drug administration was by the clinical
route.
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Table 2
Relative exposure
Study
Species & strain
Day of sampling;
(treatment period)
Dose
(µg/kg)
AUC0–168 h†
(ng·h/mL)
Exposure
ratio*
59.5
0.07
Rat (SD)
GD19;
(every second day
from GD7–GD19)
10
101948
30
644
0.8
100
2566
3
10
1001
1.2
30
4515
5
100
19040
22
10#
850
–
101949
108644
Rabbit (NZW)
GD19;
(every second day
from GD7–GD19)
Human (platelet count, 5 × 109/L)
* = calculated as animal:human AUC0–168 h ; † = estimated in laboratory animal species by multiplying AUC0–48 h by 3.5;
#
= the maximum recommended clinical dose
Placental transfer of romiplostim was demonstrated in rats. No studies were conducted in lactating
animals to examine the potential for excretion in milk. Such excretion is expected, though, based on
the presence of the IgG1 Fc domain in romiplostim.
Male and female fertility were unaffected in rats treated with romiplostim at doses ≤ 100 µg/kg,
administered 3-times weekly (estimated relative exposure, ≤ 9 [based on data from Study 100876]),
and no adverse effects on embryofetal development were observed in rats up to the same dose level,
administered on alternate days during gestation (relative exposure, ≤ 3). Higher doses could have
been used in these studies as no significant maternotoxicity was encountered. This would go some
way to compensate for the development of drug-neutralising antibodies, seen to be particularly
frequent in the fertility study (antibody analyses were not performed in the definitive embryofetal
development study). Additional embryofetal development studies were conducted in mice and
rabbits. These were limited, performed with only a small number of animals and involving only
external examination of foetuses. Post-implantation loss was increased in mice treated with
romiplostim at 100 µg/kg every third day, a maternotoxic dose (suppressing maternal body weight
gain by 8%); no increase in fetal external abnormalities was observed. In the rabbit study, a single
fetus of a dam treated at 100 µg/kg every second day displayed multiple malformations
(gastroschisis, ectrodactyly and cutis aplasia). This dose was maternotoxic, suppressing maternal
body weight gain by almost 50%. No follow-up study was conducted in rabbits to establish whether
this single finding was treatment-related. This was due to the lack of pharmacodynamic
responsiveness of the species (no increase in platelets could be demonstrated), indicating that the
rabbit is not an appropriate model for romiplostim toxicity. The set of studies examining the
potential embryofetal toxicity of romiplostim is not ideal, with a definitive study available for only
a single species and in it only low exposure multiples achieved.
Pups of rats treated at 100 µg/kg, administered every second day, were more likely to be stillborn,
with a 9.5-fold increase in incidence observed overall and a 14-fold increase apparent when
considering only pups of dams without drug-neutralising antibodies. Pup survival to PND4 was also
decreased at this dose level (88% cf. 97% in controls). Survival over PND5–PND21 was, however,
unaffected. Pup birth weight was normal and no adverse effects on development were observed at ≤
30 µg/kg or in surviving 100 µg/kg pups.
Paediatric use
Romiplostim is not proposed for paediatric use and no specific studies in juvenile animals were
submitted.
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Non-Clinical Summary and Conclusions
• The nonclinical dossier contained no major deficiencies. Certain studies that would have
been desirable were not feasible. These were a chronic study in rodents (precluded by the
development of drug-neutralising antibodies) and an embryofetal development study in a
second, non-rodent species (the usual species used, the rabbit, is an inappropriate model for
romiplostim toxicity because it is not pharmacologically responsive to the drug).
• Primary pharmacology and toxicity studies, showing large increases in platelets,
demonstrated to be functional, following treatment with romiplostim, support the drug’s use
for the proposed indication. Efficacy in a murine model of ITP was shown.
• Treatment-related findings in the toxicity studies are considered to represent desired
pharmacological effects (stimulation of megakaryopoiesis and thrombopoiesis), additional
pharmacological effects mediated by c-Mpl (a generalised stimulation of leukocyte
production), secondary effects related to megakaryocytic stimulation (inhibition of
erythropoiesis and compensatory responses to anaemia, hyperostosis of trabecular bone and
myelofibrosis) and effects related to the induced thrombocytosis (haemorrhage, artefactual
changes in clinical chemistry and probably mortality in rats). The most prominent toxic
effects — hyperostosis and myelofibrosis — were absent in monkeys.
• These exaggerated pharmacological effects, which were all demonstrated to be reversible, are
considered likely to be of limited clinical relevance. This is based on their occurrence at dose
levels beyond that required for significant stimulation of thrombopoiesis and/or their
confinement to rodents.
• The absence of studies investigating the genotoxicity and carcinogenicity of romiplostim is
acceptable. There is a concern that, as a thrombopoietin mimetic, romiplostim may
potentially stimulate the growth of existing myeloid leukaemias.
• A marked increase in stillbirths and decreased perinatal survival in pups of rats treated with
romiplostim at a relative exposure level of 3 (based on animal:human serum AUC) justify the
drug’s placement in Pregnancy Category B3.
• There are no nonclinical objections to registration of romiplostim for the proposed indication.
IV.
Clinical
Introduction
The marketing application includes data from 13 clinical studies: 9 clinical studies in subjects with
immune (idiopathic) thrombocytopenic purpura, 2 pharmacology studies in healthy subjects, and 2
studies in other indications. In total 204 ITP subjects have received romiplostim.
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Table 3
Clinical Pharmacology Studies
Pharmacokinetics
Absorption
For Study 20000109, mean romiplostim serum concentration-time profiles after IV administration
are presented in Figure 2.
After SC administration, serum romiplostim concentrations were not measurable for all subjects at
all timepoints in the 0.1, 0.3, and 1.0 μg/kg cohorts. At 2.0 μg/kg, serum concentrations of
romiplostim were not measurable at any timepoints for 3 out of 8 subjects and were measurable at
the earliest 12 hours postdose and only up to 48 hours postdose for the other 5 subjects. Half-life
and absolute bioavailability could not be reliably estimated; however it was evident that serum
exposure to romiplostim after SC administration was lower than that after IV administration. After
SC administration, peak concentrations were observed between 24 and 36 hours after dosing.
Figure 2: Study 20000109 - Mean (SD) Concentration-Time Profiles of Romiplostim after Single IV or SC
Administration of Romiplostim in Healthy Subjects (M2.7.2, v3, p14)
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Distribution
After a single IV dose, serum exposure to romiplostim (C0 and AUC0-t) increased more than
proportionally with dose and the initial volume of distribution decreased with dose. Findings
suggested that romiplostim presumably binds to c-Mpl on platelets and other cells in the
thrombopoiesis lineage, such as megakaryocytes, and is then internalised and degraded inside these
cells.
Bioavailability
Most of the studies in the clinical development programme, including the two pivotal phase III
studies, used material produced by a clinical manufacturing process known as P1. Later, the process
was optimized for commercial manufacturing (known as P2) and this material was first
administered to subjects during the open-label extension study (study 20030213).
In healthy subjects, the PK parameters of romiplostim were nonlinear after a single IV dose from
0.3 to 10 μg/kg. For romiplostim, at pharmacologically active doses < 3 μg/kg, serum
concentrations were not measurable in most samples collected from healthy subjects, and subjects
with ITP. The absolute bioavailability of romiplostim after SC administration could not be
estimated from the limited PK data available. Based on limited data from a single 2 μg/kg SC dose,
peak romiplostim serum concentrations were observed between 24 and 36 hours postdose in healthy
subjects. For subjects with ITP, peak serum concentrations after once-weekly SC administration
over a dose range of 3 to 15 μg/kg were observed about 7 to 50 hours postdose (median, 14 hours)
(study 20030213-Subset B). Romiplostim exposure after the sixth dose appeared lower than that
after the first dose in subjects with ITP (study 20000137B). After up to 26 weeks of once-weekly
SC administration of romiplostim in subjects with ITP, no clear relationship was observed between
the serum concentration-time profiles with doses over a range of 3 to15 μg/kg (study 20030213Subset B); however, higher exposures were observed in subjects with lower platelet counts at a
given dose.
Pharmacodynamics
Pharmacodynamic Effects
Two phase 1 studies (studies 20000109 and 20040134) were conducted to evaluate the PK and PD
profiles and safety of romiplostim in healthy subjects.
In study 20000109, subjects receiving romiplostim at 10.0 μg/kg IV had a 4- to 7-fold increase in
peak platelet counts from baseline. In light of this result, the planned dose escalation scheme was
modified; subsequent IV doses were 0.3 and 1.0 μg/kg, and SC dose levels were 0.1, 0.3 μg/kg, 1.0
μg/kg, and 2.0 μg/kg. 2.0 μg/kg was identified as the optimal dose in this study.
Mean platelet count-time profiles after a single IV or SC administration of romiplostim in healthy
subjects and platelet parameter values were included. The reference range of platelet counts for
healthy adults is approximately 150 to 450 x 109/L. After single IV and SC doses in healthy
subjects, romiplostim induced a dose-dependent increase in platelet counts. Platelet counts rose
above baseline 7 to 9 days postdose, reached the peak (Pmax) 11 to 15 days postdose, and returned to
the baseline level after approximately 27 days.
Platelet responses were similar after IV and SC administration, although exposure to romiplostim
was markedly lower (or not measurable) after SC administration compared with IV administration.
Platelet count profiles were essentially superimposable after IV and SC administration of
romiplostim at 1 μg/kg.
The 1.0 μg/kg dose was considered the minimally active dose, defined as the dose at which 2
subjects had a 1.5-fold increase over baseline for 2 consecutive platelet counts. The 2.0 μg/kg SC
dose was identified as the minimally effective dose, defined as the lowest dose that increased
platelet counts to ≥ 2.0-fold over baseline for 2 of 4 subjects treated with romiplostim. These
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findings guided dose selection for subsequent studies in subjects with ITP, in which romiplostim
was given SC starting at 1 μg/kg.
Results were similar in Japanese subjects to results from study 20000109. After a single 0.3 μg/kg
SC dose of romiplostim, no effect on platelet response was observed. As in study 20000109, the 1.0
μg/kg SC dose was considered the minimally active dose, and 2.0 μg/kg SC was considered the
minimally effective dose in healthy Japanese subjects.
Dose Response Studies
4 dose-finding studies were conducted in subjects with ITP (studies 20000137A, 2001218,
20000137B and 20050162).
In the early clinical studies in subjects with ITP, a target platelet response was defined as peak
platelet count achieving a doubling of baseline platelet counts and within the range of ≥ 50 x 109/L
and ≤ 450 x 109/L, in the absence of rescue medication. In study 20000137A, platelet counts were
below 50 x 109/L 1 week after the first dose in the majority of subjects who received doses of 1 and
3 μg/kg; and at these doses no subjects exceeded the platelet count of 450 x 109/L. Results
suggested that dosing once every 2 weeks was inadequate to achieve and maintain platelet counts in
a therapeutic range, and weekly dosing may be necessary. Since platelet responses were highly
variable among subjects with ITP, individual dose adjustment is warranted to produce adequate
platelet responses.
In study 20000137B, evaluating weekly dosing of romiplostim at 1.0, 3.0 and 6.0 μg/kg, 7 of 8
subjects in the 1.0 μg/kg cohort, 5 out of 8 subjects in the 3 μg/kg cohort, and 1 out of 1 subject in
the 6 μg/kg cohort achieved a platelet count ≥ 50 x 109/L after at least one dose of romiplostim.
This finding supports the use of 1.0 μg/kg as the starting dose. No subject with ITP administered 1.0
μg/kg had a platelet count > 450 x 109/L, therefore, 1 μg/kg once weekly appears to be an
appropriate starting dose for romiplostim, followed by individual dose adjustment based on the
individual observed platelet count.
Efficacy
The pivotal efficacy data are from 2 multicentre, double-blind, randomized, placebo-controlled,
phase III clinical trials of romiplostim in subjects with ITP; studies 20030105 and 20030212. Both
studies were designed in accordance with relevant regulatory guidance and in consultation with
regulatory agencies through Special Protocol Assessment (Food and Drug Administration) and
Protocol Assistance (EMEA) processes to ensure an appropriate level of clinical and statistical
robustness.
Supportive efficacy data on long-term treatment with romiplostim were provided from an openlabel extension study (20030213) that enrolled subjects with ITP who had completed a prior
romiplostim treatment study and whose platelet count subsequently fell below 50 x 109/L after
cessation of treatment in the parent study (including placebo subjects).
Study Overview - Studies 20030105, 20030212 and 20030213
Entry Criteria
Entry criteria were the same in both of the pivotal studies except that subjects in study 20030105
were refractory to splenectomy while subjects in study 20030212 had not undergone splenectomy.
Briefly the following criteria were to be met:
•
•
Subjects were required to be at least 18 years old
Subjects had to have a diagnosis of ITP according to American Society of Haematology
(ASH) guidelines (George et al, 1996)
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•
Subjects must have completed at least 1 previous treatment for ITP and had a mean of 3
platelet counts during screening and pre-treatment that was ≤ 30 x 109/L, with no individual
count > 35 x 109/L
• A haemoglobin of at least 9.0 g/dL was required at baseline to ensure a single lineage
deficiency
• Subjects over 60 years of age were required to have a documented history of chronic ITP
with a bone marrow report in order to exclude myelodysplastic syndromes
• Subjects with a known history of bone marrow stem cell disorder were excluded
• In study 20030105, splenectomy was required to have occurred at least 4 weeks prior to
study entry.
In study 20030213 subjects who completed a prior romiplostim treatment study and whose platelet
count subsequently fell below 50 x 109/L could receive romiplostim. Subjects from studies
20000137 or 20010218 entered at the initial weekly dose of 1 μg/kg. Subjects entering from a
blinded study entered the study on the same weekly dose as in the prior study. Placebo subjects
began at the initial weekly dose of 1 μg/kg.
Methodology
Randomization was stratified by baseline concurrent ITP therapy (yes or no). Both studies used a
romiplostim starting dose of 1 μg/kg, administered SC once weekly (based on data from studies
20000137A, 20000137B, and 20010218, which supported weight-based dosing to achieve a platelet
count of > 50 x 109/L).
The desired platelet range in which a constant dose was to be maintained was 50 x 109/L to 200 x
109/L. In the pivotal studies the maximum dose was15 μg/kg. In study 20030213 the maximum
dose of romiplostim was initially30 μg/kg, but was reduced to10 μg/kg in protocol amendments.
The amendments were made because of the lack of additional clinical benefit to incremental doses
above10 μg/kg. The pivotal studies were not amended.
Primary Endpoint
In the pivotal studies the primary efficacy endpoint was the incidence of durable platelet response,
defined as achieving at least 6 weekly platelet responses (platelet count ≥ 50 x 109/L) during the last
8 weeks of treatment with no rescue medications administered at any time during the treatment
period. This endpoint is consistent with treatment guidelines and was decided in consultation with
regulatory authorities.
Secondary Endpoints
Key secondary endpoints were as follows:
i.
Incidence of overall platelet response (durable and transient responders)
ii.
Number of weekly platelet responses
iii.
Proportion of subjects requiring rescue medications
iv.
Incidence of achieving durable platelet response with stable dose
Additional Efficacy Endpoints
Additional efficacy endpoints included the following:
•
•
•
•
Incidence of > 25% reduction from baseline or discontinuation of concurrent ITP therapy
Incidence of ≥ 20 x 109/L increase from baseline in platelet count
Total number of weekly platelet counts increased by ≥ 20 x 109/L from baseline
Time to first weekly platelet count increased by ≥ 20 x 109/L from baseline
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•
PRO Analyses - included health-related quality of life (HRQOL), and the ITP Patient
Assessment Questionnaire (ITP-PAQ) scales.
Statistical Methods
For the primary efficacy analyses the primary statistical inferences were based on the analysis of
results from the Cochran-Mantel-Haenszel test for the odds ratio of the 2 treatment groups,
including p-values and 95% confidence intervals (CI) and adjusting for prior splenectomy status
and baseline concurrent ITP therapy. Results from logistic regression analyses using treatment
group, prior splenectomy status, baseline concurrent ITP therapy, and baseline subgroups as
predictors were used for exploratory purposes.
Kaplan-Meier estimates were used to analyse the median time to first weekly platelet count
increased by ≥ 20 x 109/L from baseline and the time to first weekly platelet response during the
treatment period.
Demographic Data and Subject Disposition for Pivotal Studies
Demographic characteristics were well balanced between the romiplostim and placebo groups in
studies 20030105 and 20030212, and were typical of the ITP population. The median age was 52.0
years (range: 21, 88) and there were more women (64.8%) than men (35.2%). Thirteen subjects
(31.0%) in the placebo group and 18 subjects (21.7%) in the romiplostim group were ≥ 65 years
old. The median weight was 80.5 kg (range: 52, 169) in the placebo group and 78.2 kg (range: 44,
138) in the romiplostim group.
At baseline the population was severely thrombocytopenic: median 17.7 x 109/L (range: 2, 31) in
the placebo group and 15.7 x 109 /L (range: 2, 29) in the romiplostim group. Between groups and
across studies the median values for RBC, WBC, haemoglobin, and endogenous thrombopoietin
were balanced.
All subjects had received at least 1 previous ITP therapy. Most subjects in both of the pivotal
studies had received corticosteroids (94.4%), and most had received IVIG (66.1% nonsplenectomized, 93.7% splenectomized). Less tolerable therapies had been used by the
splenectomized population, for example in study 20030105 vincristine or vinblastine had been
used in 42.9% of subjects and azathioprine had been used in 23.8% of subjects. Rituximab (not
currently approved for treatment of ITP) had been used by 71.4% of splenectomized subjects.
46.8% of subjects in study 20030212 had received 1 or 2 prior ITP therapies, and another 38.7%
had received 3 or 4 prior therapies. Although they had not undergone splenectomy, these subjects
had low platelet counts despite receiving several different ITP therapies, and are therefore
representative of a chronic refractory population.
Splenectomized subjects had been extensively treated before enrolment: 27.0% had received 8 to 10
prior treatments, 54.0% had received 5 to 7 prior treatments, and no subjects had received fewer
than 3 treatments.
Study 20030105
Efficacy Results
A tabular summary of key efficacy endpoints in study 20030105 is provided in Table 4.
Romiplostim was statistically significantly superior to placebo for both the primary efficacy
endpoint and key secondary endpoints. A statistically significantly greater proportion of subjects in
the romiplostim group (16 subjects, 38.1%) than in the placebo group (no subjects) achieved a
durable platelet response (p = 0.0013).
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Table 4
Study 20030105 - Key Efficacy Endpoints
No subjects in the placebo group compared to 33 subjects in the romiplostim group (78.6%)
achieved an overall platelet response (p < 0.0001). The number of weeks with platelet response was
also significantly greater for the romiplostim group: mean 0.2 weeks, SD 0.5 weeks for placebo;
mean 12.3 weeks, SD 7.9 weeks for romiplostim (p < 0.0001).
12 (57.1%) subjects in the placebo group and 11 (26.2%) subjects in the romiplostim group
received rescue medication during the treatment period (p = 0.0175). 13 (31.0%) subjects were able
to achieve a durable platelet response at a stable dose of romiplostim compared to no subject in the
placebo group (p = 0.0046).
By the end of study (week 25), all 12 subjects in the romiplostim group who had been receiving ITP
therapies at baseline had either reduced (≥ 25%) or discontinued those therapies, compared with
only 1 placebo subject. Platelet counts increased above their baseline values by ≥ 20 x 109/L for 5
(23.8%) subjects in the placebo group compared to 37 (88.1%) subjects in the romiplostim group (p
< 0.0001). For the placebo group, the mean change from baseline in platelet counts showed no
change, whereas for the romiplostim group a rapid increase followed by steady maintenance above
50 x 109/L was observed when rescue medications were excluded from the analysis.
Results from several subscales of the ITP-PAQ indicated a positive effect of romiplostim on
measures of PRO as shown by the mean change from week 1 to week 25. The subscale Physical
Health - Symptoms showed a difference in means for romiplostim – placebo of 10.55 (p = 0.0205),
suggesting that subjects receiving romiplostim reported an improvement in their physical
symptoms. Other subscales also showed significant improvement in favour of romiplostim relative
to placebo: Physical Health - Bother subscale (p = 0.0091), Social Quality of Life (p = 0.0172) and
Women's Reproductive Health (p = 0.0272).
Overall the results from study 20030105 support superior efficacy of romiplostim over placebo in
thrombocytopenic subjects with ITP who are refractory to splenectomy. Efficacy was demonstrated
in all key efficacy endpoints.
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Study 20030212
Efficacy Results
A tabular summary of key efficacy endpoints in study 20030212 is provided in Table 5.
Romiplostim was statistically significantly superior to placebo for the primary efficacy endpoint
and for key secondary endpoints. A significantly greater proportion of subjects in the romiplostim
group (25 subjects, 61.0%) than in the placebo group (1 subject, 4.8%) achieved a durable platelet
response (p < 0.0001).
3 subjects (14.3%) in the placebo group and 36 subjects (87.8%) in the romiplostim group achieved
an overall platelet response (p < 0.0001). The mean number of weeks with platelet response was 1.3
weeks (range: 0, 15) for the placebo group and 15.2 weeks (range: 0, 24) for the romiplostim group
(p < 0.0001).
Table 5
Study 20030212 - Key Efficacy Endpoints
13 subjects (61.9%) in the placebo group and 7 subjects (17.7%) in the romiplostim group received
rescue medication during the treatment period (p = 0.0004). 21 (51.2%) subjects were able to
achieve a durable platelet response at a stable dose of romiplostim compared to no subject in the
placebo group (p = 0.0001).
At week 13, 4 romiplostim subjects (36.4%) had a > 25% reduction and 2 subjects (18.2%) had
discontinued all concurrent ITP therapies. In the placebo group 1 subject (10.0%) had a > 25%
reduction and 3 subjects (30%) discontinued all concurrent ITP treatment. At week 25, 4
romiplostim subjects (36.4%) had a > 25% reduction and 4 subjects (36.4%) had discontinued all
concurrent ITP therapies. In the placebo group 2 subjects (20.0%) had a > 25% reduction and 3
subjects (30.0%) discontinued all concurrent ITP treatment.
Platelet counts increased above their baseline values by ≥ 20 x 109/L for 38 subjects (92.7%) in the
romiplostim group compared to only 7 subjects (33.3%) in the placebo group (p < 0.0001). In the
placebo group platelet counts remained relatively steady throughout the study. In the romiplostim
group median platelet count increased to a maximum of 100 x 109/L at week 11, and then remained
at an increased level of between 62.5 x 109/L and 96 x 109/L over baseline for the remainder of the
25-week study period.
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Results showed greater improvement from week 1 to 25 on 9 out of 10 ITP-PAQ scales, with the
exception of the Work Quality of Life scale; however the Physical Health - Activity scale was the
only scale that showed a statistically significant difference in mean change for romiplostim vs
placebo (p = 0.0164). The SF-36 and EQ-5D scales, included as generic HRQOL measures, did not
show statistically significant differences between subjects treated with romiplostim and placebo;
however the scales may not have been capable of detecting small changes.
The results from study 20030212 support superior efficacy of romiplostim over placebo in
thrombocytopenic subjects with ITP who have not yet received splenectomy. As in study 20030105,
efficacy was demonstrated in all key endpoints measured.
Study 20030213
This is an ongoing long-term extension study. Data were provided from an interim analysis of
subjects from 6 studies who had completed their parent study and entered the extension study. The
data cut-off date was 28 November 2006.
Demographic Data and Subject Disposition
137 subjects were enrolled (91 women [66.4%] and 46 men [33.6%]). The median age was 53.0
years (range, 42 to 63 years). Of the 137 subjects enrolled, 136 subjects received at least 1 dose of
romiplostim. As of the data cut-off date, 120 subjects (87.6%) were continuing in the study and 17
(12.4%) had discontinued (7 due to withdrawn consent, 5 due to an adverse event, 3 due to death, 1
due to protocol-specified, and 1 due to other criterion). For the interim analysis, 136 subjects had
been on treatment for a median of 39 weeks (range, 1 week to 122 weeks).
Efficacy Results
The interim analyses showed that a platelet response (defined as doubling of baseline platelet count
and platelet count ≥ 50 x 109/L at any time on study in the absence of rescue medication within 8
weeks) was achieved in 82% of subjects (95% CI: 75%, 88%). A platelet count increase of ≥ 20 x
109/L from baseline was reached in 86% of subjects. A platelet count increase of ≥ 50 x 109/L was
reached in 82% of subjects, while a platelet count ≥ 100 x 109/L was reached in 75% of subjects.
64% of subjects reached a platelet count ≥ 150 x 109/L.
One week after the first dose of romiplostim the proportion of subjects with platelet responses was
31%. Kaplan-Meier analysis of time to first platelet response was 2 weeks (95% CI: 2, 3) for the
50th percentile (median) and 7 weeks (95% CI: 5, 11) for the 75th percentile.
The median romiplostim dose prior to first platelet response was 3μg/kg (range, 1 to 18 μg/kg).
From week 4 onwards, weekly incidence of response was in the range of 47% to 72%. At baseline,
the median platelet count was 20 x 109/L, and after the first dose (week 1) was 40 x 109/L.
The overall subject incidence of rescue medication use was 34.6%. Corticosteroids and IVIG were
the most common rescue medications used. The subject incidence of usage of rescue medication
decreased with time on study: incidences were at weeks 1 (n = 136), 13 (n = 100), 25 (n = 89), and
37 (n = 70) were 25%, 16%, 19%, and 15% respectively.
22% of subjects (30/136) entered the study on concurrent ITP therapy. In 13/30 (43%) subjects,
concurrent ITP therapy was discontinued during the study; and in 6 of these subjects (20%), dosage
was reduced by > 25%.
Trends toward improvement were observed for many of the scale scores within the various PRO
instruments used (i.e., ITP-PAQ, SF-36, EQ 5D, and Patient Global Assessment); however sample
sizes for analyses were small, and meaningful conclusions from the data could not be drawn.
The efficacy results from study 20030213 demonstrated that administration of romiplostim could
maintain platelet counts over time in subjects with ITP. Efficacy was shown in splenectomised
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subjects and in subjects who had not undergone splenectomy. Administration of romiplostim
allowed the reduction of concomitant ITP medications in a large proportion of subjects.
Safety
The sponsor presented safety data from all 13 clinical trials submitted for evaluation. Detailed
analyses of safety data were submitted from all phase III clinical studies and PK/PD studies. The
most important data consisted of analyses from the phase 3 ITP safety set (n = 125), the phase 3 ITP
long-term safety set (n=125), and the ITP safety set (n = 215). The romiplostim safety set consisted
of data from subjects with ITP, myelodysplastic syndrome (MDS), chemotherapy-induced
thrombocytopenia (CIT) and data from healthy subjects (total n=317; 284 romiplostim, 33 placebo).
Extent and Duration of Exposure
Exposure in the Phase 3 ITP Safety Set
41 subjects were exposed to placebo and 84 subjects were exposed to romiplostim in the phase 3
ITP safety set. The mean (SD) duration of exposure was 18.57 (6.82) and 22.83 (4.12) weeks for
placebo and romiplostim, respectively. The median cumulative dose during the phase III pivotal
studies was 12905 μg and 4098.0 μg for placebo and romiplostim, respectively.
Exposure in the Phase 3 ITP Long-term Safety Set
117 subjects received romiplostim, and the maximum duration of exposure for these subjects in the
phase 3 ITP long-term safety set was 83.9 weeks (1.6 years). The average (SD) weekly dose was
4.18 (3.21) μg/kg, the median average weekly dose was 3.15 μg/kg, and the maximum dose was 18
μg/kg. 39.3% of subjects had between 48 and 96 weeks of exposure as of the data cutoff.
Exposure in the ITP Safety Set
128 subjects had at least 6 months (26 weeks) of exposure to romiplostim and 74 subjects had at
least 1 year (52 weeks) of exposure.
The maximum exposure in this safety set was 128 weeks, the maximum number of doses was 126,
and the maximum dose received was 23.0 μg/kg. The median cumulative dose was 8542.7 μg with a
minimum and maximum cumulative dose of 19 and 190866 μg, respectively.
Exposure in Other Romiplostim Studies
In the 20 subjects in the MDS study, the maximum dose was 1000 μg and the maximum duration
of exposure was 31 weeks. The median cumulative dose was 7000 μg and the maximum cumulative
dose was 12800 μg.
In the 4 subjects in the CIT study at the time of the data cutoff (14 August 2006), 2 subjects had
completed the first 100-μg treatment cycle and the other 2 subjects had been dosed at 100 μg, but
had not completed the first treatment cycle.
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Adverse Events
Phase 3 ITP Safety Set
The proportion of subjects that reported AEs was 100% for romiplostim subjects vs 95.1% for
placebo subjects. The percentage of subjects that reported serious, severe, and fatal AEs is shown in
Table 6.
Table 6
Overall Summary of Adverse Events (Phase 3 ITP Safety Set)
A tabular summary of the subject incidence of AEs ≥ 5% incidence in either treatment group in the
phase 3 ITP safety set is provided in Table 7.
The most frequently reported AEs in both treatment groups were headache (31.7% placebo, 34.5%
romiplostim), fatigue (29.3% placebo, 33.3% romiplostim), and epistaxis (24.4% placebo, 32.1%
romiplostim). Dizziness, myalgia, and abdominal pain had more than a 10% higher subject
incidence in the romiplostim group compared with the placebo group.
Subgroup analyses of AE rates were conducted by age, weight, sex, country, concurrent
medications, baseline haemoglobin and years of diagnosis. There were some differences between
placebo and romiplostim in several of the subgroup analyses; however because of the small
numbers, the clinical significance of the differences is not certain. No clear trends were observed.
In the phase 3 ITP safety set, the percentage of subjects reporting an AE that led to an intervention
was similar between the placebo and romiplostim groups (82.9%; placebo vs 83.3%, romiplostim).
The most common AEs leading to an intervention were headache (26.8%, placebo; 28.6%;
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romiplostim), upper respiratory tract infection (9.8%, placebo; 13.1%, romiplostim), and arthralgia
(7.3%, placebo; 11.9%, romiplostim).
Table 7
Subject Incidence of Adverse Events ≥ 5% Incidence in Either Treatment Group by Preferred Term
(Phase 3 ITP Safety Set)
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ITP Safety Set
The percentage of subjects that reported serious, severe, and fatal AEs in the ITP safety set is shown
in Table 8. Similar proportions of subjects receiving placebo or romiplostim reported an AE: 95.7%
of placebo subjects and 95.6% of romiplostim subjects.
Table 8
Overall Summary of Adverse Events (ITP Safety Set)
Treatment-Related Adverse Events (TRAEs)
For the phase 3 ITP safety set, headache, myalgia, and fatigue were the most frequently reported
TRAEs.
For the ITP Safety Set, the proportion of subjects that reported TRAEs was 47.1% for romiplostim
subjects vs 26.1% for placebo subjects. Headache was the most frequently reported TRAE (16.7%
romiplostim, 6.5% placebo).
Deaths and Other Serious Adverse Events
Deaths
8 subjects died during a romiplostim ITP clinical study (ITP safety set); 3 (6.5%) placebo subjects
and 5 (2.5%) romiplostim subjects. None of the deaths were considered treatment-related. In study
20030105 no romiplostim subjects died, and 3 placebo subjects died. In study 20030212, 1
romiplostim subject died, and no placebo subjects died. In study 20030213, 3 romiplostim subjects
died, and no placebo subjects died.
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Table 9
Table of Deaths - ITP Safety Set
Serious Adverse Events (SAEs)
62 subjects reported at least 1 SAE during an ITP clinical study (ITP safety set); 10 (21.7%)
placebo subjects and 52 (25.5%) romiplostim subjects The study duration-adjusted SAE rate for
subjects who received placebo was 121.2/100 subject-years on study and for subjects who received
romiplostim was 76.1/100 subject-years on study.
Table 10 Other Serious Adverse Events Considered Related to Investigational Product (Excludes Deaths)
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Table 10(cont) Other Serious Adverse Events Considered Related to Investigational Product (Excludes Deaths)
Laboratory Data
Clinical laboratory evaluations were provided for subjects in the phase 3 ITP safety set and ITP
safety set. Overall, serum chemistry results for each analyte were similar between treatment groups.
Minor fluctuations were observed; however no clinically relevant trends were observed for any of
the serum chemistry analytes. Haematology laboratory results were also similar for both treatment
groups, and no clinically relevant trends in any haematology parameter were noted.
Effect on Vital Signs and ECG
No clinically important changes in vital signs were observed.
Adverse Reactions Characteristic of the Drug
Several AEs were considered of special interest because of the potential association with the
mechanism of action of romiplostim in subjects with ITP. These were:
•
•
•
•
•
•
•
bleeding event
clinically significant bleeding event (any bleeding event that was considered grade 3 or
above based on the adverse events standard grading score)
thrombotic / thromboembolic event
bone marrow abnormality
neoplasm (any preferred term that was classified in the system organ class of
neoplasms benign, malignant and unspecified [including cysts and polyps], or identified as a
neoplasm by an Amgen medical reviewer)
injection site event (any event occurring at the injection site).
Post-market Safety Data
No post-marketing data were presented for evaluation.
Clinical Summary and Conclusions
Pharmacokinetics
In healthy subjects, the PK parameters of romiplostim were nonlinear after a single IV dose from
0.3 to 10 μg/kg. For romiplostim, at pharmacologically active doses < 3 μg/kg, serum
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concentrations were not measurable in most samples collected from healthy subjects, and subjects
with ITP. The absolute bioavailability of romiplostim after SC administration could not be
estimated from the limited PK data available. Based on limited data from a single 2 μg/kg SC dose,
peak romiplostim serum concentrations were observed between 24 and 36 hours post-dose in
healthy subjects. For subjects with ITP, peak serum concentrations after once-weekly SC
administration over a dose range of 3 to 15 μg/kg were observed about 7 to 50 hours post-dose
(median, 14 hours) (study 20030213-Subset B). Romiplostim exposure after the sixth dose appeared
lower than that after the first dose in subjects with ITP (study 20000137B). After up to 26 weeks of
once-weekly SC administration of romiplostim in subjects with ITP, no clear relationship was
observed between the serum concentration-time profiles with doses over a range of 3 to15 μg/kg
(study 20030213-Subset B); however, higher exposures were observed in subjects with lower
platelet counts at a given dose.
Pharmacodynamics
Romiplostim is thought to exert its therapeutic benefit by directly stimulating platelet production by
binding to and activating c-Mpl on platelet precursors in the bone marrow. In healthy subjects,
romiplostim induced a dose-dependent increase in platelet counts after single IV doses ranging from
0.3 to 10.0 μg/kg or single SC doses ranging from 0.1 to 2.0 μg/kg. Platelet counts rose above
baseline 7 to 9 days post-dose, reached a peak 11 to 15 days post-dose, and returned to the baseline
level by 27 days after IV or SC administration. Platelet responses were similar after IV and SC
administration at the same dose level, although serum romiplostim concentrations were markedly
lower or not measurable after SC administration compared with IV administration.
Results from the dose-finding studies in subjects with ITP suggest that romiplostim increases
platelet counts in a dose-dependent manner. Dosing every 2 weeks was inadequate to maintain
platelet counts within the therapeutic range for many subjects. In study 20000137B in subjects with
ITP, 7 of 8 subjects in the 1.0 μg/kg cohort achieved the target platelet response, supporting the use
of 1.0 μg/kg once weekly as the starting dose in phase III studies. Large variability in platelet
response in the dose-finding studies of subjects with ITP supported the need for individual dose
adjustments based on platelet counts to achieve and maintain the desired target platelet count.
Efficacy
The data submitted for evaluation adequately support the efficacy of romiplostim in treatment of
subjects with ITP. Efficacy has been demonstrated in splenectomized subjects who have had an
inadequate response, and in non-splenectomized subjects who have had an inadequate response or
are intolerant to other ITP therapies. The effective dose, and appropriate dosing adjustments have
been defined from the studies submitted for evaluation.
Safety
The data presented for evaluation have demonstrated that romiplostim is effective in splenectomised
and non-splenectomised subjects with refractory chronic ITP. The safety profile of romiplostim in
this patient population appears acceptable.
V.
Overall Conclusion and Risk/Benefit Assessment
Quality
There are no objections to registration on Module 3 grounds. The initial report highlighted some issues
and the application was considered by the Pharmaceutical Subcommittee (PSC). All issues were
adequately resolved by the Sponsor.
Non-Clinical
There are no preclinical objections to registration. Administration of romiplostim to rodents and
monkeys was associated with large and long-lasting increases in platelet counts. The induced
platelets were shown to function normally.
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Toxicity was studied in rats and monkeys. Observed toxicities were consistent with the drug’s
pharmacological effect. These included:
•
•
Increased spleen weights consistent with increased demand for platelet clearance;
Enhanced platelet aggregation with incidents of haemorrhage and possibly thromboembolic
events;
• Hyperostosis of bone;
• Myelofibrosis (in rats) due to increased release of cytokines from the elevated number of
megakaryocytes;
• Increases in leukocyte counts;
• Decreases in red blood cell counts.
There was some evidence of embryofetal toxicity, with a significant increase in the incidence of
stillbirths in rats. The evaluator has therefore recommended a Pregnancy Category of B3.
Clinical
The clinical evaluator has recommended approval of the application.
Pharmacodynamics
Single doses of romiplostim administered to healthy volunteers resulted in dose-dependent
increases in platelet count, with maximum effect occurring at approximately 10-14 days. In patients
with chronic ITP, a dose dependant increase in platelet count was also observed, with maximum
effect occurring at between 3 and 15 days. Significant inter-patient variability in platelet increase
was noted.
The evaluator considered that the proposed dosage regimen was adequately justified. A weekly
dosage interval was chosen on the grounds that the majority of ITP patients required repeated
dosing after a 2 week interval due to platelet counts falling below 50 x 109 / L (study -137A). The
proposed starting dose (1.0 mcg/kg per week SC) produced platelet counts in the range 50 – 450 x
109 / L in a high proportion of subjects, whereas higher doses resulted in levels > 450 x 109 / L
(study -137B).
Pharmacokinetics
One study in healthy volunteers (-109) examined PK after IV administration. This demonstrated
non-linear PK, with greater than proportional increase in systemic exposure with increasing dose,
presumably due to saturation of the TPO receptor at higher doses. At the highest dose given, the
drug had a small volume of distribution (48 mL/kg) and a half-life of approximately 14 hours.
PK after SC administration have not been well defined due to difficulty in measuring the low
concentrations of the drug. Absolute bioavailability has not been determined. No accumulation
occurred after repeated administration for 6 weeks.
Efficacy
Evidence for efficacy comes from two randomised, double-blind, placebo-controlled trials.
•
Study 2003-0105 enrolled ITP patients who had already had a splenectomy (at least 4 weeks
previously).
• Study 2003-0212 enrolled ITP patients who had not had a splenectomy, but who had
previously received at least one prior treatment (e.g. prednisone) for ITP.
Both studies included only adult patients, who had a platelet count of < 30 x 109 / L. Patients
receiving treatment with steroids, azathioprine and/or danazol could be enrolled providing that dose
of these agents had been constant. Patients who had received treatment with immunoglobulins in
the preceding 2 weeks, or rituximab in the preceding 14 weeks, were excluded. Patients could
receive rescue therapy (eg with immunoglobulins, corticosteroids, platelet transfusions) in the case
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of bleeding or if the investigator felt that the patient was at immediate risk. The duration of both
studies was 24 weeks.
The primary endpoint was the proportion of patients who achieved a “durable platelet response” –
defined as a platelet count > 50 x 109/L for at least six of the last 8 weeks of study treatment,
without the need for rescue therapy. The endpoint was apparently designed in consultation with the
FDA and EMEA. Romiplostim treatment was associated with a statistically and clinically
significant benefit in both studies.
Several secondary endpoints, also based on platelet count, were significantly improved with
romiplostim treatment. Another secondary endpoint related to the frequency of rescue therapy.
Romiplostim treatment was associated with a reduced requirement for such therapies. A greater
proportion of patients in the romiplostim group were able to reduce or discontinue concurrent ITP
therapies that were being received at baseline.
Long term efficacy was examined in an open uncontrolled extension study (2003-0213). The
beneficial effect on platelet count appeared to be maintained for at least a further 48 weeks.
Safety
In the submitted studies, a total of 284 subjects were treated with at least one dose of romiplostim.
A total of 204 ITP subjects were treated, with 128 treated for periods of ≥ 26 weeks and 74 for
periods of ≥ 52 weeks.
The most informative safety data comes from the two double-blind, placebo controlled trials. The
overall incidences of adverse events and serious adverse events were comparable between the
romiplostim and placebo groups, but with a difference between the two groups in events considered
treatment-related by the investigators. There was no excess of discontinuations due to adverse
events, or deaths, in the romiplostim group.
Specific safety findings of note were:
•
Compared to placebo, romiplostim treatment was associated with increased incidences of
headache, myalgia, arthralgia, fatigue, dizziness, insomnia, abdominal pain and pain in an
extremity;
• The incidence of bleeding events was comparable in the romiplostim and placebo groups
overall. Romiplostim-treated patients had a lower incidence of grade II or higher bleeding
events (14.3% vs 34.1% - page 42);
• There was no excess of thromboembolic events with romiplostim compared to placebo;
• There was no excess of neoplasms with romiplostim compared to placebo;
• In ITP studies, 8.3% of romiplostim-treated subjects developed binding antibodies against
the drug. Only one patient developed neutralising antibodies and these were no longer
detectable 4 months after continuing the drug. 4.9% of romiplostim-treated subjects
developed binding antibodies against endogenous TPO, and none of these were neutralising
antibodies.
• Increased deposition of reticulin fibres in the bone marrow was documented in 6 patients
receiving romiplostim in the submitted studies. This finding raises the concern that the drug
could be associated with fibrosis of the marrow.
• Marrow fibrosis was documented in preclinical studies in rats, but not in monkeys.
Risk-Benefit Analysis
The pivotal placebo-controlled studies have demonstrated that romiplostim is effective in the
proposed patient populations. Safety experience with the drug is limited, with only approximately
200 ITP patients having been studied. The drug is intended for long-term administration but only 74
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ITP subjects had been treated for periods of greater than one year. With the exception of increased
bone marrow reticulin, the limited available safety data do not suggest any major safety issues.
It is understood from information available on the FDA website that the sponsor is proposing to
conduct a number of post-marketing studies to further investigate the drug’s potential to cause bone
marrow abnormalities. The sponsor’s feedback indicates that such studies include:
•
A prospective phase 4, open-label multi-centre study evaluating the changes in bone marrow
morphology in subjects receiving romiplostim for the treatment of thrombocytopenia
associated with ITP.
• Determination of frequency rates of bone marrow fibrosis and thrombotic / thromboembolic
events in patients with chromic ITP in Denmark.
In patients with chronic ITP refractory to splenectomy, currently available treatments are associated
with significant toxicity, and romiplostim would appear to be a useful agent in this setting. In
addition, splenectomy itself can be associated with significant morbidity and some risk of mortality,
and the drug would be of value as an alternative in patients unable to be controlled with steroids and
immunoglobulins.
Despite the limited safety data it is therefore considered that the overall risk-benefit ratio for the
drug is favourable and it is proposed to approve the application.
ADEC agreed with the delegate and noted that in the Precautions section of the product
information, under Increased Bone Marrow Reticulin, it should be stated that cytogenetic analysis
for the presence or absence of a clonal abnormality should also be undertaken on any bone marrow
biopsy sample obtained.
In addition, the TGA should seek data from the sponsor on platelet function tests performed on
patients receiving romiplostim.
Recommendation
Based on review of quality, safety and efficacy data, TGA approves the registration of Nplate®
powder for injection vial containing romiplostim rbe 375microgram and 625microgram, indicated
for:
The treatment of thrombocytopenia in adult patients with chronic immune (idiopathic)
thrombocytopenic purpura (ITP):
•
who are non-splenectomised and have an inadequate response or are intolerant to
corticosteroids and immunoglobulins;
•
who are splenectomised and have an inadequate response to splenectomy.
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