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PITT STREET HEALTH PLAN
Date of Review:
January 2010
Reason for Review: To determine whether there is sufficient evidence to support the value of platelet
growth factors eltrombopag (Promacta) and romiplostim (Nplate) for a change in formulary status.
AGENTS IN THIS CLASS
Preferred Alternatives
None
Nonpreferred Alternatives
eltrombopag (Promacta)
romiplostim (Nplate)
TABLE OF CONTENTS:
Executive Summary
Recommendations
Key Questions/Issues:
Issue 1: Efficacy
Issue 2: Comparative Effectiveness
Issue 3: Safety
Issue 4: Value Proposition
Issue 5: Cost-effective Patient Subgroups
Clinical Evidence Tables
Cost-effectiveness Evidence Tables
Background
Disease Background
Pharmacotherapy
Product Background
Methodology
Authorship
References
Abbreviations used in this monograph:
ULN - upper limit of normal, URI - upper respiratory tract infection, MDS - myelodysplastic syndrome, ITP idiopathic thrombocytopenic purpura, IVIG - intravenous immune globulin, PMPM - per member per month,
HRQOL - health related quality of life, QALY - quality adjusted life years
EXECUTIVE SUMMARY
Key Questions/Issues and Results of Investigation:
Issue 1: What is the evidence of efficacy for each drug from clinical trials?
Romiplostim has been proven in clinical trials to be more effective than placebo in raising and maintaining
platelet counts. The two studies used to gain FDA approval looked at both splenectomized and nonsplenectomized ITP patients. The overall platelet response rate, defined by at least 6 weekly platelet responses
(>50,000/mcL on a weekly scheduled dose day) during the last 8 weeks of treatment, was 88% in nonsplenectomized patients and 79% in splenectomized patients recieving romiplostim. A long-term, open-label,
extension study including patients who completed either previous clinical trial is currently ongoing to evaluate
the use of the medication for long-term treatment (>24 weeks). However, it is still uncertain whether the
increase in platelets is sustainable beyond 24 weeks.
Similar efficacy was demonstrated in two studies leading to FDA approval of eltrombopag. Like the
romiplostim trial, the first study examined both splenectomized and non-splenectomized patients with platelet
counts <30,000/mcL who failed at least one other ITP treatment. Results showed that 70% of pateints treated
with 50mg eltrombopag and 81% of patients treated with 75mg eltrombopag achieved platelet counts
>50,000/mc at day 43 of the 6 week study . A phase III study indicated that 59% patients recieveing 50mg
eltrombopag achieved a platelet count >50,000/mcL and had significanlty lower bleeding incidence (16%) than
placebo patients (36%). Study data is limited to 6 week therapy, therefore it is uncertain whether the increase in
platelets is sustainable beyond this time period.
Issue 2: Is there sufficient evidence to assess real world comparative effectiveness among the drugs in the
class?
No evidence found.
Issue 3: What is the evidence of safety?
Clincal trials have shown romiplostim to exhibit uncommon, yet serious, side effects. In the long-term, openlabel extension study, serious adverese events were reported in 9% of the patients using romiplostim. These
included bone marrow reticulin formation, worsened thrombocytopenia after discontinuation of therrapy,
thrombotic/thromboemolic complications from excessive increasees in platelet counts, and hematologic
malignancies, especially in those patients with MDS. In a single-arm study of 44 patients with MDS, 11 patients
were were reported as having possible disease progression, four of which had confirmation of acute
myelogenous leukemia (AML). More common, mild advese reactions, as identified in the Phase II and II trials,
include headache, arthralgia, dizziness, insomia, myalgia, pain in extremities/abdomen/shoulder, dyspepsia, and
paresthesia.
Eltrombopag has a similar safety profile, but also may cause hepatotoxicity. Data from all controlled clinical
trials showed serum liver tests abnormalities inreported in 10% of the treatment groups. As a result of the study
findings, warnings and precautions for eltrobopag include a black-box warning of hepatotoxicity and bone
marrow reticulin formation and risk of bone marrow fibrosis, worsened thrombocytopenia after discontinuation
of therapy leading to serious hemmorage, thrombotic/thromboembolic complications, increased risk of
hematologic malignancies and progression of malignancy in patients with pre-existing hematologic malignancy
or MDS. The most common reported side effects with a higher incidence in eltromobopag versus placebo from
the phase II and III trials included nausea, vomiting, menorrhagia, myaglia, apesthesia, cataract, dyspepsia,
ecchymosis, thrombocytopenia, increased ALT/AST, and conjunctival hemmorage.
Issue 4: What is the value proposition for this class? Does it differ significantly among the drugs in the class?
Traditional treatments for ITP have been aimed at reducing platelet destruction. Medications such as
corticosteroids and immune globulin supress the immune system while splenectomy removes the organ at which
platelet destruction occurs. Both romiplostim and eltrombopag, thrombopoietin-receptor agonists, provide a
novel treatment option for pateints with ITP by stimulating platelet production. Currently, the 1st line therapy
for ITP is corticosteroids. However, about 70% of adults experience a relapse after discontinuing this treatment.
While a new course of cotricosteriods may be pursued, long-term use of these medications could cause serious
side effects particuarily due to the suppression of the immune. IVIG and anti-D may be administered as indicated
for bleeding or imminent risk of life-threatening hemorrhage, but should only be used as a "rescue" medication
to quickly raise platelet counts and will not maintain levels beyond two weeks. Splenectomy, as a 2nd line
treatment, has been shown to provide durable complete responses in two thirds of patients with minimal risk for
surgical complications and infection. Rituximab, though not currently indicated for treatment of ITP, is
considered the first option in patients developing recurrent thrombocytopenia after splenectomy due to its
minimal long-term risk and reasonable sustained response rate. Platelet growth factors are seen as another option
to manage chronic ITP in patients who have not responded to corticosteroids, immune globulins, or splenectomy.
While these agents have been generally well tolerated, data is limited to short-term treatment and the risks
associated with long-term use are unknown. The use of thrombopoietin receptor agonists should be determined
on a case-by-case basis by both patients and health care providers, weighing the risks and benefits against the
more defined variety of immunosuppressive agents most often used in patients with chronic ITP.
Issue 5: Are there identifiable patient subgroups in which drugs in this class will be most cost-effective?
Both eltrombopag and romiplostim are currently only indicated for treatment of adults with chronic ITP who
have had an insufficient response to corticosteriods, immunoglobulins, or splenectomy. Patients who have had a
splenectomy, but have not been able to maintain safe platelet levels would be expected to benefit the most from
these medications.
RECOMMENDATIONS TO THE COMMITTEE
The potential benefits outweigh the potential risks of adding the class of Platelet Growth Factors to the formulary for the
treatment of Chronic ITP. Rare but serious risks are associated with both Promacta and Nplate, specifically a Black Box
Warning for Hepatic Toxicity related to Promacata use. Adverse effects associated with the use of both products are similar
to thsoe reported for current first line therapy, with only a change in the distribution of the side effects. However, these risks
will be continually monitored through the restricted drug distribution programs Promacta CARES and Nplate NEXUS. Both
products appear to be cost-effect therapy as second line treatment options for chronic ITP due to the relatively low
prevalance of the disease in our plan population. Based upon current available therapy and the proven effiacy of this new
class of medications, Pitt Street Health Plan has come up with the following recommendations:
Addition of this class of medications to the formulary with prior authorization as preferred drugs, with the following
restrictions:
1. Adult (over 18) Diagnosis of chronic ITP with the approval of a hematologist AND
2. Insufficient response to corticosteroids, IVIG, and/or spleenectomy AND
3. Patient has evidence or risk (platelet count < 30,000) of bleeding.
Authorization shall be reviewed at a minimum of every six months to confirm that platelet levels are less than 400,000,
and greater than 30,000 or improved from baseline (if less than 30,000) with clinical improvement. Upon receiving
authorization, patients may not recveve more than the quantity limit for each drug.
Quantity Limit
Initial Dose:
Nplate: 1mcg/kg SC once weekly
Promacta: 50mg once daily
Maintance Dosing:
Nplate: Not to exceed 10mcg/kg per week, adjusting weekly doses by increments of 1mcg/kg
Promacta: Not to exceed 75mg/kg per day, adjusting daily dose by increments of 25mg
ISSUE 1: What is the evidence of efficacy for each drug from clinical trials?
Romiplostim has been proven in clinical trials to be more effective than placebo in raising and maintaining
platelet counts. A phase III, double-blind, placebo-controlled, multicenter, international, 6-month RCT
consisted of two parallel studies; one enrolled non-spenectomized patients (Study 1: B-U/1/1A), and the
other, splenectomized patients (Study 2: B-U/1/1A). All patients had a baseline platelet count <30,000/mcL
and were randomly assigned 2:1 to receive weekly subcutaneous injections of romiplostim or placebo for 24
weeks. The overall platelet response rate, defined by at least 6 weekly platelet responses (>50,000/mcL on a
weekly scheduled dose day) during the last 8 weeks of treatment, was 88% in non-splenectomized patients
receiving romiplostim compared with a 14% response rate in those patients assigned placebo (p<0.0001). A
79% response rate was seen in splenectomized patients as compared to a zero response rate in those assigned
placebo (p<0.0001). When applied to the target population, these data provide evidence that romiplostim
may maintain platelet counts >50,000/mcL in one-third to one-half of chronic ITP patients for whom
traditional treatments (steroids, splenectomy) have been ineffective. A long-term dosing study (B/1/IB) is
currently ongoing to evaluate the use of the medication for long-term treatment (>24 weeks). Patients who
completed either study 1 or 2 were included in this open-label, multicenter, international extension study.
However, it is still uncertain whether the increase in platelets is sustainable beyond 24 weeks.
Clinical data from two randomized, double-blinded, placebo-controlled studies, phase II (TRA100773A:
B/1/IB) and phase III (TRA100773B: B/1/IB), used to gain FDA approval for eltrombopag, support the
primary efficacy outcome of patients achieving a platelet response defined as a shift from baseline platelet
count of <30,000/mcL to >50,000/mcL at any time during treatment. Both trials administered daily placebo
or eltrombopag for up to six weeks, followed by six weeks off therapy. TRA100773A examined both
splenectomized and non-spelectomized patients with platelet counts <30,000/mcL who were relapsed or
refractory to at least one other ITP treatment. After random assignment to 30mg, 50mg, or 75mg
eltrombopag or placebo, 70% of patients receiving 50mg eltrombopag and 81% of patents receiving 75mg
achieved targeted platelet counts compared to 11% of those assigned placebo (p<0.001). In TRA100773B,
the efficacy of 50mg and 75mg dosage of eltrombopag was further evaluated. Of the 114 patients, 59%
assigned to the active drug achieved platelet counts >50,000/mcL compared with 16% assigned placebo
(p<0.0001). Study data is limited to 6 week therapy, therefore it is uncertain whether the increase in
platelets is sustainable beyond this time period.
ISSUE 2: Is there sufficient evidence to assess real world comparative effectiveness among
the drugs in the class?
No evidence found.
ISSUE 3: What is the evidence of safety?
Clinical trials have shown romiplostim to exhibit uncommon, yet serious, side effects. Romiplostim increases
the risk for reticulin desposition with in the bone marrow. In clinical studies, the drug was discontinued in four of
the 271 patients due to this desposition. Reticulin was discovered in six additional patients upon bone marrow
biopsy. Bone marrow reticulin increases the risk for bone marrow fibrosis. In the extension study, one patient
with ITP and hemolytic anemia developed marrow fibrosis with collagen during romiplostim therapy. Clinical
studies have not excluded the possibility that reticulin and other fiber desposition may result in bone marrow
fibrosis with cytopenias. Discontinuation of romiplostim may result in worsened thrombocytopenia than was
present prior to the initiation of therapy. This could lead to increased risk of bleeding. In clinical studies of
patients with chronic ITP who had romiplostim discontinued, four of 57 patients developed thrombocytopenia of
greater severity than was present prior to treatment. On the other hand, high platelet counts and an increased risk
of blood clots are also a concern for patients receiving romiplostim. Thrombotic/thromboembolic complications
may result from excessive increases in platelet counts. Though the controlled studies showed the incidence of
these complications to be greater in romiplostim than placebo, results were not statistically significant.
Romipostim may also increase the risk for hematologic malignancies, especially in those patients with
myelodysplastic syndrome (MDS). In a single-arm study of 44 patients with MDS, 11 patients were were
reported as having possible disease progression, four of which had confirmation of acute myelogenous leukemia
(AML). More common, mild advese reactions, as identified in the Phase II and II trials, include headache,
arthralgia, dizziness, insomia, myalgia, pain in extremities/abdomen/shoulder, dyspepsia, paresthesia.
Based on the controlled clinical studies, eltrombopag may cause hepatotoxicity. One patient experienced Grade 4
elevations in serum liver test values during therapy, worsening of underlying cardiopulmonary disease, and
death. Though the transaminitis appeared to have been the result of pulmonary sepsis leading to multi-organ
failure, the casual relationship to eltrombopag cannot be ruled. Overall, serum liver test abnormalities were
reported in 10% of the treatment groups, compared with 8% in the placebo. In the phase II and III trials, 15
patients (six recieving eltrombopag and nine placebo) had ALT values >2x ULN. The most common reported
side effects with a higher incidence in eltromobopag versus placebo from the phase II and III trials included
nausea, vomiting, menorrhagia, myalgia, apesthesia, cataract, dyspepsia, ecchymosis, thrombocytopenia,
increased ALT/AST, and conjunctival hemhorrage. The long-term clinical study further analyzed 207 patients
for safety and found the most common adverse events to be headache (15%), URI (13%), diarrhea (10%),
nasopharyngitis (9%), and arthralgia (8%). The majority of adverse events were Grade 1 or 2 (mild-moderate
severity). As a result of the study findings, warnings and precautions for eltrobopag include a black-box warning
of hepatotoxicity and bone marrow reticulin formation and risk of bone marrow fibrosis, worsened
thrombocytopenia after discontinuation of therapy leading to serious hemhorrage, thrombotic/thromboembolic
complications, increased risk of hematologic malignancies and progression of malignancy in patients with preexisting hematologic malignancy or MDS.
ISSUE 4: What is the value proposition for this class? Does it differ significantly among the
drugs in the class?
Summary of Therapeutic Class Value
Traditional treatments for ITP have been aimed at reducing platelet destruction. Medications such as
corticosteroids and immune globulin supress the immune system while splenectomy removes the organ at which
platelet destruction occurs. Both romiplostim and eltrombopag, thrombopoietin-receptor agonists, provide a
novel treatment option for pateints with ITP by stimulating platelet production. Currently, the 1st line therapy
for ITP is corticosteroids. However, about 70% of adults experience a relapse after discontinuing this treatment.
IVIG and anti-D may be administered as indicated for bleeding or imminent risk of life-threatening hemorrhage,
but should only be used as a "rescue" medication to quickly raise platelet counts and will not maintain levels
beyond two weeks. Splenectomy has been shown to provide durable complete responses in two thirds of patients
with minimal risk for surgical complications and infection.7 Rituximab, though not currently indicated for
treatment of ITP, is considered the first option in patients developing recurrent thrombocytopenia after
splenectomy due to its minimal long-term risk and reasonable sustained response rate (40% of patients). Platelet
growth factors, romiplostim and eltrombopag, are seen as another option to manage chronic ITP in patients who
have not responded to corticosteroids, immune globulins, or splenectomy.31,36 While these agents have been
generally well tolerated, data is limited to short-term treatment and the risks associated with long-term use are
unknown. The use of thrombopoietin receptor agonists should be determined on a case-by-case basis by both
patients and health care providers. The efficacy and ambiguous long-term effects of these new agents must be
weighed against the more defined variety of immunosuppressive agents most often used in patients with chronic
ITP.
Incremental Cost-effectiveness:
The manufacture of eltrombopag uses a cost-minimization model to find the most cost-effective means to attain
safe platelet levels in patients with chronic ITP over a 4-6 week time period. The model compares eltrombopag
to IVIG, anti-D, and rituximab as monotherapy, 2nd line options for adult patients with platelet counts
<30,000/mcL who have previously failed at least one ITP treatment. Patients who fail the 2nd line treatment
switch to a 3rd option, which include platelet transfusion in addition to the other 2nd line therapies. Response
rates for pateints recieveing eltrombopag, IVIG, anti-D, and rituximab after the 2nd treatment option were 70%,
68%, 72%, and 62%, respectively. Eltrombopag, as compared to the other products, was the most effective
treatment option in avoiding platelet transfusions. Transfusions were avoided in 87% of patients receiving the
medication. Eltrombopag was also seen to have the lowest total cost of therapy ($4,713) , primarily due to the
minimal cost of administration ($88) as compared to all other interventions. In conclusion, the manufacture
stated that the model proved eltrobopag to be a cost-effective therapuetic option for treatment of ITP as
compared to IVIG, ant-D, and rituximab during the model time horizon. The primary benefit lies in the high rate
of platelet transfusions avoided at a lower total cost as compared to the other therapies. The model, however,
does not include spelenctomy as a treatment option among the comparators to eltrombopag. Splenectomy is
considered the "gold-standard" 2nd line treatment option for patients refractory to corticosteriods or IVIG. The
budget impact model, used to determine the annual budgetary implication of introducing eltrombopag an a health
plans formulary, shows an additional annual cost of $20,539 for a 10,000,000 member plan, translating to a
$0.0002 PMPM cost increase. Because the spreadsheet model was not made available, the specific cost burden
for members of Pitt Street Health Plan could not be determined.
For romiplostim, the economic model used a lifetime horizon to assess the impact of the medication on ITP
patients with platelet counts <50,000/mcL who had undergone splenectomy and those who had not. The cost
effectiveness of romiplostim was compared with standard care that assumed patients initially entered a ‘watch
and rescue’ phase where they were treated as necessary rescue therapy or were initially treated with romiplostim
followed by ‘watch and rescue’ care. Patients move through a series of treatments consisting of active therapies
and ‘watch and rescue’. Rescue treatments were not specifically stated, but, based on results reported, were
assumed to include IVIG, anti-D, intravenous corticosteriods, and platelet transfusion. The model only looked at
non-surgical options, thus excluding splenectomy as a potential treatment. When patients became refractory to an
active treatment, they moved back to the ‘watch and rescue’ phase.
When applied to Pitt Street Health Plan, the model estimates 13 cases using romiplostim for treatment of chronic
ITP. The incremental cost of romiplostim ($193,611) corresponds to a PMPM of $0.005 for a payer coverring
1,000,000 lives, a relatively minimal impact on payer budgets. However, sensitivity analysis shows that the
expected increase would be $0.016 PMPM when only the 250 and 500mg vials are stocked. This is a more
accurate representation of the PMPM cost since the 100mg vial is not currently on the market. Since a
spreadsheet model was not provided, the specific cost burden for Pitt Street Health Plan membebrs cannot be
determined. Overall, the model suggests that romiplostim is a cost-effective therapeutic option for safely
elevating and maintaining platelet counts, reducing the need for concurrent/rescue medications, and improving
HRQOL.
Table 1. Summary of incremental cost-effectiveness ratios found by studies included in this review.
Reference
Scenario
Mowatt G, et.
al.
Base case
ICER (£ per QALY)
Watch and rescue is
initial comparator
intervention (nonsplenectomized)
Rituximab is initial
comparator intervention
(non-splenectomized)
Watch and rescue is
initial comparator
intervention
(splenectomized)
Rituximab is initial
comparator intervention
(splenectomized)
14,633
21,674
15,595
29,771
24,426
17,580
33,558
28,556
91,406
109,802
21,658
15,580
21,687
21,706
15,639
29,817
36,131
22,068
26,154
1. Use of EQ-5D data from
16,503
RCTs
2. Change in number of
21,214
vials (from 0.93 to 1.0)
3. Serious adverse events 14,623
4. Cost of bone marrow
14,663
test included
5. Cost of blood
19,230
assessment included
6. Reducing frequency of
14,669
physician visits
7. Response rate for Nplate
(worst case for
16,258
censoring)
8. Response rate for Nplate
14,152
(best case for censoring)
9. Nplate effectiveness at
16,354
0.25 of base case
10. Nplate effectiveness at
14,884
0.75 of base case
21,701
15,642
29,803
57,593
17,501
106,703
18,776
15,367
24,669
165,129
17,245
446,204
26,439
15,808
39,268
Differences in Value among the Drugs in This Therapeutic Class
ISSUE 5: Are there identifiable patient subgroups in which drugs in this class will be most cost-effective?
For eltrombopag and romiplostim, the following subgroups were assessed: 2nd line treatment for nonsplenectomised patients with inadequate response to initial corticosteroid treatment, where splenectomy is
medically contraindicated and ITP patients refractory to splenectomy. Both eltrombopag and romiplostim are
currently only indicated for treatment of adults with chronic ITP who have had an insufficient response to
corticosteriods, immunoglobulins, or splenectomy. Based on published data and Amgen market research, 80% of
new ITP patients will fail corticosteriods, 67% of non-splenectomized patients will seek a new therapy each year,
and 36% of splenectomized patients will seek new treatment due to surgical failure and/or relapse.sect5p1 Patients
who have had a splenectomy, but have not been able to maintain safe platelet levels would be expected to benefit
the most from these medications.
Table 2. Clinical evidence summary
Ref. and
Evidence
Grade
Drug Regimens
TRA100773A Promacta 30 (n=30) , 50
(B/1/ IB)
(n=30), or 75mg (n=28)
or placebo (n=29) daily
n
118
Time
6 wks
Demographics
Median Age: 50 yr
Age Range: 18–85 yr
Female: 73 Male: 44
Design*
Phase II, DB, PC,
RCT, MC (44
international sites)
End Points/Comments
1o: Platelet count >50,000/mcL on day 43
Results
1o: 75mg: 81%, 50mg: 70%, 30mg: 28%, placebo: 11%.
(P<0.001 for 50 and 75mg vs. placebo)
2o: Safety and tolerability, signs of bleeding, serum
Black: 2 Asian: 21
White: 93 Mixed: 1
thrombopoietin levels, HRQOL
2o: incidence of ADEs similar across all groups, bleeds:
placebo=14%, 30mg=17%, 50mg=7%, 75mg= 4%, HRQOL
remained similar at baseline and end of study for all groups
Splenectomy: 55
Concomitant therapy: 38
Platelets ≤15,000/mcL: 56
Prior ITP Therapies
≥1: 113 ≥2: 87
≥3: 60
≥4: 42
Placebo and treatment
groups had similar baseline
demographic profiles
TRA100773B Promacta 50mg qd(n=76) 114
(B/1/1B)
or placebo (n=38);
Promacta could be
increased to 75mg qd if
pt platelet count
<50,000/mcL on day >22
6 wks
Median Age (yr): 48
Age Range: 19–84
Female: 70 Male: 44
Black: 1 White: 84
Other: 29
Phase III, DB, PC,
RCT, multicenter (63
international sites)
1. Platelet count >50,000/mcL on day 43
1.: Promacta: 58.9% vs. placebo: 16.2%. (P<0.001)
2: Safety and tolerability, signs of bleeding, serum
thrombopoietin levels, HRQOL
2. clinically significant bleeds:
Promacta=15.8% vs placebo=36.1%,
no statistically significant changes in HRQOL,
Splenectomy: 45
Concomitant therapy: 49
Platelets ≤15,000/mcL: 55
Prior ITP Therapies
≥1: 114
≥2: 82
≥3: 58
≥4: 39
≥5: 23
Placebo and treatment
groups had similar baseline
demographic profiles
83% Promacta pts “satisfied with treatment” vs. 57%
placebo,
Promacta pts experienced ADEs (59%) vs. placebo (37%)
with the majotiy being Grade 1-2 severity and headache as
the most common
EXTEND (BU/3/III)
RAISE
(B/1/IB)
Promacta 50mg qd; could 201
be increased to 75mg qd
if platelet count
<50,000/mcL on day >22
or decreased if
>200,00/mcL
Ongoing
Promacta 50mg
qd(n=135) or placebo
(n=62); Promacta could
be increased to 75mg qd
if pt platelet count
<50,000/mcL on day >22
or decreased if
>200,00/mcL
6 mo
197
Specific demographic data
not reported
pts previously enrolled in
study TRA100773A or
TRA100773B
Median Age:
47.0 (Promacta), 52.5
(placebo)
Platelets <15,000/mcL:
50%, 48%
Treatment, NonRandomized, Open
Label/Extension,
Single Group
Assignment, long
term, MC (111
international sites,
Safety Study
1: Safety and tolerability (labs, ocular exams, frequency 1. 15$ required rescue treatment, 50% decrease in baseline
of ADEs)
bleeding events after 47 wks, ADE frequency consistent with
data from TRA10073A/B
2a. clinical efficacy, pharmacodynamics, durability of
response as measured by platelet counts
2a. 79% achieved platelet count > 50,000/mcL and
b. effect of re-treatment on platelet counts in pts
16% achieved levels >400,000/mcL at least once during
previously treated with Promacta
study
c. gain dosing information
51%, 35%, and 24% maintained counts >50,000/mcL at 4,
d. reduction /discontinuation of concomitant ITP
10, and 25 wks.
therapies
b. 96% pts who previously responded in Promacta trials,
e. physical and mental health status (fatigue, bleeding,
responded with platelet counts >50,000/mcL and 2 baseline
bruising, HRQOL)
c. Not reported
d. 48% pts receiving concomitant therapy reduced or
discontinued those meds
e. Not Reported
Phase III, DB, PC, PG
RCT, MC (91
international sites),
safety/efficacy study
1. Odds of achieving platelet count 50,000 –
400,000/mcL
1.8x greater for Promacta treated pts vs. placebo (OR
[99%CI]: 8.2[3.59,18.73], p<0.001)
2a. pts receiving rescue treatment
b. pts with min 75% platelet assessments 50,000 to
400,000/mcL
c. max duration of response
d. pts responding during wks 2-6
e. reduction in concomitant therapy
f. incidence and severity of ITP symptoms
2a. 18% Promacta, 40% placebo; odds of rescue treatment
67% lower for Promacta ( p=0.001)
b. Not reported
c. mean duration of max response = 8.1 wks (Promacta), 0
wks (placebo)
d. total responses wks 2-6: Promacta - 341, placebo-29
e. 84% Promacta vs. 60% placebo reduced or discontinued
concomitant therapy
f. odds of reducing/discontinuing at least 1 other ITP med 3x
greater in Promacta group vs. placebo
Treatment, NonRandomized,
Open Label,
Single Group
Assignment,
MC,Safety/Effica
cy Study
1. Pts Responding (Platelet Count >50,000 /mcL
and >2x Baseline) to treatment in Cycle 2 or Cycle
3 given response in Cycle 1
Splenectomized:37%, 34%
Prior ITP Medication:
47%, 50%
REPEAT
(B/1/IB)
3 cycles of treatment
with each cycle defined
as an on-therapy period
of up to 6 wks and an
off-therapy period of up
to 4 wks.
Cycle 1: Promacta 50 mg
Starting Dose
Cycle 2: 50 or 75 mg
66
30 wks
(divided
into 3
cycles)
Median Age: 49.6+14.61
Females: 45 Males:
21
White/: 47
Asian/East Asian: 10
Arabic/North African: 6
African American: 2
American Indian/Alaskan 1
Cycle 3: 50 or 75 mg
Baseline Platelet Count
<20,000/mcL: 4
20,000 to 30,000/mcL: 29
30,000 to 50,000/mcL: 31
>50,000/mcL: 2
Splenectomized: 20
Prior ITP Medication: 22
1. 45 (87%)
2a. 79% cycle 1, 78% cycle 2, 70% cycle 3
2a. Pts Responding for min 80% of therapy during
weeks 2-6.
b. 22% pts maintained responses 2 wks after discontinuing
therapy
b. Changes in platelet counts during 3 Cycles of
Treatment
c. None required
c. Pts requiring rescue meds ]
d. Not reported
d. Change in anti-platelet antibody levels from
baseline through follow-up
e. Pts with indicated bleeding signs and symptoms
Using the WHO Bleeding Scale
f. Pts with indicated bleeding signs and symptoms
using the ITP Bleeding Score
e. # of bleeding events decreased after 1 wk of therapy in
each cycle. No grade 3-4 bleeds
f. Not reported
Kuter 2008
(B-U/1/1A)
Divided into 2 studies:
splenectomized (n=63)
and non-splenectomized
patients (n=62)
125
6 mo
Randomly assigned 2:1
to receive weekly subq
inj of Nplate or placebo
for 24 wks (stratified
according to concurrent
ITP treatment)
Initial Dosing: 1mcg/kg
Maintenance Dosing
Adjusted based on
platelet response
Median Age (yr): 52
Age Range: 21-88
Female: 81
Male: 44
Phase III, DB, PC,
MC (35 sites in US
and Europe), PG,
safety / efficacy RCT
1. Durable platelet response (min 6 wks with count
>50,000/mcL and no rescue meds) during the last 8
wks of treatment
White: 102
Black/African American: 9
Hispanic/Latino: 8
Other: 6
2a.Safety
Wt (kg): 79
>3 previous Treatments: 79
Avg platelet count:
16,000/mcL
Platelets ≤15,000/mcL: 55
Thrombopoietin
conc:103pg,mL
Current ITP therapy: 39
c. frequency of overall response (durable +
transient)
b. Transient response (>4 weekly counts
>50,000/mcL and no rescue meds from wk 2-25)
d. Number of weekly responses
e. Patients requiring rescue meds
f. Reductions in concurrent ITP therapies
g. Changes in Patient Reported Outcomes and
Health Resource Utilization
Max dose: 15mcg/kg.
Placebo and treatment
groups had similar baseline
demographic profiles in
each study
1. Splenectomized: 38% (Nplate) vs. 0 (placebo)
Non-splenectomized: 61% (Nplate) vs. 5% (placebo)
2a. No difference in safety profi le between
splenectomized and non-splenectomized pts assigned to
Nplate, so safety data was pooled for all patients in
placebo and Nplate.
All ADEs: 83% Nplate pts vs. 95% placebo pts
b. Splenectomized: 40% (Nplate)vs. 0 (placebo)
Non-splenectomized: 27%(Nplate) vs. not reported
c. Splenectomized: 79% (Nplate)vs. 0 (placebo)
Non-splenectomized: 88%(Nplate) vs. 14%(placebo)
d. Splenectomized: 12.3(Nplate)vs. 0.2 (placebo)
Non-splenectomized: 15.2(Nplate) vs. 1.3(placebo)
e. Splenectomized: 26%(Nplate)vs. 57%(placebo)
Non-splenectomized: 17%(Nplate)vs. 62%(placebo
f. 52% (Nlate) vs. 19% (placebo) discontinued all concurrent
ITP drugs in 1st 12 wks of study
g. Not reported
Bussel 2007
(B/1/IB)
Nplate1mcg/mL subq inj 137
weekly.
Dose adjustment based
on platelet counts and
allowed throughout the
duration of the study.
Rescue therapies are
allowed at any time
during the study.
Reductions in concurrent
ITP therapies may occur
at any time if platelet
counts are > 50,000/mcL
Ongoing
(2 yr
update)
Median Age (yr): 53 + 15
Female: 91
Male: 46
Mean platelet count:
18,000/mcL
Splenectomized: 82
Phase III, Treatment,
Non-Randomized,
Open Label/Extension,
Single Group
Assignment, Long
Term, MC (122
international sites),
Safety/Efficacy Study
1. Incidence of ADEs, including clinically significant
changes in lab values and incidence of antibody
formation.
1. most frequent ADEs: headache (31%), contusion (27%),
fatigue (24%), diarrhea (24%), epistaxis (23%),
nasopharyngitis (21%), arthralgia (20%)
2a. Incidence of platelet response (2x baseline and
count ≥ 50,000/mcL).
No trend for inc ADE frequency with inc drug exposure
b. Incidence of a platelet count increase of 20,000/mcL
over baseline.
1 pt developed neutralizing antibodies
11/137 pts had serious ADEs, 3 withdrew from study
2a. 112 pts (82%) achieved platelet response
b. Not reported
Abbreviations used in this table: AC =active control, CCS = case-control study, DB = double blind, PC = placebo control, PCS = prospective cohort study, PG = parallel group, MA = meta-analysis MC = multicenter, RCS
= retrospective cohort study, RCT = randomized controlled trial, XO = crossover
Table 3. Validation of instruments used in studies included in this review.
Instrument
Abbreviation
Immune
ITP-PAQ
Thrombocytopenic
Purpura (ITP)Patient Assessment
Questionnaire
Description
Assesses health-related
quality of life (HRQoL) in
patients with ITP.
Numerical
Scale
standardized
to 0-100
Divided into 11 scales of
interest: Symptoms, Fatigue,
Physical Health, Bother,
Physical Health-Activity,
Emotional HealthPsychological, Emotional
Health-Fear, Overall Quality
of Life, Women's
Reproductive HealthFertility, Women's
Reproductive HealthMenstrual Symptoms, and
Work
Interpretation of Values
IITP-PAQ HRQoL values are reported to analyze statistical differences between those
values in patients to evaluate prospective treatments and their impact on perceived
patient quality of life.
Values closer to 0 correspond to a patient experiencing little effect of ITP on a given
variable. Accordingly, values closer to
100 correspond to a patient experiencing a great deal of effect.
M.I.D.*
symptoms: 9.3
bother: 10.5
social activity: 10
menstrual symptoms: 25.7
fertility (not statistically significant): 14.1
overall quality of life (not statistically
significant): 10.2
fatigue and activity: 10-15
HRQoL is used to quantitatively measure differences in QoL of a population or an
individual. Stastical analyses of the scores will be compared, for example, to determine
the effect of a new medication on the HRQoL of patients with ITP from baseline
throughout the therapy.
4-7 responses per scale
Child-TurcottePugh
CTP
Utilizes 5 clinical measures
of liver disease: ascites,
encephalopathy, bilirubin,
albumin, and prothrombin
time (PT). Allots points of 1
to 3 according established
values for each measure.
Cumulative points from 5 to
15 are used to classify
chronic liver disease into
three classes.
1, 2, or 3
Chronic liver disease is classified into three classes: A, B, C.
Ascites: none,
slight, moderatesevere
Class A: 5-6 points, well-compensated disease, % of 1 and 2 year survival of 100% and
85%
Encephalopy:
none, slightmoderate,
moderate-severe
*Not found
Class B: 7-9 points, significant functional compromise, % of 1 and 2 year survival of
80% and 60%
Class C: 10-15 points, decompensated disease, % of 1 and 2 year survival of 45% and
35%
Bilirubin:
<3mg/dL, 23mg/dL, >3mg/dL
Albumin:
>3.5g/dL, 2.83.5g/dL,
<2.38g/dL
Prothrombin Time
(sec increased):
<4 sec, 4-6 sec,
>6 sec
World Health
Organization
Bleeding Scale
WHO Bleeding
Scale
Rates bleeding events on a
scale of 0 to 4
0 to 4
Grade 0: no bleeding
*Not found
Grade 1: petechiae
Grade 2: mild blood loss
Grade 3: gross blood loss
Grade 4: debilitating
* M.I.D. = minimal important difference, usually determined by the originator or owner of the instrument. This number represents a threshold below which a numerical difference is not considered to be clinically meaningful, even if
statistically significant. Differences less than this amount are usually excluded from discussions of incremental clinical effect.
Table 4. Cost-effectiveness evidence summary
Ref. and
Sponsor
Study
Design/Drug(s)
Budget impact
Romiplostim versus watch
modeling report for
and rescue
romiplostim for adult
patients with chronic
ITP. Data on file,
Amgen; August
28,2008.
Population
Splenetomized and
non-splenectomized
patients with ITP
having responded to
an initial course of
steroids and have
relapsed after
discontinuation.
Time Horizon Model Inputs and Data Sources
3-yr time period
Amgen
calculates total
Budget Impact Model expected annual costs of
treatment of chronic ITP
GlaxoSmithKline
under two alternative
treatment scenarios:
(1) before and
(2) after introduction of
eltrombopag on formulary
costs calculated on
per treatment episode
basis
Treatment episode
defined as single
uninterrupted course
of pharmacotherapy
per product label, as
observed in general
clinical practice or
reported in the
literature.
6 weeks
• 80% of new ITP patients will fail
corticosteroids and will require a new
therapy for ITP
• 70% of prevalent chronic ITP patients
had not yet undergone a splenectomy
• Of non-splenectomized patients, 67%
will seek a new therapy in each year
• 36% of splenectomized patients will
have failed splenectomy (including both
surgical failure and relapse) and will seek
a new treatment
• 1.3% of non-splenectomized patients
and 15% of splenectomized patients who
require a new treatment will use
romiplostim
-% of patients who are Rh-positive
-% of patients who are Rh-negative
-% of patients non-splenectomized
-% of patients splenectomized
Interventions
Results
Sensitivity Analysis
% of patients with Chronic ITP
-Cost per vial
-% of patients requiring new
therapy
-Utilization of Romiplostim
-Immunoglobulin Cost
-% of Splenectomized Prevalent
patients
-Frequency of bleeding events
The model assumes that a plan population of 1,000,000 lives
will have 288 ITP cases each year requiring treatment, among
whom 5 patients will receive romiplostim
.
The expected 3-year per-patient cost for romiplostim treatment
is $214,680 versus $177,306 for watch and rescue.
N= 10 million
Total number of treatment episodes iacross the
pharmacotherapy options considered = 1,959.
The incremental cost of romiplostim ($193,611)corresponds to
a per member per month (PMPM) of $0.005 for a payer
covering 1,000,000 lives.
Prevalence of chronic ITP
(default is 0.0236%)
After introduction of eltrombopag, 1% of treatment episodes
of oral corticosteroids and 10% of treatment episodes of IVIG,
Assumed proportion receiving anti-D, rituximab, and romiplostim switched to eltrombopag,
each pharmacotherapy in any yr ther will be 36 treatment episodes with eltrombopag.
Assumed # of treatment episodes Total estimated cost of managing the chronic ITP population
per patient per yr
is $1,492,978 and $1,513,517 before and after
introduction of eltrombopag, respectively.
Assumed treatment episodes
Cost per member with ITP is $633 and $641 before and
Cost per treatment episode for
after introduction of eltrombopag, respectively.
each pharmacotherapy option
applying WAC and Medicare
Cost per member per month is $0.0124 and $0.0126 before
reimbursable administration
and after introduction of eltrombopag, respectively.
rates
BACKGROUND INFORMATION
DISEASE BACKGROUND
ITP (Idiopathic thrombocytopenic Purpura) is an autoimmune disorder which causes patients to have a low platelet count and consequently increases their
chances of bleeding, especially mucocutaneous bleeding, which causes patients’ skin to look purple (purpura). Symptoms include excessive bruising with minor
trauma, severe mucocutaneous bleeding, gingivial bleeding, hematuria, menorrhagia, risk of internal bleeding, and spontaneous development of petechiae,
purpura, or ecchymoses. These symptoms, along with increasing risk for patient safety, also restrict the patient’s lifestyle and drain him or her of energy.
Disease Burden
The incidence of ITP is estimated to be 1.6 to 2.68 per 100,000 persons per year overall, and 4.62 per 100,000 persons over the age of 60.. In the United States,
the prevalence of chronic ITP is around 60,000, with adults making up 53,000 of that. The incidence of ITP appears to be increasing with age and the female sex.
Pathophysiology
The decrease in platelet count in ITP is an imbalance between platelet production and destruction. Platelets have
a life-span of about 10 days, ultimately being destroyed by macrophages in the spleen or liver. About one third of
the platelets remain stored in the spleen. Patient with ITP produce anti-platelet autoantibodies that attach to the
platelets, allowing for their premature destruction by macrophages. Along with increased platelet destruction,
platelet production plays a secondary role in ITP. Platelets are produced from megakaryocytes found in the bone
marrow. Antibodies may also bind to these megakaryocytes, leading to reduced platelet production. These
antibodies cause an increased destruction and decreased production of platelets, leading to a dramatically low
platelet count in ITP patients. Since the disease is classified as idiopathic, the root cause of the antibody
production is still unknown. Recent findings suggest that this may be due to a deficiency in TPO or
thrombopoietin, which binds to TPO receptors on megakaryocytes, which activates the maturation of
megakaryoctyes and consequently aids the process of platelet production.
TREATMENT ALTERNATIVES
The goal of treating ITP is to minimize treatment while maintaining a safe platelet count. Patients with platelet
counts less than 50 x 109/L and significant mucousal bleeding or presence of risk factors of bleeding, including
hyptertension, peptic ulcer disease, or a vigerous lifestyle and all patients with a platelet count less than 20 x
109/L are recommended to start treatment.
Preferred Existing Therapy
First line treatment, as recommended by the American Society of Hematology Adult ITP Treatment Guidelines,
is glucocorticoids, and IVIG (Intravenous Immune Globulin) for severe patients.
Other Therapeutic Alternatives
Second line option, for patients in which glucocorticoids and IVIG fail, is spleenectomy, and third line
alternative is danazol or azathioprine in addition to first and second line therapies. Platelet transfusions may also
be warranted.
PRODUCT BACKGROUND
Table 5. Comparison of Labeled Indications
romiplostim
patients with chronic
ITP who have failed
corticosteriod,
imunoglobulin, or
splenectomy treatment
(incomplete response)
eltrombopag
patients with chronic
ITP who have failed
corticosteriod,
immunoglobulin, or
splenectomy treatment
(incomplete response)
Pharmacology
Eltrombopag and romiplostim are both thrombopoietin receptor agonists that activate the thrombopoetin (TPO)
receptor. Romiplostim is an Fc-peptide fusion protein that directy binds the TPO receptor while eltrombopag
interacts with the transmembrane domain in order to activate the TPO receptor. The active TPO receptor
interacts with JAK (a tyrosine kinase) while is involved in propagating the signal through STAT proteins or the
MAPK cascade ultimately inducing the transciption of genes that affect the proliferation and differentiation of
megakaryotes from pluripotent hemopoetic stem cells and megakaryocytic progenitors. Megakaryocytes
eventually break down into smaller units and produce platelets, which also possess TPO receptors.
Pharmacokinetics
Table 6. Comparison of Pharmacokinetics, Monitoring Requirements and Key Drug Interactions
Bioavailability
Elimination T1/2
Protein Binding
Excretion: % unchanged
Other Pharmacokinetic
Factors
Dosing in RF
Dosing in HF
Monitoring
Drug Interactions
romiplostim
Not established
1-34 days
Not established
Dependent on TPO receptors
eltrombopag
52%
26-35 hours
99%
31% Kidney
20% Hepatic
Males have 27% greater clearance than
females. Dose adjustment in East Asians.
Not Established
Not established
Not Established
Need to Adjust to 25mg QD.
Liver Tests
Liver Tests
CBC
CBC
Platelet Count
Platelet Count
Blood Smears
Blood Smears
(Weekly until stability reached, then (Weekly until stability reached, then
monthly).
monthly).
No formal interaction studies have None established, but anticipate
been performed,
interaction with rosuvastatin or other
OATP1B1 substrates or other UGT
substrates CYP2C8, CYP2C9 and
CYP1A2.
Adverse Effect Profile
Both eltrombopag and romiplostim have reported adverse effects of bone marrow reticulation formation and
risk for bone marrow fibrosis as well as the a worsening of thrombocytopenia and bleeding risk after the
discontinuation of either medication. Additionally, both medications are associated with a risk for
thrombotic complications due to excessive increases in platelet levels and the progression of malignancies.
Evidence for the adverse effect of bone marrow reticulation formation is minimal as clinical studies are
unable to pinpoint either medication as the cause for bone marrow reticulation.
Very few serious adverse events were found compared to placebo in the clinical studies done to assess
either medication of this class. Additionally, the total proportion of less serious adverse events such as
headaches were generally less than or equal to the percentage of placebo patients experiencing the same side
effects. It is important to note that side effects are common to patients suffering from ITP and that even
without therapy of these agents, the majority of the side effects experienced by patients taking romiplostim
or eltrombopag were similarly experienced by those taking placebo (and presumably concomittant ITP
therapies). A summary of the comparisons of Adverse Events with significant difference between placebo
and the studied medications is as follows:
Placebo
Eltrombopag
Study
30, 50, 75mg*
Overall total Adverse Events (AE)
59%
47, 47, 61%,
Overall bleeding
14%
17, 7, 4 %
AE Grade 3 or higher
13%
7, 13, 11%
AST elevation
0%
3, 0, 7%
Rash
3%
3, 0, 7%
any AE
37%
59%
nausea
0%
8%
vomiting
0%
5%
Phase II*
Phase III
Any AE
92%
87%
severe adverse event
18%
11%
hepatobiliary AE
8%
12%
ocular -related events
20%
22%
any AE
95%
100%
headache
32%
35%
Fatigue
29%
33%
Epistaxis
24%
32%
arthralgia
20%
26%
upper respiratory tract infection
12%
17%
dizziness
0%
17%
insomnia
7%
16%
myalgia
2%
14%
pain in extremity
5%
13%
diarrhea
15%
17%
headache
31%
epistaxis
23%
fatigue
24%
diarrhea
24%
arthralgia
20%
headache
0%
29%
oral mucosal blisters
0%
29%
contusion
50%
53%
any AE
50%
44%
headache
6%
13%
sore throat
6%
13%
back pain
19%
3%
Raise
Kuter DJ 2008
Bussel
Kuter 2004
Wang
For eltrombopag, side effects that differed from placebo were nausea, vomiting, and hepatic adverse events.
For romiplostim adverse events that may be significant in romiplostim patients compared to placebo
include: epistaxis, headache, sore throat, insomnia, myalgia, upper respiratory tract infection, dizziness,
insomnia, pain in extremity, oral mucosal blisters, and arthralgia.
Drug Interactions
While there are no studied drug interactions for romiplostim there are a few known and possible drug
interactions associated with eltrombopag. Since these medications both act on the TPO receptor, although
through slightly different medications, it may be useful for physicians prescribing romiplostim to consider
the same drug interactions found with eltrombopag. Eltrombopag is known to bind to polyvanent cations in
antacids, minerals, and foods which inhibit its absorption. Additionally, invitro studies have demonstrated
that it inhibits the transport of substrates associated with OATP1BI (transporter), increasing systemic
explosure. Eltrombopag also inhibits UDP-glucuronosyltransferases (UGTs) UGT1A (1,3,4,6,9), UGT2B7,
and UGT2B15 which help to metabolize NSAIDs although there are no clinical studies evaluting the effect
of this inhibition on NSAIDs or other subtrates utilizing these UGTs. Finally, Eltrombopag is oxidatively
metabolized by CYP1A2 and CYP2C8 but again, no clinical trials have evaluated the effects of
eltrombopag on other drugs or vice versa.
METHODOLOGY OF THIS REVIEW
DATABASES SEARCHED: Medline, Clinicaltrials.gov, Others: Ovid, CEA Registry
SECONDARY SOURCES: NICE
SEARCH STRATEGY: Ovid
Cost effectiveness Studies
1. eltrombopag.mp.
2. Cost-Benefit Analysis/ or Economics, Pharmaceutical/ or incremental cost-effectiveness ratios.mp. or Health Care Costs/
3. Purpura, Thrombocytopenic, Idiopathic/ or promacta.mp.
4. 2 and 3
5. Purpura, Thrombocytopenic, Idiopathic/ or romiplostim.mp.
6. 2 and 5
Clinical Trials and Articles associated with Thrombopoetin receptor agonists
1. Purpura, Thrombocytopenic, Idopatihic/ and Receptors, Thrombopoetin
INCLUSION CRITERIA:
Abstracts, Review Articles, Humans, English Language, Full Text, Clinical Journals (AIM)
Search Results:
Study Type
Randomized controlled trials (RCT)
Meta-analyses of RCTs
Systematic reviews
Randomized pragmatic Trials
Prospective cohort studies
Retrospective cohort or case-control studies
Economic modeling studies
Case Series
RCT abstracts, not peer-reviewed
Other abstracts, posters, etc., not peer-reviewed
REVIEW PREPARED BY
Cari Cline, PharmD Candidate 2013
Shailly Shah , PharmD Candidate 2012
Brad Stevens, PharmD Candidate 2012
Nick Wytiaz, PharmD Candidate 2012
N
7
2
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