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Spotlight On... Chronic
Myeloid Leukemia
A PHARMA MATTERS REPORT.
A REVIEW OF JANUARY-MARCH 2012. PUBLISHED APRIL 2012.
Expert therapy area review of the key market players and
deals highlights for leading areas of industry investment
and development. These insightful reviews are based on the
strategic data and insights from Thomson Reuters Cortellis™.
ABSTRACT
With the advent of targeted therapy, chronic myeloid leukemia
(CML) has undergone a major transformation from a terminal
disease to an essentially manageable chronic condition. Despite
significantly improved survival rates, there still remains room for
improvement in efficacy, tolerability, and resistance potential.
Though the tyrosine kinase inhibitor Gleevec is regarded as the
poster child for rational drug design, more efficacious secondgeneration agents are starting to gain acceptance in first-line
use; however, in the absence of mature survival data, their longterm benefit over Gleevec remains to be seen. As patients remain
on therapy for increasing periods of time, management of toxicity
and cost are likely to be significant drivers of treatment choice.
The CML pipeline is primarily focused on therapies to overcome
resistance, which is particularly problematic following failure
of first-line agents and an unmet need still exists for third-line
options. For patients responding well to treatment with tyrosine
kinase inhibitors, the ultimate question is whether such therapy
can lead to a cure.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
SECTION I
INTRODUCTION
Chronic myeloid leukemia, also known as chronic myelogenous
leukemia (CML), is an acquired clonal myeloproliferative disorder
of the hematopoietic stem cell, accounting for 15 percent of all
leukemias and 20 percent of adult leukemias. Although observed
in all age groups, CML is typically a disease of later life, with
a median age of onset of 67 years. Unlike most other cancers,
CML is associated with a single oncogene product that is critical
to the pathology of the disease. The vast majority of CML cases
are caused by a reciprocal translocation between chromosomes
9 and 22 resulting in the formation of the Philadelphia (Ph)
chromosome, which is consequently used in the cytogenetic
diagnosis of CML.
CML is believed to develop when a single pluripotent
hematopoietic stem cell acquires a Ph chromosome; the Ph
chromosome confers a survival advantage to the cell and the Phpositive lineage eventually displaces normal hematopoietic cells,
leading to a loss of hematopoietic function. The Ph chromosome
contains an oncogene consisting of the breakpoint cluster region
(BCR) gene and the Abelson murine leukemia (ABL) gene. The
product of the BCR-ABL fusion gene is the p210BCR-ABL tyrosine
kinase, which contains the N-terminal domain of BCR and the
C-terminal domain of ABL. The chimeric protein is constitutively
active and has elevated kinase activity compared with the normal
ABL protein. The tyrosine kinase activity of the p210BCR-ABL
protein is associated with increased proliferation and decreased
apoptotic responses, leading to overproduction of myeloid cells
and premature release of undifferentiated myeloid cells into
the circulation. DNA repair is also dysregulated, which leads to
genetic instability associated with disease progression.
CML is a triphasic disease, typically progressing from a chronic
phase through a transient accelerated phase to the rapidly fatal
blast crisis or blastic phase. The chronic phase is characterized
by the overproduction of myeloid cells that retain their ability to
differentiate and function normally. If untreated, chronic-phase CML
generally progresses to advanced disease in approximately three to
five years. Disease progression is associated with clonal evolution
due to the accumulation of additional chromosomal abnormalities
that decrease the ability of the leukemic cells to differentiate. The
blastic phase resembles an acute leukemia, and is typified by poor
prognosis and a survival time of only 3 to 6 months due to the rapid
accumulation of undifferentiated blast cells.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
CML THERAPY: FROM THE DARK AGES TO THE
GLEEVEC ERA
Currently, the only curative treatment option for CML is an
allogeneic hematopoietic stem cell transplant (HSCT); however,
this procedure is not feasible for the majority of CML patients.
Issues include age, lack of a suitable donor, and the morbidity
and mortality associated with the procedure and its associated
complications such as opportunistic infections and graft-versushost disease. Since HSCT carries a mortality rate of 15 to 40
percent, non-curative options are more frequently utilized to
delay disease progression from the chronic to the blastic phase.
CML was historically treated with cytotoxic chemotherapeutic
agents such as busulfan and hydroxyurea, which controlled
clinical manifestations of the disease but did not eliminate
the Ph-positive malignant cells. The introduction of interferon
(IFN)-alfa significantly improved survival and resulted in durable
cytogenetic responses in 10 to 30 percent of patients, but
at the cost of significant toxicity. Nevertheless, IFN-alfa was
formerly regarded as the treatment of choice for CML. Further
improvements in response were observed with the combination
of IFN-alfa and chemotherapy, but side effects remained
problematic. Historically, the survival time from diagnosis was
just five years.
GLEEVEC: AN ARCHETYPE OF RATIONAL
DRUG DESIGN
The BCR-ABL fusion gene was the first genetic abnormality to be
associated with a specific malignancy and enabled the development
of the BCR-ABL tyrosine kinase inhibitor (TKI) Gleevec/Glivec
(imatinib) by Novartis. Due to its targeted mechanism of action,
Gleevec has a negligible effect on other cellular tyrosine kinases and
consequently fewer side effects compared with more traditional,
non-targeted cytotoxic oncology drugs.
The success of Gleevec is considered a huge victory for rational
drug discovery. In the US, Gleevec received accelerated approval
in May 2001 for the treatment of CML patients in any phase
of the disease who had failed to respond to IFN-alfa therapy,
based on the unprecedented improvements in response
observed in phase II studies. The drug’s label was expanded
soon after in December 2002 to allow first-line use, also under
the accelerated approval process. Gleevec was a huge success
for Novartis as a result of its impressive activity and favorable
tolerability, achieving sales in excess of $1 billion by its third year
of launch (see FIGURE 1).
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
Gleevec
SALES IN US $ MILLIONS
5000
4000
3000
2000
1000
0
11
20
10
20
09
20
08
20
07
20
06
20
05
20
04
20
03
20
02
20
01
20
00
20
YEAR
Figure 1: gleevec sales Figures 2000 to 2011 (Data are DeriveD
From Thomson ReuTeRs CoRTellis foR CompeTiTive inTelligenCe)
The approval of Gleevec has been hailed as a defining moment
for translational research; the drug has revolutionized CML by
transforming a fatal cancer into a chronic, often manageable
disease. With the advent of Gleevec, patients with chronic-phase
CML can now hope to remain symptom-free for at least 10 years
and may enjoy a normal lifespan. Median survival from diagnosis
can reach 30 years, with some patients never progressing to the
blastic phase. Life-long use of Gleevec is supported by long-term
follow-up data from the IRIS study, which have demonstrated
high durable response rates in Gleevec-treated patients. At eight
years follow-up, the event-free, progression-free, and overall
survival rates were estimated to be 81, 92, and 85 percent,
respectively, for Gleevec-treated patients.
The improved survival of CML patients as a result of therapeutic
advances has led to improved methods of evaluating treatment
success and failure. Response to therapy is assessed by
hematologic, cytogenetic, and molecular responses, which
correlate to increasing depths of response to treatment. The
initial treatment milestone is a complete hematologic response,
or normalization of blood cell counts, which is expected to occur
3 months after initiation of treatment and is associated with
resolution of CML symptoms. The next therapeutic goal is to
achieve a major cytogenetic response (MCyR; </= 35 percent
Ph+ metaphases in the bone marrow or blood) by 12 months
and a complete cytogenetic response (CCyR; no detectable
Ph+ metaphases) by 18 months. Currently, the ultimate
treatment aim is to achieve a major molecular response (MMR)
or a complete molecular response (CMR), defined as a 3-log
reduction in BCR-ABL transcripts and no detectable BCR-ABL
transcripts, respectively, usually assessed by quantitative or
nested PCR. Achieving the milestone of MMR after 12 months of
therapy is associated with a very low risk of disease relapse. With
the success of TKI therapy, the next conundrums to be addressed
are whether a durable CMR can be considered the equivalent of
a cure, and whether discontinuation of therapy is a viable option
for patients achieving long-lasting molecular responses.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
LIMITATIONS OF GLEEVEC
Despite the unparalleled improvements in response
observed with Gleevec, the IRIS study has its limitations. In
particular, questions have arisen over the high level of patient
discontinuation and the censoring of data in cases of study
discontinuation. Because only 55 percent of patients remained
on Gleevec at the eight year follow-up, it is possible that
the survival rates have been overestimated. Indeed, it has
been suggested that if the calculation of event-free survival
includes patients who discontinued treatment due to toxicity
or inadequate cytogenetic response, the five-year event-free
survival rate drops from 83 percent to 62.7 percent.
With the development of a highly specific, single-target therapy
for CML, it is perhaps unsurprising that drug resistance has
emerged as a significant threat to continued treatment success.
Resistance to Gleevec has been documented in 20 to 30 percent
of patients and can be categorized as either primary or secondary.
Primary hematologic resistance, defined as a failure to achieve
hematologic remission within 3 to 6 months of Gleevec initiation,
is relatively rare in newly diagnosed patients in chronic phase,
occurring in approximately 2 percent of patients. However, primary
cytogenetic resistance, defined as a failure to achieve any form of
cytogenetic response at 6 months, MCyR at 12 months or CCyR
at 18 months, is somewhat more common, documented in 15 to
25 percent of patients. Although the precise etiology of primary
resistance has not been fully characterized, over-expression of
multidrug resistance protein 1 and low expression of human
organic cation transporter 1 (hOCT1) have been associated
with suboptimal responses to Gleevec. Although not routinely
assessed at the time of diagnosis, it has been suggested that
hOCT1 may be useful as a prognostic indicator of treatment
response, as pretreatment levels have been shown to be the
most powerful predictor of response to Gleevec therapy. Studies
have demonstrated that high pretreatment hOCT1 expression is
associated with significantly superior survival outcomes.
Secondary (or acquired) resistance is defined by a loss of
response in patients previously responding to therapy and is
associated with progression to blastic-phase disease. The most
frequent cause of resistance is point mutations in the ABL kinase
domain of the BCR-ABL fusion protein. Gleevec interacts with
the ATP-binding site of the ABL kinase domain in the inactive,
closed confirmation, preventing a conformational change to the
active form of the enzyme. This rigid structural requirement for
entry and binding means that a single amino acid substitution
can confer resistance to Gleevec by disrupting the binding of
the drug to the active site. The T315I mutation in the ABL kinase
domain confers the highest resistance to Gleevec and has been
associated with a poor prognosis, particularly in more advanced
stages of the disease.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
Other mechanisms of secondary resistance have also been
documented and include over-expression and gene amplification
of BCR-ABL. Resistance is believed to be multifactorial, as
data from the START-C study demonstrated that 46 percent of
patients with Gleevec-resistant chronic-phase CML did not carry
BCR-ABL mutations.
It has been postulated that the true burden of Gleevec resistance
may be underestimated. Direct comparisons of the resistance
rates observed in clinical studies are difficult due to the different
definitions of treatment failure used across the studies. In
addition, the continued participation of only 55 percent of the
original IRIS cohort and the high level of data censoring may
compound the issue.
Patient adherence to therapy has been highlighted as critical to
the development of resistance to Gleevec. It is well recognized
that lack of adherence is a major problem associated with longterm oral therapy for chronic diseases; non-adherence to Gleevec
has been well documented and has a significant impact on
treatment efficacy. Studies have shown that poor adherence is
the most important factor contributing to treatment failure and
cytogenetic relapse. Appropriate management of side effects,
close monitoring and patient education may help to improve
adherence and consequently prevent or delay the development
of resistance. It is estimated that 5 to 10 percent of patients will
discontinue Gleevec due to side effects. As patients remain on
therapy for increasingly extended periods of time, management
of side effects becomes critical to maintaining adherence, as well
as patient quality of life and disease remission.
THE SECOND GENERATION OF TKIS:
TASIGNA AND SPRYCEL
Although Gleevec is still considered a revolutionary therapy,
resistance has necessitated the development of new therapies
to provide treatment options for patients who fail to respond.
Understanding the mechanisms of resistance to Gleevec has
aided development of the rationally-designed second-generation
TKIs Sprycel (dasatinib) and Tasigna (nilotinib).
Bristol-Myers Squibb’s (BMS) Sprycel is a dual SRC/BCR-ABL
kinase inhibitor, first approved for second-line use in 2006 and
subsequently granted first-line approval in 2010. In contrast
to Gleevec and Tasigna, Sprycel binds to both the active and
inactive forms of BCR-ABL and demonstrates enhanced efficacy
compared with Gleevec due to recognition of multiple forms of
the protein and a greater binding affinity. Sprycel has in vitro
activity against almost all Gleevec-resistant BCR-ABL mutations;
however, it is ineffective in disease with the T315I mutation.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
“These drugs have dramatically changed
the lives of patients with Cml.”
Richard Pazdur, MD, Director of the Office of
Oncology Drug Products in the FDA’s Center for Drug
Evaluation and Research
Novartis’s BCR-ABL kinase inhibitor Tasigna was developed by
modification of Gleevec, resulting in a drug that displays higher
affinity for the inactive form of BCR-ABL and demonstrates
greater efficacy than the parent compound. Tasigna was
approved for second-line use in 2007 and first-line use in 2010.
Similar to Sprycel, Tasigna has no efficacy against leukemic cells
with the T315I mutation.
WHICH TKI FOR FIRST-LINE THERAPY?
With three TKIs approved for the first-line treatment of chronicphase CML, physicians now have a choice of therapies that can
be selected according to their patients’ needs. Both Sprycel and
Tasigna have demonstrated good efficacy in the first-line setting
and so treatment choice will depend on physician familiarity,
disease risk score, patient age, presence of comorbid conditions
and the patient’s ability to tolerate therapy.
Head-to-head studies of the second-generation TKIs will be
crucial in determining the most appropriate therapy for first-line
use. Further investigation on surrogate endpoints as predictors
of survival will also be useful to determine if the higher rate
of molecular responses observed with the second-generation
TKIs confer prolonged survival over Gleevec. Although both
second-generation TKIs have been associated with significantly
higher rates of CCyR and MMR than Gleevec, the ENESTnd
and DASISION studies have not yet demonstrated significant
improvements in progression-free and overall survival. A
summary of two-year data from the ENESTnd and DASISION
studies is shown in Table 1.
TRIAL
FOLLOW UP
(MONTHS)
ENESTnd
DASISION
24
24
Tasigna
300 mg
bid
Tasigna
400 mg
bid
Gleevec
400 mg
qd
Sprycel
100 mg
qd
CCyR (%)
87
MMR (%)
71
85
77
86
82
67
44
64
46
CMR (%)
26
21
10
NA
NA
Progression-free
survival (%)
98.0
97.7
95.2
93.7
92.1
Overall survival (%)
97.4
97.8
96.3
95.3
95.2
25
22
32
19
20
Dosing
Discontinued
treatment (%)
Gleevec
400 mg
qd
NA: not available
table 1: comparison oF First-line tKis
Further follow-up data from ENESTnd have shown that both
MMR and CMR4.5 (CMR at a sensitivity of ≥ 4.5 log reduction in
BCR-ABL transcripts) were significantly higher for both doses of
Tasigna compared with Gleevec at three years, and significantly
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
fewer Tasigna-treated patients progressed to accelerated or blastic
phase. Although there was still no significant difference in overall
survival between the treatment groups at three years follow-up
(95.1, 97 and 94 percent for 300 mg Tasigna, 400 mg Tasigna and
Gleevec, respectively), significantly fewer Tasigna-treated patients
died following disease progression to accelerated or blastic phase.
The significant benefit of Tasigna in terms of delaying disease
progression could boost the drug’s first-line prospects, as such a
benefit has not yet been observed for Sprycel.
Stratification of patients by risk group could lead to preferential
prescription of second-generation TKIs over Gleevec in higherrisk patient groups, as Tasigna and Sprycel have been associated
with lower rates of progression in intermediate- and highrisk patients. The National Comprehensive Cancer Network’s
guidelines recommend determination of risk status as part of
the initial evaluation of CML patients. The patient’s mutational
status may also influence the choice of drug: Tasigna is
recommended for patients with V299L, T315A, or F317L/V/I/C
mutations, whereas Sprycel is indicated for patients with Y253H,
E255K/V, or F359V/C/I mutations.
Due to Sprycel’s potential to cause pleural effusion, Tasigna may
be more suitable in patients at risk of this complication, whereas
Sprycel may be a more appropriate choice for patients with a
history of pancreatitis or hyperglycemia. Pleural effusion is a
common side effect of Sprycel therapy, with one recent analysis of
phase I and II studies documenting its occurrence in 29 percent of
chronic-phase, 50 percent of accelerated-phase and 33 percent
of blastic-phase patients. Dose interruptions and reductions were
required in the majority of patients receiving Sprycel in these
studies (83 and 71 percent of patients, respectively). Additionally,
the high cost associated with management of pleural effusion may
influence the choice of therapy.
Tolerability and patient convenience are significant drivers of
therapy choice for diseases that require long-term therapy.
Tasigna’s twice-daily dosing and fasting requirements make
the drug less convenient compared with once-daily Gleevec
and Sprycel, and may negatively impact patient adherence. As
adherence is critical to achieving an optimal response to therapy,
dosing convenience is an important consideration. However,
while Sprycel can be administered once-daily with or without
food, it is generally not as well tolerated as Tasigna. Healthrelated quality of life data is also notably lacking and will be
useful for therapy selection.
Cost-effectiveness is also a major consideration in TKI selection
in the absence of a clear frontrunner in terms of efficacy. One
analysis demonstrated that Tasigna-treated patients had greater
adherence to therapy and incurred lower healthcare costs
compared with Sprycel-treated patients. Despite the higher
rate of molecular responses with second-generation TKIs, in
the absence of a proven survival benefit, these newer, more
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
expensive medications are unlikely to be recommended for
reimbursement if clear patient benefit over the cheaper Gleevec
cannot be demonstrated. It is likely that long-term survival
data will be required before widespread adoption of secondgeneration TKIs as first-line drugs of choice.
As chronic-phase CML patients are likely to remain on their firstline therapy for many years, the first-line setting represents the
biggest market opportunity in the CML arena. In the absence of
mature survival data and head-to-head studies, much effort has
been made by Tasigna and Sprycel’s respective marketeers to
position their drugs as the therapy of choice over Gleevec in the
first-line setting. Novartis’s presence in the hematology market
with Gleevec may confer a competitive advantage to Tasigna. In
addition to Novartis’s experience in CML, Tasigna appears to be
associated with superior cost-effectiveness; consequently, Sprycel
could see comparatively limited use in the first-line setting. Indeed,
according to Consensus data from Thomson Reuters Cortellis™ for
Competitive Intelligence, Tasigna is expected to edge out Sprycel,
with predicted sales of $2.383 billion and $1.600 billion for the two
respective agents in 2016 (see FIGURE 2).
2011
2016
Gleevec
Tasigna
Sprycel
0
1000
2000
3000
4000
5000
SALES IN US $ MILLIONS
Figure 2: 2011 versus 2016 sales For gleevec, tasigna,
anD sprycel (Data are DeriveD From Thomson ReuTeRs
CoRTellis foR CompeTiTive inTelligenCe)
For either second-generation drug to maintain a stronghold they
will need to cement their front-line position before Gleevec goes offpatent in 2015, as the looming impact of generic Gleevec is likely to
significantly change the dynamics of the first-line CML market.
GENERIC GLEEVEC: IMPACT ON MARKET DYNAMICS
The arrival of generic Gleevec in the US in 2015 has the potential
to significantly change the CML treatment paradigm. Pressure
from reimbursers may trigger a resurgence in first-line use of
imatinib due to the need to reduce healthcare costs, a point of
particular relevance in the CML market where branded drugs
command premium prices and treatment may last decades.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
Gleevec’s favorable long-term safety and efficacy data may also
drive the use of generics over Sprycel and Tasigna, which are not
expected to gain traditional FDA approval for first-line use until
at least 2015 when survival data is more mature.
Generic Gleevec may also lead to more significant changes in
treatment regimens for chronic-phase CML. Balancing the higher
efficacy of the second-generation TKIs with the lower price of
generics could lead to short-term “induction” use of Tasigna
or Sprycel, followed by long-term “maintenance” therapy with
generic imatinib.
generic gleevec
may significantly
change the
cml treatment
paradigm.
SECOND-LINE THERAPY AND BEYOND
Whilst Sprycel appears to lose out to Tasigna as the secondgeneration TKI of choice for first-line treatment, it may come into its
own as a preferred second-line agent. Sprycel has better efficacy
than Tasigna in Gleevec-resistant CML, and, unlike Tasigna, is
approved for use in Gleevec-resistant CML patients in the blastic
phase. As CML progresses, the main therapeutic considerations
shift from those of a chronic disease to an acute one. CML must
be treated aggressively once a patient fails first-line therapy, and
consequently tolerability becomes a less important concern.
Additional therapies are still needed for patients failing on the
first- and second-generation TKIs, as the duration of response
to third-line agents is typically only 3 to 20 months. Many
compounds are in development for the treatment of resistant
CML, particularly for T315I mutations where there is a high unmet
medical need. A comparison of pipeline Consensus forecast data
from Cortellis for Competitive Intelligence is shown in Figure 3.
Pfizer is developing bosutinib, a second-generation, dual SRC/
BCR-ABL kinase inhibitor that binds to an intermediate form of
BCR-ABL. The drug is currently under review by the FDA and
EMA for use in previously treated CML patients. Bosutinib is
unlikely to see utilization in the first-line, following disappointing
results from the BELA head-to-head study with Gleevec in newly
diagnosed patients. While achievement of a CCyR was more rapid
in bosutinib-treated patients than Gleevec-treated patients, no
significant difference was observed in the CCyR rate between the
two treatment groups and a higher rate of adverse events was
documented in the bosutinib arm. It has been suggested that the
failure of bosutinib to show superiority over Gleevec may be due to
dose interruptions for diarrhea, which could have been managed
with better supportive care. Nevertheless, tolerability is a major
patient concern with first-line therapy, and the high rate of adverse
events observed with bosutinib may hamper the drug’s prospects
in newly diagnosed patients. As toxicity is less of a concern with
subsequent lines of therapy, bosutinib may find its niche as a
second- or third-line treatment, although its lack of activity against
the T315I mutant may restrict its use in refractory CML patients.
Consensus estimates from Cortellis for Competitive Intelligence
appear relatively conservative, with the drug predicted to take
sales of $140.0 million in 2016.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
The dual SRC/pan-BCR-ABL kinase inhibitor ponatinib (ARIAD
Pharmaceuticals) is currently in phase III development and
is predicted to be filed in the US and Europe later this year.
The pivotal phase II PACE study is assessing the efficacy of
ponatinib in Sprycel- or Tasigna- refractory CML patients and
is expected to form the basis of the submission. Interim data
certainly appear promising: 47 percent of the heavily pretreated patients achieved an MCyR, with 39 percent achieving
a CCyR. Importantly, an MCyR was observed in 57 percent of
patients with the T315I mutation, with CCyRs in 58 percent
and MMRs in 33 percent of patients. As no effective treatment
is currently available for patients with the T315I mutation,
immediate adoption of ponatinib is predicted due to the high
unmet need in this patient population. ARIAD is also planning
a trial in newly diagnosed CML patients to compare ponatinib
with Gleevec; however, ponatinib will have to compete with
well-established first-line therapies in this space, and longterm safety and efficacy data will be required before adoption
for first-line use. According to Consensus data from Cortellis for
Competitive Intelligence, ponatinib is the clear winner among the
investigational CML therapies in late-stage development, with
predicted 2016 sales of $570.3 million.
Other kinase inhibitors with activity against T315I-mutated
ABL kinases are in earlier stages of development, and include
danusertib and AT-9283. It has also been suggested that switch
pocket kinase inhibitors such as DCC-2036 may show promise
for the treatment of refractory CML.
Looking beyond kinase inhibitors, omacetaxine mepesuccinate is
a cytotoxic alkaloid derived from the evergreen tree Cephalotaxus
harringtonia, which is being developed by Teva Pharmaceutical
Industries (formerly Cephalon) for the potential treatment of
refractory CML. Hematologic and cytogenetic responses have
been observed in the CML-202 study in patients with the T315I
mutation who had failed Gleevec, and in the CML-203 study in
patients intolerant or resistant to two TKIs. Although previously
under review in the US and Europe for Gleevec-resistant,
T315I-mutated CML, a Complete Response letter from the FDA
prompted ChemGenex (subsequently acquired by Cephalon)
to withdraw the European filing. Teva now plans to resubmit
applications for use in patients who have failed two or more
TKIs. Although the planned filings encompass a larger patient
population than previously targeted, regulatory setbacks and
the product’s inconvenient subcutaneous dosing have resulted
in relatively low near-term expectations for omacetaxine;
Consensus data from Cortellis for Competitive Intelligence predict
2015 sales of just $75.0 million (see FIGURE 3).
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
Bosutinib
Ponatinib
Omacetaxine
SALES IN US $ MILLIONS
600
480
360
240
120
0
16
20 5
1
20 4
1
20 3
1
20 2
1
20 1
1
20
16
20 5
1
20 4
1
20 3
1
20 2
1
20 1
1
20
16
20 5
1
20 4
1
20 3
1
20 2
1
20 1
1
20
YEAR
Figure 3: 2011 versus 2016 For bosutinib, ponatinib anD
omacetaXine (Data are DeriveD From Thomson ReuTeRs
CoRTellis foR CompeTiTive inTelligenCe)
WHAT NExT FOR GLEEVEC?
As the CML TKI market becomes more competitive, efforts
are being made to further drive Gleevec use in both the firstand second-line. As residual molecular disease is observed
in most patients treated with 400 mg Gleevec, the benefit of
higher starting doses in newly diagnosed patients has been
investigated. The single-arm RIGHT study demonstrated
favorable cytogenetic and molecular responses for 800 mg
Gleevec compared with historical 400 mg data from the IRIS
study. However, the randomized TOPS study designed to
evaluate the two doses head-to-head failed to show a significant
benefit in MMR for the higher dose, and the trial was terminated
early. The higher dose was also associated with higher rates of
dose interruption, reduction or discontinuation due to grade
3 or 4 adverse events. Consequently, it is likely that high-dose
Gleevec will have a limited role in first-line therapy.
Dose-escalation is an option for patients with cytogenetic
relapse who have previously achieved a cytogenetic response
with standard-dose Gleevec, and is allowed for within the drug’s
label. However, the UK’s National Institute for Health and Clinical
Excellence recently found high-dose Gleevec therapy is not costeffective due to the higher treatment costs and lower efficacy
compared with other regimens in Gleevec-resistant chronic-phase
CML patients. Dose-escalation is also unlikely to benefit patients
who have never had a cytogenetic response or patients with
hematologic failure; consequently, the use of high-dose Gleevec
also appears to have major limitations as a second-line agent.
Combination use of Gleevec with traditional chemotherapeutic
agents, such as cytarabine and pegylated IFN-alfa, is also being
investigated as a potential first-line regimen in a number of studies
in newly diagnosed chronic-phase CML patients. The Nordic CML
Study Group investigated the combination use of pegylated IFNalfa2b and Gleevec. Despite significant improvements in MMR rate
in the combination arm, toxicity resulted in 61 percent of patients
discontinuing IFN. Similar findings have been reported from the
SPIRIT and GIMEMA studies, highlighting the need to balance
tolerability with efficacy.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
FUTURE DIRECTIONS OF THERAPY
Prior to the TKI era, CML was the most common indication for
allogeneic HSCT worldwide. However, transplant rates have
dropped dramatically following the approval of Gleevec and the
excellent responses observed with TKI therapy. The use of HSCT
as a first-line treatment option for chronic-phase CML is now no
longer recommended and transplant is generally only considered
following failure of TKI therapy.
However, improvements in transplantation and the management
of complications may lead to renewed interest in HSCT as a
curative option. Cost also plays a major role in therapeutic
decision making, particularly in more financially constrained
healthcare systems. Considering the lifetime costs of TKI therapy
and patient monitoring, HSCT may seem a more attractive
option from a cost-effectiveness perspective. In Europe, the
median cost of one year of Gleevec therapy is €30,411, compared
with a median cost of €63,450 for a potentially curative HSCT. A
study in Mexico calculated that the cost of a non-myeloablative
allogeneic HSCT was equivalent to 180 days of Gleevec
therapy. With the investigation of alternative donor sources
and development of less toxic regimens, HSCT as a first-line
option may see a resurgence of interest. Transplant also remains
an option for patients who have not responded to or relapsed
after TKI therapy, although poor survival is still associated with
advanced stages of the disease.
The current approach to CML therapy is sequential treatment
with TKIs, with initiation of a second-line agent once failure
of the first-line agent has been documented. However, it has
been suggested that combination TKI therapy may be a more
rational approach to induce rapid responses and combat drug
resistance. Indeed, the concept of chronic use of highly active
combination regimens seems feasible given the transformational
success of HAART in HIV therapy. However, tolerability and
cost of such regimens for CML are likely to be important
considerations. Careful patient selection may identify patients
at high risk of resistance who would benefit the most from
combination regimens. Given the effectiveness of current TKIs,
trials of combination regimens may be hindered due to patient
reluctance to receive an investigational therapy when their
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
disease is adequately controlled with their current regimen. The
high cost of TKIs may also be a significant barrier to combination
treatment; it has been estimated that a regimen of Sprycel and
Gleevec would cost approximately $78,000 per patient per year,
which may be unfeasible given the chronic nature of therapy.
However, significantly improved efficacy may lead to such
deep and durable responses that therapy could potentially be
discontinued, thus driving down treatment costs and conferring
significant patient benefit.
With the increasingly deep and durable responses to therapy
being observed, a pertinent question is whether TKIs can
eventually be discontinued in patients with consistently
undetectable disease and the patient considered effectively
cured. The multicenter STIM trial evaluated the possibility of
stopping Gleevec treatment in patients with complete molecular
remission, defined as undetectable BCR-ABL transcripts for ≥ 2
years. Although recurrence of molecular disease was observed
in 61 percent of patients following discontinuation of Gleevec,
all patients responded to reintroduction of therapy. The findings
suggest that discontinuation might be feasible in a subset
of patients along with close molecular monitoring to catch
recurrence early. Further studies are required to assess the
duration of “cure” and to determine whether the more potent
second-generation TKIs will increase the proportion of patients
for which discontinuation may be an achievable goal.
CONCLUSION I
The development of Gleevec as the first rationally designed,
targeted oncology drug was a truly transformational event in
the treatment of CML and an inspiration wider oncology field. As
more efficacious therapies reach the market, the choice of firstline therapy will be increasingly driven by tolerability and costeffectiveness as patients remain on treatment for increasingly
extended periods of time. Striving for even greater and deeper
response rates remains a challenge for new therapies, as does the
need for new treatments to overcome resistance to the first- and
second-generation agents. With HSCT currently the only curative
option for CML, the ultimate question is now whether cure can be
effectively achieved with a small-molecule therapeutic.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
SECTION II
DEALS HIGHLIGHTS
Deals coverage on Cortellis for Competitive Intelligence indicates
that more than 40 deals related to CML have been forged since
the early 1990s.
The following section reviews the licensing portfolio of a number
of blockbuster CML therapeutics, as well as certain significant and
promising therapeutic candidates for CML, as featured in Cortellis
for Competitive Intelligence. Other notable and high-value deals are
also highlighted to give an insight into the CML market.
NOvARtis AND BRistOl-MyERs squiBB: MARkEt
lEADERs FOR CMl thERAPEutiCs
As the developer of both the blockbuster CML therapy Gleevec,
which yielded sales of over $4.6 billion in 2011, and of its secondgeneration counterpart Tasigna, which generated sales of over
$0.7 billion in 2011, expected to increase to more than $2.0
billion in 2016, Novartis is clearly at the forefront of this evolving
therapeutic market.
Novartis holds exclusive global rights to both drugs, with very little
partnering activity; the only reported deal that involves Gleevec was
more related to a non-CML oncology indication. Variagenics agreed
in May 2002 to apply its integrated cancer pharmacogenomics
platform to Novartis’s Gleevec and PKI-166, with the aim of
identifying potential markers of the efficacy of the two drugs for
prostate cancer. Novartis was to gain an exclusive license to any
markers predictive of therapeutic response and Variagenics was to
retain exclusive rights to develop any resulting DNA diagnostic tests.
The financial terms of the agreement were undisclosed.
“The expanded agreement also provides
an opportunity for Bristol-myers squibb
and otsuka to work together in oncology.
We believe that sharing our collective
resources will benefit the cancer patients
we serve.”
lamberto Andreotti, President and Chief Operating
Officer, Bristol-Myers squibb
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
BMS follows Novartis as a prominent player in the field with its
second-generation TKI, Sprycel. The company reported sales
of the drug to be more than $0.8 billion in 2011, expected to
increase to over $1.5 billion in 2016. BMS also demonstrates
limited partnering activity for Sprycel, forging only a copromotion deal with Otsuka Pharmaceutical in April 2009.
The companies agreed to co-promote BMS’s oncology assets,
Sprycel, and Ixempra, in the US, Japan and Europe, and to share
commercial expenses. BMS would pay Otsuka a collaboration fee
on aggregate annual net sales, beginning in 2010 and continuing
on a regressive tiering basis through 2020. By March 2011, it was
reported that the agreement was to start that year for the US
and Japan, and in 2012 for Europe.
liCENsiNg PORtFOliO OF NOtABlE CMl
thERAPEutiC CANDiDAtEs
Significant and promising therapeutic candidates for CML include
bosutinib, ponatinib, danusertib, AT-9283 and omacetaxine
mepesuccinate, all of which are in late clinical development or the
early stages of registration. The following section highlights known
partnering activity for these compounds.
Pfizer’s acquisition of Wyeth in October 2009 resulted in Pfizer
being granted worldwide rights to the dual SRC/BCR-ABL kinase
inhibitor bosutinib. Wyeth had entered a research collaboration
for the drug with the University of Bologna by April 2005;
however, financial details were undisclosed.
ARIAD Pharmaceuticals holds the global development and
marketing rights to the dual SRC/pan-BCR-ABL inhibitor
ponatinib. Under the Qualifying Therapeutic Discovery
Project (QTDP) program, the company was awarded three US
Government grants in November 2010, totaling approximately
$733,000, to support development of its oncology drugs
ridaforolimus, ponatinib and AP-26113.
An exclusive collaboration was entered into in March 2011 with
MolecularMD for the development and commercialization
of a companion diagnostic test for ponatinib; the test would
identify the T315I BCR-ABL mutation in patients with CML
and Ph+ acute lymphoblastic leukemia (ALL). MolecularMD
agreed to continue using its diagnostic test to sequence BCRABL mutations in patients enrolled in ponatinib clinical trials.
Under the collaboration terms, MolecularMD would further
optimize the diagnostic test and would file a Premarket Approval
Application (PMA) with the FDA to support commercialization.
At that time, it was expected that MolecularMD would submit
the PMA at the same time as ARIAD files its ponatinib NDA
in 2012. MolecularMD’s scientific founder, Dr Brian Druker
of the Oregon Health & Science University, was reported
to be a long-standing scientific and medical collaborator
of ARIAD’s in the development of ponatinib. ARIAD was to
reimburse MolecularMD for predefined expenses related to the
development of the T315I diagnostic test. MolecularMD would
also receive development and regulatory milestone payments.
“We have been working with ARiAD
throughout ponatinib’s clinical
development and share in the excitement
over the drug’s activity in resistant and
intolerant Cml patients and those with the
T315i mutation for whom current therapies
are ineffective.”
stephane Wong, Chief scientific Officer, MolecularMD
Following its acquisition of Astex Therapeutics in July 2011, Astex
Pharmaceuticals (previously known as SuperGen) is developing
a program of Aurora kinase inhibitors led by AT-9283. Cancer
Research UK reported in January 2012 that it was funding and
managing a first-in-child study of the drug for ALL and acute
myeloid leukemia (AML). The funding amount was undisclosed.
Nerviano Medical Sciences’s Aurora kinase inhibitor danusertib
remains unpartnered.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
hOsPiRA’s $120-MilliON DEAl tO COMMERCiAlizE
ChEMgENEx’s OMACEtAxiNE AND OthER AgREEMENts
FOR thE thERAPEutiC CANDiDAtE
Cephalon, a wholly owned subsidiary of Teva Pharmaceutical
Industries, owns global rights to omacetaxine mepesuccinate
following its acquisition of ChemGenex Pharmaceuticals in
March 2011.
ChemGenex and Stragen Pharma entered into a worldwide
collaboration to accelerate clinical development of
omacetaxine in June 2005. Stragen, which was to provide GMP
manufacturing, distribution and marketing expertise, had a
patented manufacturing process for a semi-synthetic purified
form of the active molecule (homoharringtonine) in omacetaxine
and had patented a suite of its derivatives. ChemGenex
exclusively licensed worldwide rights to this manufacturing
process and the novel analogs. Stragen had responsibility for
drug production, global supply and facilitation of European
regulatory approvals. Stragen’s established European clinical
network was also utilized to accelerate the drug’s development.
The companies planned to market omacetaxine under the
ChemGenex brand in Europe, with ChemGenex receiving 49
percent of profits and Stragen receiving 51 percent. Three years
later, in June 2008, ChemGenex gained full commercial control
of omacetaxine through the transfer of IP and commercial
rights from Stragen. This arrangement removed the IP royalty
on manufacturing, significantly reduced the cost of goods and
removed the need for a European joint venture, which allowed
ChemGenex to control European development and access all
profits from sales in the region. Stragen would continue to supply
the drug and became a significant shareholder in ChemGenex,
obtaining 37,235,343 new ordinary shares. As such, the original
manufacturing and commercialization agreements between
the companies were concluded and a strong combined patent
portfolio around homoharringtonine and related analogs would
provide broader and longer market exclusivity. The acquisition
allowed ChemGenex to freely pursue commercialization
opportunities for omacetaxine.
“We are very excited by the promise
omacetaxine holds to improve outcomes
for seriously ill patients who have stopped
responding to other treatments available
for their condition. This agreement is a
further step in hospira’s strategy to build
upon our strong portfolio of oncology and
hematology products.”
Michael kotsanis, President Europe, Middle East and
Africa, hospira
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
Indeed, in December 2009, ChemGenex granted Hospira
development and commercialization rights to omacetaxine for
hematological malignancies, in Europe, the Middle East and certain
African countries. Hospira agreed to pay €11.1 million (approximately
$15.9 million) upfront, milestones of up to €74.1 million
(approximately $105.9 million) and royalties. ChemGenex would
register the drug in Europe for CML while the companies explored
applications of the drug in further hematological malignancies.
Hospira would be responsible for marketing in its territories.
ChemGenex’s development of omacetaxine was supported
by a US Government grant of $244,479, obtained through
the QTDP program in November 2010. In February 2012, the
company planned to submit an NDA to the FDA by mid 2012 for
omacetaxine in CML patients who have failed two or more TKIs.
NOvARtis’s $0.5-BilliON DEAl tO liCENsE sgx’s BCRABl iNhiBitORs FOR CMl
Novartis’s presence in the CML therapy arena is further illustrated
by its $0.5 billion deal signed in March 2006 for CML therapeutic
candidates, one of the highest valued for the indication. Novartis
licensed codevelopment and commercialization rights to SGx
Pharmaceuticals’ BCR-ABL inhibitors for drug-resistant CML.
SGx received $25 million upfront, stock purchases, up to $490
million in milestones and royalties, plus a minimum of two years of
research funding. SGx retained the option to co-commercialize the
compounds in the US. The agreement was amended in September
2007; SGx acquired the right to develop and commercialize one of
the compounds from the series, SGx-393, outside of the collaboration
subject to Novartis’s reacquisition right that was exercisable at a future
date. Novartis also assumed responsibility for the selection of future
development candidates and the clinical development of additional
compounds. However, following the acquisition of SGx by Eli Lilly in
August 2008, no further development on the compounds has been
reported by either Lilly or Novartis (see TABLE 2).
DRUG
LICENSING
COMPANY
PARTNER
COMPANY
DEAL START
DATE
DEAL
VALUE
(US $)*
Gleevec
Variagenics
Novartis
May 2002
undisclosed
Sprycel
Bristol-Myers
Squibb
Otsuka
Pharmaceutical
April 2009
undisclosed
bosutinib
University of
Bologna
Wyeth
By April 2005
undisclosed
ponatinib
ARIAD
Pharmaceuticals
US Government
November
2010
0.733
million
ponatinib
MolecularMD
ARIAD
Pharmaceuticals
March 2011
undisclosed
ponatinib
Oregon Health
& Science
University
ARIAD
Pharmaceuticals
By March 2011
undisclosed
AT-9283
Astex
Pharmaceuticals
Cancer Research
UK
January 2012
undisclosed
omacetaxine
Stragen
ChemGenex
Pharmaceuticals
June 2005
undisclosed
omacetaxine
ChemGenex
Pharmaceuticals
Hospira
December
2009
<121 million
+ royalties
omacetaxine
ChemGenex
Pharmaceuticals
US Government
November
2010
0.244
million
BCR-ABL
kinase
inhibitors,
SGx-393
SGx
Pharmaceuticals
Novartis
March 2006
<515 million
+ royalties
“novartis is the leader in developing novel
targeted therapies to treat Cml. With
their extensive experience developing
and commercializing gleevec as well as
development of the novel investigational
compound, nilotinib/Amn107, we believe
they are the ideal partner with whom to
develop our series of next-generation BCRABl inhibitors.”
Mike grey, President and CEO, sgx Pharmaceuticals
table 2. summary oF notable agreements For chronic myeloiD
leuKemia therapeutics
* Approximate values based on the achievement of all milestones for the principal components
included in the deal.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
CONCLUSION II
On observing the deal landscape for CML, it is clear that Novartis
is the leading player; the company has developed two of the
top three significant blockbuster therapeutics in the market,
Gleevec and Tasigna ($5.375 billion combined sales figures
in 2011), and it has forged one of the highest-value deals for
the indication ($0.5 billion with SGx in 2006). BMS follows
on, with Sprycel sales of $0.803 billion in 2011. It is notable
that there appears to be very little partnering activity for the
blockbuster CML therapeutics. This trend is also reflected
when studying the partnering landscape for promising CML
therapeutic candidates such as bosutinib, ponatinib, danusertib,
AT-9283, and omacetaxine. Deals with Otsuka (BMS’s Sprycel),
MolecularMD (ARIAD’s ponatinib), and Stragen and Hospira
(both for ChemGenex‘s omacetaxine) are among the few that
appear significant. This could represent a gap in the market,
providing potential opportunities for investment and licensing
activity. As new therapeutics emerge (eg, bosutinib and ponatinib
with expected sales in 2016 of $140 million and $570.3 million,
respectively) and compete with more established drugs, it will be
of interest to see if the CML deals landscape is at all altered.
PHARMA MATTERS | SPOTLIGHT ON... CHRONIC MYELOID LEUKEMIA
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