- New 96-week data support
durability and safety of Treatment-free Remission (TFR) in Ph+
CML-CP patients who stop taking Tasigna [1,2]
- More than 90% of Ph+ CML-CP
patients in ENESTfreedom and ENESTop who stopped Tasigna and were
in TFR at 48 weeks remained in TFR at 96 weeks [1,2]
- 48-week data from same trials
recently added to Tasigna SmPC following EC approval; discussions
with other regulatory authorities are underway worldwide
Basel, June 23, 2017
- Novartis today announced results from
additional analyses of the ENESTfreedom and ENESTop clinical
trials, which found that approximately half of adult patients with
Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia
(CML) in the chronic phase (CP) who discontinued Tasigna [®]
(nilotinib) remain in Treatment-free Remission (TFR) nearly two
years after stopping treatment. The 96-week results from these two
open-label Phase II trials, presented at the 22nd Congress of the
European Hematology Association (EHA), add to the growing body of
evidence examining the ability to remain in TFR in patients who
achieved a sustained deep molecular response (DMR) with Tasigna and
met additional eligibility criteria prior to discontinuing
treatment. TFR is the ability to maintain molecular response (MR)
after stopping tyrosine kinase inhibitor (TKI) therapy in patients
with Ph+ CML-CP [3].
"These trials show that about half of Ph+ CML
patients that met strict eligibility criteria and discontinued
Tasigna continue to maintain TFR at 96 weeks, and demonstrate that
more than 90% of patients who were in TFR at 48 weeks remain in TFR
at 96 weeks," said Timothy P. Hughes, M.D., ENESTop study
investigator, Cancer Theme Leader at the South Australian Health
and Medical Research Institute and Clinical Professor at the
University of Adelaide, Australia. "Achieving deep molecular
response is an important eligibility criteria prior to attempting
TFR."
ENESTfreedom and ENESTop evaluate the potential to
maintain MR after stopping therapy in eligible adult patients with
Ph+ CML-CP who achieved a sustained DMR with Tasigna [ ]in the
first-line setting and in patients who achieved a sustained DMR
with Tasigna after switching from Glivec [®] (imatinib)*,
respectively.
"The findings from the 96-week analyses, as well
as the recent regulatory decisions to add TFR data to the Tasigna
product label in the European Union (EU), Chile and Ecuador, mark
significant progress in the treatment of CML," said Vas Narasimhan,
M.D., Global Head Drug Development and Chief Medical Officer,
Novartis. "We are proud that our innovation with Tasigna has
contributed directly to this progress and that physicians now have
the opportunity to consider TFR in both first- and second-line
Tasigna patients."
Results from ENESTfreedom, which evaluated the
potential for discontinuing Tasigna in eligible Ph+ CML-CP patients
who achieved a sustained DMR following at least three years of
first-line treatment with Tasigna, found that 48.9% of 190 CML
patients (confidence interval [CI] 95%: 41.6%-56.3%) were
able to discontinue therapy and remain in major molecular response
(MMR; BCR-ABL1 International Scale [IS] <= 0.1%) at 96
weeks. Of the 88 patients who restarted treatment with Tasigna due
to loss of MMR by the cut-off date, 98.9% were able to regain MMR
(n=87). One patient discontinued the study at 7.1 weeks without
regaining MMR after reinitiating treatment with Tasigna [1]. No new
major safety findings were observed in ENESTfreedom in patients
treated with Tasigna beyond those in the known safety profile of
Tasigna [1]. Among patients who remained in TFR for more than 48
weeks (n=100), the frequency of adverse events (AEs) was lower
during the second 48 weeks of TFR compared to the first 48 weeks.
AEs in the predefined musculoskeletal pain grouping also decreased
from 34.0% to 9.0% during the first and second 48 weeks of the TFR
phase, respectively [1], versus 17.0% during the treatment
consolidation phase.
ENESTop, which evaluated the potential for
discontinuing Tasigna in 126 eligible Ph+ CML-CP patients who were
able to achieve a sustained DMR following at least three years of
Tasigna therapy, but not with prior Glivec therapy, found that more
than half (53.2%) of patients were able to remain in TFR at 96
weeks (95% CI: 44.1%-62.1%) [2]. In the study, 56 patients with
confirmed loss of MR4.0 (BCR-ABL1 IS <= 0.01%) or loss of MMR
restarted Tasigna by the cut-off date. Of these patients, 92.9%
(n=52) regained both MR4.0 and MR4.5. By weeks 12.0 and 13.1 of
treatment re-initiation with Tasigna, 50% of retreated patients
achieved MR4.0 and MR4.5, respectively [2]. No new major
safety findings were observed in ENESTop in patients treated with
Tasigna beyond those in the known safety profile of Tasigna [2].
Among patients who remained in the TFR phase of the trial for more
than 48 weeks (n=73), rates of all-grade AEs were 82.2% and 63.0%
for the first 48 weeks and second 48 weeks of the TFR phase,
respectively, versus 79.5% during the treatment consolidation
phase. Rates of musculoskeletal pain-related AEs decreased from
47.9% to 15.1% during the first and second 48 weeks of the TFR
phase, respectively, versus 13.7% during the treatment
consolidation phase [2].
Discontinuation of treatment in ENESTfreedom and
ENESTop was conducted under the conditions of the trials in
patients who met the rigorous predefined criteria of the trials. An
important part of the Tasigna TFR studies is regular and frequent
molecular monitoring with a well-validated assay able to measure
BCR-ABL transcript levels down to MR4.5. Frequent patient
monitoring after discontinuation of Tasigna allows timely
determination of loss of MR4.0 and MMR and prompt re-initiation of
treatment [1,2].
On May 24, the European Commission (EC) approved
an update of the Tasigna Summary of Product Characteristics (SmPC)
to include data from the ENESTfreedom and ENESTop TFR clinical
trials. With this EC approval, Tasigna is the first and only TKI to
include information in its EU label on stopping therapy in eligible
patients with Ph+ CML-CP in both the first-line setting and after
switching from Glivec. The decision to add TFR data to the Tasigna
SmPC is applicable to all 28 EU member states plus Iceland and
Norway.
Information regarding TFR was also recently added
to the Tasigna label in Chile and Ecuador.
In all other countries, discontinuation of Tasigna
in patients who achieve a sustained DMR is being investigated and
should only be attempted in the context of a clinical study. There
is no guarantee Tasigna TFR data will be approved for inclusion in
the label by other health authorities.
Novartis commitment to
CML
Over the past several decades, Novartis research in Ph+ CML has
helped transform the disease from a fatal leukemia to a chronic
condition in most patients and, today, the company continues its
long-standing commitment to the global CML community. Evaluating
more than 1,000 patients, the Tasigna TFR studies, which include
ENESTfreedom and ENESTop as well as two other ongoing
company-sponsored TFR studies and multiple investigator-initiated
studies, are part of a large international Ph+ CML-CP clinical
trial program to assess TKI discontinuation. Novartis follows the
science and builds upon existing evidence to explore what could be
the next major contribution in the treatment of Ph+ CML through
these TFR trials as well as investigational compounds, such as
ABL001, which is currently being tested in patients who are
relapsed, refractory or intolerant to existing TKIs in a Phase I
trial as a single agent and in combination with several TKIs.
About ENESTfreedom
ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical
Trials - Following REsponsE in De nOvo CML-CP Patients) is an open
label Phase II study involving 215 Ph+ CML patients in the chronic
phase, conducted at 132 sites across 19 countries. ENESTfreedom
evaluated stopping treatment in 190 adults with Ph+ CML-CP
receiving Tasigna for at least three years, after the patients had
achieved a response of MR4.5 with Tasigna and a sustained DMR for
one year as a first-line treatment. The study is ongoing with
planned follow-up to evaluate the ability of patients to sustain
remission for longer durations following discontinuation of
Tasigna.
About ENESTop
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open
label Phase II study involving 163 Ph+ CML patients, conducted at
63 sites across 18 countries. The trial evaluated stopping
treatment in 126 adults with Ph+ CML-CP receiving Tasigna for at
least three years, after patients had achieved and sustained DMR
for one year with Tasigna following Glivec. The study is ongoing
with planned follow-up to evaluate the ability of patients to
sustain remission for longer durations following discontinuation of
Tasigna.
About Tasigna
(nilotinib)
Tasigna (nilotinib) is approved in more than 122 countries for the
treatment of chronic phase and accelerated phase Philadelphia
chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult
patients resistant or intolerant to at least one prior therapy,
including Glivec (imatinib), and in more than 110 countries for the
treatment of adult patients with newly diagnosed Ph+ CML in chronic
phase.
IMPORTANT SAFETY INFORMATION for
TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant
cardiac disease and in patients who have or may develop
prolongation of QTc. Low levels of potassium or magnesium must be
corrected prior to Tasigna administration. Monitor closely for an
effect on the QTc interval. Baseline ECG is recommended prior to
initiating therapy and as clinically indicated. Cases of sudden
death have been reported in clinical studies in patients with
significant risk factors. Avoid use of concomitant drugs known to
prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2
hours before and 1 hour after taking dose. Reactivation of
hepatitis B can occur in patients who are chronic carriers of this
virus after receiving TKI treatment.
Use with caution in patients with liver
impairment, with a history of pancreatitis and with total
gastrectomy. Patients with rare hereditary problems of galactose
intolerance, severe lactase deficiency or glucose-galactose
malabsorption should not use Tasigna. Tasigna may cause fetal harm
in pregnant women. If pregnancy is planned during the
treatment-free remission phase, the patient must be informed of a
potential need to re-initiate treatment with Tasigna during
pregnancy. Women taking Tasigna should not breastfeed.
Cases of cardiovascular events included ischemic
heart disease-related events, peripheral arterial occlusive
disease, and ischemic cerebrovascular events have been reported.
Serious cases of hemorrhage from various sites including
gastrointestinal were reported in patients receiving Tasigna. Grade
3 or 4 fluid retention including pleural effusion, pericardial
effusion, ascites and pulmonary edema have been reported. Cases of
tumor lysis syndrome have been reported in Tasigna-treated patients
who were resistant or intolerant to prior CML therapy.
Eligible patients who are confirmed to express the
typical BCR-ABL transcripts, e13a2/b2a2 or e14a2/b3a2, can be
considered for treatment discontinuation. Frequent monitoring of
BCR-ABL transcript levels in patients eligible for treatment
discontinuation must be performed with a quantitative diagnostic
test validated to measure molecular response levels with a
sensitivity of at least MR4.5 (BCR-ABL/ABL <=0.0032% IS).
BCR-ABL transcript levels must be assessed prior to and during
treatment discontinuation. Loss of major molecular response
(MMR=BCR-ABL/ABL <=0.1%IS) or confirmed loss of MR4 (two
consecutive measures separated by at least 4 weeks showing loss of
MR4 (MR4=BCR-ABL/ABL <= 0.01%IS)) will trigger treatment
re-initiation within 4 weeks of when loss of remission is known to
have occurred. It is crucial to perform frequent monitoring of
BCR-ABL transcript levels and complete blood count with
differential in order to detect possible loss of remission. For
patients who fail to achieve MMR after three months of treatment re
initiation, BCR-ABL kinase domain mutation testing should be
performed.
The most frequent Grade 3 or 4 adverse events are
hematological (neutropenia, thrombocytopenia, anemia) which are
generally reversible and usually managed by withholding Tasigna
temporarily or dose reduction. Chemistry panels, including
electrolytes, lipid profile, liver enzymes, and glucose should be
checked prior to therapy and periodically. Tasigna can cause
increases in serum lipase. The most frequent non-hematologic
adverse events were rash, pruritus, nausea, fatigue, headache,
alopecia, myalgia, constipation and diarrhea.
Musculoskeletal pain, myalgia, pain in extremity,
arthralgia, bone pain and spinal pain may occur upon discontinuing
treatment with Tasigna within the framework of attempting
treatment-free remission.
Please see full Prescribing Information including
Boxed WARNING at www.tasigna.com.
About Glivec
(imatinib)
Glivec (imatinib) is approved in more than 110 countries, for the
treatment of adult patients in all phases of Ph+ CML, for the
treatment of patients with KIT (CD117)-positive gastrointestinal
tumors (GIST), which cannot be surgically removed and/or have
metastasized and for the treatment of adult patients following
complete surgical removal of KIT+ GIST.
Not all indications are available in every
country.
Glivec Important Safety
Information
Glivec is contraindicated in patients who are
hypersensitive to imatinib or any of the excipients.
Glivec can cause fetal harm when administered to a
pregnant woman. Women should not become pregnant, and should be
advised of the potential risk to the unborn child.
Glivec has been associated with severe edema
(swelling) and serious fluid retention. Cytopenias (anemia,
neutropenia, thrombocytopenia) are common, generally reversible and
usually managed by withholding Glivec or dose reduction. Monitor
blood counts regularly. Severe congestive heart failure and left
ventricle dysfunction, severe liver problems including cases of
fatal liver failure and severe liver injury requiring liver
transplants have been reported. Caution in patients with cardiac
dysfunction and hepatic dysfunction. Monitor carefully.
Reactivation of hepatitis B can occur in patients who are chronic
carriers of this virus after receiving TKI treatment.
Bleeding may occur. Severe gastrointestinal (GI)
bleeding has been reported in patients with KIT+ GIST. Skin
reactions, hypothyroidism in patients taking levothyroxine
replacement, GI perforation, in some cases fatal, tumor lysis
syndrome which can be life threatening have also been reported with
Glivec. Correct dehydration and high uric acid levels prior to
treatment. Long-term use may result in potential liver, kidney,
and/or heart toxicities; immune system suppression may also result
from long-term use. In patients with hypereosinophilic syndrome and
heart involvement, cases of heart disease have been associated with
the initiation of Glivec therapy. Growth retardation has been
reported in children taking Glivec. The long-term effects of
extended treatment with Glivec on growth in children are
unknown.
The most common side effects include fluid
retention, muscle cramps or pain and bone pain, abdominal pain,
loss of appetite, vomiting, diarrhea, decreased hemoglobin,
abnormal bleeding, nausea, fatigue and rash. Glivec should be taken
with food and a large glass of water.
Please see full Prescribing Information available
at www.glivec.com.
Disclaimer
The foregoing release contains forward-looking statements that can
be identified by words such as "support," "underway," "growing,"
"examining," "potential," "being investigated," "will,"
"commitment," "continues," "ongoing," "investigational," "being
tested," "planned," or similar terms, or by express or implied
discussions regarding potential new indications or labeling for
Tasigna, potential marketing approvals for ABL001, or regarding
potential future revenues from Tasigna or ABL001. You should not
place undue reliance on these statements. Such forward-looking
statements are based on the current beliefs and expectations of
management regarding future events, and are subject to significant
known and unknown risks and uncertainties. Should one or more of
these risks or uncertainties materialize, or should underlying
assumptions prove incorrect, actual results may vary materially
from those set forth in the forward-looking statements. There can
be no guarantee that Tasigna will be submitted or approved for any
additional indications or labeling in any market, or at any
particular time. Neither can there be any guarantee that ABL001
will be submitted or approved for sale in any market, or at any
particular time. Nor can there be any guarantee that Tasigna or
ABL001 will be commercially successful in the future. In
particular, management's expectations regarding Tasigna and ABL001
could be affected by, among other things, the uncertainties
inherent in research and development, including clinical trial
results and additional analysis of existing clinical data;
regulatory actions or delays or government regulation generally;
the company's ability to obtain or maintain proprietary
intellectual property protection; general economic and industry
conditions; global trends toward health care cost containment,
including ongoing pricing and reimbursement pressures; safety,
quality or manufacturing issues, and other risks and factors
referred to in Novartis AG's current Form 20-F on file with
the US Securities and Exchange Commission. Novartis is providing
the information in this press release as of this date and does not
undertake any obligation to update any forward-looking statements
contained in this press release as a result of new information,
future events or otherwise.
About Novartis
Novartis provides innovative healthcare solutions that address the
evolving needs of patients and societies. Headquartered in Basel,
Switzerland, Novartis offers a diversified portfolio to best meet
these needs: innovative medicines, cost-saving generic and
biosimilar pharmaceuticals and eye care. Novartis has leading
positions globally in each of these areas. In 2016, the Group
achieved net sales of USD 48.5 billion, while R&D throughout
the Group amounted to approximately USD 9.0 billion. Novartis Group
companies employ approximately 118,000 full-time-equivalent
associates. Novartis products are sold in approximately 155
countries around the world. For more information, please visit
http://www.novartis.com.
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References
[1] |
Ross,
D.M. et al. Durable treatment-free remission (TFR) following
frontline nilotinib (NIL) in patients (Pts) with chronic myeloid
leukemia in chronic phase (CML-CP): ENESTfreedom 96-wk update.
Poster Presentation. Abstract #P601. 24 June 2017. 22 [nd] Congress
of the European Hematology Association (EHA) in Madrid, Spain. |
[2] |
Hughes,
T.P. et al. Durable treatment-free remission (TFR) after stopping
second-line nilotinib (NIL) in patients (Pts) with chronic myeloid
leukemia in chronic phase (CML-CP): ENESTop 96-wk update. Poster
Presentation. Abstract #P257. 23 June 2017. 22 [nd] Congress of the
European Hematology Association (EHA) in Madrid, Spain. |
[3] |
Hughes,
T.P. and Ross, D.M. Moving treatment-free remission into mainstream
clinical practice in CML. Blood. 2016. Advance online publication.
doi# 10.1182/blood-2016-01-694265. |
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