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Novartis long-term Phase III data show Ph+ CML patients on Tasigna® achieved significantly deeper molecular response versus Glivec®



2012-12-10 22:33:20 -


Novartis International AG /
Novartis long-term Phase III data show Ph+ CML patients on Tasigna® achieved
significantly deeper molecular response versus Glivec®
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The issuer is solely responsible for the content of this announcement.

* Both newly diagnosed patients and those switching to Tasigna after long-term
treatment with Glivec achieved deeper molecular response with Tasigna

* Data suggest correlation between early molecular response at three and six
months and survival outcome for newly diagnosed patients

* Novartis reinforces commitment to CML with new clinical trials exploring
treatment free remission in patients who achieve sustained deep molecular
response

Basel, December 10, 2012 - The latest results from two Phase III clinical trials
further establish the benefits of Tasigna(®) (nilotinib) compared to Glivec(®)
(imatinib)* in the treatment of Philadelphia chromosome-positive chronic myeloid
leukemia (Ph+ CML) in newly diagnosed patients and in those with residual
disease who switched to Tasigna after long-term treatment with Glivec.

Findings from both studies were presented in oral sessions at the 54(th) annual
meeting of the American Society of Hematology (ASH) in Atlanta.

Two-year results from ENESTcmr showed that switching to Tasigna led to deeper
molecular responses** in patients who still had evidence of residual disease
after long-term therapy with Glivec[1]. More than twice as many patients treated
with Tasigna continued to achieve undetectable BCR-ABL versus Glivec. The
difference between groups by 24 months was statistically significant (22.1% vs.
8.7%; p=0.0087) and that difference has doubled since the 12-month analysis.
Significantly more patients treated with Tasigna achieved MR4.5 or undetectable
BCR-ABL versus Glivec regardless of the BCR-ABL transcript level at baseline[1].
In studies published to date, no patients achieving and maintaining MR4.5 have
progressed to advanced stages of CML[2],[3],[4],[5],[6].

"Tasigna should be considered as a leading option for frontline therapy because
it allows many patients to achieve deeper responses earlier, which we have
associated with improved long-term outcomes," said Timothy P. Hughes, MD, ENEST
study investigator, Head of the Department of Haematology at Royal Adelaide
Hospital and Clinical Professor at the University of Adelaide, Australia.

Also presented at ASH are the results of a four-year landmark analysis from
ENESTnd which showed that more than three times as many patients achieved early
molecular response (reduction in BCR-ABL transcript levels to <=10% at months
three and six) with Tasigna as frontline therapy instead of Glivec[7]. The
investigators correlated early molecular response with future major molecular
response (MMR) and MR4.5, as well as an increased probability of progression-
free survival and overall survival[7].

In a separate four-year analysis of efficacy and safety data from ENESTnd also
presented at ASH, the difference in the rates of both MR4 and MR4.5 continued to
be significantly higher for Tasigna, with the difference in favor of Tasigna
increasing over time (MR4: 9-14% difference by one year, 17-24% difference by
four years; MR4.5: 6-10% difference by one year, 14-17% difference by four
years)[7]. Overall survival remained similar in all groups at four years, but
fewer CML-related deaths occurred in both the Tasigna 300 mg twice daily (n=5)
and 400 mg twice daily (n=4) arms versus Glivec (n=13)[7].

"We are encouraged by the continued strong findings from newly-presented CML
data at ASH," said Hervé Hoppenot, President, Novartis Oncology. "Our dedication
to ongoing research in CML over the past decades has helped to transform the
disease from a fatal diagnosis to a chronic condition. We are now starting the
next chapter in our commitment to helping patients with this disease by
exploring in Tasigna clinical trials the idea that some patients may be able to
safely stop therapy after achieving sustained and deep molecular response."

Novartis Commitment to CML
Novartis Oncology helped pioneer the transformation of Ph+ CML to a treatable,
chronic condition. As an industry leader in CML, Novartis is committed to
furthering the understanding of this disease and to redefining once again what
is possible for the future of Ph+ CML. The company plans to initiate in early
2013 a robust clinical trial program evaluating the possibility of treatment-
free remission in CML, which means sustaining deep molecular response after
stopping therapy. Nine treatment-free studies are planned to be conducted in
study centers across more than 50 countries.

Worldwide, CML is responsible for a little over 10% of all adult cases of
leukemia, with an incidence of one to two cases per 100,000 people per
year[8],[9].

ENESTcmr study details
ENESTcmr (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Complete
Molecular Response) is an open-label, randomized, prospective, multi-center
Phase III study of Tasigna 400 mg twice daily versus standard-dose Glivec (400
mg or 600 mg once daily) comparing kinetics of molecular response for patients
with Ph+ CML in chronic phase who had achieved complete cytogenetic response
(CCyR) but were still BCR-ABL positive (i.e., had evidence of residual leukemia)
after at least two years of treatment with Glivec. The study enrolled 207
patients. The patients were randomized into one of two treatment arms: Tasigna
400 mg twice daily versus continuing Glivec 400 mg or 600 mg once daily (same
dose as at study entry)[1].

The primary endpoint was the rate of confirmed best complete molecular response
by 12 months of study therapy with Tasigna or Glivec. Secondary objectives
included the kinetics of molecular response, duration of molecular response,
progression-free survival and overall survival in both arms. These data,
presented at ASH, were the 24-month follow-up[1].

More than twice as many patients treated with Tasigna continued to achieve
undetectable BCR-ABL versus Glivec. The difference between groups by 24 months
was statistically significant (22.1% vs. 8.7%; p=0.0087). Compared to the 12-
month analysis, the difference between the treatment arms doubled over time from
6.7% to 13.4%. Among patients without documented MR4.5 at baseline, cumulative
incidence of MR4.5 was over twice as high in Tasigna-treated patients versus
those who stayed on Glivec (42.9% vs. 20.8%; p=0.0006) and the difference
increased over time from 12 to 24 months. Significantly more patients treated
with Tasigna achieved MR4.5 versus Glivec regardless of the BCR-ABL transcript
level at baseline. In patients without documented MMR, MR4 and MR4.5 at
baseline, the differences were superior in all subsets (29.2% vs. 3.6%; p=0.016;
31.1% vs. 11.5%; p=0.003 and 42.9% vs. 20.8%; p=0.0006, respectively)[1].

ENESTnd study details
ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials - Newly
Diagnosed Patients) is a Phase III randomized, open-label, multicenter trial
comparing the efficacy and safety of Tasigna versus Glivec in adult patients
with newly diagnosed Ph+ CML in chronic phase. It is the largest global
randomized comparison of two oral therapies ever conducted in newly diagnosed
Ph+ CML patients[7],[10],[11].

The study is being conducted at 217 global sites with 846 patients enrolled.
Patients were randomized to receive Tasigna 300 mg twice daily (n=282), Tasigna
400 mg twice daily (n=281) or Glivec 400 mg once daily (n=283). The primary
endpoint was major molecular response (MMR) at 12 months; the key secondary
endpoint was durable MMR at 24 months (patients having MMR when evaluated at
both 12 and 24 months). MMR was defined in this study as 0.1% or less of BCR-ABL
as measured by RQ-PCR. Planned follow-up is for five years. Patients on the
Glivec treatment arm who had suboptimal response or treatment failure were
allowed to escalate dose and/or switch to Tasigna in a separate extension study.
These data, presented at ASH, were the 48-month minimum follow-up[7],[10],[11].

The ENESTnd landmark analysis was based on BCR-ABL transcript levels at three
and six months using data with a minimum follow-up of four years. The Tasigna
300 mg BID (n=282) and Glivec 400 mg QD (n=283) treatment arms were used for the
analysis. Rates of MMR, MR4.5, progression-free survival and overall survival
were evaluated among patients grouped according to their BCR-ABL transcript
levels of <=1%, >1% to <=10%, and >10% at three and six months. Among evaluable
patients at three months, 9% of patients (n=24) in the Tasigna arm versus 33%
(n=88) in the Glivec arm had BCR-ABL transcript levels of >10%. Patients with a
BCR-ABL transcript level of >10% had a significantly lower probability of future
MMR or MR4.5as well as poorer progression-free survival and overall survival
compared with patients who had BCR-ABL transcript levels <=10% at three months.
Fewer patients in the Tasigna arm versus the Glivec arm had BCR-ABL transcript
levels >10% at three and six months. Early molecular response at three and six
months correlated with future MMR and MR4.5as well as an increased probability
of progression-free survival and overall survival[7].

The four-year ENESTnd update found continued significantly higher rates of MMR,
MR4 and MR4.5by three years were achieved in Tasigna versus Glivec-treated
patients. The difference in the rates of both MR4 and MR4.5continued to be
significantly higher for Tasigna, with the difference in favor of Tasigna
increasing from year one to year four (MR4: 9-14% difference by one year,
17-24% difference by four years; MR4.5: 6-10% difference by one year, 14-17%
difference by four years). Among patients who achieved MMR, more patients
achieved MR4 or MR4.5on Tasigna 300 mg twice daily (68%) and Tasigna 400 mg
twice daily (62%) compared with Glivec (49%). No patient in any arm progressed
after achieving MR4.5. Significantly fewer patients progressed to accelerated
phase/blast crisis on Tasigna versus Glivec. Nearly twice as many patients had
emergent mutations on Glivec (n=21) versus either Tasigna arm (n=11 in each
arm), with five patients overall developing mutations between two and three
years. Overall survival remained similar in all groups at three years, but fewer
CML-related deaths occurred in both the Tasigna 300 mg twice daily (n=5) and
400 mg twice daily (n=4) arms versus Glivec (n=14). Both drugs were well
tolerated. Few new adverse events (AEs) and laboratory abnormalities were
observed between two and three years. Rates of discontinuation due to AEs were
10%, 14%, and 11% in the Tasigna 300 mg BID, Tasigna 400 mg BID, and Glivec
arms, respectively[11].

About Tasigna (nilotinib)
Tasigna(®) (nilotinib) is approved in more than 90 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, and for the treatment of adult
patients with newly diagnosed Ph+ CML in chronic phase. Take twice daily 12
hours apart. Do not take with food. No food to be consumed for 2 hours before or
one hour after dosing. Avoid grapefruit juice and CYP3A4 inhibitors.

Tasigna Important Safety Information
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. Uncommon cases (0.1 to
1%) of sudden death have been reported in clinical studies in patients with
significant risk factors.

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. Women taking Tasigna should not breastfeed.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia and
thrombocytopenia) which are generally reversible and usually managed by
withholding Tasigna temporarily or dose reduction. Monitor blood counts
regularly. Pancreatitis has been reported. The most frequent non-hematologic
adverse events were rash, pruritus, nausea, fatigue, headache, alopecia,
myalgia, constipation and diarrhea. Most of these adverse events were mild to
moderate in severity.

Please see full Prescribing Information.

About Glivec (imatinib)
Glivec(®) (imatinib) is approved in more than 110 countries for the treatment of
all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-
positive gastrointestinal stromal 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. Take with food and a large
glass of water.

Glivec Important Safety Information
Glivec can cause fetal harm in pregnant woman. 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. Use caution in patients with
cardiac dysfunction and hepatic dysfunction. Monitor carefully.

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 and 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.

Please see full Prescribing Information.

Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "suggest," "commitment,"
"exploring," "should,"
"encouraged," "committed," "plans," "planned," or
similar expressions, or by
express or implied discussions regarding potential new indications or labeling
for Tasigna, or regarding potential future revenues from Tasigna or Glivec. You
should not place undue reliance on these statements. Such forward-looking
statements reflect the current views of management regarding future events, and
involve known and unknown risks, uncertainties and other factors that may cause
actual results with Tasigna to be materially different from any future results,
performance or achievements expressed or implied by such 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. Nor can there
be any guarantee that Tasigna and Glivec will achieve any particular levels of
revenue in the future. In particular, management's expectations could be
affected by, among other things, unexpected clinical trial results, including
unexpected new clinical data and unexpected additional analysis of existing
clinical data; unexpected regulatory actions or delays or government regulation
generally; the company's ability to obtain or maintain patent or other
proprietary intellectual property protection; competition in general;
government, industry and general public pricing pressures; unexpected
manufacturing issues; the impact that the foregoing factors could have on the
values attributed to the Novartis Group's assets and liabilities as recorded in
the Group's consolidated balance sheet, and other risks and factors referred to
in Novartis AG's current Form 20-F on file with the US Securities and Exchange
Commission. Should one or more of these risks or uncertainties materialize, or
should underlying assumptions prove incorrect, actual results may vary
materially from those anticipated, believed, estimated or expected. 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,
eye care, cost-saving generic pharmaceuticals, preventive vaccines and
diagnostic tools, over-the-counter and animal health products. Novartis is the
only global company with leading positions in these areas. In 2011, the Group's
continuing operations achieved net sales of USD 58.6 billion, while
approximately USD 9.6 billion (USD 9.2 billion excluding impairment and
amortization charges) was invested in R&D throughout the Group. Novartis Group
companies employ approximately 127,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visit www.novartis.com.

Novartis is on Twitter. Sign up to follow @Novartis at
twitter.com/novartis.


* Known as Gleevec® (imatinib mesylate) tablets in the US, Canada and Israel.
** In ENESTcmr, molecular response (reduction of BCR-ABL transcripts in the
blood of patients) is measured at four levels, based on an international
standard:
* MMR (<= 0.1% BCR-ABL)
* MR4 (<= 0.01% BCR-ABL)
* MR4.5 (<= 0.0032% BCR-ABL)
* Undetectable BCR-ABL (no detectable BCR-ABL transcript level with sample
sensitivity of at least 4.5 log)

References
1. Hughes TP, Lipton JH, Spector N et al. Switching to Nilotinib Associated
with Continued Deeper Molecular Responses in CML-CP Patients with Minimal
Residual Disease After >= 2 Years on Imatinib: ENESTcmr 2-Year Follow-Up
Results. ASH abstract #694, 2012.
2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for
the treatment of patients with newly diagnosed chronic phase, Philadelphia
chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up
of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-851.
3. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly
diagnosed chronic phase chronic myeloid leukemia: 2-year follow-up from a
randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123-1129.
4. Discontinuation study of imatinib in adult CP CML patients who have a
complete molecular response to imatinib. Trial
identifier NCT01564836.  www.clinicaltrials.gov. Updated March
27, 2012. Accessed September 25, 2012.
5. Multicenter trial estimating the persistence of molecular remission in
chronic myeloid leukemia in long term after stopping imatinib (STIM2).
Trial identifier NCTO1343173. www.clinicaltrials.gov. Updated June
13, 2012. Accessed September 25, 2012.
6. Shami PJ, Deininger M. Evolving treatment strategies for patiensnewly
diagnosed with chronic myeloid leukemia: the role of second-generation BCR-
ABL inhibitors as first-line therapy. Leukemia. 2012;26(2):214-224.
7. Hochhaus A, Hughes TP, Saglio G et al. Outcome of Patients with Chronic
Myeloid Leukemia in Chronic Phase (CML-CP) Based on Early Molecular
Response and Factors Associated with Early Response: 4-Year Follow-up Data
from ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials -
Newly Diagnosed Patients). ASH abstract #167, 2012.
8. American Cancer Society. Detailed Guide: CML. What are the key statistics
about CML? (09/07/2012  Revision) Available at:
www.cancer.org/Cancer/Leukemia-
ChronicMyeloidCML/DetailedGuide/leukemia-chronic-myeloid-myelogenous-key-
statistics. Accessed October 2012.
9. Central European Leukemia Study Group. About CML. Available at:
www.cml-info.com/de/healthcare-professionals/about-cml.html.
Accessed October 2012.
10. A Study of Imatinib Versus Nilotinib in Adult Patients With Newly Diagnosed
Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in
Chronic Phase (CML-CP) (ENESTnd). Trial identifier NCT00471497.
  www.clinicaltrials.gov. Updated July, 18, 2012. Accessed November
20, 2012.
11. Kantarjian HM, Kim DW, Issaragrilsil S et al. ENESTnd 4-Year (y) Update:
Continued Superiority of Nilotinib vs Imatinib in Patients (pts) with Newly
Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia
in Chronic Phase (CML-CP). ASH abstract #1676, 2012.

# # #

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