-
Recommendation based on largest
trial in FLT3-mutated AML to date, showing 23% reduction in the
risk of death with Rydapt treatment regimen[1]
-
If approved, Rydapt would
represent the first targeted treatment for newly diagnosed
FLT3-mutated AML in the EU
-
Rydapt would be the first and
only EMA-approved therapy for advanced SM, a group of rare,
life-threatening conditions
Basel, July 21, 2017
- Novartis today announced that the European
Medicines Agency's (EMA) Committee for Medicinal Products for Human
Use (CHMP) adopted a positive opinion recommending approval of
Rydapt®
(midostaurin) for the treatment of adults with newly diagnosed
acute myeloid leukemia (AML) who are FLT3 mutation-positive. If
approved by the European Commission (EC), Rydapt will be indicated
in combination with standard daunorubicin and cytarabine induction
and high-dose cytarabine consolidation chemotherapy, and for
patients in complete response, followed by Rydapt single agent
maintenance therapy, for adult patients with newly diagnosed AML
who are FLT3 mutation-positive. Rydapt was also recommended for
approval as monotherapy for the treatment of adult patients with
aggressive systemic mastocytosis (ASM), systemic mastocytosis with
associated hematological neoplasm (SM-AHN) or mast cell
leukemia.
If approved, Rydapt will be the first targeted
treatment available in the European Union (EU) for newly diagnosed
FLT3 mutation-positive AML patients and advanced systemic
mastocytosis (SM) patients. The opinion follows the recent US Food
and Drug Administration (FDA) 2017 approval of Rydapt for
FLT3-mutated AML and advanced SM on April 28 and the Swissmedic
approval on May 4.
"Novartis is dedicated to bringing new treatment
options to patients with rare diseases, including AML and advanced
SM, which have seen limited treatment developments in the past 25
years," said Bruno Strigini, CEO, Novartis Oncology. "We are
pleased with the positive recommendation from the CHMP and excited
to move a step closer to bringing this much-needed treatment to
these patients across Europe."
AML is a rare and aggressive cancer of the blood
and bone marrow[2]. In the EU, there are over 18,000 estimated new
cases of AML each year[3]. Approximately one-third of AML patients
will have a FLT3 gene mutation[4].
FMS-like tyrosine kinase 3 (FLT3) is a type of
cell-surface receptor which plays a role in increasing the number
of certain blood cells[5] and the FLT3 gene mutation can result in
faster disease progression, higher relapse rates and lower rates of
survival than other forms of AML[4],[5],[6]. Prior to the approval
of Rydapt in the US, the AML therapeutic strategy had remained
relatively unchanged for more than 25 years[7],[8].
Advanced SM is a rare blood disorder characterized
by uncontrolled growth and accumulation of mast cells - mediators
of allergic responses - in one or more organs[9]. In advanced SM,
mast cells accumulate in such high quantities that they begin to
cause organ damage[9]. Median overall survival is currently less
than six months for mast cell leukemia[10], two years for SM-AHN
and 3.5 years for ASM[11].
The EC typically adheres to the recommendation of
the CHMP and delivers its final decision within approximately two
to three months. The decision will be applicable to all 28 EU
member states, plus Iceland, Liechtenstein and Norway.
The positive opinion is based on the Phase III
RATIFY (CALGB 10603 [Alliance]) clinical trial, which was conducted
in collaboration with the Alliance for Clinical Trials in Oncology
and 13 international cooperative groups. In the trial, newly
diagnosed FLT3 mutation-positive patients who received Rydapt plus
standard chemotherapy experienced significant improvement in
overall survival with a 23% reduction in the risk of death compared
with placebo plus standard chemotherapy, with median overall
survival of 74.7 months and 25.6 months, respectively (hazard ratio
[HR] = 0.77, 95% CI, 0.63, 0.95; one-sided p=0.0078)1. The full
data from the RATIFY trial were recently published in the New England Journal of Medicine (NEJM)[12].
Event-free survival (EFS; event defined as no
complete remission within 60 days of the start of induction
therapy, relapse or death) was significantly longer for Rydapt plus
chemotherapy versus placebo plus standard chemotherapy (median of
8.2 months compared to 3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and
one-sided p=0.0024). RATIFY is the largest worldwide clinical trial
in newly diagnosed FLT3-mutated AML to date, as 3,277 AML patients
were screened for the FLT3 mutation and 717 patients were
enrolled[1].
In the Phase III AML RATIFY trial, the most
frequent adverse reactions (incidence greater than or equal to 30%)
in the Rydapt plus standard chemotherapy arm were febrile
neutropenia, nausea, exfoliative dermatitis, vomiting, headache,
petechiae (small red skin spots) and pyrexia. The most frequent
non-hematologic Grade 3/4 adverse reaction was febrile
neutropenia[1].
The recommendation in advanced SM is based on two
single-arm open-label multicenter trials, including the Phase II
study (CPKC412D2201), which was the largest prospective trial ever
conducted in this rare disorder. The efficacy of Rydapt was
established using modified Valent criteria, with patients
demonstrating an overall response rate, defined as a major or
partial response, of 59.6% (95% confidence interval [CI], 48.6,
69.8%). Efficacy was also assessed in a post-hoc analysis using the
2013 International Working Group-Myeloproliferative Neoplasms
Research and Treatment-European Competence Network on Mastocytosis
(IWG-MRT-ECNM) consensus criteria (n=113). This assessment
estimated an overall response rate of 28.3% (95% CI, 20.2,
37.6)[1].
In advanced SM, the most frequent adverse
reactions were nausea, vomiting, diarrhea, peripheral edema and
fatigue. The most frequent Grade 3/4 adverse reactions were
fatigue, sepsis, pneumonia, febrile neutropenia and
diarrhea[1].
Rydapt Ongoing Clinical
Development
In order to further investigate the potential of Rydapt in AML,
Novartis is planning a Phase III study in
newly diagnosed AML patients without
a FLT3 mutation (wildtype).
About AML
AML is the most common acute leukemia in adults; it accounts for
approximately 25% of all adult leukemias worldwide, with the
highest incidence rates occurring in the US, Europe and
Australia[13]. It also has the lowest survival rate of all adult
leukemias[13].
AML prevents white blood cells from maturing,
causing an accumulation of "blasts," which do not allow room for
the normal blood cells[2]. Mutations in specific genes are found in
many cases of AML[4], and genetic testing for mutations in newly
diagnosed AML patients can help to determine prognosis and
potential treatment strategies[14].
About Advanced SM
In advanced SM, the uncontrolled growth of neoplastic mast cells
causes organ damage (e.g., liver dysfunction), low blood counts and
weight loss[9]. Patients also suffer from debilitating systemic
symptoms, such as pruritus (severe itching of the skin) caused by
mast cells releasing inflammatory mediators, such as histamine,
into the blood[9].
The uncontrolled proliferation of mast cells is
caused in many people by a KIT gene mutation - the most common
mutation, encoding the D817V substitution, occurs in approximately
90% of patients[15]. The KIT gene mutation results in activation of
the KIT enzyme, which triggers the abnormal proliferation and
survival of mast cells[16].
About Rydapt®
(midostaurin)
Rydapt® (midostaurin)
is an oral, multi-targeted inhibitor of multiple kinases, including
FLT3 and KIT, which help regulate many essential cell processes,
interrupting cancer cells' ability to grow and multiply[17].
In the US, Rydapt is FDA-approved for the
treatment of adults with newly diagnosed AML who are FMS-like
tyrosine kinase 3 mutation-positive (FLT3+) as detected by an
FDA-approved test, in combination with standard cytarabine and
daunorubicin induction and cytarabine consolidation
chemotherapy[17]. Rydapt is not indicated in the US as a
single-agent induction therapy for the treatment of patients with
AML. For a description of the experience with single-agent
treatment beyond induction and consolidation, healthcare
professionals in the US should refer to the Clinical Studies
section of the US Prescribing Information (14.1)[17]. Rydapt is
also approved to treat adult patients with aggressive systemic
mastocytosis (ASM), systemic mastocytosis with associated
hematological neoplasm (SM-AHN) or mast cell leukemia, collectively
referred to as advanced systemic mastocytosis (SM)[17].
The full US Prescribing Information for Rydapt can
be found at:
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/rydapt.pdf
Rydapt is also approved in Switzerland, for use in
combination with standard induction and consolidation chemotherapy,
followed by maintenance monotherapy for treatment of newly
diagnosed adult AML patients who have an FLT3 mutation. Rydapt is
indicated in Switzerland for the treatment of adult patients with
advanced SM.
Indications vary by country and not all
indications are available in every country. The safety and efficacy
profile of Rydapt has not yet been established outside the approved
indications. Because of the uncertainty of clinical trials, there
is no guarantee that Rydapt will become commercially available for
additional indications anywhere else in the world.
Rydapt Important Safety
Information FROM THE US PRESCRIBING
INFORMATION
Patients who are allergic to midostaurin or any of the ingredients
in Rydapt should not take Rydapt. If a patient taking Rydapt
develops signs of an allergic reaction, they should seek medical
help immediately. Signs of an allergic reaction include trouble
breathing, flushing, chest pain, throat tightness, and swelling of
lips, mouth or throat.
Rydapt should be not be used during pregnancy
since Rydapt may harm an unborn baby. Pregnancy testing should be
conducted for women who might become pregnant. Effective birth
control should be used during treatment and for at least four
months after stopping Rydapt. If a patient becomes pregnant or
thinks she may be, the patient should tell their doctor right away.
Women should not breastfeed during treatment with Rydapt and for at
least four months after the final dose. Men taking Rydapt who have
female partners that are able to become pregnant should use
effective birth control during his treatment with Rydapt and for at
least four months after the last Rydapt dose. Rydapt may cause
fertility problems in women and men, which may affect their ability
to have children.
Rydapt may cause lung problems that may lead to
death. Patients on Rydapt who develop a new or worsening cough,
shortness of breath, or chest discomfort should get medical help
right away. These may be signs of serious lung problems.
Common sides effects reported during Rydapt
treatment for AML included low level of white blood cells with
fever (febrile neutropenia); nausea; redness, pain or ulcers inside
the mouth (mucositis); vomiting; headache; bruising; muscle or bone
pain; nose bleeds; device-related infection; high blood sugar
levels (hyperglycemia) and upper respiratory infections.
Common side effects reported during treatment for
ASM, SM-AHM or mast cell leukemia included nausea; vomiting;
diarrhea; swelling of the hands, feet or ankles; muscle or bone
pain; stomach-area pain; tiredness; upper respiratory infection;
constipation; fever; headache and trouble breathing.
If side effects including nausea, vomiting, and
diarrhea occur, get worse or do not go away during treatment with
Rydapt, patients should contact their doctor. Depending on the side
effect and/or severity of the side effect that occur, their doctor
may decrease their dose, temporarily stop, or completely stop
treatment with Rydapt.
Patients should tell their doctor about all the
medicines they take, including prescription and over-the-counter
medicines, vitamins and herbal supplements. Rydapt may affect how
these medicines work or these other medicines may affect how Rydapt
works.
Disclaimer
This press release contains forward-looking statements, including
"forward-looking statements" within the meaning of the United
States Private Securities Litigation Reform Act of 1995.
Forward-looking statements can generally be identified by words
such as "potential," "can," "will," "plan," "expect," "anticipate,"
"look forward," "believe," "committed," "investigational,"
"pipeline," "launch," or similar terms, or by express or implied
discussions regarding potential marketing approvals, new
indications or labeling for the investigational or approved
products described in this press release, or regarding potential
future revenues from such products. You should not place undue
reliance on these statements. Such forward-looking statements are
based on our current beliefs and expectations 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 the
investigational or approved products described in this press
release will be submitted or approved for sale or for any
additional indications or labeling in any market, or at any
particular time. Nor can there be any guarantee that such products
will be commercially successful in the future. In particular, our
expectations regarding such products 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; our ability to obtain or maintain
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prescribing preferences of physicians and patients; global trends
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economic and industry conditions, including the effects of the
persistently weak economic and financial environment in many
countries; 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
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References
1. Novartis data on file.
2. National Institutes of Health (NIH)
National Cancer Institute (NCI). Adult Acute Myeloid Leukemia
Treatment (PDQ®)
http://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq.
Accessed June 19, 2017.
3. Visser O, Trama A, Maynadié M, et al.
(RARECARE Working Group). Incidence, survival and prevalence of
myeloid malignancies in Europe. Eur J Cancer.
2012;48(17):3257-3266.
4. Patel JP, Gönen M, Figueroa ME, et al.
Prognostic relevance of integrated genetic profiling in acute
myeloid leukemia. N Engl J Med. 2012;
22;366(12):1079-1089.
5. Gilliland DG, Griffin JD. The roles of
FLT3 in hematopoiesis and leukemia. Blood.
2002;100(5):1532-1542.
6. Yanada M, Matsuo K, Suzuki T, et al.
Prognostic significance of FLT3 internal tandem duplication and
tyrosine kinase domain mutations for acute myeloid leukemia: a
meta-analysis. Leukemia.
2005;19(8):1345-1349.
7. Schiller GJ. High-risk acute myelogenous
leukemia: treatment today ... and tomorrow. Hematology Am Soc Hematol Educ Program. 2013;
2013:201-208.
8. Lin TL, Levy MY. Acute myeloid leukemia:
focus on novel therapeutic strategies. Clin Med
Insights Oncol. 2012;6:205-217.
9. Arock M, Akin C, Hermine O, et al.
Current treatment options in patients with mastocytosis: status in
2015 and future perspectives. Eur J
Haematology. 2015;94(6):474-494.
10. Georgin-Lavialle S, Lhermitte L, Dubreuil P, et al. Mast
cell leukemia. Blood.
2013;121:1285-1295.
11. Lim KH, Tefferi A, Lasho T, et al. Systemic mastocytosis
in 342 consecutive adults: survival studies and prognostic factors.
Blood. 2009;113:5727-5736.
12. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin
plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.
N Engl J Med. 2017 June 23. doi:
10.1056/NEJMoa1614359. [Epub ahead of print].
13. Deschler B, Lübbert M. Acute myeloid leukemia:
epidemiology and etiology. Cancer.
2006;107(9):2009-2107.
14. Döhner H, Estey E, Grimwade D, et al. Diagnosis and
management of AML in adults: 2017 ELN recommendations from an
international expert panel. Blood.
2017;129(4):424-447.
15.Garcia-Montero AC, Jara-Acevedo M, Teodosi C, et al. KIT
mutation in mast cells and other bone marrow hematopoietic cell
lineages in systemic mast cell disorders: a prospective study of
the Spanish Network on Mastocytosis (REMA) in a series of 113
patients. Blood.
2006;108(7):2366-2372.
16.Verstovsek S. Advanced systemic mastocytosis: the impact of KIT
mutations in diagnosis, treatment, and progression. Eur J Haematology. 2013;90(2):89-98.
17.Rydapt [prescribing information]. East Hanover, NJ: Novartis
Pharmaceuticals Corp, 2017.
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