- Approval in newly diagnosed
FLT3-mutated AML represents the first new treatment in more than 25
years[1],[2]
- Rydapt treatment regimen in
FLT3-mutated AML demonstrated a significant improvement in overall
survival with a 23% reduction in the risk of
death[3]
- Rydapt is the first and only
approved therapy for three types of SM collectively known as
advanced SM, a group of ultra-rare, life-threatening
conditions
- Novartis shares this milestone
with the study collaborators and patients who participated in these
clinical trials that helped bring Rydapt to approval
The digital
press release with multimedia content can be accessed
here:
Basel, April 28, 2017
- Novartis announced today the US Food and
Drug Administration (FDA) has approved Rydapt®
(midostaurin, formerly PKC412) for two indications. The first
indication is for the treatment of acute myeloid leukemia (AML) in
newly diagnosed patients who are FMS-like tyrosine kinase 3
mutation-positive (FLT3+), as detected by an FDA-approved test, in
combination with chemotherapy[3]. Rydapt is also approved to treat
adults with advanced systemic mastocytosis (SM), which includes
aggressive systemic mastocytosis (ASM), systemic mastocytosis with
associated hematological neoplasm (SM-AHN) and mast cell
leukemia[3]. This approval follows a prior Breakthrough Therapy
designation in FLT3-mutated AML, as well as Orphan Drug designation
and Priority Review in both indications by the FDA. Worldwide
filings for Rydapt are currently underway.
"Rydapt represents a remarkable advance as the
first and only targeted therapy approved for patients who had
limited options for many years," said Bruno Strigini, CEO, Novartis
Oncology. "We are proud to continue our leadership in hematology as
we work diligently to bring innovative medicines to patients
worldwide."
Rydapt is the only approved
targeted therapy for newly diagnosed FLT3-mutated AML
AML is a rare and aggressive cancer of the blood and bone
marrow[4]. In the US, about 21,000 people are estimated to be
diagnosed with AML in 2017[5]. Approximately one-third of these AML
patients, or 7,000, will have a FLT3 gene mutation[6]. FLT3 is a
type of cell-surface receptor which plays a role in increasing the
number of certain blood cells[7]. The FLT3 gene mutation can result
in faster disease progression, higher relapse rates and lower rates
of survival than other forms of AML[6],[7],[8]. Prior to the
approval of Rydapt, the AML therapeutic strategy had remained
relatively unchanged for more than 25 years[1],[2].
"The overall survival advantage for midostaurin
plus chemotherapy seen in the RATIFY trial was a significant
advancement for newly diagnosed AML patients with the FLT3
mutation," said Dr. Richard Stone, Chief of Staff and Director of
the Adult Leukemia program at Dana-Farber Cancer Institute, and
Alliance for Clinical Trials in Oncology study chair for the RATIFY
trial. "The availability of midostaurin now helps to establish a
new standard of care in this high-risk patient population."
Rydapt is indicated for use in combination with
standard cytarabine and daunorubicin induction and cytarabine
consolidation chemotherapy, for the treatment of adult patients
with newly diagnosed AML who are FLT3 mutation-positive, as
detected by an FDA-approved test[3]. Rydapt is not indicated as a
single-agent induction therapy for the treatment of patients with
AML[3].
The FDA approval 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
its 13 contributing international cooperative groups. In the trial,
newly diagnosed FLT3+ patients who received Rydapt plus
chemotherapy experienced significant improvement in overall
survival with a 23% reduction in the risk of death compared with
chemotherapy alone (hazard ratio [HR] = 0.77, 95% confidence
interval [CI], 0.63, 0.95; 2 sided p=0.016)[3].
Event-free survival (EFS; event defined as no
complete remission within 60 days of the start of induction
therapy, relapse or death) was significantly higher for Rydapt plus
chemotherapy versus chemotherapy alone (median of 8.2 months
compared to 3.0 months, HR = 0.78, 95% CI 0.66, 0.93 and 2 sided
p=0.004)[3]. RATIFY is the largest worldwide clinical trial in
newly diagnosed FLT3-mutated AML to date, as 3,279 AML patients
were screened for the FLT3 mutation and 717 patients were
enrolled[9]. All FLT3+ patients enrolled in the trial were treated
regardless of whether or not cytogenetic status was normal or
abnormal[3].
The most frequent adverse reactions (incidence
greater than or equal to 20%) in the Rydapt plus chemotherapy arm
were febrile neutropenia, nausea, vomiting, mucositis, headache,
musculoskeletal pain, petechiae (small red skin spots),
device-related infection, epistaxis, hyperglycemia and upper
respiratory tract infections. The most frequent Grade 3/4 adverse
reactions (incidence greater than or equal to 10%) were febrile
neutropenia, device-related infection and mucositis[3].
In order to identify FLT3+ AML patients who may
benefit from Rydapt, Novartis collaborated with Invivoscribe
Technologies, Inc. on the development of LeukoStrat®
CDx FLT3 Mutation Assay, a companion molecular diagnostic test,
which was also approved by the FDA today. LeukoStrat®
CDx FLT3 Mutation Assay is the first molecular companion diagnostic
in AML and identifies both FLT3 internal tandem duplication (ITD)
and tyrosine kinase domain (TKD) mutations and is performed by The
Laboratory for Personalized Molecular Medicine, a subsidiary of
Invivoscribe Technologies, Inc.
Rydapt provides an innovative
treatment option for advanced SM
Advanced SM is a rare blood disorder characterized by uncontrolled
growth and accumulation of mast cells - or mediators of allergic
responses - in one or more organs[10]. In advanced SM, mast cells
accumulate in such high quantities that they begin to cause organ
damage[10]. Median overall survival is currently less than six
months for mast cell leukemia[11], two years for SM-AHN and 3.5
years for ASM[12].
Rydapt is approved in the US for the treatment of
adult patients with ASM, SM-AHN, or mast cell leukemia[3]. The
approval of Rydapt was based on two single-arm open-label
multicenter trials, including the Phase II study (CPKC412D2201),
which was the largest and longest-running prospective trial ever
conducted in this ultra-rare disorder. The efficacy of Rydapt was
established on the basis of confirmed complete remission (CR) plus
incomplete remission (ICR) by six cycles of treatment per the
modified Valent criteria (n=89), in which CR and ICR are the
two most rigorous subcategories of a major response. This analysis
demonstrated an overall response rate of 21% (95% CI, 13, 31)[3].
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=115)[2]. This assessment
estimated complete remission or partial remission rate of
17% (95% CI, 10, 25)[3].
The most frequent adverse reactions (incidence
greater than or equal to 20%), excluding laboratory terms, were
nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal
pain, fatigue, upper respiratory tract infection, constipation,
pyrexia, headache and dyspnea. The most frequent Grade 3 or greater
adverse reactions (incidence greater than or equal to 5%),
excluding laboratory terms, were fatigue, sepsis, gastrointestinal
hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema,
dyspnea, nausea, vomiting, abdominal pain and renal
insufficiency[3].
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[5]. Mutations in specific genes are found in
many cases of AML[6], 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[10]. 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[10].
The uncontrolled proliferation of mast cells is
caused in many people by a KIT gene mutation - the most common
mutation, encoding the D816V 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[3].
Rydapt is available in 25 mg capsules. In AML, the
recommended dosage for Rydapt is 50 mg orally twice daily on days 8
to 21 each cycle of induction therapy and on days 8 to 21 each
cycle of consolidation therapy[3]. For a description of the
experience with single-agent treatment beyond induction and
consolidation, healthcare professionals should refer to the
Clinical Studies section of the Prescribing Information
(14.1)[3].
In advanced SM, the recommended dosage for Rydapt
is 100 mg orally twice daily[3].
The full prescribing information for Rydapt can be
found at:
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/rydapt.pdf.
Rydapt Important Safety
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, SH-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
The foregoing release contains forward-looking statements that can
be identified by words such as "Breakthrough Therapy designation,"
"Priority Review," "underway," "work diligently," "may," or similar
terms, or by express or implied discussions regarding potential
additional marketing approvals for Rydapt, or regarding potential
future revenues from Rydapt. 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 Rydapt
will be submitted or approved for sale in any additional markets,
or at any particular time. Nor can there be any guarantee that
Rydapt will be commercially successful in the future. In
particular, management's expectations regarding Rydapt 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 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] Schiller GJ. High-risk acute myelogenous leukemia: treatment
today ... and tomorrow. Hematology Am Soc Hematol
Educ Program. 2013; 2013:201-208.
[2] Lin TL, Levy MY. Acute myeloid leukemia: focus on novel
therapeutic strategies. Clin Med Insights
Oncol. 2012;6:205-217.
[3] Rydapt [prescribing information]. East Hanover, NJ: Novartis
Pharmaceuticals Corp, 2017.
[4] 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 April 10, 2017.
[5] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017.
CA Cancer J Clin. 2017;67:7-30.
[6] 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.
[7] Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis
and leukemia. Blood.
2002;100(5):1532-1542.
[8] 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.
[9] Stone RM, Mandrekar S, Sanford BL, et al. The Multi-kinase
inhibitor midostaurin (M) prolongs survival compared with placebo
(P) in combination with daunorubicin (D)/cytarabine (C) induction
(ind), high-dose © consolidation (consol), and as maintenance
(maint) therapy in newly diagnosed acute myeloid leukemia (AML)
patients (pts) age 18-60 with FLT3 mutations (muts): An
international prospective randomized (rand) p-controlled
double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015: 126:6.
[10] 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.
[11] Georgin-Lavialle S, Lhermitte L, Dubreuil P, et al. Mast cell
leukemia. Blood. 2013;121:1285-1295.
[12] Lim KH, Tefferi A, Lasho T, et al. Systemic mastocytosis in
342 consecutive adults: survival studies and prognostic factors.
Blood. 2009;113:5727-5736.
[13] Deschler B, Lübbert M. Acute myeloid leukemia: epidemiology
and etiology. Cancer.
2006;107(9):2009-2107.
[14] Arber DA, Borowitz MJ, Cessna M, et al. Initial Diagnostic
Workup of Acute Leukemia: Guideline from the College of American
Pathologists and the American Society of Hematology. Arch Pathol
Lab Med. 2017 Feb 22. doi: 10.5858/arpa.2016-0504-CP. [Epub ahead
of print].
[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.
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