Novartis drug Jakavi® improved overall survival of myelofibrosis patients and impacted an underlying mechanism of disease
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Novartis drug Jakavi® improved overall survival of myelofibrosis patients and
impacted an underlying mechanism of disease
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* Jakavi(®) reduced risk of death by 52% and sustained reductions in spleen
size in new three-year COMFORT-II study data
* Analysis from a separate trial suggested that long-term treatment with
Jakavi may stabilize or improve bone marrow fibrosis, a key marker of
worsening disease
* Jakavi continues to be well tolerated in myelofibrosis patients after three
years of treatment
Basel, June 16, 2013 - Novartis today announced results from a Phase III three-
year follow-up study that showed Jakavi(®) (ruxolitinib) demonstrated improved
overall survival and sustained reductions in spleen size compared to
conventional therapy. In a separate long-term exploratory analysis, Jakavi
slowed or stabilized the advancement of bone marrow fibrosis, one of the
underlying disease mechanisms and consequences of myelofibrosis, an effect that
has not been observed with conventional therapy in advanced myelofibrosis
patients.
Findings are being presented at the 18(th) Congress of European Hematology
Association (EHA) in Stockholm, Sweden.
In a three-year follow-up analysis of the COMFORT-II study, patients treated
with Jakavi demonstrated an overall survival advantage compared to patients
receiving conventional therapy. A 52% reduction in risk of death was observed in
the Jakavi arm compared with conventional therapy (HR=0.48; 95% CI, 0.28-0.85;
p=0.009)[1], and the estimated probability of overall survival was significantly
greater with Jakavi compared to conventional therapy (81% compared to 61%,
respectively) at 144 weeks. Additionally, 51.4% of patients treated with Jakavi
achieved a >=35% reduction from baseline in spleen size. Patients continue to
maintain their spleen response, with the median spleen reduction not yet reached
in the study.
The results are consistent with previous COMFORT-II and COMFORT-I study
analyses, which demonstrate that Jakavi provides significant clinical benefits
over conventional therapy and placebo for patients suffering from myelofibrosis,
a rare blood cancer.
"Jakavi is the first drug to demonstrate an improvement in overall survival in
patients with advanced myelofibrosis," said Dr. Alessandro M. Vannucchi,
Department of Hematology, University of Florence, Italy and lead study author.
"Moreover, we are encouraged by these latest study results, which reinforce that
the rapid, positive effects of Jakavi in improving patients' symptoms are
sustained over the long-term."
Myelofibrosis develops when uncontrolled signaling in the JAK pathway - which
regulates blood cell production - causes the body to make blood cells that do
not work properly, which scars the bone marrow and results in an enlarged spleen
and other severe complications[2],[3]. Jakavi directly targets the underlying
mechanism of the disease and it significantly reduces spleen size and improves
symptoms regardless of JAK mutational status, disease subtype or any prior
treatment[4],[5],[6],[7],[8].
Data were also presented from an exploratory analysis of bone marrow morphology
from a separate Phase I/II trial of Jakavi, compared with historical controls
from patients treated with conventional therapy. After four years of Jakavi
therapy, bone marrow fibrosis improved in 22% and stabilized in 56% of patients
with myelofibrosis. A comparable effect was not seen with long-term conventional
therapy.[9]
"For the first time in advanced myelofibrosis, drug therapy showed evidence of
bone marrow fibrosis stabilization or improvement, further supporting that
Jakavi may modify the natural course of disease," said Alessandro Riva, M.D.,
Global Head, Oncology Development and Medical Affairs, Novartis Oncology. "These
data are of great interest because bone marrow transplantation, which carries a
high risk of morbidity and mortality, is the only other option proven to impact
bone marrow fibrosis in patients with advanced myelofibrosis."
COMFORT-II Three-Year Long-Term Study Background
In the three-year analysis of COMFORT-II (COntrolled MyeloFibrosis Study with
ORal JAK Inhibitor Therapy), a total of 45.2% of patients remained on the Jakavi
treatment arm, while all patients randomized to conventional therapy
discontinued treatment. For patients on conventional therapy, 61.6% crossed over
to the Jakavi treatment arm, with 48.9% of these patients ongoing in the
extension phase of the study. The median duration of Jakavi exposure (randomized
and extension phases) was 136 weeks and conventional therapy exposure
(randomized treatment only) was 45 weeks. Overall survival was estimated using
the Kaplan-Meier method.
All AEs were consistent with previous analyses of treatment with Jakavi. The
most common hematologic AEs in either arm (Jakavi, conventional therapy) were
anemia (50.0%; 16.4%) and thrombocytopenia (50.7%; 13.7%). The most common non-
hematologic abnormalities for each arm (Jakavi, conventional therapy) include
peripheral edema (swelling of extremities) (36.3%; 28.8%), diarrhea (32.2%;
17.8%) and asthenia (weakness) (24.0%; 12.3%)[1].
A total of 191 patients were exposed to Jakavi by the data cut-off date, 146
patients initially randomized to Jakavi treatment and 45 patients that
eventually crossed over from the conventional therapy arm. Treatment
discontinuations in the Jakavi arm were primarily due to adverse events (AEs)
(16.4%) and disease progression (15.1%), while discontinuations in the
conventional therapy arm were primarily due to consent withdrawal and other
reasons (12.3% each). Only two patients discontinued due to anemia (1%) and
seven patients due to thrombocytopenia (3.6%).
Long-Term Bone Marrow Morphology Analysis Background
The data from this separate exploratory analysis assessed the effect of long-
term Jakavi treatment on bone marrow morphology in patients with myelofibrosis.
An analysis of trephine biopsies were obtained from the cohort of myelofibrosis
patients treated at MD Anderson Cancer Center who participated in Study 251, a
Phase I/II trial of ruxolitinib[9].
Biopsies of myelofibrosis patients treated with Jakavi were obtained at
baseline, 24 months (68 patients) and 48 months (18 patients). Samples were also
collected from a multicenter observational database from three European Union
countries (160 biopsies in a cohort of 139 patients) in patients treated with
conventional therapy at 24 months (97 patients) and 48 months (63 patients)[9].
Bone marrow fibrosis grade (G) changes vs. baseline were categorized as
improvement, stabilization, and worsening according to the World Health
Organization (WHO) grading scale (0-3) and reviewers were blinded to patient
characteristics and outcomes. Additional analyses were performed on biopsies
from patients in the Jakavi-treated cohort: changes over time in the degree of
collagen deposition, amount of osteosclerosis (abnormal bone density) and bone
marrow cellularity[9]. Bone marrow biopsies of Jakavi treated patients who were
evaluated at baseline presented with 21% G1 fibrosis, 53% G2 fibrosis and 26% G3
fibrosis. Distribution of baseline WHO fibrosis grades between Jakavi- and
conventionally- treated groups showed no noticeable difference (p=0.441 by
Cochran Mantel-Haenszel test)[9].
About Myelofibrosis
Myelofibrosis is a life-threatening blood cancer with a poor prognosis and
limited treatment options[10],[11]. Studies show that patients with
myelofibrosis have a decreased life expectancy, with a median overall survival
of 5.7 years[12]. Although allogeneic stem cell transplantation may cure
myelofibrosis, the procedure is associated with significant morbidity and
transplant-related mortality,and is available to less than 5% of patients who
are young and fit enough to undergo the procedure[13].
About Jakavi
Jakavi(®) (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine
kinases and was approved by the European Commission in August 2012 for the
treatment of disease-related splenomegaly or symptoms in adult patients with
primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-
polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis.
Jakavi is approved in more than 45 countries, including the European Union,
Canada and some countries in Asia, Latin and South America. Additional worldwide
regulatory filings are underway.
Novartis licensed ruxolitinib from Incyte Corporation for development and
commercialization outside the United States. Both the European Commission and
the US Food and Drug Administration (FDA) granted ruxolitinib orphan drug status
for myelofibrosis. Jakavi is marketed in the United States by Incyte Corporation
under the name Jakafi(®) for the treatment of patients with intermediate or
high-risk myelofibrosis.
The recommended starting dose for Jakavi is 15 mg twice daily for patients with
a platelet count between 100,000cubic millimeters (mm(3)) and 200,000 mm(3),and
20 mg twice daily for patients with a platelet count of >200,000 mm(3). Doses
may be titrated based on safety and efficacy. There is limited information to
recommend a starting dose for patients with platelet counts between
50,000/mm(3) and <100,000/mm(3). The maximum recommended starting dose in these
patients is 5 mg twice daily and patients should be titrated cautiously[14].
Jakavi is a registered trademark of Novartis AG in countries outside the United
States. Jakafi is a registered trademark of Incyte Corporation.
Jakavi(®) Important Safety Information
Jakavi(®) can cause serious side effects, including a decrease in blood cell
count and infections. Complete blood count monitoring is recommended. Dose
reduction or interruption may be required in patients with severe hepatic or
renal impairment or in patients developing hematologic adverse reactions such as
thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended
when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use
of Jakavi during pregnancy is not recommended and women should avoid becoming
pregnant during Jakavi therapy. Women taking Jakavi should not breast feed.
The most common adverse drug reactions, occurring at any level of severity
(incidence >10%) are urinary tract infections, anemia, thrombocytopenia,
neutropenia, hypercholesterolemia, dizziness, headache, alanine
aminotransaminase increased, asparte aminotransferase increased, bruising,
bleeding and increased blood pressure. Other common adverse drug reactions
(incidence 1 to 10%) are herpes zoster, weight gain, flatulence and tuberculosis
(1%). Progressive multifocal leukencephalopathy (PML) has been reported.
Physicians should be alert for neuropsychiatric symptoms suggestive of PML[14].
Please see full Prescribing Information available at www.jakavi.com .
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "suggested," "may," "encouraged," or similar expressions,
or by express or implied discussions regarding potential future revenues from
Jakavi. 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 Jakavi to be materially different from any
future results, performance or achievements expressed or implied by such
statements. There can be no guarantee that Jakavi will achieve any particular
levels of revenue in the future. In particular, management's expectations
regarding Jakavi could be affected by, among other things, unexpected regulatory
actions or delays or government regulation generally; unexpected clinical trial
results, including unexpected new clinical data and unexpected additional
analysis of existing clinical data; government, industry and general public
pricing pressures; unexpected manufacturing issues; competition in general; the
company's ability to obtain or maintain patent or other proprietary intellectual
property protection; 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 2012, the Group
achieved net sales of USD 56.7 billion, while R&D throughout the Group amounted
to approximately USD 9.3 billion (USD 9.1 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 129,000
full-time-equivalent associates and operate in more than 140 countries around
the world. For more information, please visit http://www.novartis.com.
Novartis is on Twitter. Sign up to follow (at)Novartis at
http://twitter.com/novartis.
References
[1] Vannucchi, A, et al. Long-Term Outcomes From A Phase 3 Study Comparing
Ruxolitinib With Best Available Therapy (BAT) For The Treatment of Myelofibrosis
(MF): A 3 Year Update of Comfort II. Abstract #S1111.18(th) Congress of European
Hematology Association (EHA), 2013. Stockholm, Sweden.
[2] Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available at:
http://www.lls.org/#/diseaseinformation/myeloproliferativediseases/idiopathic
myelofibrosis/. Accessed April 2013.
[3] Mesa RA, Schwagera S, Radia D, et al. The Myelofibrosis Symptom Assessment
Form (MFSAF): an evidence-based brief inventory to measure quality of life and
symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.
[4] Verstovsek S, Mesa RA, Gotlib J, et al. A Double-Blind, Placebo-Controlled
Trial of Ruxolitinib for Myelofibrosis. New Eng J Med. 2012: March
1;366:799-807.
[5] Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK Inhibition with Ruxolitinib
versus Best Available Therapy for Myelofibrosis. New Eng J Med. 2012: March
1;366:787-98.
[6] Vannucchi A, Kiladjian JJ, Gisslinger H, et al. Reductions in JAK2V617F
Allele Burden with Ruxolitinib Treatment in COMFORT-II, a Phase III Study
Comparing the Safety and Efficacy of Ruxolitinib to Best Available Therapy
(BAT). 2012. Abstract #802. American Society of Hematology 2012. Annual Meeting,
Atlanta, GA.
[7] Harrison C, Kiladjian JJ, Gisslinger H, et al. Association of Cytokine
Levels and Reductions in Spleen Size in COMFORT-II, a Phase 3 Study Comparing
Ruxolitinib to Best Available Therapy (BAT). Abstract # 6625. American Society
of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
[8] Cervantes, F, et al. Long-Term Safety, Efficacy, and Survival Findings From
COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy
(BAT) for the Treatment of Myelofibrosis (MF) Blood. 2012. Abstract #801.
American Society of Hematology 2012 Annual Meeting. Atlanta, GA.)
[9] Kvasnicka, HM, et al. Long Term Intervention Effects on Bone Marrow
Morphology in Myelofibrosis: Patients Treated With Ruxolitinib and Best
Available Therapy. Abstract #S591.18(th) Congress of European Hematology
Association (EHA). 2013. Stockholm, Sweden.
[10] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of JAK1 &
JAK2 Inhibitor, INCB018424, in Myelofibrosis. New Eng J Med. 2010 September
16;363(12):1117-1127.
[11] Mesa RA, Schwagera S, Radia D, et al. The Myelofibrosis Symptom Assessment
Form (MFSAF): an evidence-based brief inventory to measure quality of life and
symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.
[12] Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for
primary myelofibrosis based on a study of the International Working Group for
Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.
[13] Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem
cell transplantation in myelofibrosis: the 20-year experience of the Gruppo
Italiano Trapianto di Midollo Osseo (GITMO). Haematologica.
2008;93(10):1514-1522.
[14] JAKAVI [Summary of Product Characteristics]. Basel, Switzerland: Novartis
Pharma AG; 2012.
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