Novartis announces Phase III studies of Jakavi show disease improvement in patients with myelofibrosis and polycythemia vera
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Novartis International AG /
Novartis announces Phase III studies of Jakavi show disease improvement in
patients with myelofibrosis and polycythemia vera
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* Data suggest myelofibrosis (MF) patients treated with Jakavi(®)
(ruxolitinib) after 5 years lived longer despite crossover from best
available therapy after week 48[1]
* Phase III results show Jakavi met primary endpoint in inadequately
controlled polycythemia vera (PV) patients without enlarged spleen
* Jakavi is approved globally to treat certain patients with MF and PV, rare
and life-threatening blood cancers with debilitating symptoms when not
properly managed[2],[3]
Basel, December 5, 2015 - Novartis announced today that five-year treatment with
Jakavi(®) (ruxolitinib) suggested an overall survival advantage for patients
with myelofibrosis (MF), despite crossover to Jakavi from the best available
therapy arm after the primary analysis at 48 weeks (intent-to-treat analysis:
33% reduction in risk of death, hazard ratio=0.67 [95% confidence interval (CI),
0.44-1.02], crossover-corrected hazard ratio=0.44 [95% CI, 0.18-1.04]). In the
COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy)
Phase III study, more than half of the patients with MF (53.4%) also experienced
significant reductions (>=35%) in spleen size with Jakavi therapy, and sustained
this benefit over prolonged periods of time (median duration of 3.2 years)[1].
Findings from this study were presented at the 57th American Society of
Hematology Meeting (ASH) in Orlando, Florida.
"Given that patients with myelofibrosis have shortened survival expectations and
are at an increased risk of complications, the five-year findings from COMFORT-
II demonstrate a long-term benefit with Jakavi therapy that is meaningful to the
community," said Claire Harrison, MD, study investigator and Consultant
Hematologist, Guy's and St. Thomas' NHS Foundation Trust, London. "These data
help to confirm the important role Jakavi plays in these difficult-to-treat
patients."
In addition to the Jakavi data presented at ASH, Novartis announced that a
separate Phase III study met its primary endpoint-patients with polycythemia
vera (PV) resistant to or intolerant of hydroxyurea who did not have an enlarged
spleen who were treated with Jakavi maintained hematocrit control without the
need for phlebotomy. In the Phase III RESPONSE 2 (Randomized Study of Efficacy
and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst
Available Care) study, the safety profile of Jakavi was consistent with previous
studies. Full results from the trial continue to be evaluated and will be
presented at a future medical congress.
"The growing body of research confirms the benefit of Jakavi for patients with
rare blood cancers, such as myelofibrosis and polycythemia vera, who have
limited treatment options," said Alessandro Riva, MD, Global Head, Novartis
Oncology Development and Medical Affairs. "In addition to exhibiting long-term
benefits in myelofibrosis, Jakavi also showed potential to benefit a broader
population of patients with polycythemia vera, bringing hope to another
underserved patient community."
About the COMFORT-II Study
COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) is a
randomized, open-label, Phase III study of 219 patients with primary MF, post-
polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia
myelofibrosis (PET-MF) in 56 study locations in Europe. Two-thirds of patients
(146) received Jakavi twice daily and one-third of patients (73) received best
available therapy, which was administered at doses and schedules determined by
the investigator. Best available therapy was selected by the investigator for
each patient and could have included a combination of available agents to treat
the disease and/or its symptoms. Of the patients on the best available therapy
arm, 61.6% crossed over to receive Jakavi upon protocol-defined progression
following the primary analysis after week 48. All patients randomized to best
available therapy have crossed over or discontinued. An analysis of the study at
five years was performed to evaluate the safety and efficacy of Jakavi in
patients with MF[1].
In the Phase III trial, fibrosis grades, a key indicator of disease control in
MF, improved (15.8%) or were maintained (32.2%) in nearly half of patients with
long-term Jakavi treatment. Nearly one-quarter of patients (26.7% from Jakavi
treatment arm; 24.4% who crossed over from best available treatment arm)
remained on treatment with Jakavi for five years. All adverse events (AEs) were
consistent with previous analyses of treatment with Jakavi in patients with MF.
The most common AEs in Jakavi-treated patients either after randomization or
after crossing over from best available therapy were thrombocytopenia (52.4%),
anemia (49.2%), diarrhea (35.6%) and peripheral edema (33.0%). The most common
grade 3/4 AEs included anemia (22.5%), thrombocytopenia (15.2%), pneumonia
(5.8%), general physical health deterioration (4.2%) and shortness of breath
(4.2%)[1].
About the RESPONSE 2 Study
RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with
JAK INhibitor Ruxolitinib VerSus BEst Available Care) is a multi-center, open
label, randomized, Phase IIIb study evaluating the efficacy and safety of Jakavi
versus best available therapy. The trial randomized 149 patients with PV who
were resistant to or intolerant of hydroxyurea, dependent on phlebotomy for
hematocrit control and did not have an enlarged spleen. Patients were randomized
1:1, by stratification (based on hydroxyurea resistance or intolerance) to
receive either Jakavi (10 mg twice daily) or best available therapy, which was
defined as investigator selected monotherapy or observation only. The dose was
adjusted as needed throughout the study.
About Myelofibrosis
MF is part of a group of related rare blood cancers known as myeloproliferative
neoplasms (MPNs) where a patient's bone marrow can no longer produce enough
normal blood cells, causing the spleen to enlarge[2]. As a result, patients with
MF may suffer from debilitating symptoms and have a poor quality of life[4].
After diagnosis, patients with MF have a decreased life expectancy, with an
average survival of approximately five to six years[5]. Although allogeneic stem
cell transplantation may cure MF, 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[6].
About Polycythemia Vera
Also an MPN, PV is associated with an overproduction of blood cells in the bone
marrow and affects roughly one to three people per 100,000 globally[3],[7]. The
disease is driven by the dysregulation of the JAK-STAT pathway[8]. It is
typically characterized by elevated hematocrit, the volume percentage of red
blood cells in whole blood, which can lead to a thickening of the blood and an
increased risk of blood clots, as well as an elevated white blood cell and
platelet count[3]. This can cause serious cardiovascular complications, such as
stroke and heart attack, resulting in increased morbidity and mortality[9].
Approximately 60 to 70% of patients with PV do not have enlarged spleen[10].
A common PV treatment includes phlebotomy, a procedure to remove blood from the
body to reduce the concentration of red blood cells, which is used to help
maintain a hematocrit level below 45%[3],[9]. However, for a subset of patients,
including those with high-risk PV, phlebotomy is usually unsuitable as a
permanent treatment option due to its inability to control symptoms or
effectively manage the overproduction of red blood cells, therefore
cytoreductive agents, such as hydroxyurea, may be added[9]. For patients
requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate
and remain at unsafe levels for significant periods of time[11]. Unfortunately,
approximately 25% of patients with PV become resistant to or intolerant of
hydroxyurea treatment according to European LeukemiaNet (ELN) criteria,
resulting in inadequate disease control and an increased risk of
progression[12].
About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine
kinases. Jakavi is approved by the European Commission for the treatment of
adult patients with polycythemia vera (PV) who are resistant to or intolerant of
hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in
adult patients with primary myelofibrosis (MF) (also known as chronic idiopathic
MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is
approved in more than 95 countries for patients with MF, including countries in
the European Union, Canada, Japan and countries in Asia, Latin and South
America, and in 49 countries for patients with PV, including countries in the
European Union, Japan and Canada. The exact indication for Jakavi varies by
country. Additional worldwide regulatory filings are underway in MF and PV.
Novartis licensed ruxolitinib from Incyte Corporation for development and
commercialization outside the United States. Jakavi is marketed in the United
States by Incyte Corporation as Jakafi® for the treatment of patients with PV
who have had an inadequate response to or are intolerant of hydroxyurea and for
the treatment of patients with intermediate or high-risk MF.
The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily.
The recommended starting dose of Jakavi in MF is 15 mg twice daily for patients
with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3,
and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses
may be titrated based on safety and efficacy. There is limited information to
recommend a starting dose for MF and PV patients with platelet counts between
50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these
patients is 5 mg twice daily, and patients should be titrated cautiously[13].
Jakavi is a registered trademark of Novartis AG in countries outside the United
States. Jakafi is a registered trademark of Incyte Corporation. The safety and
efficacy profile of Jakavi has not yet been established outside the approved
indications.
Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and
Polycythemia Vera (PV)
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 any hepatic impairment or
severe 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. Progressive multifocal leukoencephalopathy (PML) has been reported.
Physicians should be alert for neuropsychiatric symptoms suggestive of PML.
Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients
with chronic HBV infections. Patients with chronic HBV infection should be
treated and monitored according to clinical guidelines. Non-melanoma skin cancer
(NMSC) has been reported in Jakavi treated patients. Periodic skin examination
is recommended. Very common adverse reactions in MF (>10%) include urinary tract
infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia,
dizziness, headache, alanine aminotransferase increased, aspartate
aminotransferase increased, bruising and weight gain. Common adverse reactions
in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse
reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%)
include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia,
dizziness, alanine aminotransferase increased and aspartate aminotransferase
increased. Common adverse reactions in PV (1 to 10%) include urinary tract
infections, herpes zoster, weight gain, constipation and hypertension.
Please see full Prescribing Information available at www.jakavi.com.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by words such as "suggest," "suggested," "to be evaluated," "will," "growing,"
"potential," "hope," "underway," or similar terms, or by express or implied
discussions regarding potential new indications or labeling for Jakavi, or
regarding potential future revenues from Jakavi. 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 Jakavi
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 Jakavi
will be commercially successful in the future. In particular, management's
expectations regarding Jakavi could be affected by, among other things, the
uncertainties inherent in research and development, including unexpected
clinical trial results and additional analysis of existing clinical data;
unexpected 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; unexpected
safety issues; unexpected manufacturing or quality 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,
eye care and cost-saving generic pharmaceuticals. Novartis is the only global
company with leading positions in these areas. In 2014, the Group achieved net
sales of USD 58.0 billion, while R&D throughout the Group amounted to
approximately USD 9.9 billion (USD 9.6 billion excluding impairment and
amortization charges). Novartis Group companies employ approximately 120,000
full-time-equivalent associates. Novartis products are available in more than
180 countries around the world. For more information, please visit
http://www.novartis.com.
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References
[1] Harrison, C, Vannucchi AM, Kiladjian JJ, et al. Long-Term Efficacy and
Safety in Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available
Therapy for the Treatment of Myelofibrosis: 5-Year Final Study Results. Abstract
#59. 2015 American Society of Hematology (ASH) Annual Meeting, Orlando, FL.
[2] Leukemia & Lymphoma Society. "Myelofibrosis Facts." Available at:
http://www.lls.org/sites/default/files/file_assets/FS14_Myelofibrosis_Fact%20She
et_Final9.12.pdf. Accessed December 2015.
[3] Leukemia & Lymphoma Society. "Polycythemia Vera Facts." June 2012. Available
at
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials
/mpd/pdf/polycythemiavera.pdf. Accessed December 2015.
[4] 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.
[5] Gangat N, Caramazza D, Vaidya R, et al. DIPSS-plus: A Refined Dynamic
International Prognostic Scoring System (DIPSS) for Primary Myelofibrosis that
Incorporates Prognostic Information from Karyotype, Platelet Count and
Transfusion Status. J Clin Oncol. 2011; 29:392-397.
[6] 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.
[7] Titmarsh G, Duncombe A, McMullin M, et al. How Common are Myeloproliferative
Neoplasms? A Systematic Review and Meta-analysis. Am J Hematol. 2014:1-7.
[8] Schafer AI. Molecular Basis of the Diagnosis and Treatment of Polycythemia
Vera and Essential Thrombocythemia. Blood. 2006;107(11):4214-4222.
[9] Finazzi G and Barbui T. How I Treat Patients with Polycythemia Vera. Blood.
2007;109(12):5104-5111.
[10] Vannucchi AM. How I Treat Polycythemia Vera. Blood. 2014;124:3212-3220.
[11] Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular Events and
Intensity of Treatment in Polycythemia Vera. N Engl J Med. 2013;368:22-33.
[12] Alvarez-Larran A, Pereira A, Cervantes F, et al. Assessment and Prognostic
Value of The European LeukemiaNet Criteria for Clinicohematologic Response,
Resistance, and Intolerance to Hydroxyurea in Polycythemia Vera. Blood.
2012;119(6):1363-1369.
[13] Jakavi(®) (ruxolitinib) tablets: EU Summary of Product Characteristics.
Novartis; Mar 2015.
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Datum: 05.12.2015 - 15:30 Uhr
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