Novartis JAK inhibitor INC424 shows significant clinical benefit for myelofibrosis patients in two Phase III studies at ASCO
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Novartis International AG /
Novartis JAK inhibitor INC424 shows significant clinical benefit for
myelofibrosis patients in two Phase III studies at ASCO
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* Myelofibrosis is a life-threatening blood cancer characterized by bone
marrow failure, enlarged spleen and debilitating symptoms, including fatigue
and pain
* Phase III trial (COMFORT-II) demonstrated INC424 significantly reduced
enlarged spleen size, a major characteristic of the disease, when compared
to best available therapy at 48 weeks
* A separate Phase III trial (COMFORT-I) of INC424 showed significant spleen
size reduction and symptom improvement when compared to placebo at 24 weeks
* Both studies met their primary endpoint and provide the basis for worldwide
filings to begin in Q2 2011 in myelofibrosis, for which there are limited
treatment options
Basel, June 4, 2011 - Novartis announced today results from two pivotal Phase
III studies demonstrating the effects of investigational Janus kinase (JAK)
inhibitor INC424 (ruxolitinib) in treating patients with myelofibrosis, a blood
cancer with limited treatment options. These data are being presented at the
47(th) American Society of Clinical Oncology (ASCO) annual meeting in
Chicago[1],[2],[3]. Novartis and Incyte have a worldwide collaboration and
license agreement for INC424.
The Phase III trial COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK
Inhibitor Therapy) demonstrated that INC424 produced a volumetric spleen size
reduction of 35% or greater in 28.5% of myelofibrosis patients compared to 0% of
patients in the best available therapy arm at 48 weeks (p<0.0001). The trial
also met a key secondary endpoint with 31.9% of INC424 patients demonstrating a
35% or greater volumetric spleen size reduction by week 24 compared to 0% in
best available therapy patients (p<0.0001)[1]. Further, data showed a marked
improvement in overall quality of life measures, functioning and symptoms
relative to the best available therapy arm[1].
COMFORT-I, conducted by Incyte, is a Phase III clinical trial comparing INC424
to placebo at 24 weeks. Results showed that 41.9% of myelofibrosis patients who
received INC424 achieved at least a 35% reduction in spleen volume at 24 weeks
from baseline compared to 0.7% of patients in the placebo arm (p<0.0001).
COMFORT-I also met key secondary endpoints with statistical significance,
including improvement of debilitating symptoms and demonstrating clinically
relevant durations of spleen size reduction[2].
"These data show that INC424 may offer a significant advance in treating
patients impacted by myelofibrosis, a serious malignant disease with limited
available treatment options," said Alessandro Vannucchi, MD, Professor,
Department of Hematology, University of Florence, Hospital Careggi, Italy,
investigator for the COMFORT-II study. "By targeting the JAK pathway, which is
autonomously activated in patients with myelofibrosis even in the absence of the
most common JAK mutation, INC424 delivered rapid and durable spleen size
reduction in these patients."
Myelofibrosis is an uncommon blood cancer characterized by bone marrow failure,
enlarged spleen (splenomegaly), a variety of symptoms that can be debilitating
and serious complications. It is associated with significantly reduced quality
of life and shortened survival[4]. A high unmet medical need exists for the
treatment of myelofibrosis, caused by abnormal signaling in the JAK pathway,
which regulates blood cell production[3],[5]. Abnormal signaling initiates
faulty blood cell production resulting in an enlarged spleen and other severe
complications[5].
"The COMFORT clinical program is the largest ever conducted in myelofibrosis
patients and findings support INC424 as a significant advance for patients
affected by this life-threatening blood cancer," said Hervé Hoppenot, President,
Novartis Oncology. "These studies further demonstrate Novartis' goal of bringing
innovative, pathway-based compounds to patients with unmet medical needs."
Results of the COMFORT clinical trials will also be presented at the 16(th)
Congress of the European Hematology Association (EHA) from June 9-12 in London.
Both studies met their primary endpoint and form the basis of worldwide
regulatory filings planned to begin in the second quarter of 2011 by Novartis
and Incyte.
COMFORT-II study details
COMFORT-II is a randomized, open-label Phase III study of INC424 versus best
available therapy (BAT) that enrolled 219 patients with primary myelofibrosis
(MF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential
thrombocythemia myelofibrosis (PET-MF) in 56 study locations in Europe. Two-
thirds received INC424 (starting dose 15 or 20 mg twice daily) and one-third
received BAT, which was administered at doses and schedules determined by the
investigator[1].
The primary endpoint for COMFORT-II was the proportion of patients achieving a
reduction in spleen volume of 35% or more from baseline at week 48 as measured
by MRI (or CT scan in applicable patients). Secondary endpoints included spleen
size reduction at 24 weeks, duration of spleen size reduction, time to treatment
response, change in bone marrow histomorphology, leukemia-free survival,
progression-free survival and overall survival. Patients continue to receive
INC424 therapy and to be followed to determine longer-term outcomes[1].
The safety profile of INC424 was consistent with previous studies. Only 8.2% and
5.5% of patients discontinued the study because of an adverse event in the
INC424 and BAT arms, respectively. For patients in the INC424 arm, the most
commonly reported grade 3 or higher adverse events were hematologic. Based on
laboratory assessments, the percentage of patients with grade 3 or 4 low
platelet counts at any time during the study was 8.3% on INC424 vs 7.2% on BAT.
The percentage of patients with grade 3 or 4 low hemoglobin values at any time
during the study was 42.4% on INC424 vs 31.4% on BAT. Both thrombocytopenia and
anemia were effectively managed in this clinical setting with appropriate dose
modifications and/or transfusions. Only one patient in each arm discontinued for
thrombocytopenia and no patient discontinued for anemia. The most commonly
reported grade 3 or higher non-hematologic adverse events in the INC424 arm were
abdominal pain (3.4% vs 2.7% in the BAT arm), back pain (2.1% vs 0% in the BAT
arm), weight gain (2.1% vs 0% in the BAT arm), and fever (2.1% vs 0% in the BAT
arm)[1].
COMFORT-II was conducted by Novartis in Europe.
COMFORT-I study details
COMFORT-I is the first Phase III study of INC424 and is a randomized, double-
blind, placebo-controlled study that enrolled 309 patients with primary MF, PPV-
MF or PET-MF, conducted by the collaboration partner Incyte Corporation in 89
study locations in the US, Canada and Australia. Half of patients received
INC424 (starting dose 15 or 20 mg twice daily) and half received placebo. The
primary endpoint was the proportion of patients achieving a reduction in spleen
volume of 35% or more from baseline at week 24 as measured by MRI (or CT scan in
applicable patients)[2]. Secondary endpoints included duration of maintenance of
a 35% or greater reduction in spleen volume from baseline and the proportion of
patients with 50% or more reduction in symptom improvement as measured by the
modified Myelofibrosis Symptom Assessment Form electronic diary.[2]
In general, the safety profile of patients treated with INC424 was consistent
with the findings of the COMFORT-II trial and INC424 was well tolerated.
Overall, 10.3% and 9.3% of patients discontinued the study because of an adverse
event in the INC424 and placebo arms, respectively. For patients in the INC424
arm, the most commonly reported grade 3 or higher adverse events were
hematologic. The percentage of patients with grade 3 or 4 low platelet counts at
any time during the study was 12.9% on INC424 vs 1.3% in the placebo arm. The
percentage of patients with grade 3 or 4 low hemoglobin values at any time
during the study was 45.2% on INC424 vs 19.2% in the placebo arm. Only one
patient in each arm discontinued for thrombocytopenia and for anemia. The most
common non-hematologic adverse events of any grade reported for patients
receiving INC424 or placebo respectively were fatigue (25% vs 34%), diarrhea
(23% vs 21%), peripheral edema (19% vs 23%) and ecchymosis (19% vs 9%).
COMFORT-I was conducted by collaboration partner Incyte Corporation in the US,
Canada and Australia.
About myelofibrosis
Myelofibrosis is an uncommon, life-threatening blood cancer characterized by
bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, such
as fatigue, night sweats and pruritus, poor quality of life, weight loss as well
as shortened survival[4]. In the EU, the disease affects about 0.75 out of every
100,000 people annually[6],[7]. In the US, myelofibrosis affects about 1.5 out
of every 100,000 people annually[8]. Myelofibrosis has a poor prognosis and
limited treatment options[3],[4]. Studies show that within 10 years of
diagnosis, up to approximately 20% of myelofibrosis patients progress to fatal
secondary acute myelogenous leukemia, which is virtually untreatable[9],[10].
Although allogeneic stem cell transplantation may cure myelofibrosis, the
procedure is associated with significant morbidity and mortality and is usually
appropriate only in a very small subset of younger patients, typically less than
5% of patients[5],[11]. The five-year survival rate after transplantation is
approximately 50%[11].
About INC424
INC424 is an oral inhibitor of the JAK1 and JAK2 tyrosine kinases[3]. INC424 is
being investigated in primary myelofibrosis as well as post-polycythemia vera
myelofibrosis (PPV-MF) and post-essential thrombocythemia myelofibrosis (PET-
MF). INC424 is also being investigated in clinical trials for the treatment of
polycythemia vera (PV)[1],[2],[12].
Novartis licensed INC424 from Incyte for development and potential
commercialization outside the US. Incyte has retained rights for the development
and potential commercialization of INC424 in the US. Both the European
Commission (EC) and the US Food and Drug Administration (FDA) have granted
INC424 orphan drug status for myelofibrosis.
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "to begin in Q2 2011," "may," "will," "planned,"
"potential," "mission," "promise," "continue to receive INC424 therapy and to be
followed to determine longer-term outcomes," or similar expressions, or by
express or implied discussions regarding potential marketing submissions or
approvals for INC424, or the potential timing of such submissions or approvals,
or regarding the potential long-term impact of INC424 therapy, or regarding
potential future revenues from INC424. 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 INC424 to be
materially different from any future results, performance or achievements
expressed or implied by such statements. There can be no guarantee that INC424
will be submitted or approved for sale in any market, or at any particular time.
Nor can there be any guarantees regarding the long-term impact of treatment with
INC424. Neither can there be any guarantee that INC424 will achieve any
particular levels of revenue in the future. In particular, management's
expectations regarding INC424 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; 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 healthcare solutions that address the evolving needs of
patients and societies. Focused solely on healthcare, Novartis offers a
diversified portfolio to best meet these needs: innovative medicines, eye care,
cost-saving generic pharmaceuticals, consumer health products, preventive
vaccines and diagnostic tools. Novartis is the only company with leading
positions in these areas. In 2010, the Group's continuing operations achieved
net sales of USD 50.6 billion, while approximately USD 9.1 billion (USD 8.1
billion excluding impairment and amortization charges) was invested in R&D
throughout the Group. Headquartered in Basel, Switzerland, Novartis Group
companies employ approximately 119,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visithttp://www.novartis.com.
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http://twitter.com/novartis.
References
[1] Harrison, Claire N. Results of a randomized study of the JAK inhibitor
ruxolitinib (INC424) vs best available therapy (BAT) in primary myelofibrosis
(PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential
thrombocythemia-myelofibrosis (PET-MF). Abstract #LBA6501. American Society of
Clinical Oncology 2011 Annual Meeting.
[2] Verstovsek, S. Morgan, G. Results of COMFORT- I, a randomized double-blind
phase III trial of JAK 1/2 inhibitor INCB18424 (424) vs placebo (PB) for
patients with myelofibrosis (MF). Abstract #6500. American Society of Clinical
Oncology 2011 Annual Meeting.
[3] 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;363:1117-1127.
[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] Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available
at:http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmateri
als/mpd/pdf/idiopathicmyelofibrosis. Accessed April 2011.
[6] Girodon F, Bonicelli G, Schaeffer C, et al. Significant increase in the
apparent incidence of essential thrombocythemia related to new WHO diagnostic
criteria: a population-based study. Haematologica. 2009; 94(6):865-869.
[7] McNally RJQ, Rowland D, Roman E, Cartwright RA. Age and sex distributions of
hematological malignancies in the U.K. Hematol Oncol. 1997;15:173-189.
[8] Mesa RA, Silverstein MN, Jacobsen SJ, et al. Population-based incidence and
survival figures in essential thrombocythemia and agnogenic myeloid metaplasia:
an Olmsted County Study, 1976-1995. Am J Hematol. 1999;61:10-15.
[9] Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming
events that convert chronic myeloproliferative neoplasms to leukemia. Cancer
Res. 2010;70(2):447-452.
[10] Beer PA, Green AR. Pathogenesis and management of essential
thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009;621-628.
[11] Tefferi A. Allogeneic hematopoietic cell transplantation versus drugs in
myelofibrosis: the risk-benefit balancing act. Bone Marrow Transplant.
2010;45(3):419-421.
[12] National Institutes of Health. Study of Efficacy and Safety in Polycythemia
Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor
INC424 (INCB018424) Tablets Versus Best Available Care: The RESPONSE Trial.
Available
athttp://www.clinicaltrials.gov/ct2/show/NCT01243944?term=ruxolitinib&rank=14.
Accessed April 2011.
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Datum: 04.06.2011 - 20:30 Uhr
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