Novartis investigational JAK inhibitor INC424 data met primary endpoint in Phase III trial of patients with myelofibrosis
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Novartis International AG /
Novartis investigational JAK inhibitor INC424 data met primary endpoint in Phase
III trial of patients with myelofibrosis
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* COMFORT-I trial shows INC424 provides significant clinical improvement in
patients with myelofibrosis as measured by spleen size reduction
* High unmet medical need exists for patients with myelofibrosis, an uncommon
and debilitating blood cancer
* Full results to be submitted for presentation at upcoming medical congress;
worldwide regulatory filings planned for 2011
Basel, December 20, 2010 - Novartis announced today that a pivotal Phase III
trial of the investigational Janus kinase (JAK) inhibitor INC424 (also known as
INCB018424 and INCB18424) has met its primary endpoint of significantly reducing
spleen volume in patients with myelofibrosis (MF).
The study, called COMFORT-1 (COntrolled MyeloFibrosis Study with Oral JAK
Inhibitor Therapy), showed treatment with INC424 provided a statistically
significant reduction in spleen size in patients with primary MF, post-
polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia
myelofibrosis (PET-MF). The study also met the secondary endpoint of symptomatic
improvement as measured by the modified Myelofibrosis Symptom Assessment Form
Diary. Further, the safety profile of INC424 was consistent with previous
studies, which included reversible thrombocytopenia and anemia. Results from
COMFORT-1 are planned to be submitted for presentation at an upcoming medical
congress.
These results support findings from a Phase I/II study published in the
September 16, 2010 issue of The New England Journal of Medicine showing that
treatment with INC424 resulted in marked and durable clinical benefits in
patients with MF. These benefits included alleviation of debilitating symptoms
and reduction of spleen size, an accepted measurement for the clinical
improvement in MF [1,2].
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 US Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) have granted INC424
orphan drug status for MF.
Myelofibrosis is an uncommon, life-threatening blood cancer characterized by
bone marrow failure, enlarged spleen (splenomegaly), debilitating symptoms
including fatigue, night sweats and pruritus, poor quality of life, weight loss
and shortened survival. Myelofibrosis has a poor prognosis and limited
treatment options [1,3]. Although allogeneic stem cell transplantation may cure
MF, the procedure is associated with significant morbidity and mortality and is
usually appropriate only in younger patients[3]. The five-year survival rate
after transplantation is approximately 50% [4].
"Throughout its clinical development, INC424 has demonstrated the potential to
fill a critical need for patients with myelofibrosis, who currently have limited
treatment options," said Hervé Hoppenot, President, Novartis Oncology. "This
promising JAK inhibitor is an important part of our rich pipeline of innovative
new therapies that address unmet needs in hematology and cancer treatment."
A separate Phase III clinical trial conducted in Europe, COMFORT-II, has
completed enrollment and will evaluate the benefits of treatment with INC424
compared with best available care in patients with primary MF, PPV-MF or PET-MF.
Results are expected in the first half of 2011 and along with COMFORT-I may
form the basis of worldwide regulatory filings.
The JAK family of enzymes are key players in a number of important biologic
processes, including the regulation of immune function and the formation and
development of blood cells [5-10]. A strong association exists between abnormal
JAK signaling and the development of MF, polycythemia vera and essential
thrombocythemia, a related group of conditions referred to as Philadelphia-
chromosome negative myeloproliferative neoplasms [1-14]. Patients with these
diseases can progress to secondary acute myelogenous leukemia, which is
virtually untreatable and is associated with a dismal prognosis [15,16]. The
discovery of JAK mutations common to MF, polycythemia vera and essential
thrombocythemia has linked them on a molecular level and has led to the
development of INC424, a potent, selective inhibitor of the JAK1 and JAK2
tyrosine kinases [17].
Study details
COMFORT-I is a randomized, double-blind, placebo-controlled Phase III study of
INC424 that enrolled 309 patients with primary MF, PPV-MF or PET-MF. Half
received INC424 (starting dose 15 or 20 mg twice-daily) and half received
placebo. The primary endpoint is the proportion of patients achieving a
reduction in spleen volume of 35% or more from baseline to week 24 as measured
by a magnetic resonance imaging (MRI), or computed tomography (CT) scan in
applicable patients. COMFORT-I was sponsored by Incyte Corporation and has 112
study locations in the US, Canada and Australia [18].( )
About myelofibrosis
Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm
[1]. Of the JAK-associated myeloproliferative neoplasms, MF carries the greatest
risk of a poor prognosis, including transformation to fatal acute myelogenous
leukemia. For MF patients in general, clinical findings such as splenomegaly,
anemia and constitutional symptoms may be associated with significantly reduced
quality of life [3,19-21].
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "to be," "planned," "potential," "promising," "pipeline,"
"will," "expected," "may," or similar expressions, or by express or implied
discussions regarding potential marketing approvals for INC424, or the potential
timing of such approvals, 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 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, cost-
saving generic pharmaceuticals, preventive vaccines, diagnostic tools and
consumer health products. Novartis is the only company with leading positions in
these areas. In 2009, the Group's continuing operations achieved net sales of
USD 44.3 billion, while approximately USD 7.5 billion was invested in R&D
activities throughout the Group. Headquartered in Basel, Switzerland, Novartis
Group companies employ approximately 100,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visithttp://www.novartis.com.
References
1. 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.
2. Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG)
consensus criteria for treatment response in myelofibrosis with myeloid
metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT).
Blood. 2006;108:1497-1503.
3. The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available
athttp://www.leukemia-lymphoma.org/attachments/National/br_1190656475.pdf.
Accessed October 2010.
4. Tefferi A. Allogeneic hematopoietic cell transplantation versus drugs in
myelofibrosis: the risk-benefit balancing act. Bone Marrow Transplant.
2010;45(3):419-421.
5. Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia
vera, essential thrombocythemia, and primary myelofibrosis. Curr Hematol Malig
Rep. 2009 Jan;4(1):33-40.
6. Huang HM, Lin YL, Chen CH, Chang TW. Simultaneous activation of JAK1 and
JAK2 confers IL-3 independent growth on Ba/F3 pro-B cells. J Cell Biochem. 2005
Oct 1;96(2):361-75.
7. Murray PJ. The JAK-STAT pathway: input and output integration. J Immunol.
2007;178:2623-2629.
8. Sandberg EM, Wallace TA, Godeny MD, VonDerLinden D, Sayeski PP. Jak2
tyrosine kinase: a true Jak of all trades? Cell Biochem Biophys.
2004;41:207-231.
9. Haan C, Kreis S, Margue C, Behrmann I. Jaks and cytokine receptors-an
intimate relationship. Biochem Pharmacol. 2006;72:1538-1546.
10. Ivashkiv LB, Hu X. The JAK/STAT pathway in rheumatoid arthritis: pathogenic
or protective? Arthritis Rheum. 2003;48(8):2092-2096.
11. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the
pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer.
2007;7:673-683.
12. Kralovics R. Genetic complexity of myeloproliferative neoplasms. Leukemia.
2008;22:1841-1848.
13. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc
Hematol Educ Program. 2009:636-642.
14. Fourouclas N, Li J, Gilby DC, et al. Methylation of the suppressor of
cytokine signaling 3 gene (SOCS3) in myeloproliferative disorders.
Haematologica. 2008;93:1635-1644.
15. Beer PA, Green AR. Pathogenesis and management of essential
thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009;621-628.
16. Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition,
pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245.
17. Plo I, Vainchenker W. Molecular and genetic basis of myeloproliferative
disorders: questions and perspectives. Clin Lymphoma Myeloma.
2009;9(Suppl 3):S329-S339.
18. Controlled MyeloFibrosis Study With Oral JAK Inhibitor Treatment: The
COMFORT-I Trial. Available athttp://www.comfortstudy.com/pages/about_comfort-
1.aspx. Accessed October 2010.
19. Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polycythemia
vera, essential thrombocythemia, and primary myelofibrosis. Current Hematol
Malig Reports. 2009;4:33-40.
20. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative
neoplasms: The 2008 World Health Organization criteria and point-of-care
diagnostic algorithms. Leukemia. 2008;22(1):14-22.
21. Mesa RA, 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.
# # #
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Datum: 20.12.2010 - 22:05 Uhr
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News-ID 49907
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