Novartis JAK inhibitor provides marked and durable clinical benefits in patients with myelofibrosis, a rare, life-threatening blood cancer
(Thomson Reuters ONE) -
Novartis International AG / Novartis JAK inhibitor provides marked and durable clinical benefits in patients with myelofibrosis, a rare, life-threatening blood cancer processed and transmitted by Hugin AS. The issuer is solely responsible for the content of this announcement.
* Myelofibrosis is a blood cancer characterized by bone marrow failure,
enlarged spleen, poor quality of life and shortened survival[1]
* Phase I/II data published in NEJM demonstrate clinical benefits of JAK1 and
JAK2 inhibitor INC424, including reduction of spleen size and alleviation of
debilitating symptoms[2]
* Novartis licensed INC424 outside US from Incyte, complementing broad
oncology portfolio of potential treatments for rare diseases; Phase III
trials are fully enrolled
Basel, September 15, 2010 - Results from a Phase I/II study of the Novartis
Janus kinase (JAK) inhibitor with the investigational name INC424 (also known as
INCB018424 and INCB18424) were published today in The New England Journal of
Medicine, demonstrating marked and durable clinical benefits in patients with
myelofibrosis[2]. Novartis has 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.
Myelofibrosis is a rare, life-threatening blood cancer characterized by bone
marrow failure, enlarged spleen (splenomegaly), debilitating symptoms, poor
quality of life, weight loss and shortened survival[1]. Both the US Food and
Drug Administration and the European Medicines Agency have granted INC424 orphan
drug status for myelofibrosis.
The Phase I/II study of 153 patients showed that approximately 75% of
myelofibrosis patients receiving INC424 twice-daily experienced rapid reduction
in spleen size, which was durable for more than one year of follow-up. After
only one month of therapy, patients with debilitating symptoms including
fatigue, night sweats and pruritus (itching) also achieved more than 50%
improvement in symptom scores, as measured by the Myelofibrosis Symptom
Assessment Form. Patients, particularly those with weight loss, experienced a
clinically meaningful gain in total body weight following treatment. Additional
clinical benefits observed in the study included improved functional status and
increased exercise capacity. These clinical benefits were accompanied by
reductions in circulating cytokines, inflammation-causing proteins in the blood
that are markedly elevated in patients with myelofibrosis[2].
Two Phase III clinical trials, COMFORT-I in the US, Canada and Australia, and
COMFORT-II in Europe, have completed enrollment and are evaluating the benefits
of treatment with INC424 compared to either placebo or best available
care[3],[4].
"Effective therapies are desperately needed for patients with myelofibrosis,
which has a poor prognosis, especially when advanced," said lead investigator
Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center, Houston, Texas. "We
currently have no therapeutic options for these patients in the US, and the
rapid and durable clinical benefits observed in this study show a real potential
to provide a way to alleviate suffering."
A strong association exists between abnormal JAK signaling and the development
of myelofibrosis, polycythemia vera and essential thrombocythemia, a related
group of conditions referred to as myeloproliferative neoplasms[5]-[8]. Patients
with these diseases can progress to secondary acute myelogenous leukemia, which
is virtually untreatable and is associated with a dismal prognosis[9],[10]. The
discovery of JAK mutations common to myelofibrosis, 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[11].
"Complementing our rich hematology-oncology pipeline in rare diseases, this
promising JAK inhibitor exemplifies the Novartis commitment to developing new
therapies for patients with unmet medical needs," said Alessandro Riva, MD,
Global Head, Oncology Development & Medical Affairs, Novartis Oncology. "We are
pleased to contribute our expertise to the global development of INC424,
complementing and leveraging Incyte's work for myelofibrosis patients in the
US."
Study details
The open-label, non-randomized, dose-escalation Phase I/II study, conducted by
Incyte, included 153 patients with myelofibrosis, and was undertaken at MD
Anderson Cancer Center and Mayo Clinic. Primary outcome measures were safety and
tolerability. The secondary outcome measure was preliminary effectiveness[2].
In this study, a starting dose of 15 mg twice-daily with individualized dose
titration was found to be the most effective and safest dose of INC424. Median
duration of therapy exceeded one year. Notably, improvements occurred in
patients regardless of JAK mutational status. Investigators observed that
treatment with INC424 reduced levels of inflammatory cytokines in the blood,
which they believe could provide a rational biological explanation for the
mutation-independent response to therapy[2].
INC424 provided rapid and sustained reduction in splenomegaly, resolution of
constitutional symptoms, improvement of performance status and exercise capacity
and weight gain. At the starting dose of 15 mg twice-daily, 48% of patients
achieved at least a 35% reduction in spleen volume. Symptoms of myelofibrosis
not directly related to splenomegaly, including night sweats, fevers, fatigue,
weight loss and pruritus, also improved in response to INC424. Other clinical
benefits included normalization of elevated platelet and white cell counts.
Reduction in cytokine levels while on therapy, presumably through JAK1
inhibition, paralleled improvements in patients' systemic symptoms[2].
At the time of the data analysis, the median duration of therapy for 153
patients enrolled in the study was 14.7 months and 115 (75%) were still
receiving INC424. Non-hematologic side effects related to therapy were
infrequent (<10%) and of low grade. Hematologic side effects included anemia and
thrombocytopenia (reduced platelet counts). Thrombocytopenia was the
dose-limiting toxicity of the drug. Mean hemoglobin levels decreased during the
first three to four cycles of therapy and then stabilized or improved with
continued treatment. Serious adverse events occurred in 59 patients, of whom 12
experienced serious adverse events that were considered at least possibly
related to treatment[2].
About myelofibrosis
Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm
associated with bone marrow failure, splenomegaly, debilitating symptoms and
shortened survival. Of the JAK-associated myeloproliferative neoplasms,
myelofibrosis carries the greatest risk of a poor prognosis, including
transformation to fatal acute myelogenous leukemia. For myelofibrosis patients
in general, clinical findings such as splenomegaly, anemia and constitutional
symptoms may significantly reduce quality of life[1],[12],[13].
The disease has a high unmet medical need. Although allogeneic stem cell
transplantation may cure myelofibrosis, the procedure is associated with
significant morbidity and mortality and is usually appropriate only in younger
patients[1]. The five-year survival rate after transplantation is about 50%[14].
Disclaimer
The foregoing release contains forward-looking statements that can be identified
by terminology such as "potential," "pipeline," "promising," "commitment," or
similar expressions, or by express or implied discussions regarding the
potential future submission or approval for marketing of INC424, 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. 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 102,000 full-time-equivalent associates and
operate in more than 140 countries around the world. For more information,
please visithttp://www.novartis.com.
References
1. The Leukemia & Lymphoma Society. Idiopathic myelofibrosis. Available
athttp://www.leukemia-lymphoma.org/attachments/National/br_1190656475.pdf.
Accessed September 2010.
2. 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.
3. Controlled MyeloFibrosis Study With Oral JAK Inhibitor Treatment: The
COMFORT-I Trial. Available athttp://clinicaltrials.gov/ct2/show/NCT00952289?
term=comfort+myelofibrosis&rank=1. Accessed September 2010.
4. Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK)
Inhibitor Treatment-II: The COMFORT-II Trial. Available
athttp://www.clinicaltrials.gov/ct2/show/NCT00934544. Accessed September 2010.
5. 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.
6. Kralovics R. Genetic complexity of myeloproliferative neoplasms. Leukemia.
2008;22:1841-1848.
7. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc
Hematol Educ Program. 2009:636-642.
8. 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.
9. Beer PA, Green AR. Pathogenesis and management of essential
thrombocythemia. Hematology Am Soc Hematol Educ Program. 2009;621-628.
10. Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition,
pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245.
11. Plo I, Vainchenker W. Molecular and genetic basis of myeloproliferative
disorders: questions and perspectives. Clin Lymphoma Myeloma.
2009;9(Suppl 3):S329-S339.
12. Thiele J, Kvasnicka HM. The 2008 WHO diagnostic criteria for polcythemia
vera, essential thrombocythemia, and primary myelofibrosis. Current Hematol
Malig Reports. 2009;4:33-40.
13. 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.
14. Tefferi A. Allogeneic hematopoietic cell transplantation versus drugs in
myelofibrosis: the risk-benefit balancing act. Bone Marrow Transplant.
2010;45(3):419-421.
# # #
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Datum: 15.09.2010 - 23:00 Uhr
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