Novartis announces study in NEJM showing Jakavi® was superior to standard therapy in rare blood cancer polycythemia vera

• Jakavi^® (ruxolitinib) treatment resulted in durable hematocrit control, spleen size reduction and symptom relief for patients with uncontrolled polycythemia vera[1] 

• Polycythemia vera (PV) is a blood cancer that can cause serious cardiovascular complications, such as stroke and heart attack[2] 

• Ruxolitinib was recently recommended by the CHMP for EU approval to treat patients with PV that is resistant or intolerant of hydroxyurea

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Basel, January 28, 2015 - Novartis today announced The New England Journal of Medicine (NEJM) published results from the pivotal Phase III clinical trial demonstrating Jakavi^® (ruxolitinib) significantly improved hematocrit control without the need for phlebotomy (a procedure to remove blood from the body to reduce the concentration of red blood cells) and reduced spleen size in patients with polycythemia vera (PV) who had an inadequate response to or unacceptable side effects from hydroxyurea as defined according to the modified European LeukemiaNet (ELN) criteria[1],[2]. In PV, hematocrit control and spleen size reduction are key measures of a patient's response to therapy[2].

PV is a chronic, incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as stroke and heart attack[2]. Approximately 25% of patients with PV develop resistance to or intolerance of hydroxyurea and are considered to have uncontrolled disease, which is typically defined as hematocrit levels greater than 45%, elevated white blood cell count and/or platelet count, and may be accompanied by debilitating symptoms and/or enlarged spleen[2],[3],[4]. Elevated white blood cell count and hematocrit are also associated with an increased risk of blood clots[5].

"A key challenge in treating patients with PV is the development of resistance or intolerance to currently available therapies such as hydroxyurea, which leaves us with very limited alternative treatment options to effectively manage the disease," said Dr. Alessandro M. Vannucchi, Azienda Ospedaliera Universitaria Careggi, University of Florence, Italy and lead study author. "This study indicates that ruxolitinib may represent an important advance for this population of patients with PV, a disease that can lead to serious complications and difficult daily symptoms."

At week 32 of the study, 77% of patients randomized to ruxolitinib achieved one or both components of the composite endpoint of hematocrit control (volume percentage of red blood cells in whole blood) without use of phlebotomy or spleen size reduction in comparison with 20% of patients randomized to standard therapy[1],[2]. A significantly greater proportion of patients achieved the composite primary endpoint when treated with ruxolitinib compared to standard therapy (21% compared to 1%, respectively; p<0.001), and 91% of these patients treated with ruxolitinib maintained their response at week 48[1].

"A high unmet need exists for PV patients with uncontrolled disease on current treatments, and if approved in the EU, ruxolitinib is expected to be the first-ever targeted therapy for patients with PV," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "We are working diligently with regulatory authorities to bring ruxolitinib to patients with PV who may benefit from this treatment."

In the study, a 50% or more improvement in PV-related symptoms was seen in 49% of ruxolitinib-treated patients compared to 5% of patients treated with standard therapy[1]. Patients treated with ruxolitinib also experienced a reduction in night sweats and itchiness (approximately 99% and 95%, respectively)[1]. In addition, a greater proportion of patients in the ruxolitinib treatment arm achieved complete hematologic remission as defined by modified ELN criteria, a key secondary endpoint, when compared to the standard therapy arm (24% compared to 9%, respectively; p=0.003)[1]. Complete hematologic remission was defined as achieving hematocrit control without the use of phlebotomy, platelet count <=400 x 10⁹/L and white blood cell count <=10 × 10⁹/L, which are all important markers of disease control in PV[1].

The data also showed fewer patients treated with ruxolitinib experienced thromboembolic events when compared to those who received standard therapy (1 patient compared to 6 patients within the first 32 weeks, respectively), a key treatment objective in PV as patients are at a high risk for cardiovascular complications[1],[2]. Overall, ruxolitinib was well tolerated, and non-hematologic adverse events (AEs) were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis[1],[6],[7]. Within the first 32 weeks of treatment, the most common Grade 3 or 4 hematologic abnormalities in the ruxolitinib treatment arm were anemia (2%) and thrombocytopenia (5%)[1]. The most common non-hematologic AEs in the ruxolitinib arm were headache, diarrhea and fatigue, which were mainly Grade 1 or 2[1]. Additionally, nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks[1].

Based on the Phase III data, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recently adopted a positive opinion for ruxolitinib for the treatment of adult patients with PV who are resistant to or intolerant of hydroxyurea. Ruxolitinib is currently approved in more than 70 countries for patients with myelofibrosis, a debilitating and life-threatening blood cancer.

Study Design
RESPONSE is a global, randomized, open-label study conducted at more than 90 trial sites. 222 patients with PV resistant to or intolerant of hydroxyurea were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only[1]. Ruxolitinib dose was adjusted as needed throughout the study[1].

The primary endpoint of the study was the proportion of patients whose hematocrit was controlled without phlebotomy eligibility from week 8 through 32 (with no more than one phlebotomy eligibility between randomization and week 8) and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at week 32[1]. Patients in the study who were deemed to be eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study (e.g., at baseline)[1]. In addition, efficacy was further assessed using two key secondary endpoints: durable primary response and complete hematological remission[1]. Other endpoints include safety and symptom improvement (as measured by the MPN-SAF 14-item total symptom score)[1].

About Polycythemia Vera
PV is a chronic, incurable blood cancer associated with an overproduction of blood cells in the bone marrow that affects roughly one to three people per 100,000 globally[2],[8]. The disease is driven by the dysregulation of the JAK-STAT pathway[9]. 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[2]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[2],[5]. Additionally, patients with PV may have enlarged spleen and numerous debilitating symptoms that significantly affect their daily lives[2].

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 achieve a normal hematocrit level[2]. However, 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[2],[5]. Unfortunately, approximately 25% of PV patients become resistant to or intolerant of hydroxyurea treatment according to ELN criteria, resulting in inadequate disease control and an increased risk of progression[3],[4].

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 70 countries for patients with myelofibrosis, including the European Union, Canada, Japan and some countries in Asia, Latin and South America. Additional worldwide regulatory filings are underway in myelofibrosis and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Both the European Commission and the U.S. Food and Drug Administration (FDA) granted ruxolitinib orphan drug designation 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. Jakafi was also recently approved by the FDA for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

The recommended starting dose for Jakavi in patients with myelofibrosis 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 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[10].

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 indication.

Jakavi Important Safety Information for Treatment of Myelofibrosis
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. 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 and bruising. 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[10]. 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 "recommended," "indicates," "may," "positive opinion," "underway," "yet," 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 manufacturing 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, cost-saving generic pharmaceuticals, preventive vaccines and over-the-counter products. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58 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 130,000 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] Vannucchi A, et al. Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. The New England Journal of Medicine. 2015;372:426-35.
[2] Leukemia & Lymphoma Society. "Polycythemia Vera Facts." Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/mpd/pdf/polycythemiavera.pdf. Accessed on April 28, 2014.
[3] Alvarez-Larran A, 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.
[4] Najean Y, Dresch C, Rain JD. The Very-Long-Term Course of Polycythaemia: A Complement to the Previously Published Data of The Polycythaemia Vera Study Group. Br J Haematol. 1994;86(1):233-235.
[5] Finazzi G and Barbui T. How I Treat Patients with Polycythemia Vera. Blood. 2007;109(12):5104-5111.
[6] 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.
[7] Verstovsek S, Ruben M, Gotlib J, et al. Long-Term Outcome of Ruxolitinib Therapy in Patients with Myelofibrosis: 3-Year Update from COMFORT-I. Abstract #396. 55th American Society of Hematology (ASH) Annual Meeting and Exposition, 2013. New Orleans, LA.
[8] Titmarsh G, Duncombe A, McMullin M, et al. How Common are Myeloproliferative Neoplasms? A Systematic Review and Meta-analysis. American Journal of Hematology. 2014:1-7.
[9] Schafer AI. Molecular Basis of the Diagnosis and Treatment of Polycythemia Vera and Essential Thrombocythemia. Blood. 2006;107(11):4214-4222.
[10] Jakavi^® (ruxolitinib) Summary of Product Characteristics. Basel, Switzerland: Novartis Pharma AG; January 2015.

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