Pivotal Phase III data show polycythemia vera patients on Novartis drug Jakavi® achieved significant improvement in disease control

Pivotal Phase III data show polycythemia vera patients on Novartis drug Jakavi® achieved significant improvement in disease control

77% of patients on Jakavi® (ruxolitinib) vs 20% on best available therapy achieved hematocrit control or spleen reduction, key treatment goals in PV

Nearly half of ruxolitinib-treated patients had a 50% or more reduction in debilitating PV symptoms compared to 5% on best available therapy

Global regulatory filings are underway based on these data; if approved, ruxolitinib will be the first JAK 1/2 inhibitor available for PV patients

Basel, June 3, 2014 - Novartis today announced results from the first-ever pivotal Phase III study evaluating a JAK 1/2 inhibitor for the treatment of polycythemia vera (PV). 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[2]) and reduced spleen size in patients with PV who are resistant to or intolerant of hydroxyurea[1]. Findings are being presented at the 50th Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.

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]. Currently, there are limited treatments for polycythemia vera and a high unmet need exists for new therapies that provide effective disease control[3].

"Patients with polycythemia vera may not have their disease controlled with existing therapies, increasing their risk for cardiovascular complications," said Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center, Houston, Texas and lead study author. "In the RESPONSE trial, patients treated with ruxolitinib showed better disease control, including controlled hematocrit levels without the need for phlebotomy, reduced spleen size and improved symptom management compared to current therapies."

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[2]) or spleen size reductionin comparison with 20% of patients randomized to best available therapy[1]. A significantly greater proportion of patients achieved the composite primary endpoint when treated with ruxolitinib compared to best available therapy (21% compared to 1%, respectively; p< .0001), and 91% of these patients treated with ruxolitinib maintained their response at week 48[1].

"New treatments for polycythemia vera are greatly needed, as this is a disease that causes debilitating daily symptoms, which are as severe as symptoms associated with myelofibrosis, and also puts patients at risk for serious cardiovascular complications, such as stroke and heart attack," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "These findings reinforce ruxolitinib's significant clinical benefit and potential to become an important new treatment option for polycythemia vera patients who are no longer responding to or are intolerant of prior therapy."

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 best available therapy[1]. Patients treated with ruxolitinib also experienced a reduction in night sweats and itchiness (approximately 99% and 95%, respectively)[4]. In addition, a greater proportion of patients on the ruxolitinib treatment arm achieved complete hematologic response as defined by the modified 2009 European LeukemiaNet (ELN) criteria, a key secondary endpoint, when compared to the best available therapy arm (24% compared to 9%, respectively; p=.003)[1].

Ruxolitinib was well tolerated and adverse events (AEs) were consistent with those previously seen in ruxolitinib studies in PV and myelofibrosis[1],[5],[6]. Within the first 32 weeks of treatment, Grade 3 or 4 hematologic AEs in the ruxolitinib treatment arm were anemia (1.8%) and thrombocytopenia (5.5%), and fewer patients treated with ruxolitinib experienced thromboembolic events when compared to those who received best available therapy (1 patient compared to 6 patients, respectively)[1]. The most common non-hematologic AEs were headache, diarrhea and fatigue, which were mainly Grade 1 or 2[1]. Additionally, 3.6% of patients randomized to the ruxolitinib treatment arm discontinued treatment due to AEs compared to 1.8% on the best available therapy arm[4].

Data from the RESPONSE trial will support worldwide regulatory submissions planned this year. The data will also be presented at the upcoming 19th Congress of the European Hematology Association in Milan, Italy.

Ruxolitinib is currently approved in more than 60 countries for patients with myelofibrosis, a debilitating and life-threatening blood cancer.

Study Design
RESPONSE is a global, randomized, open-label study conducted at 109 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 best available therapy, which was defined as investigator selected monotherapy or observation only. 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 from week 8 through 32 and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at 32 weeks. In addition, efficacy was further assessed using two key secondary endpoints: durable primary response and complete hematological remission. Other endpoints include safety, symptom improvement (as measured by the MPN-SAF 14-item total symptom score) and quality of life[1].

About Polycythemia Vera
PV is a chronic, incurable blood cancer associated with an overproduction of blood cells in the bone marrow[2] that affects roughly one to three people per 100,000 globally[7]. It is typically characterized by an 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[2]. This can cause serious cardiovascular complications, such as stroke and heart attack[2], resulting in increased morbidity and mortality[8]. Phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, is commonly used to maintain a normal hematocrit level[2].

Additionally, patients with PV often have enlarged spleen and numerous debilitating symptoms that significantly affect their daily life[2]. A proportion of patients become intolerant or resistant to currently available therapies. In fact, approximately 25% of PV patients become resistant to or intolerant of hydroxyurea treatment, which results in inadequate disease control and an increased risk of progression[9],[10].

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 60 countries, including the European Union, Canada and some countries in Asia, Latin and South America. Additional worldwide regulatory filings are underway.

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 status 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.

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[11].

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[11]. Please see full Prescribing Information available at www.jakavi.com.

The foregoing release contains forward-looking statements that can be identified by words such as "underway," "will," "being presented," "can," "may," "potential," "to become," "planned," "upcoming," "should," "has not 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 diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2013, the Group achieved net sales of USD 57.9 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 135,000 full-time-equivalent associates and sell products in more than 150 countries around the world. For more information, please visit http://www.novartis.com.

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[1] Verstovsek S, et al. Results of a prospective, randomized, open-label Phase III study of ruxolitinib in polycythemia vera patients resistant to or intolerant of hydroxyurea: The RESPONSE Trial. Abstract #7026. 50th American Society of Clinical Oncology (ASCO) Chicago, IL.
[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] Barbui T, Finazzi G. Treatment of polycythemia vera. Haematologica.1998:83:143-149.
[4] Novartis Data on File.
[5] 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 #S1111.18th Congress of European Hematology Association (EHA), 2013. Stockholm, Sweden.
[6] 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.
[7] 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.
[8] Finazzi G and Barbui T. How I treat patients with polycythemia vera. Blood. 2007;109(12):5104-5111.
[9] 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.
[10] 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.
[11] JAKAVI [Summary of Product Characteristics]. Basel, Switzerland: Novartis Pharma AG; 2012.

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