Data in The Lancet show Novartis drug Arzerra® plus chlorambucil improved median progression-free survival by 71% in CLL patients

• Significant improvement in PFS seen with Arzerra plus chlorambucil in previously untreated patients with CLL for whom fludarabine-based therapy was inappropriate
   
• Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed adult leukemia in Western countries, accounting for approximately 1 in 4 cases of all leukemia[1],[2]
   
• 75% of CLL patients are over 65 years of age at time of diagnosis and majority have at least one comorbidity such as hypertension, diabetes, heart disease or COPD[3],[4],[5]

Basel, April 15, 2015 - Phase III data published in The Lancet showed that treatment with Arzerra^® (ofatumumab) plus chlorambucil, a chemotherapy, resulted in a statistically significant improvement in progression free survival (PFS) versus chlorambucil alone in treatment-naïve patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy was considered inappropriate, mainly due to advanced age or the presence of comorbidities.

CLL, the most commonly diagnosed adult leukemia in Western countries, accounts for approximately 1 in 4 cases of all leukemia[1],[2]. The average age at the time of diagnosis is approximately 71 years[2], and the majority of patients with CLL have at least one comorbidity such as hypertension, diabetes, heart disease or COPD[4],[5].

"Finding effective treatments with clinically acceptable safety profiles for elderly patients with CLL and for those with co-existent chronic and potentially life-threatening conditions continues to be a challenge," said Prof. Peter Hillmen, St. James's University Hospital, Leeds, United Kingdom and lead study author. "The results published in The Lancet reinforce our understanding that the combination of ofatumumab plus chlorambucil provides this patient population a treatment option that improves clinical health outcomes in CLL."

The primary endpoint of the study was PFS according to the International Workshop for Chronic Lymphocytic Leukaemia (iwCLL) updated 2008 National Cancer Institute-sponsored Working Group (NCIWG) guidelines[6]. In this clinical study, median PFS was improved by 71% in the group receiving ofatumumab plus chlorambucil compared to the chlorambucil alone group (22.4 months vs 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors. More patients in the group receiving ofatumumab plus chlorambucil (50%) experienced adverse events (AEs) of grade 3 or greater compared to chlorambucil alone (43%), with neutropenia being the most common adverse event (26% vs. 14%). Grade 3/4 infusion-related reactions (IRRs) were reported in 10% of patients receiving ofatumumab plus chlorambucil leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported.

"The results presented in The Lancet demonstrate that the addition of Arzerra to chlorambucil resulted in a significant improvement in progression free survival, with an acceptable safety profile," said Alessandro Riva, M.D., Global Head, Novartis Oncology Development and Medical Affairs. "We are excited that Arzerra is now part of the Novartis Oncology portfolio of products, and look forward to building upon the body of evidence that supports the clinical benefit of Arzerra for appropriate patients with CLL."

These Phase III data formed the basis for regulatory approvals in the United States (US) and European Union (EU) in 2014, as well as the recent inclusion of Arzerra plus chlorambucil in the National Comprehensive Cancer Network (NCCN) treatment guidelines.

About the Study
This prospective, randomized, open-label, Phase III study (COMPLEMENT 1, NCT00748189) included 447 patients with previously untreated CLL for whom fludarabine-based therapy was considered inappropriate.  Patients in the study were randomized 1:1 to treatment with up to twelve cycles of ofatumumab in combination with chlorambucil or up to twelve cycles of chlorambucil alone. 

The primary endpoint of the study was PFS according to the iwCLL updated 2008 NCIWG guidelines[6], using a blinded independent endpoints review committee. Secondary endpoints included overall survival (OS), time to progression, overall response rate (ORR), complete response (CR) rate, time to response, duration of response, time to next therapy (TTNT), safety assessments, pharmacokinetics, pharmacogenetics, and quality of life.

Findings from the study showed a 71% improvement in median PFS in the group receiving ofatumumab plus chlorambucil compared to the group receiving chlorambucil alone (22.4 months vs 13.1 months, respectively; HR 0.57 [95% CI 0.45, 0.72]; p<0.0001). Patients in the group receiving ofatumumab plus chlorambucil [n=221] showed similar improvements in PFS across age groups compared to the chlorambucil alone [n=226]. Improvement in PFS was observed in most subgroups irrespective of age, gender, disease stage and prognostic factors.  

Additionally, patients in the combination arm also experienced significantly longer TTNT when compared to chlorambucil alone (39.8 months vs 24.7 months, respectively; HR 0.49 [95% CI: 0.36, 0.67]; p<0.0001). Patients in the combination arm had a higher ORR (82% of patients vs 69% of patients, respectively; odds ratio 2.16 [95% CI: 1.36-3.42]; p=0.001), with a better CR rate (14% of patients vs 1% of patients, respectively). Compared to those on chlorambucil alone, patients in the combination arm had a duration of response of 22.1 months versus 13.2 months (HR 0.56 [95% CI: 0.43, 0.74]; p<0.001).

More patients in the group receiving Arzerra plus chlorambucil (combination) experienced AEs of grade 3 or greater (50%) compared to chlorambucil alone (43%). The most common AEs (>=2%) reported were neutropenia, thrombocytopenia, anemia, infections, and infusion-related reactions. Overall, AEs leading to treatment withdrawal were similar in both groups (13% vs 13%). AE frequency with Arzerra plus chlorambucil was similar for older patient groups (>=65 years old) compared with chlorambucil alone. Neutropenia occurred more frequently in the combination group, but did not result in a higher rate of infection, and thrombocytopenia and anemia were more frequently observed in the chlorambucil alone group. The most common infections were respiratory tract infections (27% for combination vs 31% for chlorambucil alone) and there were similar frequencies of sepsis (3% vs 2%) and opportunistic infections (4% vs 5%) reported in the combination and chlorambucil alone groups, respectively.

Grade 3/4 IRRs were reported in 10% of patients receiving Arzerra plus chlorambucil leading to drug withdrawal in 3% of patients and hospitalization in 2% of patients. No fatal IRRs were reported. Deaths during treatment or within 60 days after the last dose were similar in both groups (3% vs 3%).

About Arzerra
Arzerra (ofatumumab) is a human monoclonal antibody that is designed to target the CD20 molecule found on the surface of chronic lymphocytic leukemia (CLL) cells and normal B lymphocytes.

In the United States, Arzerra is approved for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate. In the European Union, Arzerra is approved for use in combination with chlorambucil or bendamustine for the treatment of patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. Arzerra is also approved for first-line use in Russia, Iceland, Norway, Luxembourg and Brazil.

In more than 50 countries worldwide, Arzerra is also indicated as monotherapy for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.

Arzerra is marketed under a co-development and collaboration agreement between Genmab and Novartis, as successor in interest to GSK.

Important Safety Information for Arzerra (ofatumumab)
Treatment with Arzerra may cause side effects, some of which are serious and life-threatening.

Treatment with Arzerra may cause a side effect called an infusion reaction, which may be serious and possibly life-threatening. Before treatment with Arzerra, doctors will prescribe 3 types of medicine to their patients to help reduce the risk of an infusion reaction including, a steroid (to reduce swelling and other symptoms of inflammation), a pain reliever, and an antihistamine (to reduce allergic reactions). Even though patients receive these medicines, they may still have an infusion reaction. If an infusion reaction occurs, the doctor will stop their patient's treatment with Arzerra so the infusion reaction can be treated.  Patients should tell their doctor or seek medical treatment right away if they have any of these symptoms while receiving Arzerra or within 24 hours after receiving Arzerra: fever, chills, rash, hives, chest pain, back pain, stomach pain, swelling, dizziness, blurred vision, drowsiness, headache, cough, wheezing, or trouble breathing.

Treatment with Arzerra may cause hepatitis B virus (HBV) infection to reoccur, which may cause serious liver problems and death. Patients should tell their doctor if they have had HBV infection or are a carrier of HBV. Before starting Arzerra, doctors will do a blood test to check for HBV infection. In some patients, additional blood tests may be done during and several months after treatment. Patients should call their doctor right away if they feel more tired than usual or notice a yellowing of the skin or eyes. These may be symptoms of hepatitis.

Progressive multifocal leukoencephalopathy (PML) is a rare brain infection that can occur with treatment with Arzerra. PML causes severe disability and can lead to death. Patients should call their doctor right away if they notice new medical problems or problems that are getting worse, such as confusion, dizziness or loss of balance, difficulty talking or walking, or strength, vision or other problems that have lasted over several days.

Tumor lysis syndrome (TLS) can occur with treatment with Arzerra. TLS is caused by the fast breakdown of cancer cells, which then release their contents into the blood. This may lead to serious problems, including kidney failure or an abnormal heartbeat. Doctors may do a blood test to check their patients for TLS and may give medicines before starting treatment with Arzerra to help prevent TLS.

Treatment with Arzerra can increase patients' chances for getting infections. Some infections, such as pneumonia, bronchitis, and sepsis (a blood infection), can be serious, and in some cases, life-threatening. Patients should call their doctor right away if they have a cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Arzerra. These symptoms may be signs of a serious infection.

Arzerra can cause low blood cell counts (white blood cells, platelets, and red blood cells). These low blood cell counts can be severe and, in some cases, lead to death. Low white blood cells counts (neutropenia), can happen during treatment. Neutropenia can occur 42 days or longer after the end of treatment with Arzerra and may also last between 24 and 42 days after the last treatment dose. Doctors should regularly check their patient's blood to see if they have low blood cell counts. Patients should call their doctor right away if they have any bleeding, bruising, red or purple spots on their skin, paleness, worsening weakness, tiredness, cough that will not go away, fever, chills, congestion, or any flu-like symptoms while receiving Arzerra.

After a patient receives Arzerra, they should not receive live vaccines until the doctor who prescribed Arzerra has told them that they may do so.

The most common side effects with Arzerra include infusion reactions, feeling tired, low white blood cell count, shortness of breath, pneumonia, rash, fever, nausea, cough, bronchitis, diarrhea, upper respiratory tract infection and low red blood cell count.

Please see full Prescribing Information, including Boxed WARNING for Arzerra (ofatumumab).

Disclaimer
The foregoing release contains forward-looking statements that can be identified by words such as "continues," "excited," "look forward," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Arzerra, or regarding potential future revenues from Arzerra. 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 Arzerra 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 Arzerra will be commercially successful in the future. In particular, management's expectations regarding  Arzerra 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 and cost-saving generic pharmaceuticals. 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). As of December 31, 2014 Novartis Group companies employed approximately 133,000 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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Arzerra is a trademark of Novartis Pharma AG.

References
[1] Chronic Lymphocytic Leukemia. Leukemia & Lymphoma Society Website. http://www.lls.org/diseaseinformation/leukemia/chroniclymphocyticleukemia/. Accessed April 8, 2014.
[2] What are the key statistics for chronic lymphocytic leukemia? American Cancer Society Website. http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-key-statistics. Published February 26, 2015. Accessed April 8, 2015.
[3] Shanafelt TD. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology. 2013,1:158-167. doi: 10.1182/asheducation-2013.1.158
[4] Eichhorst B, Hallek M, Dreyling M. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2011;22 Suppl 2, 50-54. http://annonc.oxfordjournals.org/content/22/suppl_6/vi50.full. Accessed April 8, 2014.
[5] Shanafelt, TD, et al. Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients. British Journal of Hematology. 2007;139, 255-264.
[6] Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008; 111: 5446-56.

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