Novartis investigational therapy crizanlizumab (SEG101) receives FDA Breakthrough Therapy designation for the prevention of vaso-occlusive crises in sickle cell disease

• Crizanlizumab is a monthly infusion under development to prevent pain crises (also called vaso-occlusive crises, or VOCs) in patients with sickle cell disease
   
• Sickle cell VOCs, which are triggered by multi-cell adhesion or clusters of cells that block or reduce blood flow, are associated with increased morbidity and mortality¹
  
  
• FDA filing of crizanlizumab anticipated in first half of 2019

Basel, January 8, 2019 - Novartis announced today that the US Food and Drug Administration (FDA) has granted crizanlizumab (SEG101) Breakthrough Therapy designation for the prevention of vaso-occlusive crises (VOCs) in patients of all genotypes with sickle cell disease (SCD). Also known as sickle cell pain crises, VOCs are unpredictable and extremely painful events that can lead to serious acute and chronic complications². VOCs happen when multiple blood cells stick to each other and to blood vessels, causing blockages^1,3. Treatments that make blood cells and blood vessels less sticky may help reduce the number of days patients experience VOCs.

"Painful sickle cell crises matter because they can disrupt patients' lives, and often require hospital visits and medical attention," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "We look forward to working closely with the FDA over the coming months toward making crizanlizumab, a therapy that has the potential to prevent sickle cell pain crises, available in the US as soon as possible."

According to FDA guidelines, treatments that receive Breakthrough Therapy designation are those that treat a serious or life-threatening disease or condition and demonstrate a substantial improvement over existing therapies on one or more significant end points based on preliminary clinical evidence.

The FDA granted Breakthrough Therapy designation for crizanlizumab based on positive results of the Phase II SUSTAIN trial, which compared the P-selectin inhibitor crizanlizumab with placebo in patients with sickle cell disease. SUSTAIN showed that crizanlizumab reduced the median annual rate of VOCs leading to health care visits by 45.3% compared to placebo (1.63 vs 2.98, P=0.010) in patients with or without hydroxyurea therapy. The study also demonstrated that crizanlizumab significantly increased the percentage of patients who did not experience any VOCs vs placebo (35.8% vs 16.9%, P=0.010) during treatment⁴.

Patients taking crizanlizumab (5 mg/kg) experienced a similar incidence of treatment-emergent adverse events (AEs) (86.4% vs 88.7%) and serious AEs (25.8% vs 27.4%) compared to placebo, and a low incidence of discontinuations (3%) due to adverse events. Adverse events that occurred in 10% or more of the patients in either active-treatment group (2.5 mg/kg; 5 mg/kg) and at a frequency that was at least twice as high as that in the placebo group included arthralgia, diarrhea, pruritus, vomiting, and chest pain. There were no apparent increases in infections with crizanlizumab treatment⁴.

About Sickle Cell Disease (SCD)
Sickle cell disease is a debilitating genetic blood disorder that affects the shape of your red blood cells and can make blood cells and blood vessels stickier than usual^1,5. When blood cells stick to one another they can form clusters in the bloodstream. These clusters can block the flow of blood and oxygen, which can cause damage to the blood vessels and organs^1,3. These blockages also can lead to painful crises called vaso-occlusive crises, or VOCs. VOCs are painful complications of the disease and the main reason why patients seek medical care in hospitals¹. Treatment of sickle cell disease is also associated with a high economic burden. The average sickle cell disease patient is estimated to face nearly $1 million in total lifetime health care costs with annual costs of more than $30,000 for adults⁶.

About crizanlizumab (SEG101)
Crizanlizumab (SEG101) is a humanized anti-P-selectin monoclonal antibody being investigated for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). Crizanlizumab binds to a molecule called P-selectin on the surface of platelets and endothelium in the blood vessels and has been shown to inhibit interactions between endothelial cells, platelets, red blood cells, sickled red blood cells, and leukocytes, causing a blockade and thereby preventing these cells from being able to bind to P-selectin. P-selectin is one of the major drivers of the vaso-occlusive process. Our goal is to deepen understanding of the true impact of VOCs on patients' bodies and lives and to explore how crizanlizumab can help to achieve more pain-crisis-free days for patients with SCD⁴.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations 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 the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, 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 is reimagining medicine to improve and extend people's lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world's top companies investing in research and development. Novartis products reach nearly 1 billion people globally and we are finding innovative ways to expand access to our latest treatments. About 125 000 people of more than 140 nationalities work at Novartis around the world. Find out more at www.novartis.com.

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References
[1]   Gutsaeva D, Parkerson J, Yerigenahally S, et. Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood. 2011;117(2):727-735.
[2]   Yale SH. Approach to the vaso-occlusive crisis in adults with sickle cell. Am Fam Physician. 2000 Mar 1;61(5):1349-1356.
[3]   Steinberg M. Management of sickle cell disease. N Engl J Med. 1999;340(13):1021-1030.
[4]   Ataga KI, Kutlar A, Kanter J et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017. 376(5):429-439.
[5]   Sparkenbaugh E, Pawlinski R. Interplay between coagulation and vascular inflammation in sickle cell disease. J Haematol. 2013;162(1):1-22.
[6]   American Society of Hematology. State of sickle cell disease 2016 report. Available from: http://www.scdcoalition.org/pdfs/ASH%20State%20of%20Sickle%20Cell%20Dis…%
202016%20Report.pdf. Accessed on July 17, 2018.

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