Novartis analysis shows crizanlizumab (SEG101) increased the number of patients free of sickle cell pain crises vs placebo during SUSTAIN study

• Data published in the American Journal of Hematology show more than twice as many patients taking crizanlizumab did not experience a disease-related pain crisis (also called vaso-occlusive crisis, or VOC) vs placebo
   
• VOCs are the most common, painful complication of sickle cell disease and the main reason patients seek medical care in hospitals
   
• Discussions with health authorities continue; FDA filing anticipated in 2019

Basel, October 9, 2018 - Results from a post hoc analysis of the Phase II SUSTAIN study of crizanlizumab, a humanized anti-P-selectin monoclonal antibody being investigated for the treatment of sickle cell disease (SCD), have been published in the American Journal of Hematology. The analysis showed that more patients treated with crizanlizumab did not experience a vaso-occlusive crisis (VOC) vs those treated with placebo (35.8% vs 16.9%), specifically patients with a history of 2-10 VOCs in the previous year.

VOCs are a painful complication of SCD and the main reason why patients seek medical care in hospitals[1],[2]. VOCs, which are triggered by multi-cell adhesion, are associated with increased morbidity and mortality, and can result in stroke, as well as organ damage or failure[3],[4]. Currently, treatment options for VOCs are limited[5].

"The unpredictable, intense painful crises that patients with sickle cell disease experience are the hallmark of the disease and the primary cause of hospitalizations in this patient population," said Abdullah Kutlar, MD, Director, Sickle Cell Center at the Medical College of Georgia, Augusta University, Augusta, Georgia, and primary author of the SUSTAIN analysis. "I am encouraged that results from this post hoc analysis of SUSTAIN study data found that crizanlizumab could substantially delay or prevent these crises, which also may mean less organ damage in the long run." 

The post hoc analysis reviewed 52-week results from 132 patients, including 67 treated with crizanlizumab 5 mg/kg and 65 who received placebo. All evaluated patients had a history of at least 2 VOCs in the year prior to the study, with 62.9% (n=83) having experienced 2-4 events and 37.1% (n=49) with 5-10 events. The most common genotype in SCD, homozygous hemoglobin S (HbSS), was identified in most SUSTAIN patients (n=94; 71.2%), and patients with this genotype were evenly distributed between study arms.

The analysis found that treatment with crizanlizumab may prevent VOCs, both in patients who had 2-4 and 5-10 disease-related pain events in the year prior to the study, as well as those with HbSS.

Of the subgroups evaluated, a considerable number of patients across multiple subgroups treated with crizanlizumab did not experience a VOC compared with those treated with placebo, including:

• Those with 2-4 events in the year prior to participating in the study (17 out of 42 patients or 40.5% vs 10 out of 41 patients, or 24.4%)
• Those with 5-10 events in the year prior to participating in the study (7 out of 25 patients or 28.0% vs 1 out of 24 patients, or 4.2%)
• Those with the HbSS genotype (15 out of 47 patients or 31.9% vs 8 out of 47 patients, or 17.0%)
• Those also with concomitant use of hydroxyurea (14 out of 42 patients 33.3% vs 7 out of 40 patients, or 17.5%)

No new safety concerns emerged in the post hoc analysis as adverse events attributed to treatment were similar between the crizanlizumab and placebo arms across all subgroups.

"The insights gained from this analysis and others from the SUSTAIN study, strengthen our belief that crizanlizumab may become an important new therapeutic option for sickle cell patients who continue to need step changes in medical innovation," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "This is another example of what we mean when we say we are reimagining medicine."

About the SUSTAIN trial
The Phase II SUSTAIN trial was a multicenter, multinational, randomized, placebo-controlled, double-blind,12-month study to assess safety and efficacy of the anti-P-selectin antibody crizanlizumab with or without concomitant use of hydroxyurea therapy in sickle cell disease patients with sickle cell-related pain crises. Primary results were published in The New England Journal of Medicine and showed that crizanlizumab reduced the median annual rate of sickle cell pain crises (SCPCs) by 45.3% compared to placebo (1.63 vs 2.98, p=0.010) in patients with or without hydroxyurea therapy[6].

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 were arthralgia, diarrhea, pruritus, vomiting, and chest pain. There were no apparent increases in infections with crizanlizumab treatment[6].

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)[6]. Crizanlizumab binds a molecule called P-selectin on the surface of endothelial cells and platelets in the blood vessels, causing a blockade of P-selectin[6]. P-selectin is one of the major drivers of the vaso-occlusive process[6]. Results from the Phase II SUSTAIN study demonstrated that crizanlizumab reduced the median annual rate of VOCs that lead to a healthcare visit compared to placebo in patients with SCD regardless of whether or not they were taking hydroxyurea[6].

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]   Puri L, Nottage KA, Hankins JS, et al. State of the art management of acute vaso-occlusive pain in sickle cell disease. Paediatr Drugs. 2018;(1)20:29-42.
       [2]   Gutsaeva D, Parkerson J, Yerigenahally S, et al. Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood. 2011;117(2):727-735.
       [3]   Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012:120(18):3647-3656
       [4]   Piel F, Steinberg M, Rees D. Sickle cell disease. N Engl J Med. 2017;376(16):1561-1573.
       [5]   Ballas SK, Lusardi M. Hospital readmission for acute adult sickle cell painful episodes: frequency, etiology, and prognostic significance. Am J Hematol. 2005;79(1):17-25.
       [6]   Ataga KI, Kutlar A, Kanter J et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2;376(5):429-439.

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