Positive phase III results for Roche's Hemlibra for haemophilia A without factor VIII inhibitors published in New England Journal of Medicine

• Hemlibra prophylaxis significantly reduced bleeds compared to no prophylaxis
• Hemlibra is the first medicine to demonstrate superior efficacy to prior factor VIII prophylaxis based on a statistically significant reduction in treated bleeds in an intra-patient comparison
• Hemlibra is currently under Priority Review by the FDA for people with haemophilia A without factor VIII inhibitors

             
Basel, 30 August 2018 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that pivotal data from the phase III HAVEN 3 study, which evaluated Hemlibra® (emicizumab) prophylaxis administered every week or every two weeks in adults and adolescents aged 12 years or older with haemophilia A without factor VIII inhibitors, were published in the 30 August 2018 issue of the New England Journal of Medicine (NEJM).

"In the HAVEN 3 study, Hemlibra showed a significant and clinically meaningful reduction in bleeds in people with haemophilia A without factor VIII inhibitors, while offering multiple subcutaneous dosing options," said Johnny Mahlangu, Faculty of Health Sciences, University of the Witwatersrand and NHLS, Johannesburg, South Africa. "The publication of these results in the New England Journal of Medicine represents a major advance for haemophilia research and reinforces the potential of Hemlibra to change the standard of care for people with haemophilia A."

"Current prophylactic treatment options for people with haemophilia A can require frequent intravenous infusions, and despite treatment, many continue to have bleeds that can lead to long-term joint damage," said Sandra Horning, MD, Roche's Chief Medical Officer and Head of Global Product Development. "Given the challenges many people face managing their haemophilia, we believe Hemlibra could make a meaningful difference, and we are working with health authorities to hopefully make this treatment available to people with haemophilia A without factor VIII inhibitors as soon as possible."

Data from the HAVEN 3 study showed that Hemlibra prophylaxis administered subcutaneously every week or every two weeks significantly reduced treated bleeds by 96% (rate ratio [RR]=0.04; p<0.0001) and 97% (RR= 0.03; p<0.0001), respectively, compared to no prophylaxis. Results also showed that 55.6% (95% CI: 38.1; 72.1) of people treated with Hemlibra every week and 60% (95% CI: 42.1; 76.1) of people treated with Hemlibra every two weeks experienced zero treated bleeds, compared to 0% (95% CI: 0.0; 18.5) of people treated with no prophylaxis. In an intra-patient comparison of people who previously received factor VIII prophylaxis in a prospective non-interventional study and switched to Hemlibra prophylaxis, Hemlibra demonstrated a statistically significant reduction of 68% (RR=0.32; p<0.0001) in treated bleeds, making it the first medicine to show superior efficacy to prior factor VIII prophylaxis treatment, the current standard of care. There were no unexpected or serious adverse events (AEs) related to Hemlibra in the HAVEN 3 study, and the most common AEs were consistent with previous studies. The most common AEs occurring in 5% or more of people were injection site reactions, joint pain (arthralgia), common cold symptoms (nasopharyngitis), headache, upper respiratory tract infection and influenza.

Earlier this year, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation and Priority Review to Hemlibra for people with haemophilia A without factor VIII inhibitors based on data from the HAVEN 3 study. The FDA is expected to make a decision on approval by 4 October 2018. Breakthrough Therapy Designation is designed to expedite the development and review of medicines intended to treat a serious condition with preliminary evidence that indicates they may demonstrate substantial improvement over existing therapies. Priority Review designation is granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a serious disease. In addition, the company's Marketing Authorisation Application (MAA) variation of Hemlibra for haemophilia A without factor VIII inhibitors is under review by the European Medicines Agency (EMA). Submissions to other regulatory authorities around the world are ongoing.

About HAVEN 3 (NCT02847637)
HAVEN 3 is a randomised, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics of Hemlibra prophylaxis versus no prophylaxis (episodic/on-demand factor VIII treatment) in people with haemophilia A without factor VIII inhibitors. The study included 152 patients with haemophilia A (12 years of age or older) who were previously treated with factor VIII therapy either on-demand or for prophylaxis. Patients previously treated with on-demand factor VIII were randomised in a 2:2:1 fashion to receive subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk for at least 24 weeks (Arm A), subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 3 mg/kg/2wks (Arm B) for at least 24 weeks or no prophylaxis (Arm C) for at least 24 weeks. Patients previously treated with factor VIII prophylaxis received subcutaneous Hemlibra prophylaxis at 3 mg/kg/wk for 4 weeks, followed by 1.5 mg/kg/wk until the end of study (Arm D). Episodic treatment of breakthrough bleeds with factor VIII therapy was allowed per protocol.

The phase III HAVEN 3 study in people with haemophilia A without factor VIII inhibitors met its primary endpoint and key secondary endpoints. Data from the study showed:

• Hemlibra prophylaxis every week or every two weeks resulted in a 96% (RR=0.04; p<0.0001) and 97% (RR=0.03; p<0.0001) reduction in treated bleeds, respectively, compared to no prophylaxis.
• 55.6% (95% CI: 38.1, 72.1) of people treated with Hemlibra every week and 60% (95% CI: 42.1, 76.1) of people treated with Hemlibra every two weeks experienced zero treated bleeds, compared to 0% (95% CI: 0.0; 18.5) of people treated with no prophylaxis.
• 91.7% (95% CI: 77.5, 98.2) of people treated with Hemlibra prophylaxis every week and 94.3% (95% CI: 80.8, 99.3) of people treated with Hemlibra prophylaxis every two weeks experienced three or fewer treated bleeds, compared to 5.6% (95% CI: 0.1, 27.3) of people treated with no prophylaxis.
• Hemlibra prophylaxis every week or every two weeks resulted in a 95% (RR=0.05; p<0.0001) and 95% (RR=0.05; p<0.0001) reduction in treated target-joint bleeds, respectively, compared to no prophylaxis.
• Hemlibra prophylaxis every week or every two weeks resulted in a 95% (RR=0.05; p<0.0001) and 94% (RR=0.06; p<0.0001) reduction in all bleeds, respectively, compared to no prophylaxis.
• Hemlibra prophylaxis every week demonstrated a statistically significant reduction of 68% (RR=0.32; p<0.0001) in treated bleeds compared to prior factor VIII prophylaxis based on an intra-patient comparison of people who were previously enrolled in a prospective non-interventional study.
• There were no unexpected or serious AEs related to Hemlibra, and the most common AEs were consistent with previous studies. No thrombotic events or cases of thrombotic microangiopathy were observed. The most common AEs occurring in 5% or more of people were injection site reactions, joint pain (arthralgia), common cold symptoms (nasopharyngitis), headache, upper respiratory tract infection and influenza.

About Hemlibra® (emicizumab)
Hemlibra is a bispecific factor IXa- and factor X-directed antibody. It is designed to bring together factor IXa and factor X, proteins required to activate the natural coagulation cascade and restore the blood clotting process for people with haemophilia A. Hemlibra is a prophylactic (preventative) treatment that can be administered by an injection of a ready-to-use solution under the skin (subcutaneously) once-weekly. The clinical development programme is assessing the safety and efficacy of Hemlibra and its potential to help overcome current clinical challenges: the short-lasting effects of existing treatments, the development of factor VIII inhibitors and the need for frequent venous access. Hemlibra was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed globally by Chugai, Roche and Genentech. It is marketed in the United States by Genentech as Hemlibra (emicizumab-kxwh) for people with haemophilia A with factor VIII inhibitors, with kxwh as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the US Food and Drug Administration.

About haemophilia A
Haemophilia A is an inherited, serious disorder in which a person's blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Haemophilia A affects around 320,000 people worldwide, ^[1,2] approximately 50-60% of whom have a severe form of the disorder. ^[3] People with haemophilia A either lack or do not have enough of a clotting protein called factor VIII. In a healthy person, when a bleed occurs, factor VIII brings together the clotting factors IXa and X, which is a critical step in the formation of a blood clot to help stop bleeding. Depending on the severity of their disorder, people with haemophilia A can bleed frequently, especially into their joints or muscles.^[1] These bleeds can present a significant health concern as they often cause pain and can lead to chronic swelling, deformity, reduced mobility, and long-term joint damage. ^[4] A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. ^[5] Inhibitors are antibodies developed by the body's immune system that bind to and block the efficacy of replacement factor VIII,^[6] making it difficult, if not impossible to obtain a level of factor VIII sufficient to control bleeding.

About Roche in haematology
For more than 20 years, Roche has been developing medicines that redefine treatment in haematology. Today, we are investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines MabThera®/Rituxan® (rituximab), Gazyva®/Gazyvaro® (obinutuzumab), and Venclexta®/Venclyxto(TM) (venetoclax) in collaboration with AbbVie, Roche's pipeline of investigational haematology medicines includes Tecentriq® (atezolizumab), an anti-CD79b antibody drug conjugate (polatuzumab vedotin/RG7596) and a small molecule antagonist of MDM2 (idasanutlin/RG7388). Roche's dedication to developing novel molecules in haematology expands beyond malignancy, with the development of Hemlibra® (emicizumab), a bispecific monoclonal antibody for the treatment of haemophilia A.

About Roche
Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people's lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare - a strategy that aims to fit the right treatment to each patient in the best way possible.

Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management.
Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. Thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Roche has been recognised as the Group Leader in sustainability within the Pharmaceuticals, Biotechnology & Life Sciences Industry nine years in a row by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2017 employed about 94,000 people worldwide. In 2017, Roche invested CHF 10.4 billion in R&D and posted sales of CHF 53.3 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com.
All trademarks used or mentioned in this release are protected by law.

References
[1] WFH. Guidelines for the management of haemophilia. 2012 [Internet; cited 2018 July]. Available from:
http://www1.wfh.org/publications/files/pdf-1472.pdf
[2] Berntorp E, Shapiro AD. Modern haemophilia care. The Lancet 2012; 370:1447-1456.
[3] Marder VJ, et al. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 6th Edition, 2013. Milwakee, Wisconsin. Lippincott Williams and Wilkin.
[4] Franchini M, Mannucci PM. Haemophilia A in the third millennium. Blood Rev 2013; 179-84.
[5] Gomez K, et al. Key issues in inhibitor management in patients with haemophilia. Blood Transfus. 2014; 12:s319-s329.
[6] Whelan, SF, et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of haemophilia A patients. Blood 2013; 121:1039-48.

Roche Group Media Relations
Phone: +41 61 688 8888 / e-mail: media.relations@roche-global.com
- Nicolas Dunant (Head)
- Patrick Barth
- Ulrike Engels-Lange
- Simone Oeschger
- Anja von Treskow