Europeisk godkjenning av Hemlibra® (emicizumab) for profylaktisk behandling av pasienter med hemofili A som har utviklet antistoff mot faktor VIII

-Dette er det første nye medikamentet i Europa på over 20 år til behandling av hemofili A hos pasienter som har utviklet antistoff mot faktor VIII

-Hemlibra viste bedre effekt sammenlignet med behandling med bypass-midler i to fase III-studier hos voksne og barn (over 12 år)

-Hemlibra administreres som subkutan injeksjon en gang i uken, som kan lette behandlingsbyrden for disse pasientene

Les Roches internasjonale pressemelding for nærmere informasjon:

Basel, 27 February 2018

European Commission approves Roche's Hemlibra for people with haemophilia A with inhibitors

• First new medicine in over 20 years to treat people with haemophilia A with inhibitors in Europe
• Hemlibra demonstrated superior efficacy compared to prior treatment with bypassing agents in two phase III studies in adults, adolescents and children
• Once-weekly subcutaneous (under the skin) administration may help reduce treatment burden

Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the European Commission has approved Hemlibra® (emicizumab) for routine prophylaxis of bleeding episodes in people with haemophilia A with factor VIII inhibitors. Hemlibra can be used in all age groups. Nearly one in three people with severe haemophilia A can develop inhibitors to factor VIII replacement therapies, putting them at greater risk of life-threatening bleeds or repeated bleeding episodes that can cause long-term joint damage.1 People with haemophilia A with inhibitors have a 70% increased risk of death compared to those without inhibitors.2

"This approval is great news for people in Europe with haemophilia A with inhibitors to factor VIII. The development of inhibitors not only puts them at greater risk of frequent and severe bleeds, but also makes the disorder more difficult to manage, with limited treatment options available to date," said Professor Johannes Oldenburg, Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Germany. "The bleed reduction and improvements in quality of life shown with Hemlibra compared to current treatments support its potential to advance the management of haemophilia A with inhibitors."

"We're delighted that the European Commission has approved Hemlibra, providing people with haemophilia A with inhibitors a new medicine for the first time in over 20 years," said Sandra Horning, M.D., Roche's Chief Medical Officer and Head of Global Product Development. "We believe Hemlibra has the potential to make a meaningful difference in the lives of people with haemophilia A with inhibitors, and are committed to working with EU member states to provide access to this important medicine as quickly as possible."

The approval is based on two of the largest pivotal clinical studies in people with haemophilia A with inhibitors, in which Hemlibra demonstrated superior efficacy compared to prior treatment with bypassing agents (BPA) as prophylaxis or on-demand.

• In the HAVEN 1 study in adults and adolescents (12 years of age or older) with haemophilia A with inhibitors, Hemlibra prophylaxis showed a statistically significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, p<0.0001) compared to no prophylaxis. In a first-of-its-kind intra-patient analysis, Hemlibra prophylaxis resulted in a statistically significant reduction in treated bleeds of 79% (RR=0.21, p=0.0003) compared to previous treatment with bypassing agent (BPA) prophylaxis collected in a non-interventional study (NIS) prior to enrolment.
• Interim results from the HAVEN 2 study in children younger than 12 years of age with haemophilia A with inhibitors showed that 87% (95% CI: 66.4; 97.2) of children who received Hemlibra prophylaxis experienced zero treated bleeds. In an intra-patient analysis of 13 children who had participated in the NIS, Hemlibra prophylaxis resulted in a 99% (RR=0.01, 95% CI: 0.004; 0.044) reduction in treated bleeds compared to previous treatment with a BPA.

The most common adverse events (AEs) from pooled clinical studies occurring in 10% or more of people treated with Hemlibra were injection site reactions and headache. In the HAVEN 1 study, three people experienced thrombotic microangiopathy (TMA) events and two people experienced serious thrombotic events when on average, a cumulative amount of more than 100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) (FEIBA®) was administered for 24 hours or more while receiving Hemlibra prophylaxis.

These data also led to the approval of Hemlibra for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with haemophilia A with factor VIII inhibitors by the US Food and Drug Administration (FDA) on 16 November 2017. Hemlibra was reviewed by the FDA under Priority Review and granted Breakthrough Therapy Designation by the FDA in people 12 years of age or older with haemophilia A with inhibitors in September 2015. Updated analyses from both the HAVEN 1 and HAVEN 2 studies were presented last December at the 2017 American Society of Hematology (ASH) Annual Meeting and showed that after longer follow-up, Hemlibra continued to substantially reduce bleeds in people with haemophilia A with inhibitors.

Hemlibra is being studied in a robust clinical development programme that includes two additional phase III studies, HAVEN 3 and HAVEN 4. Results from HAVEN 3 showed a statistically significant and clinically meaningful reduction in the number of treated bleeds over time in adults and adolescents (12 years of age or older) with haemophilia A without inhibitors who received Hemlibra prophylaxis every week or every two weeks, compared to those receiving no prophylaxis. Interim results from HAVEN 4 showed a clinically meaningful control of bleeding in adults and adolescents (12 years of age or older) with haemophilia A with or without inhibitors who received Hemlibra prophylaxis once every four weeks. Data from both these studies will be presented at an upcoming medical conference and submitted to health authorities around the world for approval consideration.

About HAVEN 1 (NCT02622321; Study BH29884)

HAVEN 1 is a randomised, multicentre, open-label, phase III study evaluating the efficacy, safety and pharmacokinetics of once-weekly subcutaneous administration of Hemlibra prophylaxis compared to no prophylaxis in adults and adolescents with haemophilia A with inhibitors to factor VIII. The study included 109 patients (12 years of age and older) with haemophilia A with inhibitors to factor VIII, who were previously treated with BPAs on-demand or as prophylaxis. Patients previously treated with on-demand BPAs were randomised in a 2:1 ratio to receive Hemlibra prophylaxis (Arm A) or no prophylaxis (Arm B). Patients previously treated with BPAs as prophylaxis received Hemlibra prophylaxis (Arm C). Additional patients previously treated with on-demand BPAs were also enrolled in a separate arm (Arm D). On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.

Below is a summary of key data from the HAVEN 1 study.

• The primary endpoint showed a statistically significant reduction in treated bleeds of 87% (risk rate [RR]=0.13, p<0.0001) with Hemlibra prophylaxis compared to no prophylaxis.
  • In addition, 62.9% (95% CI: 44.9; 78.5) of patients who received Hemlibra prophylaxis experienced zero treated bleeds compared to 5.6% (95% CI: 0.1; 27.3) of patients who received no prophylaxis.
• All 12 secondary endpoints were positive. In a first-of-its-kind intra-patient analysis, Hemlibra prophylaxis resulted in a statistically significant reduction in treated bleeds of 79% (RR=0.21, p=0.0003) compared to previous treatment with BPA prophylaxis collected in the NIS prior to enrolment. Additionally, 70.8% (95% CI: 48.9; 87.4) of patients experienced zero treated bleeds with Hemlibra prophylaxis compared to 12.5% (95% CI: 2.7; 32.4) with previous treatment with BPA prophylaxis during the NIS.
• Improvements in bleed rate with Hemlibra prophylaxis compared to no prophylaxis included an 80% (RR=0.20, p<0.0001) reduction in all bleeds, a 92% (RR=0.08, p<0.0001) reduction in treated spontaneous bleeds, an 89% (RR=0.11, p=0.0050) reduction in treated joint bleeds and a 95% (RR=0.05, p=0.0002) reduction in treated target joint bleeds.
• Hemlibra prophylaxis showed a statistically significant and clinically meaningful improvement in the Haemophilia-specific Quality of Life (Haem-A-QoL) Total Score and Physical Health scale compared to no prophylaxis. This was measured 24 weeks after start of treatment in adults 18 years of age and older and evaluated haemophilia-related symptoms (painful swellings and presence of joint pain) and physical function (pain with movement and difficulty walking far).
• Hemlibra prophylaxis also showed a statistically significant and clinically meaningful improvement in the EuroQoL Five-Dimension-Five Levels Questionnaire (EQ-5D-5L) index utility scale and visual analogue scale of the EQ-5D-5L compared to no prophylaxis. This was measured 24 weeks after start of treatment in adults and adolescents 12 years of age or older, and evaluated measures of overall health status (mobility, self-care, usual activities, pain/discomfort and anxiety/depression).

About HAVEN 2 (NCT02795767; Study BH29992)

HAVEN 2 is a single-arm, multicentre, open-label, clinical study in children younger than 12 years of age with haemophilia A with inhibitors to factor VIII. The study is evaluating the efficacy, safety and pharmacokinetics of once-weekly subcutaneous administration of Hemlibra prophylaxis. The interim efficacy analysis, after at least 12 weeks of treatment, included 23 children.

• After a median observation time of 38.1 weeks, the interim analysis showed that 87% (95% CI: 66.4; 97.2) of children who received Hemlibra prophylaxis experienced zero treated bleeds. Interim data also showed:
  • 34.8% (95% CI: 16.4; 57.3) of children experienced zero bleeds overall, which includes all treated and non-treated bleeds.
  • 95.7% (95% CI: 78.1; 99.9) of children experienced zero treated spontaneous bleeds.
  • 95.7% (95% CI: 78.1; 99.9) of children experienced zero treated joint bleeds.
  • 100% (95% CI: 85.2; 100) of children experienced zero treated target joint bleeds.
• In an intra-patient analysis, 13 children who had participated in the NIS had an annualised bleeding rate (ABR) for treated bleeds of 17.2 (95% CI: 12.4; 23.8) on previous treatment with a BPA either as prophylaxis (n=12) or on-demand (n=1) compared to 0.2 (95% CI: 0.1; 0.8) on Hemlibra prophylaxis, corresponding to a 99% (RR=0.01, 95% CI: 0.004; 0.044) reduction in bleed rate. On Hemlibra prophylaxis, 11 children (84.6%) experienced zero treated bleeds.

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 by Chugai, Roche and Genentech. It is marketed in the United States as Hemlibra (emicizumab-kxwh) for people with haemophilia A with factor VIII inhibitors, with kxwh as the suffix designated in compliance 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,3,4 approximately 50-60% of whom have a severe form of the disorder.5 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.3 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.6 A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies.7 Inhibitors are antibodies developed by the body's immune system that bind to and block the efficacy of replacement factor VIII,8 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™ (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.

References

1. European Haemophilia Consortium [Internet; cited 2018 January]. Available from: https://www.ehc.eu/bleeding-disorders/inhibitors/
2. www.cdc.gov/ncbddd/hemophilia/features/inhibitor-severe-hemophilia-a.html
3. WFH. Guidelines for the management of haemophilia. 2012 [Internet; cited 2017 December]. Available from: http://www1.wfh.org/publications/files/pdf-1472.pdf
4. Berntorp E, Shapiro AD. Modern haemophilia care. The Lancet 2012; 370:1447-1456.
5. Marder VJ, et al. Hemostasis and Thrombosis. Basic Principles and Clinical Practice. 6th Edition, 2013. Milwakee, Wisconsin. Lippincott Williams and Wilkin.
6. Franchini M, Mannucci PM. Haemophilia A in the third millennium. Blood Rev 2013; 179-84.
7. Gomez K, et al. Key issues in inhibitor management in patients with haemophilia. Blood Transfus. 2014; 12:s319-s329.
8. 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