Positive Phase III Results for Genentech’s Emicizumab in Hemophilia A Published in The New England Journal of Medicine

South San Francisco, CA   July 10, 2017   Genentech Press Release 

Positive Phase III Results for Genentech’s Emicizumab in Hemophilia A Published in The New England Journal of Medicine

HAVEN 1 showed emicizumab reduced bleed rate by 87 percent compared with on-demand bypassing agents

All 12 secondary endpoints in HAVEN 1 were positive, including an intra-patient comparison that showed emicizumab reduced bleed rate by 79 percent compared to prior prophylactic bypassing agents

Data from HAVEN 1 in adults and adolescents and interim data from HAVEN 2 in children with hemophilia A with inhibitors are being presented today at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress

Data from both studies have been submitted to FDA and EMA for approval consideration

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that data from HAVEN 1, a Phase III study evaluating once-weekly subcutaneous emicizumab prophylaxis (preventative) in adults and adolescents with hemophilia A with inhibitors, were published in The New England Journal of Medicine (NEJM). The primary endpoint showed a clinically meaningful and statistically significant reduction in treated bleeds of 87 percent (risk rate [RR]=0.13, p<0.0001) with emicizumab prophylaxis compared with on-demand (no prophylaxis; episodic use only) bypassing agents (BPAs). All 12 secondary endpoints were positive, including a statistically significant reduction of 79 percent (RR=0.21, p=0.0003) in treated bleeds in a first-of-its-kind intra-patient analysis in a subset of patients comparing two prophylaxis regimens (emicizumab and BPAs). Data from HAVEN 1 and the interim analysis of the Phase III HAVEN 2 study of emicizumab in children are being presented at the 26th International Society on Thrombosis and Haemostasis (ISTH) Congress today.

“Nearly one in three people with hemophilia A develop inhibitors to standard factor VIII therapy, leaving them at greater risk of life-threatening bleeds and long-term joint damage,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “Based on the bleed reduction shown in the HAVEN 1 and HAVEN 2 studies, we believe emicizumab has the potential to make a meaningful difference for people with hemophilia A with inhibitors, while also reducing the burden of managing the condition with a subcutaneous, once-weekly administration.”

Further data from HAVEN 1 showed that, after a median observation time of 31 weeks, substantially more patients experienced zero bleeds with emicizumab prophylaxis than with on-demand BPAs across all bleed measurements, including zero treated bleeds (62.9 percent vs. 5.6 percent), zero treated spontaneous bleeds (68.6 percent vs. 11.1 percent), zero treated joint bleeds (85.7 percent vs. 50.0 percent), zero treated target joint bleeds (94.3 percent vs. 50.0 percent) and zero bleeds overall, which includes all treated and non-treated bleeds (37.1 percent vs. 5.6 percent). A clinically meaningful and statistically significant improvement in health-related quality of life (HRQoL) measured at 25 weeks, using two validated instruments (Haem-A-QoL and EQ-5D-5L), was also observed.

In an additional study arm (Arm C, n=49), patients who had previously received BPA prophylaxis were treated with emicizumab prophylaxis. A subset of patients in this arm (n=24) had previously participated in a non-interventional study (NIS), allowing for a first-of-its-kind intra-patient analysis comparing two prophylaxis regimens. This analysis showed a 79 percent (RR=0.21, p=0.0003) reduction in treated bleeds in patients receiving emicizumab compared with their prior BPA prophylaxis during the NIS. Data also showed that 70.8 percent of patients in this subset experienced zero treated bleeds with emicizumab prophylaxis, whereas only 12.5 percent of these patients had experienced zero bleeds with their prior BPA prophylaxis during the NIS.

“The HAVEN 1 study is one of the most robust clinical studies conducted to date in people with hemophilia A with inhibitors to factor VIII, including a first ever intra-patient comparison to prior prophylaxis with bypassing agents,” said Professor Johannes Oldenburg, Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Germany. “The reduction in bleeding events across all measures seen with emicizumab compared to either on-demand or prophylactic bypassing agents supports that it may be one of the most significant scientific innovations in the treatment of hemophilia A in over 30 years.”

Adverse events (AEs) occurring in five percent or more of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection and joint pain (arthralgia). As previously reported, serious adverse events of thromboembolic events (TE) and thrombotic microangiopathy (TMA) occurred in two patients and three patients, respectively, while receiving emicizumab prophylaxis. One event occurred after the clinical cut-off date for the primary analysis. The common aspect of these TMA and TE events is the patients were on emicizumab prophylaxis and received more than 100 u/kg/day of the BPA activated prothrombin complex on average for 24 hours or more before the onset of the event. Two of these patients had also received recombinant factor VIIa (rFVIIa). Neither TE event required anti-coagulation therapy and one patient restarted emicizumab. The cases of TMA observed were transient, and one patient restarted emicizumab.

Interim results from the single arm HAVEN 2 study in children younger than 12 years of age with hemophilia A with inhibitors who received emicizumab prophylaxis are consistent with the positive results from the HAVEN 1 study. After a median observation time of 12 weeks, the study showed that only one of 19 children receiving emicizumab reported a treated bleed. There were no reported joint or muscle bleeds.

An intra-patient comparison (n=8) in a subset of these children who were previously enrolled in the NIS showed that all experienced a 100 percent reduction in treated bleeds following treatment with emicizumab (previous annualized bleeding rate [ABR] ranged from 0 to 34.24); this group included seven children who had received prior BPA prophylaxis, and one who had received prior on-demand BPA. The data also indicate that the same dose of emicizumab is appropriate for children as for adults and adolescents, based on the levels of emicizumab in the blood (pharmacokinetics) of the children compared with the levels of emicizumab in the blood of adults and adolescents. The most common AEs with emicizumab in the HAVEN 2 study were mild injection site reactions and common cold symptoms (nasopharyngitis). No TE or TMA events were observed.

“Managing hemophilia A with inhibitors to factor VIII can be especially challenging for children and their caregivers. Not only can bleeding be difficult to control, but current treatments can require frequent intravenous infusions, which can often involve the long-term use of a central venous access device or port,” said Guy Young, M.D., director of Hemostasis and Thrombosis Program, Children’s Hospital Los Angeles, and professor of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, California. “The HAVEN 2 interim results indicate that emicizumab may help prevent bleeding in children with inhibitors. Given the once-weekly subcutaneous dosing, it may also help alleviate some of the burden of hemophilia treatment for these children and their parents.”

Data from both HAVEN 1 and HAVEN 2 have been submitted for approval consideration to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The FDA granted Breakthrough Therapy Designation for emicizumab in adults and adolescents with hemophilia A with inhibitors in September 2015. Additional studies evaluating emicizumab in people with hemophilia A both with and without inhibitors and exploring less frequent dosing regimens are ongoing.

About HAVEN 1 (NCT02622321)

HAVEN 1 is a randomized, multicenter, open-label, Phase III study evaluating the efficacy, safety, and pharmacokinetics of emicizumab prophylaxis compared to on-demand BPA (no prophylaxis; episodic use only) in adults and adolescents with hemophilia A with inhibitors to factor VIII. The study included 109 patients (12 years of age or older) with hemophilia 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 randomized in a 2:1 fashion to receive emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B). Patients previously treated with prophylactic BPAs received emicizumab prophylaxis (Arm C). Additional patients previously on BPA (on-demand or prophylaxis) were also enrolled in a separate arm (Arm D). On-demand treatment of breakthrough bleeds with BPAs was allowed per protocol in all arms.

The primary endpoint of the study is the number of treated bleeds over time with emicizumab prophylaxis (Arm A) compared with no prophylaxis (Arm B). Secondary endpoints include all bleed rate, joint bleed rate, spontaneous bleed rate, target joint bleed rate, HRQoL/health status, intra-patient comparison to bleed rate on their prior prophylaxis regimen with BPAs (Arm C) or no prophylaxis (Arm B). The study also evaluated safety and pharmacokinetics.

A summary of the HAVEN 1 study results to be presented at ISTH is included below.

*Negative binomial regression model

*Third TMA event occurred after primary data cut-off; patient also experienced fatal rectal hemorrhage

**Serious thromboembolic events comprised skin necrosis/superficial thrombophlebitis in one participant, and cavernous sinus thrombosis in a second participant

No participants tested positive for anti-drug antibodies (ADAs)

About HAVEN 2 (NCT02795767)

HAVEN 2 is a single-arm, multicenter, open-label, Phase III study evaluating the efficacy, safety, and pharmacokinetics of once-weekly subcutaneous administration of emicizumab. The interim analysis after a median of 12 weeks of treatment included 19 children younger than 12 years of age with hemophilia A with inhibitors to factor VIII, who require treatment with BPAs. The objectives of the study are to evaluate the number of treated bleeds over time with emicizumab prophylaxis, safety, pharmacokinetics, HRQoL and proxy HRQoL with aspects of caregiver burden.

A summary of the HAVEN 2 study interim results presented at ISTH is included below.

*Serious AEs: bleeding of the mouth and gums (mouth hemorrhage), appendicitis, catheter site infection

**All related AEs were mild injection site reactions

No TE or TMA events were observed

No participants tested positive for ADAs

About emicizumab (ACE910)

Emicizumab is an investigational bispecific monoclonal antibody designed to bring together factors IXa and X, proteins required to activate the natural coagulation cascade and restore the blood clotting process. Emicizumab can be administered by an injection of a ready-to-use solution under the skin (subcutaneously) once weekly. Emicizumab is being evaluated in pivotal Phase III studies in people 12 years of age and older, both with and without inhibitors to factor VIII, and in children under 12 years of age with factor VIII inhibitors. Additional trials are exploring less frequent dosing schedules. The clinical development program is assessing the safety and efficacy of emicizumab 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. Emicizumab was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Chugai, Roche and Genentech.

About hemophilia A

Hemophilia A is an inherited, serious disorder in which a person’s blood does not clot properly, leading to uncontrolled and often spontaneous bleeding. Hemophilia affects around 20,000 people in the United States, with hemophilia A being the most common form and approximately 50-60 percent of people living with a severe form of the disorder. People with hemophilia 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 hemophilia A can bleed frequently, especially into their joints or muscles. 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. In addition to impacting a person’s quality of life, these bleeds can be life threatening if they go into vital organs, such as the brain. A serious complication of treatment is the development of inhibitors to factor VIII replacement therapies. Inhibitors are antibodies developed by the body’s immune system that bind to and block the efficacy of replacement factor VIII, making it difficult, if not impossible to obtain a level of factor VIII sufficient to control bleeding. Most people with hemophilia A who develop inhibitors will infuse BPA therapies, either on-demand (episodic) or as prophylaxis, to control bleeding. This approach is known to be less effective and less predictable than factor VIII replacement therapy in people with hemophilia A without inhibitors.

About Genentech in hemophilia

In 1984, Genentech scientists were the first to clone recombinant factor VIII in response to the contaminated hemophilia blood supply crisis of the early 1980s. For more than 20 years, Genentech has been developing medicines to bring innovative treatment options to people with diseases of the blood within oncology, and is investigating emicizumab as a potential treatment option for hemophilia A. Genentech is committed to improving treatment and care in the hemophilia community by delivering meaningful science and clinical expertise. For more information visit http://www.gene.com/hemophilia.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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