A 'HAVEN' for hemophilia sufferers in emicizumab?

Genentech optimistic about emicizumab in hemophilia A thanks to recently published positive Phase 3 trial results

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SOUTH SAN FRANCISCO, Calif.—The 26th International Society on Thrombosis and Haemostasis (ISTH) Congress served as the venue for Genentech, a member of the Roche Group, to share results from the HAVEN 1 in adults and adolescents and interim data from HAVEN 2 in children with hemophilia A with inhibitors. Some of the highlights of these data were that HAVEN 1 showed emicizumab reduced bleed rates by 87 percent compared with on-demand bypassing agents, and that 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.
HAVEN 1 is a Phase 3 study designed to study prophylactic use of once-weekly subcutaneous emicizumab in adults and adolescents with hemophilia A with inhibitors, the results having been published in the New England Journal of Medicine. As noted above, the primary endpoint showed a clinically meaningful and statistically significant reduction in treated bleeds of 87 percent with emicizumab prophylaxis compared to on-demand (no prophylaxis; episodic use only) bypassing agents (BPAs); in addition, all 12 secondary endpoints were positive, including a statistically significant reduction of 79 percent in treated bleeds in what is a subset of patients comparing two prophylaxis regimens (emicizumab and BPAs).
Interim results from the single-arm HAVEN 2 study—also a Phase 3 trial, 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.
“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 Dr. Sandra Horning, chief medical officer and head of global product development for Genentech. “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 measured at 25 weeks, using two validated instruments (Haem-A-QoL and EQ-5D-5L), was also observed.
As part of HAVEN 1, there was also an additional study arm in which patients who had previously received BPA prophylaxis were treated with emicizumab prophylaxis, as alluded to above. A subset of patients in this arm had previously participated in a non-interventional study (NIS), which Genentech says provided a first-of-its-kind intra-patient analysis comparing two prophylaxis regimens. This analysis showed a 79-percent 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,” remarked Prof. Johannes Oldenburg of the Institute of Experimental Haematology and Transfusion Medicine at the University of Bonn in 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.”
Of course, some adverse events (AEs) occurred—such as local injection site reactions, headache, fatigue, upper respiratory tract infection and joint pain—in some 5 percent of patients treated with emicizumab. As has been previously reported, serious adverse events of thromboembolic events (TE) in two patients and thrombotic microangiopathy (TMA) in three others while receiving emicizumab prophylaxis. One event occurred after the clinical cut-off date for the primary analysis.
According to Genentech, there was a common theme to the TMA and TE events, occurring in those patients who 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. Neither TE event required anti-coagulation therapy and one patient restarted emicizumab. The cases of TMA observed were transient, and one patient restarted emicizumab.
Getting back to HAVEN 2, an intra-patient comparison in a subset of the children in that study who were previously enrolled in the NIS showed that all experienced a 100-percent reduction in treated bleeds following treatment with emicizumab; according to the company, previous annualized bleeding rate 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.
HAVEN 2 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 of the children compared with the levels of emicizumab in the blood of adults and adolescents. The most common adverse events with emicizumab in the HAVEN 2 study were mild injection site reactions and common cold symptoms. 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 Dr. Guy Young, director of the Hemostasis and Thrombosis Program at Children’s Hospital Los Angeles and professor of pediatrics at the University of Southern California Keck School of Medicine. “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 to both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. 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.
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, Genentech explains. It was created by Chugai Pharmaceutical Co. Ltd. and is being co-developed by Chugai, Roche and Genentech.

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