Phase III HAVEN 3 and Phase III HAVEN 4 Study in Hemophilia A Show Efficacy

This morning, Roche released results from its phase III HAVEN 3 and phase III HAVEN 4 studies, which assessed the administration of Hemlibra (emicizumab) prophylaxis every week or every 2 weeks in people with hemophilia A without factor VIII inhibitors, and its phase III HAVEN 4 study, which assessed the administration of Hemlibra prophylaxis administered every 4 weeks in people with hemophilia A with or without factor VIII inhibitors.

“Hemlibra is the first medicine to show superior efficacy to prior factor VIII prophylaxis, the current standard of care therapy, as demonstrated by a statistically significant reduction in treated bleeds in the HAVEN 3 study intra-patient comparison,” stated Johnny Mahlangu, Faculty of Health Sciences, University of the Witwatersrand and NHLS, Johannesburg, South Africa in a recent statement. “Even with current prophylactic treatments, many people with hemophilia A continue to have bleeds that can lead to long-term joint damage, and there is a need for more treatment options.”

Emicizumab prophylaxis is a bispecific factor IXa- and factor X-directed antibody engineered to join factor IXa and factor X, which are necessary proteins in the activation of natural coagulation cascade and restoration of the blood clotting process for people with hemophilia A. It is a prophylactic (preventative) treatment that can be given once weekly by an injection of a ready-to-use solution under the skin (subcutaneously).

Regarding the phase III HAVEN 3 study, adults and adolescents aged 12 years or older without factor VIII inhibitors who received emicizumab prophylaxis every week or every 2 weeks respectively showed a 96% (p<0.0001) and 97% (p<0.0001) reduction in treated bleeds compared to those who received no prophylaxis. Additionally, 60% (95% CI: 42.1; 76.1) of people treated with emicizumab prophylaxis every 2 weeks and 55.6% (95% CI: 38.1; 72.1) of people treated with emicizumab prophylaxis every week encountered 0 bleeds compared to 0% (95% CI: 0.0; 18.5) of people treated with no prophylaxis.

Primarily, in patients who were previously enrolled in a prospect non-interventional study (NIS) in an intra-patient comparison, once weekly emicizumab prophylaxis showed superior efficacy compared to prior factor VIII prophylaxis, which is currently the standard of care for people with hemophilia A without factor VIII inhibitors, as demonstrated by a 68% reduction in (p<0.0001) in treated bleeds. In addition, 93.7% (n=89/95; 95% CI, 86.8; 97.7) of all participants who completed a treatment preference survey favored emicizumab prophylaxis to their previous hemophilia treatment; 97.8% (n=45/46) of those in the intra-patient comparison preferred emicizumab prophylaxis to their prior factor VIII prophylaxis.

No unexpected or serious adverse events (AEs) related to emicizumab prophylaxis were experienced, and the most common AEs were consistent with previous studies and occurred in 5% or more of the HAVEN 3 study subjects as injection site reactions, joint pain (arthralgia), common cold symptoms (nasopharyngitis), headache, upper respiratory tract infection, and influenza.

“These new pivotal data show that Hemlibra controlled bleeds in people with haemophilia A, while offering the flexibility of less frequent subcutaneous dosing options,” added Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. “With this data, we now have positive results from all four of our phase III trials that reinforce the overall efficacy and safety of Hemlibra and its potential to improve care for all people with hemophilia A.”

Regarding the single-arm phase III HAVEN 4 study, adults and adolescents aged 12 years or older with or without factor VIII inhibitors who received emicizumab prophylaxis every 4 weeks exhibited a median annualized bleeding rate for treated bleeds of 0.0 (IQR: 0.0; 2.1) with 56.1% (95% CI: 39.7; 71.5) of people experiencing 0 treated bleeds and 90.2% (95% CI: 76.9; 97.3) experiencing 3 or fewer treated bleeds. Based off of these results, it can be assumed that administering emicizumab prophylaxis every 4 weeks can provide clinically meaningful control of bleeding in people with hemophilia A with or without factor VIII inhibitors.

Furthermore, it was reported that all participants (n=41/41; 95% CI, 91.4; 100.0) who responded to a patient preference survey preferred emicizumab prophylaxis to their previous hemophilia treatment. No unexpected or serious adverse events (AEs) related to emicizumab prophylaxis were experienced, and the most common AEs parallelled with previous studies. Injection site reactions were the most common AEs, which occurred in 9 participants in the HAVEN 4 study.

In a separate assessment, real-world data was presented from the NIS on the impact of hemophilia A on health-related quality of life (HRQoL) and the burden of current treatment (either on-demand or prophylactic bypassing agents or factor VIII replacement therapy, depending on inhibitor status and local clinical guidelines).

From a group of the NIS in children with hemophilia A with factor VIII inhibitors, results displayed a substantially negative impact on physical and emotional health in living with and managing the hemophilia A. This impact in turn places a significant burden on caregivers. From a separate group of adults and adolescents with hemophilia A without factor VIII inhibitors, higher HRQoL with prophylactic factor VIII treatment compared to episodic factor VIII treatment was reported (based on validated tools, such as Haem-A-QoL and Haemo-QoL-SF). Additionally, fewer missed school and work days were experienced in correlation with prophylactic factor VIII therapy as compared to episodic treatment.

Previously, based on data from the HAVEN 3 study, the FDA granted Breakthrough Therapy Designation to emicizumab prophylaxis for people with hemophilia A without factor VIII. In addition, based on results from the HAVEN 1 study and interim results from the HAVEN 2 study, the FDA approved emicizumab prophylaxis in November 2017 for routine prophylaxis in an effort to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors.

Other countries have also recognized and approved emicizumab prophylaxis in varying degrees; the European Commission approved emicizumab prophylaxis in February 2018 for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors. Currently, the collected data from the HAVEN 3 and HAVEN 4 studies are being submitted globally to health authorities for approval consideration.

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