One Death in the HAVEN 1 Trial Complicates Roche’s Entry into the Hemophilia A Market

March 13, 2017
By Chiara Marchetti, BioSpace.com Contributor

Safety concerns over Roche ’s highly anticipated emicizumab (ACE-910) has the potential to downsize the impact of the new treatment’s entry into the hemophilia A market, after the company announced the death of one of the participants enrolled in its pivotal HAVEN 1 trial.

These safety results represent a major setback to emicizumab’s entry in the hemophilia A space, where the drug was expected to be a game changer.

Replacement therapy, which consists of the continuous administration of the missing factor VIII (FVIII) (or downstream coagulation factors in patients with inhibitors), has always been the standard of care among hemophilia A patients. Emicizumab, by exploiting a different mechanism of action through the activation of downstream effectors in the coagulation cascade, provides many advantages compared to standard replacement therapies. It is effective in hemophilia A patients with and without inhibitors, does not induce the development of antibodies to FVIII that makes replacement therapies ineffective, and has an advantageous weekly prophylactic dosing schedule. The last point addresses one of the main unmet needs among hemophilia A patients, namely the unfavorable prophylactic dosing frequency of FVIII concentrates and bypassing agents that require administration every two to four days.

However, despite being highly anticipated in the field for several years, hints regarding shortcomings in the safety profile of emicizumab first emerged in late 2016.

On December 22, 2016, Roche reported positive efficacy data confirming that the primary endpoint of HAVEN 1 had been met, with emicizumab causing a statistically significant reduction in the annual bleeding rate in hemophilia A patients with inhibitors. The filing for the hemophilia A inhibitor market segment was expected later this year, followed by a label expansion to include hemophilia A patients without inhibitors in 2018.

However, there was some concern over emicizumab’s safety profile, as the administration of the drug was associated with thromboembolic events in two patients enrolled in HAVEN 1, as well as with two cases of thrombotic microangiopathy (TMA). In all the patients, the adverse events followed the administration of emicizumab in combination with a bypassing agent to control the bleeding events. However, according to Roche’s press release, both cases of TMA were resolved and two out of four patients had restarted emicizumab.

While the current standards of care for hemophilia patients include the use of inhibitors (Novo Nordisk ’s NovoSeven RT and Shire ’s Feiba NF), both drugs carry boxed warnings regarding serious arterial and venous thrombotic events and TMA is not usually associated with their administration.

More recently, on February 21, 2017, in a letter sent to the European Hemophilia Consortium (EHC), Roche reported another serious adverse event, the death of one of the HAVEN 1 participants. According to the statement, the patient was administered bypassing agents, including repeated doses of Feiba NF, to treat a rectal hemorrhage while receiving emicizumab prophylaxis. Following the administration of Feiba NF, signs of TMA were observed, which led to Feiba NF discontinuation and death due to serious hemorrhage, after the patient refused blood transfusions.

GlobalData believes that this death, while judged not related to emicizumab by investigators , might be due to the discontinuation of Feiba NF and is therefore related to the negative synergistic activity of the two drugs.

Regardless of the outcome of the independent data monitoring committee investigation, GlobalData expects the events registered in HAVEN 1 to undermine the success of emicizumab among hemophilia A patients with inhibitors. However, the low number of therapeutic options available in the inhibitor segment could still lead to a decent uptake of the drug, providing that the developer is able to define a modified protocol to ensure that breakthrough bleeding events are treated with a safe dose of bypassing agents.

In the hemophilia A market the use of a wide variety of FVIII concentrates is supported by a very long history of safety and efficacy data, and physicians are reluctant to switch patients who are adequately treated. Emicizumab could still be considered a therapeutic option for hemophilia A patients without inhibitors, for whom breakthrough bleeding does not require the administration of bypassing agents, as they can be controlled with FVIII concentrates.

However, even if TMA occurred in HAVEN 1 only after the co-administration of emicizumab and bypassing agents, further studies are required to understand if this serious safety issue is related to emicizumab monotherapy and to the intrinsic long half-life of the monoclonal antibody, and to assess the lack of synergy between Roche’s antihemophilic drug and the administration of FVIII.

Therefore, results from HAVEN 3, which is evaluating the efficacy of emicizumab in hemophilia A patients without inhibitors, are awaited to dismiss safety concerns in this subset of patients, which constitutes the larger patient pool, thus keeping alive Roche’s hope to successfully enter the hemophilia market.

Chiara Marchetti, PhD, is an Oncology and Hematology Analyst working within the GlobalData Healthcare Pharmaceuticals team in London. Driven by her passion for science and research, after completing her PhD in Chemistry, she worked as a postdoctoral research associate at the University of Cambridge. During her academic experience, she also worked as external consultant for an Italian based biotech.