Anti-Inhibitor Coagulant Complex (Baxalta US)

The drug will be used to prevent or reduce the frequency of bleeding episodes in certain patients. The U.S. Food and Drug Administration approved Genentech ’s hemophilia drug Hemlibra (emicizumab-kxwh), which will be used to prevent or reduce the frequency of bleeding episodes in certain patients. Genentech , a division of Swiss drug giant Roche , said Hemlibra will soon be commercially available , but did not provide a timeline. The drug was reviewed by the FDA under a priority review. Hemlibra will be released with a boxed warning that concerns possible blood clots in patients, the FDA said. During trials, the clots were seen in patients who were “also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.” In October 2016, it was reported that four patients taking part in the trial suffered serious adverse events. Roche disclosed two of the patients developed thromboembolic events and two patients developed thrombotic microangiopathy. Genentech said nearly one-third of hemophilia A patients can develop antibodies known as factor VIII inhibitors. During clinical trials, Hemlibra was shown to substantially reduce bleeds in adults and children who have hemophilia A with the inhibitors. In the Phase III HAVEN 1 study, hemophilia A patients 12 years of age or older who received Hemlibra prophylaxis had a statistically significant reduction in treated bleeds of 87 percent. Similar results were seen in the HAVEN 2 study in children younger than age 12. In that study, 87 percent (of children who received Hemlibra prophylaxis) experienced zero treated bleeds. Sandra Horning , Genentech’s chief medical officer, said the approval of Hemlibra is an important advancement for this type of hemophilia patients who have struggled with being able to manage their bleeding issues. She said Hemlibra is the first type of medication to address this in nearly 20 years. In its announcement, Genentech released statements from some Hemlibra patients. Amber Hill, the mother of a 7-year-old hemophilia A patient with inhibitors, said before Hemlibra, her son needed intravenous infusions that could take up to two hours at least three times a week. Hill said the family’s life revolved around their son’s treatment. Now with Hemlibra, he can administer the medication himself, she said. With the newly approved drug he has fewer bleeds and has a greater quality of life, Hill said. “Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” Richard Pazdur , acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation, said in a statement. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.” Hemophilia A is a genetic blood-clotting disorder that can lead to uncontrolled bleeding. There are about 20,000 people in the United States diagnosed with hemophilia and 320,000 worldwide. Hemophilia A is the most common form. People with hemophilia A either lack or do not have enough of a clotting protein called factor VIII. The bleeding, which often occurs in joints, can cause significant pain and can lead to chronic swelling, deformity, reduced mobility and long-term joint damage. The annual hemophilia market is about $11 billion and Genentech hopes its indications of Hemlibra will secure a chunk of that market. With approval of Hemlibra, Genentech will rival drugs FEIBA and NovoSeven, developed by Shire Pharmaceuticals and Novo Nordisk respectively, for a share of the 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 pro 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.