A new era of treatment for patients with haemophilia A?

Abstract

Treatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bi-specific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII. Due to the different structure of this antibody it cannot be neutralized by factor VIII inhibitors and has the possibility to achieve haemostasis in patients with severe haemophilia A with and without inhibitors. First studies in healthy volunteers and in patients showed a shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. The half-life of the drug was 4 to 5 weeks. There were no clinical signs of thrombosis and no laboratory abnormalities indicating hypercoagulability. In a first study with 18 patients with severe haemophilia A with and without inhibitors a remarkable reduction in the annualised bleeding rate occurred. Safety of the drug has to be proven in ongoing research. Mimicking the cofactor activity of factor VIII by a bispecific antibody for the treatment of severe haemophilia A is so far safe and seems to be effective and is one highlight in haemostasis 2016.

Emicizumab: Review of the literature and critical appraisal

“…The clinical development programme for emicizumab included the five phase 3 trials (HAVEN‐1, HAVEN‐2, HAVEN‐3, HAVEN‐4, HAVEN‐5 and STASEY) summarized in Tables and . In these tables, the level of evidence of the studies reported so far can be seen.…”

“…Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. The PK and PD profiles of emicizumab were similar in healthy Japanese and white subjects suggesting that emicizumab will be an effective and convenient prophylactic treatment of haemophilia A The clinical development programme for emicizumab included the five phase 3 trials (HAVEN-1, HAVEN-2, HAVEN-3, HAVEN-4, HAVEN-5 and STASEY) summarized in Tables 1 26,29,[35][36][37][38][40][41][42][43][44][45][46][47][48]54 and 2. 26,[49][50][51][52] In these tables, the level of evidence of the studies reported so far can be seen.…”

Congenital hemophilia A with low activity of factor XII: a case report and literature review

“…The presence of inhibitors is a common adverse effect of human coagulation factor VIII therapy in patients with hemophilia [ 13 , 14 ]. Generally, 30 % of patients with severe hemophilia A may develop inhibitors during the first 20 days of exposure to recombinant coagulation factor VIII [ 15 ]. The presence of inhibitors may be an immune response to foreign proteins in patients with severe hemophilia A [ 16 ].…”

Thromboembolic Risks of Non-Factor Replacement Therapies in Hemophilia

“…These issues set the scene for the development of the novel non-factor replacement therapies (17). Representing diverse mechanisms of action, they have in common (i) efficacy independent of the presence of inhibitors, (ii) long half-life, (iii) subcutaneous administration, and (iv) reduced or absent risk of anti-drug antibodies.…”

“…Of note, breakthrough bleeds in non-inhibitor patients were managed with low doses of FVIII (18 bleeds; mean 17 [range 5-31] IU/kg for a mean of 1.1, [range 1-2] doses) or FIX (7 bleeds; 18 [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] IU/kg for 3.9 [1][2][3][4][5][6][7][8] doses). All patients used less than or same amount of factor per bleed as prior to fitusiran.…”