In today’s blog post, I will discuss three issues relevant to patients with Hemophilia. One is about Emicizumab, a Factor VIII mimetic that in November 2016 was approved for patients with Hemophilia A with Factor VIII inhibitors by the FDA. Two is about a successful trial of gene therapy for Hemophilia B, and three is about two successful trials of gene therapy for Hemophilia A.
Emicizumab, formerly known as ACE910, now marketed as Hemlibra by Roche, is a recombinant humanized bispecific antibody that binds to activated factor IX and X, thus continuing the coagulation reaction, even if factor VIII was absent or neutralized by factor VIII antibodies. In 64 healthy volunteers (Uchida et al, Blood 2016; 127(13):1633-1641) no serious adverse events were observed after a single subcutaneous dose. In a non-randomized trial on 18 patients with severe Hemophilia A with or without inhibitors, an initial dose of emicizumab 1mg/kg followed by a weekly dose of 0.3mg/kg resulted in a fall in the median annualised bleeding rate (ABR) from 32.5 to 4.4, while an initial dose of 3mg/kg followed by a weekly dose of 1mg/kg resulted in a fall in the median ABR from 18.3 to 0, and an initial dose of 3mg/kg followed by a weekly dose of 3mg/kg resulted in a fall in the median ABR from 15.2 to 0 (Shima et al. NEJM 2016;374:2044-53). This dose finding Phase 2 study led to HAVEN-1 and HAVEN-2, randomized clinical trials that enrolled large numbers of patients with hemophilia. In HAVEN-1, 53 patients 12 years of age or older with hemophilia A with inhibitors who were previously treated with episodic treatment were randomized 2:1 to emicizumab 3mg/kg weekly subcutaneously for four weeks followed by 1.5mg/kg weekly thereafter or no prophylaxis. The annualized bleeding rate was 2.9 (95% confidence interval 1.7-5.0) in the treatment group versus 23.3 (95% confidence interval 12.3-43.9) in the group without prophylaxis, resulting in an 87% reduction in ABR (p<0.0001). 24 patients who had previously received prophylactic treatment with bypassing agents were prophylactically treated with emicizumab and showed a reduction in ABR by 79% (p<0.001) compared to the rate with previous prophylaxis with bypassing agent. Thrombotic microangiopathy and thrombosis were reported in two participants, both of whom had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. (Oldenburg et al. NEJM 2017;377:809-818) In HAVEN-2, patients 12 years old or younger or 12-17 years old and weighing less than 40kg with hemophilia A and with inhibitors who were previously treated with bypassing agents were treated prophylactically with emicizumab. In the interim analysis, the annualized bleeding rate for treated bleeds in 23 patients was 0.2, and for 13 of these patients, this was a reduction of 99% versus prior treatment. 64.9% of patients had no bleeds and 94.7% of patients had zero treated bleeds. (Young et al, Oral abstract, ASH 2017) This led to approval by the FDA of this drug as prophylaxis for patients with hemophilia A with inhibitors. (FDA approval here; full prescribing information here) A Phase III study on patients with hemophilia A without inhibitors is underway. Emicizumab is priced at $482000 a year for the first year and $448000 a year for subsequent years. (source) Financial assistance is available according to the Hemlibra website.
Even more exciting though, has been the success of gene therapy in seven men with severe hemophilia A who were given a single intravenous dose of adeno-associated virus serotype 5 vector encoding a B-domain deleted human factor VIII. Two other patients who received the same therapy at lower doses had Factor VIII levels at 3IU/dL or less. In the seven patients who received a high dose, factor VIII activity levels exceeded 5IU/dL 2-9 weeks after gene transfer and in six patients, the level exceeded 50IU/dL and was maintained at 1 year. Annualised bleeding rate among participants who had received prophylactic therapy declined from 16 to 1 and by week 22 after gene transfer, factor VIII use for reported bleeding ceased in all participants. The primary adverse event was an elevation in liver enzymes to 1.5 times the upper limit of normal or less. (Rangarajan et al. NEJM;2017:377(26):2519-2530). Phase 3 trials are eagerly awaited.
A similar success was reported in the same month by another group for Hemophilia B (Miesbach et al. Blood 2017;epub-2017-09-804419). Using the same adeno-associated virus 5 (AAV5) vector, with a liver-specific promotor driving expression of a codon-optimized human factor IX gene, a single dose of 5 x 10∧12 and 2 x 10∧13 copies/kg were each administered to five adults with hemophilia B whose factor IX activity levels were 2% or less and had severe bleeding phenotype. Factor IX level rose to 4.4 IU/dL in the low dose cohort and 6.9IU/dL in the higher dose cohort. Annualized spontaneous bleeding rate decreased from 9.8 to 4.6 in the low dose cohort and from 3.0 to 0.9 in the higher dose cohort. There was no reduction in traumatic bleeds. Factor IX prophylaxis was stopped in eight of nine patients who were receiving prophylaxis at time of study entry. Alanine aminotransferase was elevated in three patients, which were asymptomatic, limited and transient and were treated with prednisolone. In another report, (George et al. NEJM 2017;377(23):2215-2227), a single dose of AAV vector with liver-specific promotor and factor IX-Padua transgene at a dose of 5 x 10∧11/kg body weight was infused into ten men with hemophilia B with factor IX activity levels less than or equal to 2%. They were followed for for 28 to 78 weeks. Mean steady-state factor IX activity was 33.7 +/- 18.5% and annualized bleeding rate was reduced from 11.1 before vector administration to 0.4 after vector administration. Factor IX use declined from 2908 iu/kg to 49.3 IU/kg (p< 0.004). 8 patients did not use factor and 9 did not have bleeds after vector administration. An asymptomatic liver-enzyme elevation was noted in two patients and resolved with short term prednisolone treatment. This study is notable for using the Factor IX Padua variant which is a gain-of-function mutation associated with thrombophilia, with individuals carrying the mutation demonstrating 5-10 times the normal factor IX activity.
Thus, in the last three months, significant steps forward have been recorded for patients with hemophilia A and B. For patients with severe hemophilia A with inhibitors who hitherto have had no other options apart from treatment or prophylaxis with expensive bypassing agents, they now have emicizumab, which is more effective and cheaper. For all patients with hemophilia A and B, gene therapy effecting a one-time cure is coming closer to reality.