One of the challenges in treating patients with hemophilia A is that when they receive the standard treatment for the disease — factor VIII replacement therapy — many develop neutralizing antibodies (inhibitors) that make factor therapy ineffective.
“Up to 30% or more of patients with severe hemophilia, when they start getting factor VIII for the first time, will develop antibodies against factor VIII, and these antibodies end up neutralizing the function of the factor VIII molecule,” Steven Pipe, MD, of the University of Michigan in Ann Arbor, told MedPage Today. “And these patients have a considerable disadvantage in their care – you can’t use factor VIII anymore, so you have to rely on alternative hemostatic agents, which are called bypassing agents.”
For these patients, the two options are recombinant activated factor VII (rFVIIa, Novoseven), or FEIBA (factor eight inhibitor bypassing activity). However, according to Pipe, while these agents are effective in treating bleeding, they are less effective as a prophylaxis strategy.
So for years, patients with inhibitors have had far inferior outcomes, he said, with more bleeding, more joint disease, and higher rates of hospitalization.
The only known solution to this problem had been immune tolerance induction (ITI) therapy, in which factor concentrate is given repeatedly over a period of time until the immune system is trained to recognize the treatment product without reacting to it. But this carries a heavy burden for patients and their families since it involves frequent injections of factor concentrate — often via a central venous catheter — and is very expensive.
Which means that alternative strategies to enhance blood clotting in hemophilia have been sorely needed.
Pipe explained that factor VIII acts “as a scaffold” to help bring factor IXa and X together on the platelet surface, enhancing the enzymatic function of factor IXa on factor X and helping to advance clotting.
Therefore, researchers began asking whether a substitute could be found that could mimic factor VIII. Emicizumab (Hemlibra) is a bispecific monoclonal antibody that does just that.
Developed by Japanese researchers, the agent was shown in an early study by Midori Shima, MD, PhD, and colleagues, to be particularly effective in treating patients with inhibitors. The participants in this study had annualized bleeding rates that decreased markedly, and eight of 11 patients with factor VIII inhibitors had no bleeding at all, the researchers reported.
Emicizumab’s efficacy was further demonstrated in the HAVEN 1 phase III trial, where 109 male hemophilia A patients with inhibitors were randomly assigned to either emicizumab prophylaxis, or no prophylaxis. The annualized bleeding rate was 2.9 events among participants in the emicizumab prophylaxis group compared with 23.3 events among those assigned to no prophylaxis — a difference of 87% in favor of emicizumab. Twenty-two patients of the participants in the emicizumab group (63%) had no bleeding events, compared with just one (6%) in the no-prophylaxis group.
HAVEN 2 examined the efficacy of emicizumab in children with hemophilia A with inhibitors and showed that once-weekly dosing was safe and effectively controlled bleeding.
“We were amazed,” said Pipe. “We’d never seen any kind of prophylactic treatment that provided this degree of protection for patients.”
These results led to FDA approval of emicizumab for both adult and pediatric hemophilia A patients with inhibitors.
“Once they got those results in the inhibitor population there was no reason why this monoclonal antibody substitute wouldn’t work effectively in non-inhibitor patients as well, and with a lower burden of administration this was a very attractive next step,” Pipe said.
And HAVEN 3 did, in fact, show that emicizumab performs well in this population when compared with no prophylaxis, as well as previous factor VIII prophylaxis, leading the FDA to extend its approval to the non-inhibitor hemophilia A population.
“Because [emicizumab] is a monoclonal antibody, it has other advantages,” said Pipe. “Antibodies have very good bioavailability, so you can give it subcutaneously, and it has an incredibly long half-life – about 30 days — compared to factor VIII, which has a half-life of 8 to 12 hours.”
Which means that unlike traditional hemophilia therapies, emicizumab may be administered much less frequently.
While HAVEN 3 involved dosing regimens of 1 and 2 weeks, HAVEN 4 examined emicizumab dosing every 4 weeks, and showed that a 4-week dosing schedule still provides clinically meaningful control of bleeding in patients with and without factor VIII inhibitors.
“Which is really a remarkable place to come to from the burden of treatment factor VIII,” said Pipe, whose center is involved in the HAVEN 4 trial. “The move to a therapy that is given subcutaneously every 4 weeks is just an incredible move forward in reducing the burden of care for this disease.”
With the efficacy shown by emicizumab, Pipe said that management of hemophilia A “is going through a pretty significant transition.”
According to Robert Sidonio, Jr., MD, MSc, of the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, emicizumab offers inhibitor patients “the only reasonable option to prevent bleeding events outside of immune tolerance.”
“The quality of life is much better considering the weekly/biweekly/monthly subcutaneous injections, compared to daily [factor VIII] injections and bypassing agent prophylaxis at least 3 times a week,” Sidonio told MedPage Today. “And parents appreciate the lack of a need of a central line.”
As for non-inhibitor patients, a major benefit of emicizumab is the easier route of administration, with at least similar to superior bleeding control in the majority of patients, Sidonio said. “It has been particularly helpful in my experience with those patients with poor IV access, or short [factor VIII] half-life, or worse than expected bleeding phenotype.”
“If you ask the patients, it is clear that there is an improved quality of life,” he continued. “You see it in many forms such as less distress and constant worry about life-threatening bleeding events. The parents tell us the route of administration alone is a significant improvement. They don’t need to wake up early to infuse their children before school and before sporting events.”
Despite the efficacy shown by emicizumab, is there an argument to be made to continue recommending immune tolerance induction therapy in inhibitor patients?
“This is a bit controversial and an area that warrants significantly more research,” said Sidonio. “There are a few of my colleagues that have advocated ITI in inhibitor patients prior to starting emicizumab. Although emicizumab prevents bleeds and offers great protection against bleeding it does not eradicate inhibitors as ITI does.”
Sidonio noted that last year that he and several colleagues began piloting a program in which inhibitor patients would start emicizumab, and following the loading doses start a modified version of factor VIII ITI (100 units/kg/dose 3 times a week).
“It is early, but we are seeing success and have achieved complete tolerance in some patients with no increase in bleeding or clotting events or thrombotic microangiopathy,” Sidonio said, adding that he and his colleagues have received funding for further study.
Pipe reported financial relationships with Bayer HealthCare Pharmaceuticals, BioMarin Pharmaceutical Inc., Bioverativ, CSL Behring, Novo Nordisk, Pfizer Inc., Roche, Spark, Shire, and uniQure NV.
Sidonio reported financial relationships with Shire, Bioverativ, Grifols, CSL Behring, Bioverativ, Novo Nordisk, and Bayer.