Prophylactic treatment with emicizumab (Hemlibra) could soon replace the current standard treatment for hemophilia A patients without factor VIII inhibitors, and at a largely reduced treatment schedule, results of the manufacturer-sponsored HAVEN 3 and HAVEN 4 trials suggested.
The trials showed that emicizumab prevented or significantly reduced bleeds in these patients. Compared with no prophylaxis, emicizumab every week or 2 weeks yielded 96% and 97% reductions in bleeds requiring treatment (P<0.0001 for both), reported Michael Callaghan, MD, of Children’s Hospital of Michigan in Detroit, and colleagues.
In addition, bleeds were reduced by 68% among patients who previously received standard of care factor VIII prophylaxis (P<0.0001).
“In the long run, as long as there aren’t any unexpected safety events … I think this will be the standard of care,” Callaghan told MedPage Today.
Results of both trials were presented at the World Federation of Hemophilia’s World Congress in Glasgow.
During the study period, 55.6% of patients on the once-weekly emicizumab schedule (95% CI 38.1-72.1) and 60% of those on the every 2-week schedule (95% CI 42.1-76.1) experienced no bleeds. None of the patients randomized to no prophylaxis were free from bleeds.
Callaghan said he did not see many hurdles in terms of emicizumab becoming the preferred first-line therapy for hemophilia A. While the price of the drug is high, annual cost-effectiveness estimates place it lower than current factor VIII prophylaxis.
According to a report from the Institute for Clinical and Economic Review (ICER) based on patients with factor VIII inhibitors, the average wholesale price of emicizumab (Genentech) would be approximately $482,000 in the first year of treatment and $448,000 thereafter.
But in reducing bleeding events (about $50,000 per bleed), this would reduce medical costs each year by approximately $1.85 million per patient. Per-patient costs, accounting both for bleeds and prophylaxis, can range from $300,000 to $2.5 million per year, according to the ICER report.
“Hopefully there will be very good access, because they’ve priced it in line with the current treatments,” said Callaghan.
And in the clinic he said he imagined it would play out on a “patient-by-patient, doctor-by-doctor,” basis. “There are some patients who are on factor VIII prophylaxis who are doing well, and they may choose to take a wait-and-see approach,” he said. “On the other hand, there will be a lot of people who say, ‘This looks better, it’s easier, it looks very safe, it should be the first-line treatment — I’m going to put everybody on this.'”
As measured by the EmiPref questionnaire, 93.7% of respondents in HAVEN 3 said they preferred emicizumab over their prior therapy. And in HAVEN 4, which tested emicizumab every 4 weeks for hemophilia A patients with or without factor VIII inhibitors, 100% of patients said they preferred emicizumab.
Among the 41 evaluable patients in HAVEN 4, the annualized bleeding rate was 2.4 (95% CI 1.4-4.3) and 56% of patients experienced zero bleeds during the median 25.6-week study period, reported Steven Pipe, MD, of the University of Michigan in Ann Arbor, and colleagues.
“That we can now offer a subcutaneously administered therapy for hemophilia A, which provides excellent bleed control with once-per-month dosing is simply remarkable and an amazing advance for this community,” Pipe told MedPage Today.
Only about 20% of patients experienced more than one bleed in HAVEN 4, and fewer than 10% of patients experienced more than three bleeds.
The phase III HAVEN 3 trial randomized 152 patients, ages ≥12 years, to two dosing schedules of emicizumab or to no prophylaxis. Patients who previously received on-demand factor VIII were randomized to:
- Weekly emicizumab (3 mg/kg) for 4 weeks, then 1.5 mg/kg every week (n=36)
- Weekly emicizumab (3 mg/kg) for 4 weeks, then 3 mg/kg every 2 weeks (n=35)
- No prophylaxis (n=18)
Patients with prior factor VIII prophylaxis received weekly emicizumab (3 mg/kg) for 4 weeks, then 1.5 mg/kg every week (n=63).
Patients in the single-arm HAVEN 4 trial received weekly injections of emicizumab at a dose of 3 mg/kg for 4 weeks, followed by 6 mg/kg every 4 weeks after that, for at least 24 weeks.
The long half-life — almost 28 days — and high bioavailability of emicizumab allowed investigators to assess an every 4-week dosing schedule. Callaghan noted that weekly subcutaneous injections were already a “pretty big advance” over IV infusions of factor VIII prophylaxis, which are typically administered two or three times per week.
Emicizumab was well tolerated, with no unexpected or serious adverse events. Of note, there were no thrombotic events, which had previously been reported in an earlier study of the drug. The most common adverse events (≥5% of patients) were injection site reactions (25.3%), arthralgia (19%), nasopharyngitis (12%), headache (11%), and influenza (6%).
“The safety data came out as clean as they possibly could, which is reassuring,” said Callaghan.
Administered via subcutaneous injections, emicizumab is a first-in-class, bispecific humanized monoclonal antibody that bridges factors IX and X to restore the function of factor VIII.
In November 2017 the drug gained FDA approval, given in weekly injections, for adult and pediatric hemophilia A patients with factor VIII inhibitors. Those with factor VIII inhibitors comprise 5% to 7% of the broader hemophilia population, have the most morbidity and mortality, and had the greatest need for treatment options.
Data from HAVEN 3 and HAVEN 4 are being submitted for regulatory approval.
The trials were supported by Genentech/Roche.
Pipe disclosed multiple relevant relationships with industry including Bayer, Novo Nordisk, Pfizer, Roche, Shire, and uniQure.
Callaghan disclosed relevant relationships with Shire, Roche, Genentech, Bayer, Pfizer, Novo Nordisk, and Bioverativ.