Patients with hemophilia A and B may benefit from the less-frequent dosing regimens of two recently FDA-approved fusion protein therapies: recombinant coagulation factor VIII (FVIII) Fc fusion protein for hemophilia A and recombinant coagulation factor IX (FIX) Fc fusion protein for hemophilia B.
“This is truly an exciting time in clot factor management,” said Margaret Ragni, MD, MPH, who discussed the safety, efficacy, and clinical implications of these new therapies during a Special Education Session on drugs newly approved by the U.S. Food and Drug Administration, at the 56th ASH Annual Meeting. “They represent what may be a paradigm shift in treatment because there is the potential for fewer infusions with longer protection from bleeds, improved quality of life, and possibly reduced immunogenicity.”
However, there are lingering questions about the appropriate use of these recently approved agents, Dr. Ragni noted, such as: “Will it be necessary to perform pK assessments on each patient? Will children require more frequent dosing than adults? Will each protein require different laboratory monitoring?”
Three presentations at the annual meeting provided more information about optimizing the use of these newer, longer-lasting clotting factor proteins in hemophilic patients.
Predicting Factor Activity in A-LONG and B-LONG
Currently, there are few data on clotting factor activity levels and efficacy in hemophilic patients on routine prophylaxis who received rcFVIIIFc and rcFIXFc for treatment of bleeding episodes. At the annual meeting, two analyses looked at the effect of these drugs in patients receiving routine prophylaxis:
- rFVIIIFc in previously treated patients with severe hemophilia A in the A-LONG trial
- rFIXFc in previously treated patients with hemophilia B in the B-LONG trial
In A-LONG, patients were treated with either 50 IU/kg of rFVIIIFc every 4 days or 50 IU/kg every 3 days (Arm 1) or weekly prophylaxis (Arm 2); in B-LONG, patients were treated with weekly prophylaxis (Arm 1) of rFIXFc or individualized interval prophylaxis (Arm 2).
Number of bleeding episodes, annualized bleeding rates, median dose per infusion, and the percentage of bleeding episodes resolved with one infusion were reported. Both agents were well-tolerated, with no observed vascular thrombotic events.
Using a pharmacokinetic modeling approach, investigators predicted factor VIII and IX activity levels in scenarios in which bleeding episodes were treated in close proximity to a scheduled prophylactic dose. In both the A-LONG and B-LONG trials, predicted factor activity levels were within the normal range for the majority of patients, even among patients on prophylactic regimens with short intervals (TABLE).
rFVIIIFc in Children with Severe Hemophilia A
As Dr. Ragni mentioned in her discussion of rFVIIIFc, prophylactic treatment of hemophilia A in pediatric patients is difficult. “In children, prophylaxis requires placement of ports that could be associated with infection and sepsis,” she noted, “so it is not standardly used in this population.”
In the global, multicenter, phase 3 Kids-ALONG trial, investigators evaluated the safety and efficacy of rFVIIIFc in previously treated young patients with severe hemophilia A.
Guy Young, MD, presented results from 71 patients (<6 years, n=36; 6 to <12 years, n=35) in the study who received twice-weekly prophylactic infusions of rFVIIIFc (25 IU/kg on day 1, 50 IU/kg on day 4). Dose and frequency were adjusted as needed.
As with adult and adolescent patients, the half-lives of rFVIIIFc in children was prolonged compared with FVIII:
- 67 hours (95% CI 11.23-14.11) in patients <6 years
- 88 hours (95% CI 11.98–17.77) in patients 6 to <12 years
Forty-six of 62 subjects (74%) who were on a prior prophylactic regimen were also able to reduce their dosing frequency and the amount of rFVIIIFc they received – the median average weekly prophylactic dose administered was 88.1 IU/kg. rFVIIIFc prophylaxis was well-tolerated and no subjects developed inhibitors.
Overall median on-study ABR was 1.96–1.50 in the <6 years cohort, and 2.50 in the 6 to <12 years cohort. As in the adult populations, most bleeding episodes (81.4%) were controlled with one infusion.
“Prophylaxis requires frequent infusions of FVIII, and children in particular require more frequent infusions,” Dr. Young said, mainly due to their shorter FVIII circulating half-lives. “Long-acting FVIII products may allow for prophylaxis with less frequent infusions.”
- Powell JS, Ozelo M, Ragni MV, et al. “Predicting FIX activity in prophylaxis in patients using recombinant FIX Fc fusion protein for treatment of bleeding episodes.” Abstract #2842. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.
- Quon DV, Mahlangu JN, Shapiro AD, et al. “Predicting FVIII activity in patients who use recombinant FVIII Fc fusion protein for prophylaxis and treatment of bleeding episodes.” Abstract #1522. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.
- Young G, Mahlangu JN, Kulkarni R, et al. “Safety, efficacy, and pharmacokinetics of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously-treated children with severe hemophilia A (Kids-ALONG).” Abstract #1494. Presented at the American Society of Hematology Annual Meeting, December 7, 2014.