ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.
“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.
Dr. Johnny Mahlangu
Barriers to prophylaxis include “the need to inject the clotting factor concentrate at least two or three times a week, poor venous access, and, of course, poor adherence and compliance from our patients. Essentially, the extended half-life products were developed to mitigate these limitations,” he said.
Dr. Mahlangu and Guy Young, MD, a pediatric hematologist at Children’s Hospital Los Angeles, discussed results from published clinical trials of EHL products in children and adults.
The X factor
Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).
More recent products created through pegylation technology include recombinant FVIII products.
Factor IX EHL CFCs
The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.
In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:
• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days
• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days
• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.
All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.
Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.
There were no deaths from thromboembolic episodes and no drug-related serious adverse events.
Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.
Factor VIII EHL CFCs
Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.
In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.
Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.
All patients had at least 50 exposures to these products, and none have developed inhibitors to date.
Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.
In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.
Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.