Researchers have reported positive results from trials of patients with hemophilia A and B, including patients who are more difficult to treat. These trials were presented at the 16th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD).
Results from the phase 3 HOPE-B trial showed that the gene therapy etranacogene dezaparvovec can increase factor IX (FIX) activity levels and reduce bleeds in patients with hemophilia B, even in the presence of adeno-associated virus 5 (AAV5) neutralizing antibodies (NAbs).1
The phase 3b/4 FEIBA STAR trial showed that patients with hemophilia A and inhibitors can safely receive activated prothrombin complex concentrate (aPCC) at a 50% reduced volume and faster infusion rate.2
Patient-reported outcomes from the phase 3 explorer7 study showed that concizumab was the preferred option for preventing bleeding episodes among patients who have hemophilia A or B with inhibitors.3
And results from the CHESS II study suggest that personalized treatment can help patients with hemophilia A be more active while maintaining bleeding protection.4
HOPE-B: Gene Therapy Appears Effective Regardless of NAbs
In the phase 3 HOPE-B trial (ClinicalTrials.gov Identifier: NCT03569891), researchers compared etranacogene dezaparvovec with FIX prophylaxis in patients with moderately severe hemophilia B, with or without AAV5 NAbs.1
The study included 54 adult men, 33 of whom were AAV5 NAb-negative at baseline and 21 of whom were AAV5 NAb-positive.
Before receiving gene therapy, the patients received FIX prophylaxis for a lead-in period of least 6 months. They then received a single infusion of etranacogene dezaparvovec. There was 1 patient who had a high baseline AAV5 NAb titer (1:3212), did not express FIX Padua, and continued to receive FIX prophylaxis.
The researchers compared annualized bleeding rates (ABRs), FIX activity, and FIX infusions during the lead-in period and at 6-month intervals during the follow-up period.
In the entire cohort, there was a 64% reduction in ABR after gene therapy. The adjusted ABR was 4.18 during the lead-in period, 1.51 at months 7-18 post-treatment (rate ratio [RR], 0.36; 95% CI, 0.20-0.64; P =.0002), and 1.51 at months 7-24 post-treatment (RR, 0.36; 95% CI, 0.21-0.63; P =.0002).
There was a 79% reduction in ABR for patients who were AAV5 NAb-negative (P <.0001) and a 62% reduction in ABR for patients who were NAb-positive but had titers of less than 700 (P =.0065).
The researchers noted that median FIX activity levels were sustained throughout the follow-up period. There was no significant correlation between a patient’s baseline AAV5 NAb titer level and FIX activity level, as long as the NAb titers were below 700.
The researchers concluded that a single dose of etranacogene dezaparvovec can increase FIX activity levels, reduce bleeds, and provide freedom from FIX prophylaxis, even in patients with AAV5 NAb-positive hemophilia B.
Data on FIX prophylaxis use after gene therapy were not presented at the meeting but were recently published in The New England Journal of Medicine.5 According to that report, 15 patients received a total of 134 FIX infusions during months 7-18 after gene therapy. The annualized FIX infusion rate per patient decreased from 72.5 infusions during the lead-in period to 2.5 infusions after treatment (P <.001).
FEIBA STAR: Reduced Volume, Faster Infusion of aPCC Well Tolerated
In the phase 3b/4 FEIBA STAR study (ClinicalTrials.gov Identifier: NCT02764489), researchers evaluated the safety and tolerability of aPCC given at a reduced volume and various infusion rates in patients with hemophilia A with inhibitors.2
The study enrolled 33 adult men. Most (87.9%) had severe hemophilia A, and 12.1% had moderate hemophilia A. They had a mean 8.5 bleeding events per year (range, 0-40).
In part 1 of this study, patients were randomly assigned to receive 3 infusions of aPCC (85 ± 15 U/kg), given at 2 U/kg/min, at the regular volume or a 50% reduced volume. Patients then crossed over to receive 3 infusions of the alternate treatment (regular or reduced volume).
In part 2, patients who had no safety issues in part 1 received 3 sequential infusions of aPCC in a 50% reduced volume infused at 4 U/kg/min. If there were no safety issues with this approach, patients received 3 infusions at the reduced volume infused at 10 U/kg/min.
All 33 patients received the regular volume at 2 U/kg/min, 30 received the reduced volume at 2 U/kg/min or 4 U/kg/min, and 28 received the reduced volume at 10 U/kg/min.
There were 15 treatment-emergent adverse events (TEAEs) overall (45.5%). The rate of TEAEs was 24.2% when patients received the regular volume at 2 U/kg/min, 23.3% when they received the 50% reduced volume at 2 U/kg/min, 3.3% when they received the reduced volume at 4 U/kg/min, and 14.3% when they received the reduced volume at 10 U/kg/min.
Most TEAEs were mild or moderate in severity, and there were no thromboembolic TEAEs. There were 2 serious TEAEs considered related to aPCC, and both were observed when patients received the regular volume at 2 U/kg/min.
The researchers concluded that these data support the potential use of aPCC at a 50% reduced volume and faster infusion rate to help reduce treatment burden.