New Treatment Strategies for Prophylaxis in Severe Hemophilia: Moving from Clinical Trials into Real World Practice

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 7th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD)

Brussels, Belgium / February 26-28, 2014

Brussels - The focus of care in hemophilia A and B has shifted from the management of acute bleeding episodes (on-demand therapy) toward prophylaxis to prevent bleeding episodes and disease sequelae. Currently, hemophilia A patients administer rFVIII 3-4 times per week, and hemophilia B patients use rFIX 2-3 times per week in order to maintain circulating FVIII and FIX above 1% of normal level (1 IU/dL), a level considered protective against most spontaneous bleeding episodes.  However, due to their half-life (8-12 h for rFVIII and 18-24 h for rFIX), current therapies are still limited in a number of ways. Strategies have been applied to extend the plasma half-life of these coagulation factors, and several of these new products are in late stage development and expected to start becoming available for widespread use in 2014. New safety and efficacy data on some of these products were presented, with discussions about the changes in approaches to treatment that these therapies will require in clinical practice.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

At the Congress, major topics of discussion included safety of currently available clotting factors, the implications of using new longer-lasting clotting factor therapies expected to become available soon, and the possibility of personalized therapy rather than weight-based prophylaxis. It was noted by the presenters that new long-acting factors may have the potential to increase the adoption of prophylaxis, improve adherence, and improve clinical outcomes, but require a full understanding of the pharmacokinetics and new dosing options.

Extended Half-life

Extending the half-life of rFVIII and rFIX has been the major focus of current efforts to improve therapy. One of the leading approaches to long acting clotting factor therapies for hemophilia A and B have been developed by fusion with another protein with a much longer half-life, the fragment crystallizable (Fc) region of immunoglobulin G. The efficacy and safety of rFVIIIFc and rFIXFc have been demonstrated in two Phase 3 clinical trials in previously treated patients (PTPs) with severe hemophilia A and B, respectively:  A-LONG (Mahlangu J et al. Blood 2014;123:317-25) and B-LONG (Powell JS et al. N Engl J Med 2013;369:2313-23). In A-LONG, rFVIIIFc was used
1 to 2 times per week and in B-LONG, rFIXFc was dosed every 1-2 weeks. No subject in either trial developed inhibitors, and annualized bleeding rates (ARBs) were low in both trials. New results were presented from both the A-LONG and B-LONG trials providing additional insight into the prophylactic dosing regimens, including patients who switch from currently available FVIII and FIX products, and the safety and effective maintenance of hemostasis in patients undergoing surgery.

Minimum Therapeutic Threshold

The importance of a minimum therapeutic threshold of 1 IU/dL (1%) for prophylactic rFVIIIFc and FIX were confirmed in 2 post hoc analyses of data from A-LONG and B-LONG, respectively. In A-LONG, people assigned to prophylactic dosing with rFVIIIFc spent a shorter duration of time under the 1 IU/dL trough level compared with subjects on episodic treatment, reported Prof. A John Pasi (Barts and the London School of Medicine and Dentistry, Queen Mary University of London [QMUL], UK). Significant associations were observed between increased time spent under target therapeutic FVIII activity level (1, 3, or 5 IU/dL) and increased overall, spontaneous, traumatic, and joint bleeding tendencies (P≤0.0003). In B-LONG, the majority of subjects on prophylaxis did not spend any time under 1 IU/dL during the trial (Abstract PO113). There were significant increases in overall ABR of 0.5%, 0.3%, and 0.2% for every additional day spent under the target trough levels of 1, 3, 5 IU/dL (P<0.05). These were the first reports to demonstrate a relationship between bleeding tendency and time spent under 3 different factor activity levels in subjects with hemophilia A or B, the investigators noted.

Switching Regimens

Patients switching from their current regimens to prophylaxis with rFVIIIFc or rFIXFc can achieve lower bleeding rates and better protection with an extended dosing interval, the trial investigators reported. In addition, rather than performing extensive individual pharmacokinetic (PK) analyses, clinicians can use information about patients’ current regimens to guide empiric conversion to rFVIIIFc treatment, suggested Prof. Johnannes Oldenburg (Institut für Experimentelle Hämatologie und Transfusionsmedizin, Universitätsklinikum Bonn, Germany) (Abstract PO076). In A-LONG, 79 out of 80 subjects previously on prophylaxis with rFVIII at 3 infusions per week were able to reduce their dosing frequency with individualized prophylaxis. Among the 37 subjects on the 50 IU/kg dose, the most frequent dosing intervals were every 5 days (51%) or every 3 days (43%). A-LONG subjects in the prior prophylaxis/individualised subgroup reported a median of 6.0 bleeding episodes during the   12 months prior to the study compared with a median ABR of 0.0 during the last 3 months on study (P<0.0001); this lower on-study ABR persisted when these subjects were stratified according to their final on-study rFVIIIFc dosing interval, indicating that “empiric conversion to rFVIIIFc can succeed in maintaining low bleeding rates with an extended dosing interval compared with patients’ current regimens, using a comparable amount of replacement factor,” the investigators said.

Population PK modeling and simulations based on A-LONG and Phase 1/2 data confirmed that 50 IU/kg administered every 3-5 days is a “rational and effective prophylaxis for patients with severe hemophilia A.” In the B-LONG study, subjects who switched to a prophylaxis regimen with rFIXFc extended their dosing interval to 1-2 weeks and reduced overall FIX consumption while maintaining protection from bleeding without an increased risk of bleeding or inhibitors. Further, Prof. Claude Négrier (Hopital Edouard Herriot, Lyon, France) and co-investigators reported that nearly all subjects on weekly prophylaxis were treated on-study with less frequent dosing and 50% lower total weekly consumption of FIX than their prophylaxis regimen prior to the study. Patients on individualized interval prophylaxis had approximately 30% lower total weekly consumption of FIX and an increase in dosing interval compared with their reported pre-study FIX usage. Simulations from population PK models based on both Phase 1 and Phase 3 trial data showed a consistently greater percentage of subjects at above a trough FIX level of 1% with rFIXFc compared with rFIX.

Maintenance of Hemostasis During Surgery

Data supporting the safety and efficacy of rFVIIIFc and rFIXFc for surgical hemostasis in patients with severe hemophilia were presented by Dr. Robert Klamroth (Vivantes–Klinikum im Friedrichshain, Berlin, Germany) (Abstract PO101). A total of 23 surgeries, mostly orthopedic (17), were carried out in 9 patients in A-LONG and 12 in B-LONG, with outcomes rated as excellent (21) or good (1 in each study). Factor consumption was lower than observed historically with other factor replacement therapies, ranging from 184.4-1067.8 IU/kg (A-LONG) and 174.8-1349.2 IU/kg (B-LONG) on Days 0-14 of surgery/rehabilitation. Intra- and postoperative blood loss was comparable to that expected with similar surgeries in patients without hemophilia, ranging from 0-1600 mL (A-LONG) and 0–800 mL (B-LONG). Dr. Klamroth pointed out one patient, a 29-year-old man enrolled in A-LONG who underwent laparoscopic right inguinal hernia repair. The preoperative loading dose was 50.0 IU/kg and intra- and postoperative blood loss were ~2 and 0 mL, respectively. Total consumption on Days 0-14 of surgery/rehabilitation was 184.4 IU/kg and hemostasis was rated as excellent. “Normally you have to inject with continuous infusion or you have to inject at the beginning 3 times a day for the first 2 days. In this case there were 2 injections on the day of surgery and then 1 injection per day to cover FVIII level for surgery,” he recounted. “So the prolonged half-life of rFVIIIFc made it very easy to do the surgery in this patient.”

Future Options and Challenges

“The promise of individualized therapy for hemophilia can be realized with new products, giving us the opportunity to rethink how we approach treatment,” Prof. Pasi declared. “Some important implications of the new longer-acting generation FVIII and FIX products need to be borne in mind,” he stressed. “We will see higher levels for longer intervals, but we will also see lower levels for longer periods, because of the shape of the decay curves, and there will be longer durations above target trough level. This will have implications, particularly for very active individuals, because if they are infusing less frequently, they are going to have far fewer peaks following infusions,” he noted. “We should start to think about relevant peaks and troughs for the individual, rather than solely the trough levels, as we have in the past.”

Dr. Dan Hart (Barts and The London School of Medicine, QMUL. UK) noted that, “In A-LONG, 81.4% of patients on individualized prophylaxis required 0 or 1 dose adjustment, meaning that about 1 in 5 needed 2 or more dose adjustments. This may be a culture change for centres and patients if they are not already used to PK studies/dose optimizing.” Addressing concerns about the resources and time involved in PK analysis, he suggested using simplified population-based approaches. “That sort of data can help empirically move patients over without the necessity for PK analysis at an individual level in everyone,” he stated. “We need to move away from fixed outcome-based thinking and use opportunities to individualize dosing to optimize therapy.” Doctors, nurses, and on-call teams must familiarize themselves with trial data and be able to counsel patients on their treatment choices. Patients themselves will need to be educated or re-educated about the options, with PTPs being more likely to resist changing treatment and/or dosing, he suggested.  

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