Reports

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 - 64th Annual Meeting of the National Hemophilia Foundation

Orlando, Florida / November 8-10, 2012

Orlando - Conservative therapy in the management of joint and muscle bleeding in patients with hemophilia has consisted primarily of interventions known collectively as RICE: rest, ice, compression and elevation. A critical assessment of available evidence has suggested that some components of RICE have little objective support. While factor replacement therapies are mainstay for hemophilia A and B, available agents are limited by their short half-life and require multiple injections on a weekly basis to maintain protective levels of the deficient clotting factor. The evolution of fusion protein technology created the potential to develop longer-lasting agents. Clinical experience with recombinant factor VIII fusion protein and recombinant factor IX fusion protein has confirmed the long-lasting clotting activity of the products, which offer the potential for improved quality of life for patients with no loss of clinical effectiveness.

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

Joint and muscle bleeding is a common occurrence among individuals with severe hemophilia A, noted Dr. Leonard Valentino, Rush University Medical Center, Chicago.

The primary goal of therapy is to prevent bleeding episodes from causing synovitis and arthropathy and to promote healing. Secondary objectives are to control pain, restore range of motion, increase strength, prevent recurrence and promote overall joint health.

“We know that factor therapy is good, but we really don’t know whether each component of RICE (rest, ice, compression and elevation) is helpful in achieving the goals of treatment,” remarked Dr. Valentino.

According to James Munn, RN, University of Michigan, Ann Arbor, rest permits less blood accumulation at the site of injury, less stress and demand on injured tissue and less disruption of the healing process. It may also interfere with healing processes, notably waste products accumulating at the injury site. Long-term inactivity can cause muscle atrophy and wasting leading to joint instability and susceptibility to reinjury, noting that evidence-based literature on the benefits of rest in hemophilia is nonexistent.

Similarly, evidence to support of ice among patients with hemophilia is scant and are taken from areas, such as trauma and sports medicine noted, Ms. Angela Forsyth, Rush University Medical Center.

Some studies have shown that applying ice can increase bleeding time, prolong clot formation, decrease factor activity, and decrease platelet aggregation and adhesion. Whether it is the same in hemophilia remains unclear.

Compression helps reduce bleeding and swelling by minimizing capillary leakage into interstitial tissue and intra-articular spaces, explained Mr. Munn. However, compression also carries the potential for counterproductive effects in patients with hemophilia.

Elevation reduces blood pressure at the site of injury and increases lymphatic drainage of proinflammatory cytokines, 2 effects believed to be beneficial to the healing process. However, objective evidence to support the use of elevation is virtually nonexistent, said Mr. Munn.

Increased Half-life

For hemophilia A and B, factor replacement agents are the mainstay of therapy but are limited by a short half-life. As a consequence, patients require multiple injections weekly to maintain protective levels of the deficient clotting factor. Whereas various longer-acting factor agents are being researched, only 2 treatment regimens were presented at the NHF congress.

Fusion protein technology applied to factor-replacement therapy has increased their half-life. Clinical experience with recombinant factor VIII fusion protein (rFVIIIFc) and recombinant factor IX fusion protein (rFIXFc) has confirmed a longer-lasting clotting activity with no loss of clinical effectiveness and improved quality of life.

rFVIIIFc Evaluation

These results provided impetus for the open-label multicentre phase III A-LONG trial in previously treated severe hemophilia A patients. Trial design was described in a poster at the meeting.

It comprised of 3 rFVIIIFc treatment arms: individualized prophylaxis (n=118), weekly prophylaxis (n=24) and episodic (on-demand) treatment (n=23). Each arm included a subgroup of patients requiring major surgery and rFVIIIFc was evaluated in the perioperative management of those patients. The primary outcomes were safety, tolerability and efficacy of rFVIIIFc.

Preliminary results as shown herein were released publicly prior to the congress. Consistent with early clinical experience, rFVIIIFc was well tolerated and no patient developed anaphylaxis or inhibitors to rFVIIIFc. Excluding the surgical patients, the most common AEs (≥5%) were nasopharyngitis, arthralgia, headache and upper respiratory tract infection.

Median annualized bleeding rates (ABRs) were 1.6 and 3.6 with individualized and weekly prophylaxis, and 33.6 with episodic treatment. In 98% of cases, bleeding episodes were controlled by 1 or 2 injections of rFVIIIFc. Among patients who received individualized prophylaxis, the median dosing interval was 3.5 days and during the last 3 months of the study, 30% had a mean dosing interval of 5 days.

According to Dr. Pasi and colleagues, Fc fusion is a proven technology that extends the activity of therapeutic agents through the naturally occurring FcRn recycling process that protects proteins from catabolism. The prolonged half-life of rFVIIIFc has the potential to improve overall health outcomes and patient quality of life by reducing dosing frequency and the burden of treatment.

rFIXFc for Hemophilia B

Another poster by Luk et al. described the design of a phase I/IIa trial in patients with severe, previously treated hemophilia B. It  evaluated 6 doses of rFIXFc ranging from 1 to 100 IU/kg.

Here too, preliminary results were made public prior to the NHF congress. Compared with conventional FIX, the fusion-protein product demonstrated a threefold increase in half-life and mean residence time and a 2.5-fold reduced clearance rate. No serious drug-related AEs occurred and only 1 case of dysgeusia and 1 of headache. No evidence of inhibitor development—anti-FIXFc antibodies or anaphylaxis—was found.

In proceeding to phase III clinical evaluation, 123 severe hemophilia B patients aged ≥12 years were enrolled. The trial consisted of 4 treatment arms: weekly prophylaxis (n=63), individualized prophylaxis (n=29), episodic treatment (n=27) and perioperative management (n=12, 14 surgeries).

Primary outcome measures were safety, tolerability of rFIXFc and the number of ABRs (excluding surgical patients). The most frequent AEs were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension and headache. One possibly drug-related serious AE (obstructive uropathy associated with hematuria, resolved without discontinuing treatment) was observed.

ABRs were 2.95 and 1.38 with weekly and individualized prophylaxis, and 17.69 with episodic treatment. In the individualized prophylaxis group, the median dosing interval during the last 6 months on study was 14 days. More than 90% of bleeding episodes were controlled by a single injection of rFIXFc.

In the subgroup of surgical patients, the hemostatic efficacy of rFIXFc was judged as good or excellent in all cases.

The prolonged half-life of rFIXFc may reduce the required dosing frequency, provide prolonged protection and reduce the ABR of patients with severe hemophilia B, investigators concluded. These advancements have the potential to reduce treatment burden and positively impact patient compliance and health outcomes.

Burden and Challenges

According to a pharmacokinetic study, dosing based on ideal body weight might reduce the amount of factor administered without increasing a patient’s risk of bleeding. All patients dosed according to ideal body weight instead of actual weight who completed the study had peak factor levels and half-life within the expected range, reported Ms. Kristen Jaworski, Hemophilia Center of Western Pennsylvania, Pittsburgh.

The study evolved from the recognition of the ongoing obesity epidemic and its potential implications for managing hemophilia. The standard approach to factor dosing is to use actual body weight. However, the influence of obesity on drug distribution is not well understood, remarked Ms. Jaworski. Dosing on the basis of ideal body weight or lean body mass might improve safety and reduce costs.

Ideal-body-weight dosing is 50 kg +2.3 kg/inch higher than 5 feet for males and 45.5 kg +2.3 kg/inch for females. Using that standard, 6 patients with hemophilia A were administered replacement factor. The patients’ age ranged between 25 and 47, body weight from 200 to 333 pounds, height from 67 to 75 inches, and body mass index from 30 to 48. They found factor VIII levels peaked within the normal range for all 6 patients.

To illustrate the difference between actual-weight and ideal-weight dosing, Ms. Jaworski described a case involving administration of FIX to a patient with hemophilia B and an actual body weight of 400 pounds. Using ideal body weight, dosing was based on 176 pounds. With actual-weight dosing, the FIX level peaked at 78% 30 minutes after dosing compared with 107% at 30 minutes when the same patient was dosed on the basis of ideal body weight plus 25%.

“From these results, our centre is recommending obese patients undergo a pharmacokinetic study based on ideal body weight,” investigators concluded. “Factor levels appear adequate with rFVIII dosing based on ideal body weight. Patients with >100% variance between actual body weight and ideal body weight may need a dose adjustment.” A larger multicentre trial is needed in order to generalize the findings and to have a potential change in clinical practice.