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Weekly prophylaxis with nonacog beta pegol safe, effective for hemophilia B

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October 31, 2014

Nonacog beta pegol effectively treated bleeding episodes and was associated with low annualized bleeding rates in patients with hemophilia B, according to study results.

Peter W. Collins, MD, of the Arthur Bloom Hemophilia Center at Cardiff University in the United Kingdom, and colleagues sought to evaluate the safety and efficacy of nonacog beta pegol (N9-GP, Novo Nordisk) — a recombinant glycoPEGylated Factor IX with an extended half-life — in 74 previously treated patients with hemophilia B.

Thirty patients received with 10 IU/kg weekly for 52 weeks, and 29 patients received 40 IU/kg weekly for 52 weeks. The other 15 patients received on-demand treatment for 28 weeks.

The mean number of exposure days was 54 days in the weekly prophylaxis arms and 14 days in the on-demand arm.

Fifty-five patients (74%) experienced a combined 345 bleeding episodes; of these, 202 occurred in the weekly prophylaxis arms and 143 occurred in the on-demand treatment arm. Most bleeding episodes (78.5%) occurred in joints. Researchers classified 65.8% episodes as spontaneous and 33.6% as traumatic.

Researchers calculated a 92.2% (95% CI, 86.9-95.4) success rate for treating bleeding episodes. A greater proportion of bleeding episodes resolved after one injection of nonacog beta pegol in the 40 IU/kg arm (98.6%) than in the 10 IU/kg arm (84.1%) and the on-demand treatment arm (83.9%).

Fifty-two percent of patients in the 40 IU/kg arm did not require treatment for any bleeding episodes, compared with 17% of patients in the 10 IU/kg arm and 7% of patients in the on-demand arm. The median annualized bleeding rate also was lower in the 40 IU/kg arm (1.04; interquartile range [IQR], 0-4) than in the 10 IU/kg arm (2.93; IQR, 0.99-6.02) and the on-demand arm (15.58; IQR, 9.56-26.47).

Researchers used the EuroQOL-5 Dimensions visual analogue scale to assess health-related quality of life in each study arm. Patients in the 40 IU/kg arm experienced the greatest improvements in quality of life, from a median score of 75 (range, 35-100) at baseline to 90 (range, 60-100) at the end of the trial.

Sixty patients (81%) experienced a combined 215 adverse events. The most commonly reported adverse events were nasopharyngitis (13.5%), influenza (10.8%) and upper respiratory tract infection (10.8%).

No patients developed an inhibitor, and researchers reported no deaths, thromboembolic events or allergic reactions related to treatment.

“Nonacog beta pegol was effective for the treatment of bleeding episodes in both prophylaxis and on-demand patients,” Collins and colleagues wrote. “Low bleeding rates were observed in patients on prophylaxis and are likely related to high trough levels due to the extended half-life of nonacog beta pegol. These data suggest that once-weekly prophylaxis with nonacog beta pegol may provide a new and safe alternative for the prevention and treatment of bleeding episodes in patients with hemophilia B.”

Disclosure: The study was funded in part by Novo Nordisk A/S. The researchers report honoraria and research funding from, advisory/consultant roles with and employment with Baxter, Bayer, Biogen Idec, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Sanquin and Swedish Orphan Biovitrum.

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PERSPECTIVE
Katherine A. High

Katherine A. High

This article reports the results of a multinational trial of Novo Nordisk’s extended half-life product for Factor IX, recombinant glycoPEGylated Factor IX. Among 74 patients with severe hemophilia B — identified from 39 sites in 13 countries, an impressive effort — 15 elected to receive on-demand therapy, whereas 59 others were randomly assigned to receive either 40 U/kg weekly or 10 U/kg weekly in a prophylactic regimen. The annualized bleeding rates in the groups on prophylaxis were markedly low (1.04 and 2.93, respectively) compared with those on demand (15.58), and bleeds that did occur were successfully managed by factor infusion.
Previous pharmacokinetic studies had established that this product has a half-life in the range of 107 to 111 hours, even longer than the half-life of the Biogen Idec extended half-life product. The difference in study designs for the pivotal trials makes direct comparison of the two products very difficult. Nonetheless, an interesting finding from the current study is that — despite high trough levels (27% and 8.5% on average in the two prophylaxis groups) — bleeds were not completely eradicated. The authors considered several explanations, including the presence of hemophilic arthropathy, with the damaged joint at greater risk for bleeding, and misdiagnosis (ie, both the patient and the physician mistaking hemophilic arthropathy pain for a joint bleed). Reports of resolution of pain with factor infusion would seem to refute this argument.
Another potential explanation is that patients become more active in the setting of higher factor levels and are pushing activity limits beyond their norms. Another possibility, of course, is that the in vitro activity levels measured in the coagulation laboratory do not entirely reflect activity in vivo for these novel molecules. Additional clinical experience with the product will help to answer this question.

Katherine A. High, MD
HemOnc Today Editorial Board member
Spark Therapeutics
The Children’s Hospital of Philadelphia

Disclosure: High reports no relevant financial disclosures.