CSL654 (Idelvion; albutrepenonacog alfa) is an approved recombinant human factor IX that is fused with recombinant human albumin, the main transport protein that binds water, ions, and hormones in the blood.
CSL654 was approved by the U.S. Food and Drug Administration (FDA) in 2016 for the treatment and prevention of bleeding in patients with hemophilia B. It is developed and marketed as Idelvion by CSL Behring. Because it was granted orphan drug status by the FDA, Idelvion has seven years of marketing exclusivity in the United States.
In Idelvion (CSL654), a blood clotting protein called factor IX is linked to albumin via a linker, which is cleaved off during the normal blood-clotting process releasing the active clotting factor.
Albumin fusion increases the half-life of factor IX since albumin binds to Fc receptors found on the surface of various cell types. This binding results in protection of the clotting factor from degradation, thereby increasing its half-life.
CSL654 is available as an injection (lyophilized powder) for intravenous use, containing 250 IU, 500 IU, 1,000 IU, or 2,000 IU of the drug in single-use vials. In routine prophylaxis or preventative treatment, the recommended dose is 25 to 40 IU per kg body weight for patients older than 12, or 40-55 IU/kg for patients younger than 12 every seven days.
The pharmacokinetics (the drug properties profile), efficacy, and safety of CSL654 were evaluated in a large clinical trial program called PROLONG-9FP that included Phase 1, Phase 2, and Phase 3 trials as well as a surgical study.
The Phase 1 trials (NCT01233440, NCT01361126) included 40 patients who were previously treated with standard factor IX without albumin-fusion. The mean half-life of albumin-conjugated factor IX after a single dose was 92-95 hours, greater than that of the unmodified factor IX.
A mutinational, open-label, non-randomized Phase 3 trial (NCT01496274) evaluated the pharmacokinetics, efficacy, and safety of CSL654 for the prevention as well as the treatment of bleeding episodes in 63 previously treated adults and adolescents (ages 12-61) with severe or moderately severe hemophilia (who had factor IX levels lower than 2 IU/dl).
The mean half-life of CSL654 was 102 hours, 4.3-fold longer than that of the unmodified factor IX. With 40 IU/kg of CSL654, factor levels reached 20 IU/dl. The median annualized bleed rate, or the number of bleeds a person experiences over the course of one year, was zero. A 100 percent resolution of target joints (particular joints with recurrent bleeding) was achieved. Overall, 94 percent of bleeding episodes were successfully treated with a single injection of CSL654. None of the patients developed inhibitors and there were no safety concerns.
A Phase 3 trial (NCT01662531) evaluated the pharmacokinetics, efficacy, and safety of Idelvion in 27 previously treated children ages 1-11 with severe and moderately severe hemophilia. The mean half-life of Idelvion was 91.4 hours, confirming the results of the pivotal trial. Around 89 percent of bleeds were successfully managed with one injection. No patient developed anti-factor IX inhibitors and no safety issues were observed.
Finally, the efficacy and safety of CSL654 was assessed in 21 surgical procedures performed in 19 patients. The fusion protein was well-tolerated and effectively maintained blood clotting activity during and after surgery. Stable factor IX was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available long-acting recombinant factor IX products.
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