Clinical Trials

Date: 2013-12-04

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: BiogenIdec (USA) Swedish Orphan Biovitrum SOBI (Sweden)

Product: Alprolix® (eftrenonacog alfa - long-lasting recombinant Factor IX Fc fusion protein (rFIXFc) - BIIB 029

Action mechanism:

fusion protein. Recombinant FIXFc is a clotting factor developed using Biogen Idec's novel and proprietary monomeric Fc fusion technology, which makes use of a natural pathway to recycle rFIXFc in circulation and enable it to remain in the body longer. With this technology, rFIXFc is designed to provide long-lasting protection from bleeding and reduce the treatment burden associated with hemophilia B, which currently requires more than 100 injections annually for prophylaxis with commercially-available Factor IX products.

Disease: hemophilia B

Therapeutic area: Hematologic diseases - Genetic diseases - Rare diseases

Country: International study

Trial details:

B-LONG was a global, open-label, multi-center Phase 3 study that evaluated the efficacy, safety and pharmacokinetics of intravenously-injected rFIXFc. The study was designed to evaluate rFIXFc in the control and prevention of bleeding, routine prophylaxis and perioperative management in patients with hemophilia B. B-LONG involved 50 hemophilia treatment centers in 17 countries on 6 continents, and is the largest registrational study conducted in hemophilia B. The B-LONG study had four treatment arms. - In Arm 1 (weekly prophylaxis; n=63), patients were treated weekly with a starting dose of 50 IU/kg, which was adjusted to maintain trough factor levels sufficient to prevent bleeding. - In Arm 2 (individualized interval prophylaxis; n=29), patients were treated with 100 IU/kg, at an initial interval of 10 days, which was subsequently individualized to maintain trough factor levels sufficient to prevent bleeding. - In Arm 3 (episodic treatment; n=27), patients received rFIXFc episodic treatment as needed for bleeding. -In Arm 4 (perioperative management; n=12 patients), rFIXFc was evaluated in the surgical setting; 8 patients in the surgery arm were also enrolled in other treatment arms. The primary efficacy and safety measures were the annualized bleeding rate and the incidence of adverse events and inhibitor development in patients studied for up to 77 weeks. Secondary endpoints included response to treatment of bleeding episodes and the pharmacokinetics of rFIXFc versus BeneFIX®. Ongoing clinical studies of rFIXFc include the Kids B-LONG and the B-YOND studies. Kids B-LONG is a Phase 3, open-label study in previously treated children with hemophilia B under age 12, which is actively recruiting patients. B-YOND is a long-term open-label extension study for patients who completed the B-LONG study or who complete the Kids B-LONG study.

Latest news:

• On December 4, 2013, Biogen Idec and Swedish Orphan Biovitrum have announced the publication of detailed results from the pivotal Phase 3 study of Alprolix®, the companies’ investigational long-lasting recombinant factor IX Fc fusion protein candidate for hemophilia B. The study appears in the Online First edition and will appear in the December 12 print issue of The New England Journal of Medicine (NEJM).
The study of Alprolix® showed that people with severe hemophilia B safely and effectively prevented or reduced bleeding episodes with prophylactic infusions every one to two weeks. The study, called B-LONG, is the largest Phase 3 clinical study in hemophilia B ever completed. It examined the effect of Alprolix® therapy delivered with multiple dosing regimens, including prophylactic (weekly or longer), episodic (on-demand) and surgical (perioperative management). Results of B-LONG formed the basis of regulatory applications for Alprolix® which are currently under review in several countries including the United States, Canada, Australia and Japan.
The overall median annualized bleeding rates (ABR), or projected rate of bleeding episodes per year, were 3.0 for weekly prophylaxis arm and 1.4 for individualized-interval prophylactic regimens, compared to 17.7 for the episodic therapy group. The median dosing interval with individualized-interval prophylaxis (arm 2) was 12.5 days. Bleeding episodes for participants in arms 1-3 were documented and more than 90 percent of all bleeding episodes were controlled by a single infusion of Alprolix®. Alprolix® was assessed in the perioperative management of 12 study participants undergoing 14 major surgical procedures. The treating physicians rated response to surgery of Alprolix® as “excellent” or “good” in 100 percent of these surgeries.
No participants in the study developed inhibitors to Alprolix® (antibodies that may interfere with the activity of the therapy). There were no reports of vascular clots or serious allergic reactions. Overall, safety events were consistent with those expected in the general hemophilia population. The most common adverse events (incidence of ?5 percent) occurring outside of the perioperative period were nasopharyngitis (common cold), influenza (flu), arthralgia (joint pain), upper respiratory infection, hypertension (high blood pressure) and headache. One participant had a single serious adverse event that was considered to be possibly related to treatment with Alprolix®. The participant, who had a history of hematuria (presence of blood in the urine), developed an obstructive clot in the urinary collecting system; he continued Alprolix® treatment and the event resolved with medical management.
* On July 2, 2013, Biogen Idec and Swedish Orphan Biovitrum have presented new findings for their long-lasting recombinant factor IX candidate Alprolix® for haemophilia B at the XXIV International Society on Thrombosis and Haemostasis (ISTH) Congress in Amsterdam. Three oral presentations showcase new data that reinforce the potential safety, efficacy and pharmacokinetic profile of the product candidate. The data highlight the consistency of results with Alprolix® across patient types and favourable physician ratings of its efficacy in treating acute bleeding episodes and controlling bleeding during and after major surgery.

Treatment of Bleeding: An evaluation of the treatment of acute bleeding episodes across the prophylaxis and episodic (on-demand) treatment arms of the phase 3 B-LONG study showed that more than 90% of bleeds were controlled with a single injection of Alprolix® and more than 97% were controlled with two or fewer injections. These data were showcased in the e-poster presentation:Treatment of Bleeding Episodes in Subjects with Haemophilia B with the Long-Lasting Recombinant Factor IX Fc Fusion Protein (rFIXFc) in the Phase 3 B-LONG Study

Surgery Analysis: Results from an analysis of the phase 3 B-LONG study showed that Alprolix® consistently controlled bleeding during and after 14 major surgeries in 12 patients with haemophilia B. Physicians reported high efficacy levels of Alprolix® during surgery, with haemostasis (the stoppage of bleeding) rated as "excellent" for 13/14 surgeries and "good" for 1/14 surgeries. According to investigator analyses, the results were comparable to that for similar surgeries in people without haemophilia. These data were showcased in the e-poster presentation: Long-Lasting Recombinant Factor IX Fc Fusion (rFIXFc) for Perioperative Management of Subjects with Haemophilia B in the Phase 3 B-LONG Study

Population Pharmacokinetics (PK) Analysis: Analysis of a population pharmacokinetics (popPK) model developed for Alprolix® demonstrated that the model accurately predicts peak and trough factor IX activity levels achieved in the B-LONG clinical study at a variety of Alprolix® doses. These data were showcased in the e-poster presentation: Clinical Implications of Population Pharmacokinetics of rFIXFc in Routine Prophylaxis, Control of Bleeding and Perioperative Management for Haemophilia B Patients

A Biologics License Application (BLA) for Biogen Idec's long-lasting haemophilia product candidate Alprolix® is currently under review with the FDA for the treatment of haemophilia B. Marketing Applications for Alprolix® have been submitted in Canada and Australia for the treatment of haemophilia B. Additional regulatory filings are planned.

• On February 8, 2013, Biogen Idec and Swedish Orphan Biovitrum have released data that confirmed the ability of investigational recombinant factor IX Fc fusion protein (rFIXFc) to provide long-lasting protection from bleeding with fewer injections than are required with the current standard of care for people with hemophilia. The data, from the largest phase 3 registrational studies conducted in hemophilia to date, were presented this week at the 6th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD).

The studies compared the pharmacokinetic activity of rFIXFc for hemophilia B to currently available treatments. In the study, the long-lasting candidate stayed active in the body longer, enabling study participants to prevent bleeding with less frequent injections than are required with the current standard of care. In the B-LONG study, rFIXFc allowed patients with hemophilia B to use prophylactic injections every one to two weeks with low bleeding rates.

The current standard of care for hemophilia B requires frequent injections, which are a burden for patients. Prophylactic treatment requires injections 2-3 times per week for the treatment of hemophilia B, according to the National Hemophilia Foundation's Medical and Scientific Advisory Council guidelines. People with severe hemophilia who do not follow a prophylactic injection schedule remain vulnerable to bleeding that can cause irreversible joint damage and life-threatening hemorrhages.

The B-LONG results presented at EAHAD confirm the long-lasting characteristics of rFIXFc; specifically, the data show that rFIXFc stays in the body for more than twice as long as BeneFIX® [Coagulation Factor IX (Recombinant)], the only recombinant factor IX therapy currently approved for prophylactic use. The terminal half-life for rFIXFc was 82 hours compared to 34 hours for BeneFIX. Other measures of rFIXFc's activity in the body reinforce its long-lasting characteristics: the mean time for maintaining a normal clotting factor activity level (time to 1 percent) was 11 days for rFIXFc compared to 5 days for BeneFIX and the average rate at which rFIXFc was cleared from the body was 3.2 mL/hr/kg compared with 6.3 mL/hr/kg for BeneFIX. All patients in the individualized interval prophylaxis arm of the study were able to go at least one week between rFIXFc injections and 50 percent were able to go 14 days or longer before needing another dose to prevent bleeding. The median weekly dose was 45 IU per kg, comparable to the recommended dose for the current standard of care. Overall, the B-LONG data support the potential for rFIXFc to become the first product to offer hemophilia B patients long-lasting protection from bleeding with a more convenient injection schedule than the current standard of care.

The B-LONG data were presented in poster 115, "Safety, efficacy, and improved pharmacokinetics (PK) demonstrated in a phase 3 clinical trial of extended half-life recombinant FC fusion factor IX (B-LONG)."

Importantly, the difference in the duration of activity of rFVIIIFc and rFIXFc was expected and consistent with the differences between the natural clotting factors that these products augment. Fc Fusion technology extends FVIII and FIX differently based on the biological differences in hemophilia A and B. The length of time that FVIII stays active is dictated by its own duration as well as that of the blood protein that it binds to, known as von Willebrand factor. The activity of FIX is not restricted in this way.

• On September 26, 2012, Biogen Idec and Swedish Orphan Biovitrum (Sobi) have announced positive results from B-LONG, a clinical study that evaluated a new long-lasting clotting factor candidate in people with hemophilia B. Top-line results from B-LONG, a global, multi-center, Phase 3 clinical study of the companies' long-lasting recombinant Factor IX Fc fusion protein (rFIXFc), showed that rFIXFc was effective in the control and prevention of bleeding, routine prophylaxis, and perioperative management. Recombinant FIXFc was generally well-tolerated. Additional analyses of the B-LONG study are ongoing and the companies anticipate presenting further results at a future scientific meeting.

Biogen Idec plans to submit a Biologics License Application (BLA) to the FDA in the first half of 2013. Consistent with guidelines published by the European Medicines Agency (EMA) that require a study in children less than 12 years of age prior to filing, Biogen Idec and Sobi expect to file a Marketing Authorization Application with the EMA upon completion of the ongoing Kids B-LONG study.

In the B-LONG study, 123 male patients aged 12 years and older were enrolled. The B-LONG study had four treatment arms: weekly prophylaxis, individualized interval prophylaxis, episodic treatment and perioperative management (Arms 1, 2, 3 and 4, respectively). Overall, 93.5 percent of patients completed the study. Recombinant FIXFc was generally well-tolerated. No inhibitors to rFIXFc were detected and no cases of anaphylaxis were reported in any patients, all of whom switched from commercially-available Factor IX products. One serious adverse event was assessed to be possibly related to drug by the investigator. The patient experienced obstructive uropathy in the setting of hematuria; he continued rFIXFc treatment and the event resolved with medical management.

The most common adverse events (incidence of more than / equal 5 percent) occurring outside of the perioperative management arm (i.e., Arms 1, 2 and 3, but not Arm 4) were nasopharyngitis, influenza, arthralgia (joint pain), upper respiratory infection, hypertension and headache.

The overall median annualized bleeding rates (including spontaneous and traumatic bleeds) were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm. In the individualized interval prophylaxis arm, the median dosing interval during the last 6 months on study was 14 days.

Control of bleeding was assessed in all patients who experienced a bleeding episode during the study. Overall, 90.4 percent of bleeding episodes were controlled by a single injection of rFIXFc.

Recombinant FIXFc was assessed in the perioperative management of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of rFIXFc as excellent or good in 100 percent of these surgeries.

B-LONG included a pharmacokinetic (PK) analysis of rFIXFc in all patients in the study. In a protocol-defined subset of patients with extensive PK sampling, the approximate terminal half-life of rFIXFc was 82 hours compared to 34 hours for BeneFIX® [Coagulation Factor IX (Recombinant)].

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