Clinical Trials

Date: 2017-12-10

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting in Orlando

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

Product: Elocta™/Eloctate™ (recombinant factor VIII Fc fusion protein - rFVIIIFc)

Action mechanism:

• protein/coagulation factor. Eloctate® (efmoroctocog alfa) is  a recombinant clotting factor therapy developed for hemophilia A by fusing factor VIII to the Fc portion of immunoglobulin G subclass 1, or IgG1 (a protein commonly found in the body). It is believed that this enables Eloctate® to use a naturally occurring pathway to prolong the time therapy remains in the body. While Fc fusion has been used for more than 15 years, Biogen Idec is the only company to apply it to the treatment of hemophilia.

Disease: hemophilia A

Therapeutic area: Hematologic diseases - Genetic diseases

Country: International study

Trial details:

• A-LONG was a global, open-label, multi-center Phase 3 study that evaluated the efficacy, safety and pharmacokinetics of intravenously-injected rFVIIIFc. The study was designed to evaluate rFVIIIFc in the control and prevention of bleeding, routine prophylaxis and perioperative management in patients with hemophilia A. A-LONG involved 60 hemophilia treatment centers in 19 countries on six continents. The A-LONG study had three treatment arms. In Arm 1 (individualized prophylaxis; n=118), patients were treated with 25-65 IU/kg of rFVIIIFc, at an interval of every three to five days, which was individualized to maintain factor trough levels sufficient to prevent bleeding. In Arm 2 (weekly prophylaxis; n=24), patients were treated with a weekly dose of 65 IU/kg. In Arm 3 (episodic treatment; n=23), patients received rFVIIIFc as needed for bleeding. In a subgroup of patients across treatment arms, rFVIIIFc was evaluated in the surgical setting.
• The primary efficacy and safety measures were the annualized bleeding rate and the incidence of adverse events including inhibitor development in patients studied for up to approximately 52 weeks. Secondary endpoints included response to treatment of bleeding episodes and the pharmacokinetics of rFVIIIFc versus Advate.
• Ongoing clinical studies of rFVIIIFc include the Kids A-LONG and ASPIRE studies. Kids A-LONG is a Phase 3, open-label study in previously-treated children with hemophilia A under age 12, which is actively recruiting patients. ASPIRE is a long-term open-label study for patients who completed the A-LONG study or who complete the Kids A-LONG study.

Latest news:

• • On December 10, 2017, Swedish Orphan Biovitrum and Bioverativ announced the results of a new, post-hoc, longitudinal analysis of the pivotal Phase 3 A-LONG study and ASPIRE long-term extension study, showing that weekly prophylactic dosing with its extended half-life therapy Elocta® (efmoroctocog alfa) marketed as Eloctate® [Antihemophilic Factor (Recombinant), Fc Fusion Protein] in the US, has the potential to provide improved bleed protection over episodic treatment, resolve target joints and reduce the treatment burden associated with more frequent dosing intervals. The analysis is being presented in a poster session at the 59th Annual Meeting of the American Society of Hematology.
• Elocta was developed using Fc fusion technology to prolong circulation in the body and its efficacy and safety have been studied in haemophilia A patients since 2010. This new, post-hoc analysis supports a growing body of clinical data showing prophylactic treatment with Elocta can positively impact long-term joint health. Elocta is currently not indicated for weekly dosing.
• Prophylactic treatment with factor therapy is recognized as the optimal therapy for severe haemophilia A, yet, according to the World Federation of Hemophilia guidelines, this treatment regimen traditionally involves injections three times per week with conventional factor based products. With Elocta’s extended half-life, patients can extend dosing intervals up to five days resulting in less frequent injections. Using data spanning four years from the pivotal Phase 3 A-LONG study, and ASPIRE, the long-term extension study, researchers examined subjects who were exposed to a seven-day dosing (65 IU/kg/wk) interval to assess long-term outcomes as determined by annualized bleeding rates (ABR), adherence and resolution of target joints.
• In the study, 43 adults and adolescents (?>12 years) were exposed to an Elocta weekly dosing interval for a median study duration of 3.1 years. Researchers also analysed results of those who maintained a weekly dosing interval throughout the study period (n=19). For those subjects in the ever-on-weekly dosing group who had pre-study episodic treatment (n=32), transition to weekly prophylaxis dosing resulted in a change in median ABR (IQR) of -23.7 (-35.8, -12.8). For those subjects who were always on a weekly dosing regimen throughout the study period (n=19), the median pre-study ABR (IQR) for subjects on a pre-study episodic regimen was 29 (18, 45) compared to an on-study ABR (IQR) of 1.7 (0.5, 6.7). Subjects experienced protection from spontaneous bleeds (median spontaneous ABR (IQR) of 1.2 (0.2, 2.8) for subjects ever-on-weekly dosing and 0.7 (0, 1.6) for subjects always-on-weekly-dosing and from spontaneous joint bleeds (median ABR (IQR) of 0.8 (0, 2.5) in subjects ever-on-weekly dosing and 0.2 (0, 1.0) in subjects always-on-weekly-dosing).
• All subjects were highly adherent while on the weekly dosing regimen (median duration of 3.1 years) and among subjects who chose to initiate a weekly dosing regimen on Elocta at any point of the study, the majority stayed on weekly dosing. One hundred percent of all evaluable target joints in both the ever-on-weekly dosing group and always-on-weekly dosing group resolved during the study period. Study findings suggest weekly dosing may be a reasonable prophylaxis regimen for patients receiving episodic treatment, who would prefer the benefit of prophylaxis and better bleed protection, but with minimal treatment burden.
• * On November 13, 2013, Biogen Idec and Swedish Orphan Biovitrum have announced that the detailed phase 3 data for Eloctate™ were published online in Blood, the journal of the American Society of Hematology (ASH). Results from the A-LONG study showed that people with severe hemophilia A may achieve effective prevention or reduction of bleeding episodes with one or two prophylactic infusions a week
• The A-LONG study evaluated weekly and individualized prophylaxis to reduce or prevent bleeding episodes, and episodic dosing to treat bleeding episodes. In the individualized arm, each study participant’s PK parameters were used to guide adjustments to dosing interval (from three to five days), and dose (25 to 65 IU/kg) to target a trough, or minimum, factor VIII level of 1–3 IU/dL or higher as needed to maintain good control of breakthrough bleeding episodes. The dose in the weekly prophylaxis arm was 65 IU/kg.
• The median annualized bleeding rates (ABR), or projected number of yearly bleeding episodes, was 1.6 in the individualized arm and 3.6 when Eloctate™ was administered once weekly. People in the episodic treatment arm had an ABR of 33.6. Eloctate™ controlled more than 87 percent of bleeding episodes with a single infusion, and physicians rated hemostatic response (the control and prevention of a bleeding episode) as excellent or good in all (n=9) major surgeries.
• There were no drug-related serious adverse events, and no inhibitors (neutralizing antibodies) were detected. Adverse events were representative of events occurring in the general hemophilia population; the most common (incidence of ?5 percent) occurring outside of the perioperative period, included nasopharyngitis (common cold), arthralgia (joint pain), headache and upper respiratory infection. Results of A-LONG were included in marketing applications in several countries, including the United States, Canada and Australia.
• • On July 4, 2013, Biogen Idec and Swedish Orphan Biovitrum (SOBI) have presented new data that support the clinical and safety profile of their long-lasting recombinant factor VIII candidate Eloctate™ for hemophilia A. Five platform and oral presentations at the XXIV International Society on Thrombosis and Haemostasis (ISTH) Congress in Amsterdam,  highlight the new FVIII candidate’s potential to reduce the number of intravenous injections people with hemophilia A require, its efficacy in controlling bleeding during and after surgery, and its efficacy in treating acute bleeding episodes.
• An evaluation of the treatment of acute bleeding episodes across the prophylaxis and episodic (on demand) treatment arms of the phase 3 A-LONG study showed that more than 87% of bleeds were controlled with a single injection of Eloctate™ and more than 97% of were controlled with two or fewer injections. These data were showcased in the e-poster presentation: Treatment of Bleeding Episodes in Subjects with Haemophilia A With Long-Lasting Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Phase 3 A-Long Study Novel Assay Clinical Research. Biogen Idec also shared results of evaluations of the performance of Eloctate™ when evaluated using two investigational hemostasis assays. Results from a large scale, global clinical evaluation of Eloctate™ by thrombin generation assay (TGA), using a standardized sample collection procedure and an optimized and validated assay performed at a central laboratory showed that, despite inherent patient-to-patient differences in thrombin generation activity, Eloctate™ and Advate® showed equivalent thrombin generation potential post-infusion. Eloctate™ also showed prolonged thrombin generation activity relative to Advate®, correlating with the pharmacokinetic data observed in these subjects.
• Results from a rotation thromboelastometry (ROTEM®) analysis conducted on 44 patients treated with Eloctate™ from 13 A-LONG study sites showed that Eloctate™ was fully active in patient samples. Additionally, the FVIII activity as measured by clotting time seen for Eloctate™ at 72 hours after dosing was comparable to the activity of Advate at 48 hours after dosing (mean clotting times of 1,238 seconds and 1,213 seconds, respectively).
• The data presentations were consistent with conventional assay results from the A-LONG study. These data were showcased in two oral platform presentations: Evaluation of The Thrombin Generation Potential of a Recombinant Factor VIII Fc Fusion Protein in a Phase III Multi-National Clinical Trial and Evaluation of Whole Blood Clotting Activity of Recombinant Factor VIII Fc Fusion Protein by ROTEM Analysis in a Multi-Center Phase 3 Clinical Trial
• Results from an analysis of the phase 3 A-LONG study showed that Eloctate™ consistently controlled bleeding during and after 9 major surgeries in 9 patients with hemophilia A. Physicians reported high efficacy levels of Eloctate™ during surgery, with hemostasis (the stoppage of bleeding) rated as “excellent” for 8/9 surgeries and “good” for 1/9 surgeries. According to the investigators’ analysis, the results were comparable to that for similar surgeries in people without hemophilia. These data were showcased in the e-poster presentation:
• Long-Lasting Recombinant Factor VIII Fc Fusion (rFVIIIFc) for Perioperative Management of Subjects with Haemophilia A in the Phase 3 A-LONG Study
• Population Pharmacokinetics (PK) Analysis: Analysis of a population pharmacokinetics (popPK) model developed for Eloctate™ demonstrate that the model accurately predicts peak and trough factor VIII activity levels achieved in the A-LONG clinical study at a variety of Eloctate™ doses. These data were showcased in the e-poster presentation: Population Pharmacokinetic Analysis of Long-Lasting Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Patients with Severe Haemophilia A. A Biologics License Application (BLA) for Biogen Idec’s long-lasting hemophilia product candidate Eloctate™is currently under review with the FDA for the treatment of hemophilia A. If approved, Eloctate™ would be the first major treatment advance for the hemophilia A community in more than two decades. A Marketing Application for Eloctate™ has been submitted in Australia for the treatment of hemophilia A. Additional regulatory filings are planned.
• • On February 8, 2013, Biogen Idec and Swedish Orphan Biovitrum (Sobi) have released data that confirmed the ability of investigational recombinant factor VIII Fc fusion protein (rFVIIIFc) 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 rFVIIIFc for hemophilia A 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 A-LONG study, patients with hemophilia A were able to use once to twice weekly prophylactic (preventative dosing) injections of rFVIIIFc while maintaining low bleeding rates. The current standard of care for hemophilia A requires frequent injections, which are a burden for patients. Prophylactic treatment for hemophilia A typically requires injections three times per week or every other day, 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 A-LONG results confirm the long-lasting characteristics of rFVIIIFc; specifically, the data show that rFVIIIFc stays in the body for 50 percent longer than Advate® [antihemophilic factor (recombinant), plasma/albumin-free method], the most frequently used factor VIII therapy. In the trial, the terminal half-life for rFVIIIFc was 19 hours compared to 12 hours for Advate. Other measures of rFVIIIFc's activity in the body reinforce its long-lasting characteristics: the mean time for maintaining a clotting factor activity level associated with less bleeding (time to 1 percent) was approximately 5 days for rFVIIIFc compared to 3.5 days for Advate and the average rate at which rFVIIIFc was cleared from the body was 2.0 mL/hr/kg compared with 3.0 mL/hr/kg for Advate. In the study's individualized prophylaxis arm, patients received rFVIIIFc at a median dosing interval of 3.5 days and a median weekly dose of 78 IU per kg to prevent bleeding, which compares favorably to the recommended dose for the standard of care. Nearly one-third of patients were able to achieve every 5 day dosing in this arm. Overall, the A-LONG data indicate that rFVIIIFc has the potential to become the first product to offer hemophilia A patients long-lasting protection from bleeding with less frequent dosing than the current standard of care. The A-LONG data were presented in the late-breaking oral abstract session and in poster 104, "Phase 3 clinical study of recombinant FC fusion factor FVIII (rFVIIIFc) demonstrated safety, efficacy, and improved pharmacokinetics (A-LONG)." • On October 31, 2012, Biogen Idec and Swedish Orphan Biovitrum (Sobi) have announced positive results from A-LONG, a clinical study that evaluated a new long-lasting clotting factor candidate in people with hemophilia A. Top-line results from A-LONG, a global, multi-center, Phase 3 clinical study of the companies’ long-lasting recombinant Factor VIII Fc fusion protein (rFVIIIFc), showed that rFVIIIFc was effective in the control and prevention of bleeding, routine prophylaxis and perioperative management. Recombinant FVIIIFc was generally well-tolerated. Additional analyses of the A-LONG study are ongoing, and the companies anticipate presenting detailed results at a future scientific meeting. Overall, 93 percent of patients completed the study. Recombinant FVIIIFc was generally well-tolerated. No inhibitors to rFVIIIFc were detected and no cases of anaphylaxis were reported in any patients, all of whom switched from commercially-available Factor VIII products. No serious adverse events were assessed to be related to drug by the investigator. The most common adverse events (incidence of ?5 percent) occurring outside of the perioperative management period were nasopharyngitis, arthralgia, headache and upper respiratory tract infection. The median annualized bleeding rates (ABR), including spontaneous and traumatic bleeds, were 1.6 in the individualized prophylaxis arm, 3.6 in the weekly prophylaxis arm and 33.6 in the episodic treatment arm. In the individualized prophylaxis arm, the median dosing interval was 3.5 days. During the last three months on study, 30 percent of patients in the individualized prophylaxis arm achieved a mean dosing interval of five days. Control of bleeding was assessed in all patients who experienced a bleeding episode during the study. Overall, 98 percent of bleeding episodes were controlled by one or two injections of rFVIIIFc. In addition, rFVIIIFc was assessed in the perioperative management of nine patients undergoing nine major surgical procedures. The treating physicians rated the hemostatic efficacy of rFVIIIFc as excellent or good in 100 percent of these surgeries. A-LONG included pharmacokinetic (PK) analysis of rFVIIIFc in all patients in the study. In a protocol-defined subset of patients with extensive PK sampling, the approximate terminal half-life of rFVIIIFc was 19.0 hours compared to 12.4 hours for Advate® [antihemophilic factor (recombinant), plasma/albumin-free method], consistent with the results obtained in the Phase 1/2a study of rFVIIIFc. 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 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 A-LONG study.

Is general: Yes