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Horizon Scanning Centre

September 2013

Efraloctocog alfa (Eloctate) for
haemophilia A in adults and children
SUMMARY

This briefing is
based on
information
available at the time
of research and a
limited literature
search. It is not
intended to be a
definitive statement
on the safety,
efficacy or
effectiveness of the
health technology
covered and should
not be used for
commercial
purposes or
commissioning
without additional
information.

NIHR HSC ID: 5305

Efraloctocog alfa (Eloctate) is intended for the treatment of haemophilia A in
adults and children. If licensed, it will offer an additional treatment option for
haemophilia A, with the potential to reduce the frequency of prophylactic
dosing. Efraloctocog alfa is a long-acting factor VIII-Fc fusion protein,
comprised of a single copy of factor VIII linked to the Fc region of human
immunoglobulin G1 (IgG1). Fc fusion allows drugs to remain active in the
body for an extended period of time by protecting them from catabolism.
Haemophilia A is the most common inherited bleeding disorder with
significant clinical severity, affecting approximately 1 in 10,000 total births.
Acquired haemophilia A has an incidence of 1.34 cases per million
population per year. There were 5,424 patients with haemophilia A in the UK
in 2011. Insufficient or incorrect treatment of recurrent spontaneous
haemorrhage into the soft tissue and joints may lead to motor impairment
with severe disability associated with stiffness, joint deformation and
paralysis. Inadequate treatment can also lead to an increased risk of death.
In patients with haemophilia A, coagulation factor replacement (plasmaderived or recombinant concentrates of factor VIII) may be given in response
to a haemorrhage (on-demand therapy) or given regularly to prevent
haemorrhage. Efraloctocog alfa is currently in two phase III clinical trials
measuring its effect on the frequency of inhibitor development and the
annualised number of bleeding episodes. One trial has completed and the
other is expected to complete in October 2014.

This briefing presents independent research funded by the National Institute
for Health Research (NIHR). The views expressed are those of the author
and not necessarily those of the NHS, the NIHR or the Department of Health.
NIHR Horizon Scanning Centre, University of Birmingham
Email: nihrhsc@contacts.bham.ac.uk
Web: http://www.hsc.nihr.ac.uk

the fusion protein is protected from degradation and can be re-released into the circulation. BIIB-031. or 65IU/kg as weekly prophylaxis.NIHR Horizon Scanning Centre TARGET GROUP • Haemophilia A: severe. DEVELOPER Biogen Idec. AVAILABILITY. Current factor VIII products have a half-life of 8-12 hours. efraloctocog alfa has been shown to induce immune tolerance in mice and thus may reduce the development of inhibitors (neutralizing anti-factor VIII antibodies) in humans. In addition. Swedish Orphan Biovitrum Ltd. Efraloctocog alfa is administered by intravenous (IV) infusion at 10-50IU/kg as episodic (ondemand) treatment. The Fc region may also induce neonatal tolerance to efraloctocog alfa while also providing protection from bleeding during delivery3. INNOVATION and/or ADVANTAGES If licensed. Upon binding. FVIII-Fc. 25-65IU/kg as individualised prophylaxis every three to five days. effraloctocog alfa will offer an additional treatment option for haemophilia A. The Fc domain binds to receptors found in endothelial cells in blood vessels.4. Fc fusion allows drugs to remain active in the body for an extended period of time by protecting them from catabolism 1. it therefore has the potential to extend the half-life of efraloctocog alfa. 2 . adults and children – treatment and routine prophylaxis of bleeding. recombinant factor VIII Fc fusion protein) is a long-acting factor VIII-Fc fusion protein comprised of a single copy of factor VIII linked to the Fc region of human immunoglobulin G1 (IgG1). causing those with severe haemophilia to require prophylactic injections three times per week or every other day to maintain factor VIII levels above 1%. LAUNCH OR MARKETING Efraloctocog alfa is a designated orphan drug in the EU and USA. the level required to protect against spontaneous bleeding episodes 2. It has the potential to reduce the frequency of prophylactic dosing. It is in phase III clinical trials. Efraloctocog alfa is intended for the treatment of haemophilia A in adults and children. long-lasting factor VIII fusion protein. Factor VIII-Fc. The half-life of IgG in humans is approximately 3 weeks 3. which occurs in 15% to 30% of previously untreated patients3. rFVIIIFc. TECHNOLOGY DESCRIPTION Efraloctocog alfa (Eloctate.

In 2012. with three categories comprising severe (<1% of normal activity). Insufficient or incorrect treatment of recurrent haemarthroses and haematomas may lead to motor impairment with severe disability associated with stiffness. The prognosis for haemophilia A is favourable if therapy is administered early. there were 2. Females born to affected fathers can have the disease due to homozygosity for the gene.66 per 100. CLINICAL NEED and BURDEN OF DISEASE Haemophilia A is the most common inherited bleeding disorder with significant clinical severity. although spontaneous haemorrhage is usually only associated with severe disease 7. and 15-31% have mild disease.424 patients with haemophilia A in the UK in 2011 (a prevalence of 8. which usually presents before the age of two years.492 finished consultant episodes (492 in those aged 0-14 years) 11. Severity of disease is classified according to factor VIII activity in blood. The total international units (IUs) of factor VIII concentrate consumed/purchased in the UK in 2011 was over 457 million (88% recombinant and 12% plasma-derived)10.000 population). of whom 1. which generally presents in infancy. Approximately 43-70% a of people with haemophilia A have severe disease.000 total births 9. Inheritance is usually X-linked recessive. moderate (1–5%) or mild (>5% to <40%) disease 8. affecting males born to carrier mothers6.NIHR Horizon Scanning Centre PATIENT GROUP BACKGROUND Haemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation factor VIII 5. 3 . affecting approximately 1 in 10.247 admissions for hereditary factor VIII deficiency (ICD-10 D66) in England and Wales. Haemophilia A results in prolonged bleeding after trauma. 15-26% have moderate disease. resulting in 2.34 cases per million population per year6. and the treatment is administered as prescribed7. Haemophilia A is usually treated with either plasmaderived factor VIII or recombinant factor VIII products5. This results from heterogeneous mutations in the factor VIII gene that maps to Xq28 6. and recurrent spontaneous haemorrhage into the soft tissue (haematomas) and joints (haemarthroses)5. Inadequate treatment can also lead to an increased risk of death due to deep internal muscle bleeding. Acquired haemophilia A has an incidence of 1. joint deformation and paralysis7. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to the National Service Framework for long-term conditions (including long-term neurological conditions) (2005).523 bed-days and 2. There is normally a clear family history but sporadic cases can also occur6. There were 5. a The wide ranges are due to genetic variability of differing populations. which usually presents after the age of two years6. joint damage and infections5.057 patients were aged 0-13 years 10. however this is rare6.

Guideline on the management of haemophilia in the fetus and neonate. Complete but unpublished. coagulation factor replacement (plasma-derived or recombinant concentrates of factor VIII) may be given in response to a haemorrhage (ondemand therapy) or given regularly to prevent haemorrhage (prophylactic therapy)13. 17 manufacturer . The treatment of choice for severe haemophilia A is recombinant factor VIII14. crossover. manufacturer. 19 Trial registry . rFVIIIFc. Australia. Kids ALONG. UKHCDO. and to cover surgical interventions15. Ongoing. aged ≥12 years. USA. desmopressin (and tranexamic acid as adjunct) is preferred instead of coagulation factor concentrates14. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. rFVIIIFc (efraloctocog alfa). Guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Non-randomised. EU (incl UK). NCT01181128. 2011 12. 4 . 8HA01EXT. phase II/III. Biogen Idec. 16 Trial registry . 2008 14. Biogen Idec. uncontrolled. Non-randomised. Canada and other countries. EU (incl UK). USA. Biogen Idec. South Africa. and it may also be used in some cases of moderate disease15. factor VIIa (recombinant) and plasma-derived preparations with Factor VIII Inhibitor Bypassing Activity (FEIBA)14 are recommended for the treatment of acute bleeds. For mild haemophilia A. Orthopaedic surgical intervention may be required where joint damage has occurred. but this should be conducted in specialised centres7. USA. aged ≤11 years. In patients who develop factor VIII inhibitors. 2010 13.NIHR Horizon Scanning Centre PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance • No relevant guidance. EU (incl UK). uncontrolled. phase III extension. Hong Kong. NCT01458106. Ongoing. EFFICACY and SAFETY Trial Sponsor Status Source of information Location Design ALONG. phase III NCT01454739. manufacturer.15. Other Guidance • • • Paediatric Working Party of the United Kingdom Haemophilia Doctors’ Organization (UKHCDO). Canada and other countries. 18 Trial registry . 8HA02PED. rFVIIIFc. UKHCDO. EXISTING COMPARATORS and TREATMENTS In patients with haemophilia A. Single arm. 997HA301.

Follow-up Active treatment for 52 weeks.6 and 33. including modified prophylaxis.5 days. severe. severe . Frequency of inhibitor development. The number of annualised bleeding episodes per subject. 1. total number of days exposure. - - Severe haemophilia A defined as <1IU/dL (<1%) endogenous Factor VIII. Subjects continue in study for up to 4 years. pharmacokinetics. assessments of response to treatment with rFVIII Fc for bleeding episodes. or follow up 14-21 days after last dose.6. 98% of all bleeding episodes were controlled by one or two injections of Active treatment and follow up for 28 weeks. health outcomes. or until rFVIIIFc is commercially available in the applicable participating country. rFVIIIFc 25IU/kg to 65IU/kg IV administered every 3 to 5 days as individualized prophylaxis. or rFVIIIFc 65IU/kg IV administered as weekly prophylaxis. weight ≥13kg. haemophilia A.NIHR Horizon Scanning Centre n=165. aged ≤11 years. 3. aged ≥12 years. assessment of treatment response. efficacy of rFVIIIFc in surgery. males. or current detectable factor VIII inhibitors. 5 . or current detectable factor VIII inhibitors. weekly prophylaxis (n=24) and episodic treatment (n=23). rFVIIIFc 25IU/kg and 50IU/kg IV administered twice weekly. Individualized prophylaxis arm: median dosing interval. previously treated. At study completion. no other coagulation disorders. 30% achieved a mean dosing interval of five days during the last three months of study. 3. ABR: annualized bleeding rates. subjects enrol in the extension study (NCT01454739). completed NCT01181128 or NCT01458106.6. b haemophilia A. Primary outcomes Inhibitor development. Subjects are allowed to change from prophylaxis. or rFVIIIFc administered 10-50IU/kg IV as episodic (ondemand) treatment. Individualized prophylaxis (n=118). males. Number of annualised bleeding episodes. Dose may be adjusted to a maximum of 80IU/kg and the frequency of administration increased to a maximum of every 2 days. weight ≥40kg. no history of. or from ondemand to prophylaxis during the study. n=50 (planned). Annualized rFVIIIFc consumption. Participants Schedule Secondary outcomes Results b c n=200 (planned). no history of. or rFVIIIFc 65IU/kg IV administered as weekly prophylaxis. including spontaneous and traumatic bleeds. respectively: c median ABR . quality of life. Frequency of inhibitor development. to ondemand. rFVIIIFc 25-65IU/kg IV as individualized prophylaxis. annualised number of bleeding episodes (spontaneous and traumatic).

SPECULATIVE Impact on Patients and Carers  Reduced mortality/increased length of survival  Reduced symptoms or disability: Expert commented that if efraloctocog alfa can prevent the development of inhibitors.NIHR Horizon Scanning Centre rFVIIIFc. Expert commented that this would improve the patient’s quality of life.  None identified 6 . headache and upper respiratory tract infection.4 hrs for Advate [antihaemophilic factor (recombinant). reduce hospital attendances and reduce the need to train and support family members to administer factor concentrate. Common AEs (≥5%): nasopharyngitis.  Other: reduced dosing frequency for prophylaxis. AEs Expected reporting date Terminal half-life of rFVIIIFc was 19. ESTIMATED COST and IMPACT COST The cost of efraloctocog alfa is not yet known. Study completion date reported as Dec 2015. plasma/albumin-free method].  No impact identified Impact on Services  Increased use of existing services  Decreased use of existing services  Re-organisation of existing services  Need for new services  Other: Expert commented that efraloctocog alfa may remove the need for central line insertion in young children. potentially preventing the associated severe bleeds and disabilities. - - - Study completion date reported as Oct 2014. then this would be a very important development. It could also reduce the need to attend haemophilia centres or have home visits. IMPACT . arthralgia. Physicians rated the haemostatic efficacy of rFVIIIFc as excellent or good in 100% in the perioperative management of 9 patients undergoing major surgical procedures.0 hrs compared to 12.

Richards M.wfh.14:671–684. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Liu T. September 2013. Report on the Annual Global Survey 2011. Liu Z.1365-2516. http://onlinelibrary. Orphanet. Haemophilia (2011).nhs. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Haemophilia A (Factor VIII Deficiency). The International Society of Thrombosis and Haemostasis.4.154(2):208-215. NHS England 2011-12 HES data.02487. Oral presentation. Abstract OC 56.php?lng=EN&Expert =98878 Accessed 29th July 2013. Williams M.orpha. June 2013.co.patient.119(13):3024-3030. Montreal. Hemophilia A. New England Journal of Medicine 2007. Jiang H. Tait C and Makris M. http://www1. Guideline on the management of haemophilia in the fetus and neonate. Thrombosis and Haemostasis 2001.2010. British Medical Association and Royal Pharmaceutical Society of Great Britain.357(6):535– 544. et al. 7 .1111/j.NIHR Horizon Scanning Centre Impact on Costs  Increased drug treatment costs  Reduced drug treatment costs  Other increase in costs:  Other reduction in costs:  Other: uncertain unit cost compared to existing treatments  None identified Other Issues  Clinical uncertainty or other research question identified:  None identified REFERENCES 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Luk A. 3. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. Specialised services for haemophilia and other related bleeding disorders (all ages) definition No.wiley. Krishnamoorthy S. Canada: WFH. Definitions in hemophilia. British National Formulary. BNF 65. Haemophilia 2008.net/consor/cgi-bin/OC_Exp. Brennand J et al. February 2011.co. Abshire TC.11(1):132141 Patient. Specialised services national definitions set (3rd edition). Toby G.nhs. Dumont JA.85:560. Poster abstract. Chalmers E et al. Aledort LM et al.uk/library/26/Specialised_Services_for_Haemophilia_and_Oth er_Related_Bleeding_Disorders_all_ages. 352–380. Hospital episode statistics. Blood 2012. www. A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Lu Q et al. Keeling D. British Journal of Haematology 2010.uk Chalmers E. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. Williams M. Drager D et al.pdf Health and Social Care Information Centre. 17.org/publications/files/pdf-1488. Clinical trial for long-lasting recombinant factor VIII-FC (rFVIIIFc) in subjects with haemophilia A (A-LONG).x/pdf Manco-Johnson M. 2013. Low SC et al.uk/doctor/haemophilia-a-factor-viii-deficiency Accessed 26 July 2013. http://www. 4th Annual Congress of the European Association for Haemophilia and Allied Disorders. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.hesonline.uk. Sommer J et al. Shapiro A. British Journal of Haematology 2011.pdf World Federation of Hemophilia. Rosendaal F. http://www. Peters RT. December 2012.com/doi/10.149(4):498-507. Mechanisms of immune tolerance induction by rFVIIIFc in hemophilia A mice. White GC.specialisedservices. Journal of Thrombosis and Haemostasis 2013. http://www. London: BMJ Group and RPS Publishing.

http://www. BIIB 031. pharmacokinetics and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with severe hemophilia A. Biogen Idec and Sobi Announce Positive Top-Line Results from Phase 3 Study Investigating Long-Lasting Recombinant Factor VIII Fc Fusion Protein in st Hemophilia A.gov/ct2/show/NCT01454739 Accessed 31 July 2013 8 .gov. http://clinicaltrials. in pediatric PTP subjects with hemophilia A.biogenidec. http://clinicaltrials. 31 October 2012. Long-term safety and efficacy of recombinant human coagulation factor VIII fusion protein (rFVIIIFc) in the prevention and treatment of bleeding episodes in previously treated subjects with hemophilia A.com/press_release_details. http://clinicaltrials. Study of recombinant coagulation factor VIII Fc fusion protein.gov.gov.NIHR Horizon Scanning Centre 16 ClinicalTrials. Study to evaluate the safety.gov/ct2/show/NCT01458106 Accessed 30th July 2013 19 ClinicalTrials.aspx?ID=5981&ReqId=1752097 18 ClinicalTrials.gov/ct2/show/study/NCT01181128 Accessed 30 July 2013 17 Biogen Idec Press release details.