The safety profile of ELOCTATE® has remained consistent over 4 years

In A-LONG and Kids A-LONG,1

  • One 25-year-old patient had a transient, positive, neutralizing antibody of 0.73 BU at Week 14, which was not confirmed upon repeat testing 18 days later and thereafter
  • Formation of neutralizing antibodies (inhibitors) to factor VIII has been reported following administration of ELOCTATE, including in previously untreated patients
  • Monitor all patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests
  • The most frequently occurring adverse reactions (>0.5% of patients) in clinical trials were arthralgia, malaise, myalgia, headache, and rash

In ASPIRE,2,6

100%

of all serious adverse events (AEs) were assessed as unrelated to ELOCTATE treatment

  • 1.4% experienced nonserious, mild AEs related to ELOCTATE
  • These AEs were chromaturia, headache, and hot flush (hot flashes). Each resolved spontaneously without treatment and did not recur despite continued study participation
  • Six pediatric patients experienced a total of 7 serious AEs
  • All serious AEs had resolved by the time of the interim data cut, and none led to withdrawal from the study

ELOCTATE® is the longest-investigated EHL rFVIII2

>2500 PATIENTS

*Based on specialty pharmacy dispensing records, specialty distributor shipment records, 3PL shipment records, and internal retention estimates from July 2014 through February 2018.

PreviouslyUntreatedPatients10(N=125;5yearsofage)Extensionstudy20112018Adults andadolescents20102012Pediatric20122013PUPsstudy2015est.2020ASPIRE2,8(N=211;266yearsofage)Kids1,9(N=71;<12yearsofage)1,7(N=165;1265yearsofage)SeestudydesignSeestudydesignSeestudydesignSeestudydesign
  • Multicenter, prospective, open-label, phase 3 study that evaluated the safety and efficacy of ELOCTATE in previously treated male patients aged 12 to 65 years with severe hemophilia A (<1% endogenous FVIII activity or a genetic mutation consistent with severe hemophilia A) that compared the efficacy of each of 2 prophylactic treatment regimens (individualized interval and fixed weekly) to episodic (on-demand) treatment. Hemostatic efficacy was determined during treatment of bleeding episodes and during perioperative management in patients undergoing major surgical procedures1

    • 165 adult and adolescent previously treated patients were enrolled; 164 patients were evaluable for safety, and 163 were evaluable for efficacy

      Arm1Dosing Regimens1
      Individualized prophylaxis (n=117)25 IU/kg on Day 1, 50 IU/kg on Day 4
      • Regimen adjusted within the range of 25 to 65 IU/kg every 3 to 5 days to maintain trough levels 1% to 3% above baseline or higher, as clinically indicated
      Once-weekly prophylaxis* (n=23)65 IU/kg every 7 days
      On demand (n=23)As required for bleeding episodes

      *Not a labeled dosing regimen.

Subgroups

Pharmacokinetics (PK) (individualized prophylaxis arm)1,3

  • Following a washout period of at least 96 hours, the pharmacokinetics of ELOCTATE were evaluated after a single dose of 50 IU/kg in 28 adult patients
  • PK samples were collected before dosing and then at 7 subsequent time points up to 120 hours after dosing

Surgery (all arms)3,5

  • Dose adjusted to type of surgery
  • 9 major surgeries in 9 patients; 12 minor surgeries in 12 patients

Primary Endpoints1

  • Evaluated the safety and tolerability of ELOCTATE
  • Evaluated the efficacy of prophylaxis, on-demand treatment, and perioperative management

Secondary Endpoints7

  • Evaluated the PK profile of ELOCTATE
  • Characterized the range of doses and schedules required to adequately prevent bleeding on a prophylaxis regimen, maintain hemostasis in a surgical setting, or treat bleeding episodes

Key Inclusion Criteria3

  • Diagnosed with severe hemophilia A (FVIII:C <1% or a genetic mutation consistent with hemophilia A)
  • Male ≥12 years of age
  • Weighing ≥40 kg
  • ≥150 EDs with any FVIII therapy
  • Platelet count ≥100,000 cells/μL; CD4 lymphocytes ≥200 cells/mm3 if HIV positive
  • Viral load <400 copies/mL if HIV positive

Key Exclusion Criteria3

  • Bleeding disorder other than hemophilia A
  • Kidney or liver dysfunction
  • Any history of inhibitors
  • History of hypersensitivity or anaphylaxis associated with FVIII or IVIG administration

EDs=exposure days; FVIII:C=FVIII activity; IVIG=intravenous immunoglobulin.

  • Multicenter, open-label, phase 3 study that evaluated the safety and efficacy of ELOCTATE in previously treated male patients aged <12 years with severe hemophilia A (<1% endogenous FVIII activity or a genetic mutation consistent with severe hemophilia A). Surgeries were allowed after 5 EDs1,9

    • 71 male patients were enrolled; 69 patients (1 to 5 years of age, n=35; 6 to 11 years of age, n=34) were evaluable for safety and efficacy; 61 patients (88.4%) had ≥50 ELOCTATE EDs on study

      Arm1Dosing Regimens1
      Individualized prophylaxis (n=69)25 IU/kg on Day 1, 50 IU/kg on Day 4
      • Regimen could be adjusted within the range of 25 to 80 IU/kg with a minimum dosing interval of every 2 days to maintain trough of 1% above baseline or as clinically indicated to prevent bleeding

Subgroups

Pharmacokinetics (PK)1,3

  • Following a washout period of at least 72 hours, the PK of ELOCTATE were evaluated after a single dose of 50 IU/kg
  • 54 patients were evaluable for PK (1 to 5 years of age, n=23; 6 to 11 years of age, n=31)

Primary Endpoint9

  • Development of inhibitors (identified by a Nijmegen-modified Bethesda assay titer of ≥0.6 BU/mL and confirmed in 2 separate samples drawn approximately 2 to 4 weeks apart)

Secondary Endpoints3,9

  • Evaluated the PK profile of ELOCTATE
  • ABR
  • Dose administered for treatment of a bleeding episode
  • Patient’s rating of response to ELOCTATE for the treatment of bleeding

Key Inclusion Criteria9

  • Diagnosed with severe hemophilia A (FVIII:C <1% or a genetic mutation consistent with hemophilia A)
  • Male <12 years of age
  • Weighing ≥13 kg
  • ≥50 EDs with any FVIII therapy
  • Platelet count ≥100,000 cells/μL; CD4 lymphocytes ≥200 cells/mm3 if HIV positive
  • Viral load <400 copies/mL if HIV positive

Key Exclusion Criteria3,9

  • Bleeding disorder other than hemophilia A
  • Kidney or liver dysfunction
  • Any history of inhibitors
  • History of hypersensitivity or anaphylaxis associated with FVIII or IVIG administration

ABR=annualized bleed rate; BU=Bethesda unit; EDs=exposure days; FVIII:C=FVIII activity; IVIG=intravenous immunoglobulin.

  • Open-label, multicenter, nonrandomized evaluation of ELOCTATE in 150 previously treated males ≥12 years of age and 61 previously treated males <12 years of age with severe hemophilia A who completed the A-LONG or Kids A-LONG pivotal trials. Interim data were cut January 6, 2014. At the interim data cut, the median time on ASPIRE among patients from A-LONG was 80.9 weeks; among Kids A-LONG patients, the median time on ASPIRE was 23.9 weeks2

    • Of the 150 patients ≥12 years of age from A-LONG, 140 continued with the study at the time of the data cut, and of the 61 patients <12 years of age from Kids A-LONG, all continued with the study at the time of the data cut

      Arm2Dosing Regimens2
      Individualized prophylaxis
      (A-LONG, n=105; Kids A-LONG, n=59)
      • 25 to 65 IU/kg every 3 to 5 days or twice weekly (20 to 65 IU/kg on Day 1, 40 to 65 IU/kg on Day 4)
      Weekly prophylaxis
      (A-LONG, n=22)
      • 65 IU/kg every 7 days
      Modified prophylaxis
      (A-LONG, n=9; Kids A-LONG, n=2)
      • Personalized beyond the individualized and weekly prophylaxis group regimens
      Episodic treatment
      (A-LONG, n=14)
      • Based on the type and severity of the bleeding episode

Primary Endpoint2

  • Development of inhibitors (identified by a Nijmegen-modified Bethesda assay titer of ≥0.6 BU/mL and confirmed in 2 separate samples drawn approximately 2 to 4 weeks apart)

Secondary Endpoints2

  • ABR
  • Exposure days
  • Assessment of response to treatment of a bleeding episode

Key Inclusion Criteria2

  • Diagnosed with severe hemophilia A (FVIII:C <1% or a genetic mutation consistent with hemophilia A)
  • Male patients who previously completed A-LONG or Kids A-LONG

Key Exclusion Criteria2,8

  • Confirmed positive high-titer inhibitor (≥5.00 BU/mL)

ABR=annualized bleed rate; BU=Bethesda unit; FVIII:C=FVIII activity.

  • This open-label study is expected to be completed in 2020 and will investigate inhibitor development and ABR, joint bleeds, number of infusions and dose per infusion to resolve a bleeding episode, and patient’s rating of response to treatment in previously untreated patients 5 years of age or younger10

ABR=annualized bleed rate.

EHL=extended half-life; rFVIII=recombinant factor VIII.

Important Safety Information

CONTRAINDICATIONS: ELOCTATE is contraindicated in patients who have had life-threatening hypersensitivity reactions to ELOCTATE or its excipients.

WARNINGS AND PRECAUTIONS: Hypersensitivity reactions have been reported with ELOCTATE. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with Factor VIII replacement products. Immediately discontinue ELOCTATE and initiate appropriate treatment if hypersensitivity reactions occur. Formation of neutralizing antibodies (inhibitors) to Factor VIII has been reported following administration of ELOCTATE, including in previously untreated patients. Patients using ELOCTATE should be monitored for the development of Factor VIII inhibitors. Clotting assays (e.g., one-stage) may be used to confirm that adequate Factor VIII levels have been achieved and maintained.

ADVERSE REACTIONS: The most frequently occurring adverse reactions (>0.5% of subjects) in clinical trials were arthralgia, malaise, myalgia, headache, and rash.

INDICATIONS

ELOCTATE® [Antihemophilic factor (recombinant), Fc fusion protein] is a recombinant DNA derived, antihemophilic factor indicated in adults and children with Hemophilia A (congenital Factor VIII deficiency) for: on-demand treatment and control of bleeding episodes, perioperative management of bleeding, and routine prophylaxis to reduce the frequency of bleeding episodes.

Limitation of Use
ELOCTATE is not indicated for the treatment of von Willebrand disease.

References: 1. ELOCTATE® [package insert]. Waltham, MA: Sanofi Genzyme, 2017. 2. Nolan B, et al. Haemophilia. 2016;22:72-80. 3. Data on file, Bioverativ Therapeutics Inc., an affiliate of Sanofi. 4. Blanchette VS, et al. J Thromb Haemost. 2014;12(11):1935-1939. 5. Mahlangu JN, et al. Thromb Haemost. 2016;116:1-8. 6. Nolan B, et al. Haemophilia. 2016;22(1)(suppl):1-10. 7. Mahlangu J, et al. Blood. 2014;123(3):317-325. 8. Clinicaltrials.gov. NCT01454739. https://clinicaltrials.gov/ct2/show/NCT01454739. Accessed April 25, 2018. 9. Young G, et al. J Thromb Haemost. 2015;13:1-11. 10. Clinicaltrials.gov. NCT02234323. https://clinicaltrials.gov/ct2/show/NCT02234323. Accessed April 25, 2018. 11. Shapiro A. Expert Opin Biol Ther. 2013;13(9):1287-1297. 12. Kaneko Y, et al. Science. 2006;313:670-673. 13. ADVATE® [package insert]. Westlake Village, CA: Baxalta US Inc.; 2016. 14. ADYNOVATE® [package insert]. Westlake Village, CA: Baxalta US Inc.; 2016. 15. AFSTYLA® [package insert]. Kankakee, IL: CSL Behring LLC; 2017. 16. ALPHANATE® [package insert]. Los Angeles, CA: Grifols Biologicals Inc.; 2015. 17. HEMOFIL M® [package insert]. Westlake Village, CA: Baxalta US Inc.; 2016. 18. HUMATE-P® [package insert]. Kankakee, IL: CSL Behring LLC; 2014. 19. KOATE®-DVI [package insert]. Research Triangle Park, NC: Grifols Therapeutics Inc.; 2012. 20. KOGENATE FS® [package insert]. Whippany, NJ: Bayer HealthCare LLC; 2016. 21. KOVALTRY® [package insert]. Whippany, NJ: Bayer HealthCare LLC; 2016. 22. MONOCLATE-P® [package insert]. Kankakee, IL: CSL Behring LLC; 2014. 23. NOVOEIGHT® [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2016. 24. NUWIQ® [package insert]. Hoboken, NJ: Octapharma USA, Inc.; 2015. 25. RECOMBINATE® [package insert]. Westlake Village, CA: Baxalta US Inc.; 2017. 26. REFACTO® [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2007. 27. XYNTHA® [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2014. 28. Lara M, Duncan N, Andres R. Effect of hemophilia treatment center digital monitoring on bleeding rates: 12 month study. Am J Hematol. 2016;91(9):E408.