For use by US Medical in response to unsolicited requests only. Do not copy or modify. H9-US-0133 Long-acting recombinant factor IX Fc fusion protein (rFIXFc)

For use by US Medical in response to unsolicited requests only. Do not copy or modify. H9-US-0133

Long-acting recombinant factor IX Fc fusion protein (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B-LONG studyJerry S. Powell, Shashikant Apte, Herve Chambost, Cedric Hermans, Shannon Jackson, Neil C. Josephson, Johnny N. Mahlangu, Margareth C. Ozelo, Kathelijne Peerlinck, John Pasi, David Perry, Margaret V. Ragni, Xuefeng Wang, Haiyan Jiang, Shuanglian Li, Lynda M. Cristiano, Alison Innes, Karen Nugent, Aoife Brennan, Alvin Luk, Geoffrey Allen, Glenn F. Pierce and Brian Robinson

November, 2014

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Table I. Surgical assessments

Category EndpointrFIXFc dosing • Number of rFIXFc infusions

• Median dose per infusion (iu/kg)

• Total dose (iu/kg) required to maintain surgical haemostasis

rFIXFc consumption • Total consumption (iu/kg per surgery) on the day of surgery

• Total consumption (iu/kg per surgery) in the 2-week period following

surgery (stratified by Days 1–3, 4–14 and 1–14)

Estimated blood loss • Perioperative estimated blood loss

• Postoperative estimated blood loss

Transfusions • Number of transfusions required during surgery

• Type of blood component(s) transfused

Bleeding episodes • Total number per major surgery on Day 0 (day of surgery) through

postoperative Day 14

Surgical haemostasis • Assessment of haemostatic response (i.e, excellent, good, fair,

poor/none)

rFIXFc, recombinant factor IX Fc fusion protein.

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Table II. Four-point scale for assessment of surgical haemostasis*

Rating CriteriaExcellent • Intraoperative and postoperative blood loss similar to or less than a

person without haemophilia

Good • Intraoperative and/or postoperative bleeding slightly increased over expectations for a person without haemophilia, but not significantly different

Fair • Intraoperative and/or postoperative blood loss increased over expectations for a person without haemophilia, with need for additional treatment

Poor/none • Significant intraoperative and/or postoperative bleeding substantially increased over expectations for a person without haemophilia, requiring intervention, unexplained by a surgical/medical issue other than haemophilia

*Adapted from World Federation of Haemophilia guidelines (Srivastava et al, 2013).

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Table III. Haemostatic response to surgical dosing (Major surgeries)

Subject Study arm Type of surgery

Age at screening (years)

Investigator/ surgeon rating of haemostatic response

Pre-operativerFIXFc loadingdose (PK-based,iu/kg)

Total number of rFIXFc infusions Days 0-14

Total rFIXFc consump-tion Days 0-14 (iu/kg)

Intra-opera-tive

Post-operative

Bloodtrans-fusions

Thrombo-prophylaxis

1 4Total L knee replacement

32 Good 105.5 10 607.9 100 0 None Y§§


38 Excellent 124.2 7 500.4 75 0 None N

3 4Total R knee replacement

61 Excellent 99.7 9 590.2 56 140 None Y¶¶


34 Excellent 100.8 14 1081.6 <100 75 None N

5† 4Total R knee replacement

30 Excellent 142.3 9 649.3 250 0RBCs (3 total units)

N

6 1R knee arthroscopy

35 Excellent 79.3 11 597.7 10Not provided

None N

7 3R ankle arthroscopic fusion

50 Excellent 122.8 10 754 <5 0 None N

8 4External fixation of R knee

17 Excellent 120.2 9 787.2 100 0 None N

9 1R arm tendon transfer

54 Excellent 82.1 10 373.3 130 40 None N

10‡ 4Closure of intestinal fistula

43 Excellent 59.3 27 1348.7 300 500§

FFP,RBCs

(7 units total) ¶

N

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Table 3. Haemostatic response to surgical dosing (Major surgeries) (Continued)

Subject Study arm Type of surgery

Age at screening (years)

Investigator/ surgeon rating of haemostatic response

Pre-operativerFIXFc loadingdose (PK-based,iu/kg)

Total number of rFIXFc infusions Days 0-14

Total rFIXFc consump-tion Days 0-14 (iu/kg)

Intra-operative

Post-operative

Bloodtrans-fusions

Thrombo-prophylaxis

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Incision and drainage of dental abscess, with multiple extractions 24

Excellent 58.3 5 291.5 0 0 None N

Incision and drainage of abscessed pilonidal cyst††

Excellent 51.3 5 261.1 0 0 None N

12 1

Debridement, fracture dislocation, partialamputation** 22

Excellent 49.4††

12‡‡ 684.8‡‡

0 0 None N

Amputation L middle finger**

Excellent 49.4 iu/k 0 0 None N

rFIXFc, recombinant factor IX Fc fusion protein; PK, pharmacokinetic; L, left; R, right; RBC, red blood cell; FFP, fresh frozen plasma.*Assessment of haemostasis was to be recorded by surgeon/investigator approximately 24 h postoperatively, but some assessments were recorded days to a week after surgery.†Subject continued on a postsurgical rFIXFc regimen into the extension study.‡Subject received study-prohibited medication in the postoperative period and was discontinued from study.§Early postoperative blood loss primarily owing to diffuse oozing from surgical wound; wound was closed by secondary intention.¶Subject received 2 units intraoperatively, 5 units within 2 weeks of surgery.**Emergency surgical procedure for trauma (all others were elective).††Subject self-administered 1062 iu/kg rFIXFc on day of surgery, before surgical loading dose; an unauthorized 987 iu/kg dose of rFIXFc was administered 28 h post-surgery.‡‡Includes both surgeries and Days 0–17. Day 17 is 14 days after the second surgery.§§Subject received tranexamic acid 1 g every day for 1 day and enoxaparin sodium 04 ml every day for 15 days.¶¶Subject received dalteparin sodium 5000 units every day for 10 days, heparin 300 units as needed for 10 days and enoxaparin 40 mg twice a day for 44 days.

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Table IV. Haemostatic responseto surgical dosing (Minor surgeries)

Subject Type of surgeryInvestigator/surgeonrating of haemostaticresponse

Arm 1

1 Third molar extraction Excellent

2 Surgical extraction of tooth 14 Good

3 Left ankle arthroscopic removal of osteophyte Excellent

4 Dental extraction Excellent

5 PCI with stentingCoronary angiography

ExcellentExcellent

Arm 26 Wart removal Not Provided

7 Biopsy of alleged paratonsillar abscess Excellent

8 Dental crown Excellent

9 Dental extractionDental extraction

ExcellentFair

Arm 310 Extraction of multiple teeth and alveoplasties Excellent

11 Removal of 4 wisdom teeth Excellent

12 Root canal treatment Not provided

Arm 413 Extraction of teeth Not provided

PCI, percutaneous coronary intervention.

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Figure 1. Mean nominal dose of rFIXFc administered per day across all subjects in Arm 4 (n = 12).

[Some subjects received >1 dose on a given day, but means were calculated assuming independence (i.e., the denominator was the number of doses rather than the number of subjects)]. The mean nominal dose is represented by a solid black circle, and the standard deviation is represented by a dashed vertical line. rFIXFc, recombinant factor IX Fc fusion protein; SD, standard deviation.

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Figure 2A. Surgical pharmacokinetic profiles: Population pharmacokinetics model.

(A) Predicted FIX activity using the population pharmacokinetics model. In all 14 major surgeries, there was an excellent correlation (R2 = 0.9586; P<.001) between central laboratory observed FIX activity and that predicted by the pharmacokinetics model [relative prediction error, 0.332% (95% confidence interval, 2.08% to 1.42%)]. The solid line represents unity, and the dashed line represents the regression line.

FIX, factor IX.

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Figure 2B. Surgical pharmacokinetic profiles:Representative central laboratory measurements.

(B) Central laboratory measurements of FIX activity over time for 3 representative subjects.

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Figure 2C. Surgical pharmacokinetic profiles:Representative local laboratory measurements.

(C) Local laboratory measurements of FIX activity over time for 3 representative subjects.

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Figure 3A. Surgical dosing regimen and FIX activity over time for 3 representative subjects: Subject 1.

Target trough levels varied with the type of procedure and local standard of practice. Solid data points and connecting lines indicate FIX activity over time as measured by the central laboratory. Arrows at the top of the plot indicate timing and actual dose in iu/kg; the dosing regimen (iu/kg) recommended by the dosing committee is also noted above the horizontal line at the top of each panel. FIX, factor IX; rFIXFc, recombinant factor IX Fc fusion protein; ND, no dose.

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Figure 3B. Surgical dosing regimen and FIX activity over time for 3 representative subjects: Subject 2.


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Figure 3C. Surgical dosing regimen and FIX activity over time for 3 representative subjects: Subject 3.


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Safety

• Overall, 10 (83.3%) of the 12 subjects who underwent major surgery reported ≥1 adverse event during the surgical/rehabilitation period.

- Each reported adverse event was experienced by 1 subject, except for anaemia and dizziness (n = 2 for each).

- Adverse events reported during the surgical and rehabilitation period were generally mild or moderate in severity; all were assessed by the investigators as unrelated to rFIXFc treatment.

• Three (25%) of the 12 subjects who underwent major surgery experienced ≥1 serious adverse event during the surgical/rehabilitation period.

• All 6 serious adverse events were assessed by the investigator as unrelated to rFIXFc treatment; all resolved, and no action was taken with the study treatment as a result.

• No subjects developed inhibitors to rFIXFc, and no subjects experienced anaphylactic or vascular thrombotic events during the study.

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Documents

For use by US Medical in response to unsolicited requests only. Do not copy or modify. H9-US-0133 Long-acting recombinant factor IX Fc fusion protein (rFIXFc)