haemophilia develop inhibitors … · pathway inhibitor fitusiran & tfpi remain in clinical...

Challenges when people with haemophilia develop inhibitors Huyen Tran

Haemophilia Treatment Centre, The Alfred, Melbourne

Australian Centre for Blood Diseases, Monash University

Short clinical review

• Inhibitor development and treatment

• New data on inhibitors

• Surgery in inhibitors (context of emicizumab)

Factors influencing inhibitors

Inhibitors

Patient genetics

TreatmentPatient

environmentType of factor

quantityAge of first infusion

Immune system challenges

Type of mutation

MHC class I/II genotype

Race

FHx

Polymorphic genes

of cytokines

Sumit PARIKH, PhD (Health Informatics)

ABDR Senior Research Fellow

Methods/Results

0.00%

10.00%

20.00%

30.00%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 30 35 36 39 40 43 50

% In

hib

ito

r D

eve

lop

me

nt

Exposure days

Cumulative incidence of Inhibitor Development

Inhibitor status of HA patients in Australia

• Incidence • Severe HA, 27%

• Non-severe, 8%

• Paediatrics, 71%

• Likelihood for tolerisation for patients with inhibitors, • Severe 63% vs non-severe 0%

• Inhibitor no longer present, 78% had tolerisation

McRae et al., Blood congress 2018

TAC – 2018/19

Sumit PARIKH, PhD (Health Informatics)

ABDR Senior Research Fellow

Methods/Results

Therapeutic options for patients with inhibitors

Non-factor replacement therapy Emicizumab Fitusiran

(siRNA)Tissue factor

pathway inhibitor

Fitusiran & TFPI remain in clinical trials and has potential benefits for haemophilia B with inhibitors

Patient TimelineDOB 16/06/14

Date of Diagnosis 20/09/2018

Severe Haemophilia A

Inhibitor detected 31/10/18

67 presentations to hospital post inhibitor detection over 104 days.17 presentations to hospital post commencement of emicizumab over 106 days and NO BLEEDS

Courtesy of Dr Heather Tapp & Team

21.4(15.2–30.1)

15.7(11.2–22.0)

1.0(0.4–2.4)

1.8(0.7–4.6)

0

5

10

15

20

25

Arm A (n = 24) Arm C (n = 24)

95% reduction in ABR (relative risk 0.05; p < 0.0001)

88% reduction in ABR(relative risk 0.12; p < 0.0001)

*Comparison with data obtained from the NISABR; annulaised bleeding rate; BPAs, bypassing agents; NIS, non-interventional study

HAVEN-1: Comparison of emicizumab vs prior BPA treatment: treated bleeds* (September 8 2017 cut-off)

Mancuso ME et al. ASH 2017; poster 1071

Emicizumab prophylaxis Emicizumab prophylaxisPrior episodic BPAs Prior prophylactic BPAs

AB

R(9

5%

CI)

Mean ABRs over time were consistent between studies, in children

and adults with or without FVIII inhibitors

19

*Based on the calculated annualised bleed rate for bleeds treated with coagulation factors; †Only data for time intervals with ≥10 participants are reported

NE, not estimable

n 109 101 97 73 86 64 49 18 148 144 129 23 48 45 9 0

0

1

2

3

4

5

6

7

8

9

10

HAVEN 1 HAVEN 2 HAVEN 3 HAVEN 4

Mean A

BR

* (9

5%

CI)

1–24 weeks 25–48 weeks 49–72 weeks 73–96 weeks

NE† NE†

3.1

0.4

1.82.1

0.60.3

0.9

1.5

0.4 0.3

0.90.4

0.1 0.2

ABRs* over consecutive 24-week treatment intervals by study

The proportions of participants with zero bleeds† increased over time

20

*Only data for time intervals with ≥10 participants are reported†Bleeds treated with coagulation factors

Proportion of participants with 0 or 1–3 bleeds† over time

71.6

84.287.6 86.3

17.4

14.9 10.3 13.7

0

10

20

30

40

50

60

70

80

90

100

1–24 25–48 49–72 73–96

Perc

en

tage

of pa

rtic

ipa

nts 87.2 87.5 87.8

94.412.8 12.5 12.2

5.6

1–24 25–48 49–72 73–96 Weeks

HAVEN 1 HAVEN 2

62.8

72.977.5

91.330.424.3 19.4

8.7

1–24 25–48 49–72 73–96

64.6

77.8

27.117.8

1–24 25–48 49–72 73–96

HAVEN 3 HAVEN 4

NE* NE*

n 109 101 97 73 86 64 49 18 148 144 129 23 48 45 9 0

Over 99% of target joints resolved in patients on

emicizumab prophylaxis

21

*Target joints were defined as major joints (e.g. hip, elbow, wrist, shoulder, knee, and ankle) in which ≥3 bleeding events occurred over a

24-week period. Target joint resolution was defined as ≤2 bleeding events in a 52-week period in a joint previously defined as a target joint 1. Blanchette VS, et al. J Thromb Haemost. 2014;12:1935–39

▪ Target joint resolution was defined as ≤2 spontaneous

bleeding events in a 52-week period in a joint

previously defined as a target joint1

▪ 195 of 217 (90%) participants had no spontaneous or

traumatic bleeding into a target joint while on

emicizumab

▪ 498 of 519 (96%) of target joints had ≤2 spontaneous

or traumatic bleeding events while on emicizumab

Proportion of resolved target joints

98.7 100 99.2 100 99.2

0

10

20

30

40

50

60

70

80

90

100

HAVEN 1 HAVEN 2 HAVEN 3 HAVEN 4 Total

99.2%of target joints

resolved*

Patients with

target joint(s)

at baseline, n68 23 97 29 217

# of target joints

at baseline159 45 238 77 519

Haem-A-QoL, Haemophilia-Specific Quality of Life questionnaire; Haemo-QoL-SF, Haemophilia-Specific Quality of Life Assessment for Children Short Form; HRQoL, health-related quality of life; QoL, quality of life

QoL – Haem-A-QoL scores

1.Oldenburg J, et al. EAHAD 2018. P120.2. Oldenburg J, et al. N Engl J Med 2017;377(9):809-18.

Me

an

sco

re

Clinically meaningful improvement at week 25

Arm A: 52% Arm A: 72%

Arm B: 7% Arm B: 29%

Statistically significant, clinically meaningful improvements in HRQoL and health status were

seen with emicizumab prophylaxis versus no prophylaxis2

Lower

scores

reflect

better

HRQoL

Arm A: emicizumab prophylaxis (n = 31)

Arm C: emicizumab prophylaxis (n = 23)

Arm B: no prophylaxis (n = 16)

Clinically meaningful difference = -7 points Clinically meaningful difference = -10 points

Total score (adults)1 Physical health (adults)1

Haemo-QoL-SF (adolescents)1

Change in mean score from

baseline to week 25:

• Total score -11

• Physical health -25

23

Fitusiran (siRNA-AT)

• Subcutaneous administration

• Long duration of effect (4 weekly dosing)

• Synthetic siRNA – no inhibitors

• Prophylaxis for both HMA & HMB without

and with inhibitors

• ?Breakthrough bleeds can be safely managed

with FC replacement

• Thrombosis - rescue with antithrombin

concentrate?

• ?benefit for rarer bleeding disorders

1Kurnik et al., Haematologica; 92:982-5 (2007); 2Ettingshausen et al., Thromb Haemost; 85:218-20 (2001); 3Negrier et al., Blood;

81:690-5 (1993); 4Shetty et al., Br J Haematol; 138:541-4 (2007); 5Seghal et al., Nat Med, 21:492-7 (2015); 6Sorensen B, et al, ISTH

(2015)

• Investigational RNAi Therapeutic for the Treatment of Hemophilia

ASGPR(pH>5)

Fitusiran

Clathrin-coated pit

Clathrin-coated vesicle

Endosome

Recycling ASGPR

mRNA

Nucleus

AT

RISC

AT

FIX

FVIII

FIXa

FVIIa FVII

FVIIIa

FVa FV

FX

FXa

Fibrinogen Fibrin

ThrombinProthrombin

Blood clot

Hemophilia B

Hemophilia A

FVIII

FIXAT

Anti-TFPI Mechanism of Action

XPF-06741086

- TFPI limits production of Xa from the extrinsic pathway

- Anti-TFPI (PF-06741086) enables Xaproduction from the extrinsic pathway, in part compensating for loss from intrinsic pathway

Hemophilia A or B (including inhibitors), insufficient quantities of Xa are generated via the intrinsic pathway

Is ITI still valid?

Pros

• Simple treatment of breakthrough bleeds

• Simple management for surgery

• (Rare) or long-term adverse effects of non factor replacement therapy unknown

Cons

• Treatment burden and cost

• Low efficacy among high-risk patients

• Uncertain strategy following success

Julie Chris

HAVEN 1 and HAVEN 2 surgical procedure criteria

▪ Patients with planned surgeries, with the exception of minor procedures,

were excluded from both studies

▪ Unplanned emergency surgeries and minor procedures were performed in

patients receiving emicizumab

▪ Perioperative management was at the investigator’s discretion based on

individual clinical assessment, without specific guidance (per protocol) on

surgical management provided

– BPA dosing guidance provided during the studies was not specific for surgery, but for

BPA use for any reason1

31

1. Callaghan MU, et al. Use of Bypassing Agents Prior to and Post Bypassing Agent Dosing Guidance During Emicizumab Prophylaxis: Analyses from the HAVEN 1 Study Title. Presented at: 59th American Society of

Hematology Annual Meeting & Exposition; Atlanta, GA; December 9–12, 2017. Poster 3668.

Demographics and baseline characteristicsPatients undergoing surgical procedures from HAVEN 1 & 2

Characteristic

HAVEN 1

N=17

HAVEN 2

N=5

Total

N=22

Median (range) age (years) 20.0 (12–75) 11.0 (3–12) 14.5 (3–75)

Hemophilia severity at baseline, n (%)

Mild 1 (5.9) 0 1 (4.6)

Moderate 1 (5.9) 0 1 (4.6)

Severe 15 (88.2) 5 (100.0) 20 (90.9)

Median (range) number of bleeds in the

24 weeks before study entry12 (3–180) 5 (3–12) 11 (3–180)

32

• Unplanned emergency surgeries and minor procedures were performed in patients receiving emicizumab

• Perioperative management was at the investigator’s discretion based on individual clinical assessment, without

specific guidance (per protocol) on surgical management provided

• BPA dosing guidance provided during the studies was not specific for surgery, but for BPA use for any reason1

1. Callaghan MU, et al. Use of Bypassing Agents Prior to and Post Bypassing Agent Dosing Guidance During Emicizumab Prophylaxis:

Analyses from the HAVEN 1 Study

All surgical procedures

▪ Surgeries included

– Tooth extractions (6)

– CVAD procedures (13)

– Other (10)

33

29 surgeries

10 managed withprophylactic BPAs

8 procedures led to no post-op bleeds

2 procedures led to treated post-op surgical bleeds

19 managed withoutprophylactic BPAs

14 procedures led to no post-op

bleeds

2 procedure led to treated post-op surgical bleeds

3 procedures led to untreated post-op

surgical bleeds

CVAD, central venous access device.

34% 66%24 procedures in 17 patients in HAVEN 1

5 procedures in 5 patients in HAVEN 2

11%

26%

11%

6 extractions


1 procedure led to no post-op bleed

1 procedure led to treated post-op surgical bleeds


1 procedure led to no post-op bleed


1 procedure led to untreated post-op

surgical bleeds

Tooth extractions

▪ Antifibrinolytics were used for:

– 1 extraction managed with

prophylactic BPAs, with 1 treated

post-operative bleed

– 3 extractions managed without

prophylactic BPAs, with 2 treated

post-operative bleeds

34

33% 67%5 patients underwent 6 tooth extractions

(all in HAVEN 1)

50%

75%

50%

13 procedures


4 procedures led to no bleeds

0 procedures led to treated post-op surgical bleed


8 procedures led to no bleeds


1 procedure led to untreated post-op

bleed

CVAD insertion, replacement or removal

35

CVAD, central venous access device.

31% 69%10 procedures in 7 patients in HAVEN 1


0% 0%

Other procedures

9 patients underwent 10 other procedures

36

Right knee arthroscopy/ synovectomy/

debridement of arthrofibrosis and

chondroplasty

– 12 year old patient in HAVEN 1

– Prophylactic rFVIIa on day of surgery and

one day post surgery (total dose 1016 µg/kg)

– 1 post-operative bleed treated with rFVIIa;

total cumulative dose for 15 days after

surgery, 3326.3 µg/kg)

Laparoscopic appendectomy

– 12 year old in HAVEN 2

– Prophylactic aPCC (dose 2250 units,

49.8 U/kg) one day prior to surgery

– No post-operative bleeds

aPCC, activated prothrombin complex concentrate.



Major surgeries: synovectomy*

39

Synovectomy Synovectomy Arthrofibrosis +

chrondroplasty + joint

debridement +

synovectomy

Type of prophylaxis Standard rFVIII Standard rFVIII rFVIIa

Cumulative dose

Only pre-operative 55.0 U/kg 106.7 U/kg 170.2 mg/kg

Cumulative dose post-procedure 192.6 U/kg – 4087.8 mg/kg

Number of total doses post-procedure, n 4 – 49

Total post-op days on prophylaxis or

treatment

3 – 15

Bleed due to surgery No No Yes

Additional medication – – –

Adverse events of special interest No TE or TMA No TE or TMA No TE or TMA

*There was one additional major surgical case of synovectomy, which was managed without prophylaxis

Summary

▪ Inhibitors among PwHA remains an important morbidity

▪ Emicizumab reduces ABR over time and maintains a low bleed rate

– (potentially other NFRT to follow)

▪ Carefully plan for surgery among patients with chronic inhibitors receiving

emicizumab

42

haemophilia develop inhibitors … · pathway inhibitor fitusiran & tfpi remain in clinical...

Documents