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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
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
2 managed withprophylactic BPAs
1 procedure led to no post-op bleed
1 procedure led to treated post-op surgical bleeds
4 managed withoutprophylactic BPAs
1 procedure led to no post-op bleed
2 procedures led to treated post-op surgical bleeds
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 managed withprophylactic BPAs
4 procedures led to no bleeds
0 procedures led to treated post-op surgical bleed
9 managed withoutprophylactic BPAs
8 procedures led to no bleeds
0 procedures led to treated post-op surgical 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
3 procedures in 3 patients in HAVEN 2
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.
8 procedures in 7 patients in HAVEN 1
2 procedures in 2 patients in HAVEN 2
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