EAHAD 2022 Congress Review

EAHAD 2022 Virtual Congress Review
Thinking Differently in Haemophilia:
Gene Therapy at EAHAD 2022
Welcome to the EAHAD 2022 Congress Review.
The 2022 EAHAD Congress was once again a virtual event,
welcoming over 2300 attendees from 76 countries, with a
wealth of sessions delivered across four days.
For this review, we have selected abstracts and presentations
from the scientific sessions that are most relevant to
those of us with an interest in gene therapy for people with
haemophilia. This includes GENEr8-1 – with key efficacy
and safety updates [page 2], and HRQoL data shared in an
abstract from O’Mahony et al. [page 2] – plus presentations
on the new 2-year analyses from the HOPE-B trial [page 5].
I hope you enjoy our summary of the key data from
this congress.
Professor Johannes Oldenburg
MORE INSIDE:
Advances in RNA Therapy page 10
Real-World Data page 12
Adherence, Preference, and Satisfaction page 13
Providing Haemophilia Education page 14
The abstracts and poster presentations can be found here
Developments in
Haemophilia A
Data from GENEr8-1,
plus a selection of abstracts
focused on ROCTAVIAN ®
(valoctocogene roxaparvovec),
giroctocogene fitelparvovec,
and emicizumab.
Read more on page 2
Developments in
Haemophilia B
Results from HOPE-B,
and abstracts looking at
etranacogene dezaparvovec
and verbrinacogene
setparvovec.
Read more on page 5
Advances in Gene Therapy
Clinical studies of
recombinant AAV vectors are
ongoing for the treatment
of severe haemophilia.
Read more on page 7
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EAHAD 2022 Virtual Congress Review
Developments in Haemophilia A
New data were presented in haemophilia A across a range of
treatments, from novel gene therapies to emicizumab. This included
the 2-year data from GENEr8-1.
In an EAHAD-supported research session,
Professor Johnny Mahlangu shared the 2-year
analysis looking at the efficacy and safety of
valoctocogene roxaparvovec gene transfer for
severe haemophilia A. ROCTAVIAN ® is indicated
for the treatment of severe haemophilia A in
adult patients without a history of factor VIII
inhibitors and without detectable antibodies
to AAV5. Please read the ROCTAVIAN ® SmPC
before prescribing. An overview of the safety
results from GENEr8-1 was presented,
highlighting that in this 2-year analysis the
most common AE remains ALT elevation,
which was seen in 89% of participants. Overall,
83% received immunosuppression treatment
in response to these elevations, and 53% of
those were off immunosuppression at Week
52, and 99% by Week 104. Other AEs included
headache, arthralgia, nausea, AST elevation,
and fatigue. There were no thrombotic events,
FVIII inhibitors, or non-cutaneous cancers. Four
new SAEs occurred in the last year of the study,
but none were attributed to valoctocogene
roxaparvovec or immunosuppression.
Professor Mahlangu briefly touched on the
FVIII activity by CSA over 3 years for the main
mITT and subset populations, before looking
at the mean ABR results, which suggest gene
therapy with valoctocogene roxaparvovec
is superior to FVIII prophylaxis. The mean
change from baseline was 4.1 treated
bleeds per year, reaching the threshold
for statistical superiority (P

EAHAD 2022 Virtual Congress Review
and without history of inhibitors received a
6x10 13 vg/kg infusion. Participants completed
HRQoL questionnaires at baseline and
26 and 52 weeks after gene therapy. Overall,
core outcomes of mental health, pain and
discomfort, and ability to perform daily activities
improved following gene therapy compared
to baseline. Mean baseline Haem-A-QoL
total score was 75.7, which improved above
the clinically important difference to 81.2
and 82.2 at Weeks 26 and 52, respectively
(P

EAHAD 2022 Virtual Congress Review
single dose of etranacogene dezaparvovec
resulted in a stable and durable increase
in mean FIX activity into the near-normal
range at 18 months, and gave haemostatic
protection following discontinuation of
prophylactic FIX infusions. [PO143]
Gomez et al. shared multi-year durable
FIX expression data from a Phase 2b study
of etranacogene dezaparvovec demonstrating
proof of concept of disease correction
using the gain-of-function FIX variant in
participants with pre-existing AAV5 NAbs.
Participants in this ongoing open-label,
single-dose, single-arm study (N=3) received
a single intravenous dose (2×10 13 gc/kg).
The primary efficacy endpoint was FIX activity
≥5% 6 weeks after dosing. All participants
discontinued routine FIX prophylaxis, and
FIX activity increased from ≤1% to a mean
of 31% at Week 6, and continued to rise to
an average of 50% at 2.5 years. A sustained
reduction in bleeds and FIX replacement
was demonstrated at 2.5-year follow-up.
FIX consumption
Fix consumption for 54 participants
(IU/year/ participant)
450,000
400,000
350,000
300,000
250,000
200,000
150,000
100,000
50,000
Data are for 54 participants.
0
257,339
12,913
Lead-in 0–6 months 7–12 months
One participant experienced bleeds (one
traumatic, and one spontaneous and mild)
requiring a single dose of FIX replacement.
Two TRAEs resolved without intervention
in one participant, with no new TRAEs over
the last 2 years of follow-up, including no
clinically significant transaminase elevations.
No participant developed inhibitors
to FIX. There was no requirement for
immunosuppression. [PO098]
The study design for B-LIEVE – a Phase
1/2 dose confirmation clinical trial of
verbrinacogene setparvovec (previously
known as FLT180a) for haemophilia B – was
presented by Young et al. The starting dose
for B-LIEVE was selected based on the
results of B-AMAZE and multiple modelling
approaches. In B-AMAZE, FIX activity showed
a dose-dependent response that ranged from
therapeutic levels below the normal range
to FIX levels >150%. Based on this, a dose of
7.7×10 11 vg/kg with a dose cap of 6.93×10 13 vg
was selected for the first patients in
8,399
8,487
13–18 months
p-value

EAHAD 2022 Virtual Congress Review
to identify what place gene therapy has in
haemophilia care, now and in the future.
Fletcher et al. presented data from
65 interviews completed to date among
patients, family members, and healthcare
professionals. The results highlight that gene
therapy is a new and potentially life-changing
therapy for people with haemophilia. In
order for its potential to be realised by all
stakeholders, the EXIGENCY group makes
three key recommendations. The first
suggests that patient education around
gene therapy should begin well in advance
of it being offered as a treatment option.
Secondly, psychosocial support should be
built into all stages of the process. And
finally, there is a need for greater integration
between research and clinical care teams to
improve knowledge of gene therapy, and the
impact it might have on any individual who
chooses it as a treatment option. [PO063]
Skinner et al. provided an integrated analysis
of gene therapy outcomes from a systematic
review of published data, and from coreHEM
– a separate initiative to evaluate the efficacy,
safety, comparative effectiveness, and
value of gene therapy. CoreHEM outcomes
were frequency of bleeds, factor activity
level, duration of expression, chronic
pain, healthcare resource utilisation, and
mental health. The value framework was
based around three tiers: health status
achieved/retained, process of recovery, and
sustainability of health. Mapping the value
framework to coreHEM outcomes showed
broad overlap, most prominently in duration
of expression and factor activity level. The
authors noted that a gap analysis identified
several coreHEM outcomes – particularly
patient-reported outcomes of chronic pain
and mental health transformation – where
data collection should be prioritised or
rapidly published to enable a complete
data-driven evaluation of the differentiating
features. [PO066]
Konkle et al. gave an overview of the
WFH gene therapy registry set up and
aims. The primary objective is to determine
long-term safety of FVIII and FIX gene
therapies. Secondary objectives focus on
efficacy and durability, and the long-term
quality of life and burden of disease after
gene therapy infusion. The core data set
also includes information on demographics,
medical history, vector infusion details,
surgeries, and mortality. Data will be
collected at 3, 6, 9, 12, 18, and 24 months
post-infusion, and annually thereafter and
will be captured directly from participating
HTCs or through data linkage with existing
registries. Patient-reported outcomes will
be collected via a mobile application. The
registry will provide the community with a
global tool to collect long-term follow-up
data on people with haemophilia who receive
gene therapy, and will be able to monitor
efficacy as well as known and unknown
safety issues. [PO139]
Dr Paul Batty presented an overview of the
current status of gene therapies, with a focus
on recent efficacy and safety data. To date,
the longest reported follow-up in clinical
studies is 5 years for haemophilia A and
8 years for haemophilia B, with ongoing
FVIII or FIX expression and reduction in
bleeding episodes – although questions
remain surrounding variability in response
and the long-term durability. Although
infusion reactions have been reported
in small numbers, these have generally
been mild. The predominant AE has been
elevations in liver enzymes, some of which
have been assigned to activation of a
cytotoxic T-cell immune response. In view
of the loss of vector expression that has
occurred with this reaction, studies have
incorporated immunosuppressive mitigation
strategies to preserve transgene expression.
Key long-term safety considerations relate
to liver health and whether vector integration
might result in genotoxicity. Currently four
Phase 3 studies are ongoing, and the speaker
expressed the view that licensing approvals
will be seen in the near future for the first
AAV-based approach for haemophilia.
[SP012]
Professor Thierry Vandendriessche’s
abstract focused on the future prospects for
non-AAV gene and cell therapy, addressing
the advantages, limitations, and prospects for
the treatment of patients with haemophilia.
Questions remain about whether the AAVbased
expression will be life-long, and –
since AAV is mostly non-integrating –
FVIII and FIX expression will likely decline
due to dilution of viral genomes in the
face of cell division. This limitation could
be especially important when considering
treating paediatric patients given that
hepatocyte proliferation is even more
pronounced than in adults. This justifies
the use of integrating systems such as
lentiviral vectors to deliver FVIII and FIX
genes into the target cells, allowing stable
expression even upon cell division. Lentiviral
vectors can also be employed in the context
of ex vivo gene therapy for haemophilia
based on gene-modified hematopoietic
stem or progenitor cells. Alternatively, to
achieve targeted integration into predefined
loci, gene editing can be employed based
on CRISPR/Cas. [SP014]
Haemophilia is a rare, life-long disease that
requires comprehensive care. Retrospective
data suggests that comprehensive care
centres can deliver a number of benefits,
including reductions in absence from
school or work, reduced hospitalisation and
mortality, increased self-efficacy, and lower
annual treatment costs. Within a session on
the delivery of care, Professor Ana Boban
gave an update on the accreditation of
haemophilia and gene therapy treatment
centres – an initiative launched in 2013 by
EUHANET, in coordination with EAHAD
and the EHC. The current accreditation
process is run by EAHAD, and centres are
designated as EHCCC or EHTC, based on
evaluation of their ability to provide care
for haemophilia and allied disorders. At
present, there are 159 centres registered
across 34 countries – 117 as EHCCC, and
42 as EHTC. Novel treatment possibilities
improve prophylaxis and provide better
quality of life, but often require increased
medical expertise, patient education,
information exchange, and reorganisation.
Gene therapy calls for a new set of practices,
reassessment of the infrastructure and an
update of current processes in haemophilia
centres. To facilitate these changes, EAHAD,
in collaboration with EHC, has taken steps to
define necessary measures for improvement,
build a novel model for implementation of
gene therapy, and provide a new auditing
8 9

EAHAD 2022 Virtual Congress Review
and certification protocol. New European
guidelines for the certification of EHTCs
will provide a set of standards, and outline
the specialised services needed to monitor
patients on new treatments. Alongside this,
the on-site auditing process will create a
culture of quality improvement, offering
education to participants and assessing
patient care. EHTCs will form a tight network
through the hub and spoke model, with the
aim to address all aspects of gene therapy
Advances in RNA Therapy
– from dosing and surveillance immediately
post-infusion to long-term follow-up.
Three main gene therapy work streams
will be implemented around supervision,
infusion, and follow-up. The EAHAD audit
and accreditation process has a challenging
task to help haemophilia centres to improve
the delivery of care by a multidisciplinary
integrated comprehensive care model and
equal access to all novel therapies, including
gene therapy to all patients. [SP019]
Professor Robert Klamroth presented data from the ATLAS-A/B trial
of fitusiran – an investigational siRNA targeting antithrombin for the
treatment of haemophilia.
Rebalancing haemostasis is the goal of
haemophilia therapy. Factor replacement
is one of the standard approaches, but
non-factor therapies can restore thrombin
generation sufficient to achieve haemostasis
by intervening at different points in the
coagulation cascade. In Phase 1 and 2
studies, monthly SC prophylaxis with
fitusiran resulted in sustained antithrombin
lowering and reduced ABR in people with
haemophilia A or B, regardless of inhibitor
status. ATLAS-A/B was an open-label
Phase 3 study in 120 adult haemophilia
patients without inhibitors.
Fitusiran met the primary efficacy
endpoint, with significant reductions in
treated bleeds for both all treated bleeds
and treated joint bleeds. Subgroup analyses
by haemophilia subtype confirmed the
results, with bleeding rates reduced to
0.0 in haemophilia A, and 2.7 in haemophilia
B. Furthermore, in the fitusiran arm
50.6% of participants had zero bleeds,
and 83.5% experienced three or fewer
bleeding events. Professor Klamroth
noted that the results consistently favoured
fitusiran prophylaxis over on-demand
factor concentrate. Quality of life was
also improved, with clinically meaningful
improvements in both total Haem-A-QoL,
as well as in the key domain of physical
health score. The results seen in ATLAS-A/B
were consistent with those observed in
the ALTAS-INH study, assessing fitusiran
prophylaxis versus on-demand treatment
in haemophilia A or B with inhibitors.
Overall, 78.5% of patients receiving fitusiran
experienced a TEAE, compared to 45.0%
Bleeding events during the efficacy period
Median ABR
35
30
25
20
15
10
5
0
Observed median ABR
for all treated bleeds (IQR)
21.8
(8.4, 41.0)
On Demand
factor concentration
(n=40)
Estimated ABR † reduction 89.9%
(95% Cl, 84.1, 93.6)
(p10) and randomisation era of haemophilia type (A vs B) as fixed effects, and the logarithm of the duration that each
patient spends in the efficacy period matching the bleeding episode being analysed as an offset variable
(P value vs null hypothesis of ratio = 1).
Professor Robert Klamroth
in the on-demand factor concentrate
arm. There were no reports of thrombosis,
and the differences in reported TEAEs of
special interest between the two arms were
consistent with the previously identified
risks of fitusiran.
Professor Klamroth concluded that
fitusiran prophylaxis results in a statistically
Reduced bleeding rate
Median Observed Annualized Bleeding Rate for Treated Joint Bleeds
35
30
25
20
15
10
5
0
Observed median ABR
for treated joint bleeds (IQR)
15.9
(4.2, 33.5)
On Demand
factor concentration
(n=40)
Estimated ABR † reduction 90.3%
(95% Cl, 83.9, 94.1)
(p

EAHAD 2022 Virtual Congress Review
Real-World Data
Understanding the experiences of real-world patients is important to be able
to assess the impact of different treatment options on outcomes in clinical
practice. Key questions remain around the impact of prophylaxis regimens on
quality of life, as well as long-term issues such as joint health.
CHESS II was a burden of illness study.
New data were presented from a
retrospective analysis in a subset of
314 people from France, Germany, Italy,
Spain, and the UK, with the aim of examining
the association between bleeding events and
quality of life in adults with haemophilia A.
85% of participants experienced at least one
annual bleeding event, and the frequency
of bleeds was inversely related to HRQoL.
Mean EQ-5D-VAS in those with no bleeding
events was 25.7 points higher than in the
group who experienced ≥5 annual events.
Overall, quality of life was highest in those
with no bleeding events. Additional factors
that may affect the relationship between
bleeding frequency and patient-reported
outcomes merit further study. [PO034]
CHESS II data were also shared in a poster
from Kar et al., with a focus on joint health in
177 young adults (aged 18 to 30) with severe
haemophilia receiving primary prophylaxis
and without current inhibitors. The analysis
found joint morbidity in 36%, and an ABR of
2.5. Problem joints were reported in 29% of
the cohort; of those, 62% suffered from one
problem joint, while 38% had two or more.
The results in this real-world population
of young patients with severe haemophilia
align with findings from the Joint Outcome
Continuation Study, and indicate that chronic
joint morbidity remains a significant area of
unmet need despite physician-reported use
of prophylaxis. [PO083]
Real-world data on bleeding pattern in a
cohort of haemophilia A patients treated
with emicizumab were presented by
Levy-Mendelovich et al. This longitudinal
prospective observational cohort study
included 70 patients with ≥18 months’
follow-up. The incidence of traumatic
and spontaneous bleeding episodes
was not significantly different during
selected timepoints. Most trauma-related
treated bleeds resulted from either
haemarthrosis (53%) or head trauma (33%).
Spontaneous bleeding episodes were mostly
haemarthroses (80%). Logistic regression
was used to look for potential associations
between spontaneous bleeds, patient age,
ABR before emicizumab treatment, and the
presence of inhibitors. The odds of bleeding
while on emicizumab increased by a factor
of 1.029 for every 1 year of age (P=0.034).
No difference was found for the presence of
inhibitors. This real-world analysis reveals
that the risk of bleeding persists despite
emicizumab, especially in older patients.
The authors suggest the data may help
clinicians in counselling patients, and in
planning their management. [PO113]
Arcudi et al., presented their single-centre
experience in 17 patients receiving emicizumab
over a median time of 48 weeks. After switch
to emicizumab, ABR showed a 73% reduction
from 2.62 to 0.71 (P

EAHAD 2022 Virtual Congress Review
selection of attributes in a new discretechoice
experiment to quantify the drivers of
patient preference and risk tolerance for new
therapies in a larger sample of people living
with haemophilia. [PO112]
Treatment satisfaction was the topic of
a poster from Zozulya et al. using data
from an online survey of 100 adults with
haemophilia A from the Moscow region.
In this group, compliance was low, with more
than 40% reporting that they did not visit
their haematologist annually, and 85% did
not undergo regular laboratory examination.
Overall, 73% were prescribed plasma-derived
products, and 42% received therapy 3-times
a week or more often. Recombinant factor
therapy was more often given to patients
aged 19 to 40. The results showed 47% of
respondents were not satisfied, or were only
partially satisfied with their health status.
Physical activity limitation was observed in
all age groups, with 73% reporting joint pain
and 60% experiencing restricted movement.
In total, 92% wanted to improve their quality
of life, and one-third would like to reduce the
frequency of injections. Participants in the
study believed their quality of life would be
improved by changing the frequency, route of
administration, and dosage of their treatment
regimen, as well as by strengthening the
musculoskeletal system. [PO141]
Providing Haemophilia Education
There is an ongoing need for education around inherited bleeding
disorders. Many new models are emerging for both the funding and
development of innovative new technologies to help boost knowledge
and increase patient empowerment.
Prior to the marketing authorisation of
emicizumab, in 2018 the French Medicines
Agency gave exceptional authorisation for
use of emicizumab in a cohort of severe
haemophilia A patients with inhibitors.
The French Haemophilia Association was
asked to indicate the advantages and
disadvantages of the drug for people with
or without inhibitors. In view of the major
changes compared with previous treatment,
the association informed the authorities that
educational programmes should be set up.
In their poster, Sannié et al. described the
obligation for the manufacturer to finance
education, and the process of designing the
programme. The educational programme
was designed by an interdisciplinary working
group, which devised seven themed in-person
workshops and four video-conferences.
Carers and patient resource facilitators were
trained to implement the programme. The
authors conclude that the experience is a
useful precedent for associations and carers.
It also paves the way to an innovative solution
for support and funding, where programmes
are not the financial responsibility of the
community, but retain independence over
content and design. [PO079]
Education was also covered in a poster
from Robinson et al. on behalf of the EHC.
A community working group was tasked with
developing a mobile phone app to engage a
wide range of learners wherever they are in
their knowledge journey around inherited
bleeding disorders. The output is EHCucate
app, which contains educational content
developed by a team with diverse expertise
in consultation with the community. The app
includes self-assessment opportunities,
multimedia audio-visual components,
gamification elements, deep-dive resources,
and individualised quick reference
collections. The resulting resource makes
complex information broadly accessible and
engaging. EHCucate aims to personalise the
learner experience, and to change and adapt
as the treatment landscape evolves.
[PO195]
LIST OF ABBREVIATIONS
AAV – adeno-associated virus
ABR – annualised bleeding rate
AE – adverse event
ALT – alanine aminotransferase
AST – aspartate transaminase
BDD – B-domain deleted
CHESS – Cost of Haemophilia Across
Europe: a Socioeconomic Survey
CI – confidence interval
CSA – chromogenic substrate assay
CV – cardiovascular
EQ-5D-VAS – EuroQoL-5D visual
analogue scale
EHC – European Haemophilia
Consortium
EUHANET – European Haemophilia
Network
EHCCC – European Haemophilia
Comprehensive Care Centres
EHTC – European Haemophilia
Treating Centres
FIX – factor IX
FVIII – factor VIII
gc – genome copy
Haem-A-QoL – haemophilia quality
of life questionnaire for adults
HCV – hepatitis C virus
HJHS – Haemophilia Joint Health
Score
HIV – human immunodeficiency virus
HRQoL – health-related quality of life
HTC – haemophilia treatment centre
IQR – interquartile range
LFT – liver function test
Santamaria et al. gave a poster on increasing
empowerment in the self-treatment of people
with haemophilia, looking specifically at
virtual reality as a training tool for children
with congenital coagulopathies. Inside the
virtual reality experience, a 3D animated
character (Nixi) interacts with a 17-year-old
boy with haemophilia (Nacho). Nixi and the
spectator travel back in time to discover how
Nacho administered his medication for the
first time when he was 8 years old. In order
to assess the effectiveness and psychological
aspects of the training, the group intend to
perform three questionnaires to measure
satisfaction, anxiety, and quality of life.
The authors believe that new technologies
such as these can be useful in supporting
children’s journey to autonomy in a chronic
disease. [PO197]
MAFLD – metabolic-associated fatty
liver disease
mITT – modified intent to treat
NASH – non-alcoholic fatty
liver disease
NAb – neutralising antibody
PCR – polymerase chain reaction
SAE – serious adverse event
SC – subcutaneous
SE – standard error
siRNA – small interference RNA
TEAE – treatment-emergent
adverse event
TRAE – treatment-related adverse
event
vg – vector genomes
WFH – World Federation of Hemophilia
14 15