EAHAD 2021 Congress Review

EAHAD 2021 Congress Review
Thinking Differently in Haemophilia:
Gene therapy at EAHAD 2021
Welcome to the EAHAD 2021 Congress Review.
EAHAD 2021 was held as a virtual congress on 2–5 February
2021, showcasing high-quality scientific research and
dialogue, with engaging plenary sessions, symposiums
and several posters focused on the topic of gene therapy.
This review covers new data in gene therapy trials for
haemophilia A and B, discussion of seroprevalence of NAbs,
clearance of vector, details of the immune reaction in gene
therapy and the perspectives of individual members of the
MDT involved in the patient journey.
We hope you enjoy this summary of gene therapy at
the congress.
Professor Víctor Jiménez Yuste
MORE INSIDE:
Novel therapies in haemophilia page 2
The progression of gene therapy for haemophilia page 2
Is integration a concern in gene therapy? page 13
Symposiums review page 15
The abstract presentations, plenary presentations and
symposiums can be found here using your congress log in.
Advances in haemophilia A
Phase 1/2 results of TAK-754,
SPK-8016 and seroprevalence
to the BAY 2599023 capsid
were presented.
Read more on page 5
Advances in haemophilia B
Discussion of the Phase 3
HOPE-B study, Phase 1/2
results of FLT180a and
AMT-060, and Phase 2b
results of AMT-061.
Turn to page 8
The Exigency programme
The UK-based programme,
evaluating the expectations
of gene therapy in the
haemophilia community,
presented abstracts from
three sub-studies.
Find out more on page 12
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EAHAD 2021 Congress Review
Novel Therapies in Haemophilia
Professor Hervé Chambost chaired a plenary session that provided
an overview of the novel therapies in use and on the horizon for the
management of haemophilia, including gene therapy.
Dr David Lillicrap reviewed FVIII biology and the
pros and cons of alternative treatment options
including non-FVIII replacement therapies and
gene therapy to answer the question Will there
be a role for FVIII concentrate in haemophilia in
the future? The pros and cons of gene therapy
were reviewed. A single administration offering
long term treatment, the avoidance of peaks
and troughs, and the potential that it may
be less immunogenic than FVIII replacement
therapies were cited as pros. The key
downsides were presented as non-eligibility
due to pre-existing anti-AAV immunity, early,
usually transient hepatotoxicity, variability
of attained factor levels, the potential for
long term genotoxicity, and the uncertain
durability of response, although Dr Lillicrap
acknowledged that response up to 5 years
is feasible. Dr Lillicrap concluded that
there will be a place for FVIII replacement
therapies in the future for the treatment of
breakthrough bleeds, to obtain reliable levels
of laboratory-measured haemostatic activity,
to enable global access to therapy to manage
haemophilia A and, speculatively, to address
non-haemostatic functions.
The Progression of Gene Therapy
for Haemophilia
There were several sessions at EAHAD 2021 demonstrating the progress
of gene therapy, including an abstract providing a snapshot of gene therapy
trials as of October 2020, a plenary session covering key Phase 3 data,
an update on the development of the WFH Gene Therapy Register, and
considerations for optimising sharing of knowledge in clinical practice.
Moon and Moon presented an update on gene
therapy clinical trials for haemophilia. As of
October 2020 there were two completed and
five terminated/suspended trials in HB, and
30 ongoing/upcoming (17 HA, 13 HB). Three
quarters of the trials listed were in Phase 1
or 2, and all trials recruited participants with
a severe phenotype, with moderately severe
participants included in 14. Two trials included
paediatric patients and one, participants with
inhibitors. Of the terminated/suspended trials,
none attributed discontinuation to safety
findings. Of the ongoing HA trials, 13 include
an AAV vector, three a lentiviral vector and one,
cell therapy with a non-viral vector. In the HB
trials 12 used an AAV vector and two a lentiviral
vector. The authors concluded that publication
of results from gene therapy trials will provide
insight for future research. [ABS079]
Dr Glenn Pierce reviewed Gene therapy in
haemophilia: where are we now? He provided
a brief overview of AAV as a vector and of the
developments made in the AAV expression
cassette. He outlined the progress made
in both haemophilia A and B, commenting
that stable expression up to 8 years had
been observed following gene therapy with
FIX, and that the introduction of FIX-Padua
enabled high factor levels to be achieved. The
results of the Phase 3 trial of etranacogene
dezaparvovec (AAV5-Padua hFIX) up to
1 year were presented (see Dr Steven Pipe’s
presentation on p10). In the Phase 3 trial of
ROCTAVIAN ® (valoctocogene roxaparvovec),
(AAV5-FVIIISQ), FVIII expression was observed
in most participants at 1 year, although an
approximately 75% loss of expression over
4 years in the Phase 1/2 study was observed.
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.
Dr Pierce presented the Phase 3 results,
showing that FVIII stabilised at approximately
30% by 20 weeks, although variability was
observed with one participant experiencing up
to 450 IU/dl and another 0 IU/dl. Of the first
16 patients evaluated at the 1-year timepoint,
two had no response to gene therapy. The
median and mean ABR at 1 year was 0 and 0.8,
respectively and 80% of participants were bleed
free. All patients were receiving prophylactic
FVIII at baseline, however by 1 year infusions
were reduced to a median of 0 (mean of 2),
and 67% of participants were infusion-free.
Dr Pierce commented that the significance of
elevated transaminases is less clear in FVIII
than FIX; prednisolone appears less effective in
managing elevations in ALT, and in managing
any potential loss of FVIII activity. The shortand
long-term safety considerations for
gene therapy were reviewed and Dr Pierce
Valoctocogene roxaparvovec Phase 3 results: FVIII activity levels for N=112 rollover population in the
mild haemophilic range at 1 year 1
Factor VIII Activity
(IU/dL, chromogenic)
500
450
400
350
300
250
200
150
100
50
0
150 IU/dL
50 IU/dL
Baseline
1–4 5–8 9–12 13–16 17–20 21–24 25–28 29–32 33–36 37–40 41–44 45–48 49–52
Weeks
Dr Glenn Pierce
2 3

EAHAD 2021 Congress Review
outlined the need to understand how gene
therapy works from a cellular and molecular
perspective to improve safety and potentially
to better comprehend the variability.
Konkle et al outlined the development of
the WFH gene therapy register (GTR), a
prospective, observational and longitudinal
registry designed to collect data on the
long-term safety, variability and duration
of efficacy after gene therapy, either as
part of a clinical trial or post-approval.
The GTR was developed in collaboration with
ISTH, EAHAD, EHC, the US NHF, ATHN, and
industry partners, through an iterative process
with guidance from the EMA and FDA. The
core data set is in press (Konkle et al 2020),
and includes data on demographics, vector
infusion, safety, efficacy and quality of life.
WFH GTR Core Data Set
Demographics
Medical/Clinical History
Gene Therapy Infusion Details
Safety Data
Adverse Events of Interest:
FVIII/FIX Inhibitors
Thromboembolic Events
Autoimmune Disorders
Malignancies
Liver function
Death
Efficacy Data
Bleeding Events
Factor Activity Levels
Use of Hemostatic Treatment
Patient Reported Outcome Measures
Quality of Life
Burden of Disease
Mortality
Konkle et al [ABS203]
Developed through an iterative process,
and following guidance of the European Medicines
Agency and the US Food and Drug Administration.
Data will be collected at 3, 6, 9, 12, 18, and
24 months either directly from haemophilia
treatment centres or through existing
haemophilia registries that meet outlined
criteria, such as ATHN in the US. The registry
will be ready to receive data mid-2021.
The WFH GTR will enable rare adverse
events in a small patient population over
a large geographical area to be detected.
Konkle et al concluded that the unknowns
of gene therapy make it important that
all those in the haemophilia community
receiving gene therapy are followed up
over their lifetime. [ABS203]
Declan Noone, EHC President, reviewed
the Delivery of gene therapy in haemophilia
in Europe. He outlined that capturing and
efficient reporting of data related to the
rapid roll out of previous novel therapies has
been challenging. With only a small number
of patients likely to be treated with gene
therapy there is the potential that patients
and clinicians may lack information that is
available in the healthcare system but that
is not being shared in a timely and efficient
way. Optimising outcomes for gene therapy
will be essential, and this may be possible
through the EAHAD/EHC hub-and-spoke
model, with the hub collating all outcome
data. This may enable greater understanding
of response including capsid differences,
variability, and immunosuppressant
protocols. Mr Noone concluded that
coordination and international collaboration,
such as through the WFH GTR, will be
essential in maximising limited data and
ensuring that each patient is able to learn
from the collective experience of all gene
therapy patients who have gone before them.
Advances in Gene Therapy for
Haemophilia A
Results from the Phase 1/2 studies of SPK-8016 and TAK-754 were
presented, as was a study investigating the seroprevalence of NAbs against
the capsid for BAY 2599023, and in vitro primary hepatocyte models to
screen novel liver-targeted AAV capsids for transduction efficiency.
Dr Spencer Sullivan presented data on the
first four patients to complete 1 year follow
up of SPK-8016: Preliminary results from a
Phase 1/2 clinical trial of gene therapy for
hemophilia A. This safety and dose finding
study began at a dose of 5x10 11 vg/kg.
The patients experienced no SAEs and
no inhibitor development. FVIII levels
were variable over the first 12 weeks and
three participants experienced a decline
in expression that prompted initiation of
corticosteroid therapy. Steroid use exceeded
4–5 months so steroid-sparing co-therapy
was used to limit exposure. Dr Sullivan
confirmed during the panel discussion that
this is a standard approach for treating
autoimmune hepatitis. One patient receiving
azathioprine had elevated transaminases
which resolved on discontinuation. One
participant had isolated ALT elevations above
the ULN at 11 and 15 months that did not
correlate with a change in FVIII expression.
FVIII activity levels of 5–6% at 1 year were
approximately 4 times lower in participants
who received corticosteroids than for the one
who did not. Good preliminary durability was
observed in all participants, and annualised
infusion and bleeding rates were reduced by
98% and 85%, respectively. Three patients
receiving prophylaxis prior to gene therapy
were able to discontinue use and one patient
using on-demand therapy, with 18 bleeds in
the year prior, experienced no bleeds after
gene therapy. All patients converted to a
mild phenotype. Dr Sullivan concluded that
the ongoing trial of SPK-8016 demonstrated
acceptable safety and sustained FVIII activity
levels ranging from 5.9–21.8% at ≥52 weeks
follow up.
The results of an ongoing Phase 1/2 safety
and dose-escalation study of TAK-754, a
modified AAV8 capsid containing a BDD
coagulation FVIII transgene with liver-specific
promoter, were presented by Chapin et al.
Four men with severe haemophilia A, who
were using FVIII prophylaxis prior to the study,
received an infusion of TAK-754 at a dose of
2x10 12 cp/kg or 6x10 12 cp/kg (2 participants per
cohort). All participants completed ≥10 months
follow up. No infusion reactions, development
of inhibitors or thrombosis were observed.
Minor transaminase elevations were seen in
all participants, and all received corticosteroids
(n=3) or corticosteroid prophylaxis (n=1).
A total of 61 AEs were reported, with 8 related
to the product and 14 related to corticosteroid
use. Dose-dependent FVIII expression
4 5

EAHAD 2021 Congress Review
peaked 4–9 weeks following infusion
(2x10 12 cp/kg, 3.8% and 11%; 6x10 12 cp/kg,
54.7% and 69.4%), and significantly declined
during tapering of corticosteroids. Three
participants resumed FVIII prophylaxis.
Analysis of the loss of FVIII expression is
on-going. [ABS185]
Ferrante et al investigated the seroprevalence
of pre-existing NAbs and anti-drug antibodies
(ADA) against AAVhu37, the capsid for
BAY 2599023 (AAVhu37.hFVIIIco), a
non-replicating AAV vector containing a
single-stranded DNA genome encoding
a BDD FVIII, driven by a liver-specific
promoter/enhancer combination. In this
Phase 1/2 study, 100 participants with
severe haemophilia A with no detectable
neutralising immunity against AAVhu37
above a titer of 5, received a single infusion
of BAY 2599023. Low seroprevalence was
observed for both NAbs and ADAs with
a maximum titer of 26 and 182 against
AAVhu37, respectively. Five patients (83.3%)
had durable and sustained FVIII levels,
with cohorts 1 (0.5x10 13 gc/kg, n=2)
2 (1.0x10 13 gc/kg, n=2) and 3 (2.0x10 13 gc/kg,
n=2) completing 21, 16 and 11 months of
follow up, respectively. Once protective
levels of FVIII were achieved (>11 IU/dL)
no spontaneous bleeds or bleeds requiring
treatment were observed. No SAEs were
reported in any cohort. The authors
concluded that BAY 2599023 has broad
eligibility in haemophilia A due to low
seroprevalence to AAVhu37, a good safety
profile and sustained FVIII expression.
[ABS057]
Liu et al presented the results of a study
to evaluate whether an in vitro primary
hepatocyte culture could predict in vivo
liver-directed AAV-mediated FVIII expression
in different species, and the effects of
isotretinoin on FVIII expression. In vitro
AAV transduction assays were developed
in cultured primary hepatocytes from
humans, mice, dogs and cynomolgus
and rhesus monkeys. AAV5-human FVIII
and a novel liver-targeting capsid were
transduced into mouse, human, and
NHP hepatocytes, and AAV5-canine FVIII
transduced into mouse, dog, and human
hepatocytes. Relative vector DNA and
RNA levels across species obtained in vitro
correlated with in vivo data. Isotretinoin
had no effect on hFVIII-SQ vector DNA
but hFVIII-SQ RNA was decreased by
approximately 50%; removal of isotretinoin
reversed this effect. hFVIII-SQ RNA was
restored after approximately 4 days. Liu et al
concluded that in vitro primary hepatocyte
models may be valuable in screening novel
liver-targeted AAV capsids for transduction
efficiency, assessing variability of liverdirected
AAV-mediated gene expression,
and for evaluating MOAs mediating drug-drug
interactions. [ABS020]
Continuous isotretinoin exposure (A) and withdrawal after 4 days in transduced primary human hepatocytes (B)
A)
B)
FVIII DNA/ug DNA
FVIII DNA/ug DNA
2.5 x 10 9
2 x 10 9
1.5 x 10 9
1 x 10 9
5 x 10 8
0
DNA
**
*
3 x 10 9 1 x 10 5
8 x 10 4
2 x 10 9 6 x 10 4
4 x 10 4
1 x 10 9
2 x 10 4
0
0
Vehicle 5ng/ml 500ng/ml
Vehicle 5ng/ml 500ng/ml
Isotretinoin
Isotretinoin
*
****
Vehicle 5ng/ml 5ng/ml, 500ng/ml
withdrawal
Isotretinoin
*P

EAHAD 2021 Congress Review
Advances for Gene Therapy in
Haemophilia B
Efficacy and safety results up to 5 years from the Phase 1/2 study of
AMT-060 were presented, along with the 2-year follow-up data from
the Phase 2b trial of etranacogene dezaparvovec (AMT-061), and the
Phase 3 HOPE-B study. In addition the time to clearance from body
fluids of fidanacogene elaparvovec, and results from a Phase 1/2 study
to evaluate the safety and efficacy of FLT180a were reviewed.
Leebeek et al presented the results of a
Phase 1/2 study into the safety and efficacy
of AMT-060 up to 5 years. AMT-060 is an
AAV5 vector with codon-optimised wild-type
human FIX gene and liver-specific promoter.
Estimated mean annualized total
FIX replacement (IU)
400000
350000
300000
250000
200000
150000
100000
50000
0
400000
350000
300000
250000
200000
150000
100000
50000
0
354,800
Cohort 1
Pretreatment
Year 1 Year 2 Year 3 Year 4 Year 5
173,200
82%
64,000
91% 83% 89% 84%
31,700
60,842
Cohort 2
38,026
57,913
78% 92% 96% 99% 99%
38,600
14,600 7,605 2,395 1,378
Pretreatment
Year 1 Year 2 Year 3 Year 4 Year 5*
It was evaluated in 10 adult males with severe
haemophilia who received a single infusion at
a dose of 5x10 12 (cohort 1, n=5) or 2x10 13 gc/kg
(cohort 2, n=5). Mean FIX activity in cohort 1
and 2 was 5.2% and 7.4% at the 5- and
Mean annualized total bleeds (n)
Prophylaxis was tapered and discontinued by 12 weeks if FIX activity was maintained at ≥2%;
*Cohort 2 data for year 5 represents 6 months.
16
14
12
10
8
6
4
2
0
16
14
12
10
8
6
4
2
0
14.4
Cohort 1
47% 81% 57% 69% 55%
Pretreatment
Year 1 Year 2 Year 3 Year 4 Year 5
4.0
7.6
2.8
5.2
Cohort 2
4.4
6.5
65% 85% 80% 90% 100%
1.4
0.6 0.8 0.4 0
Pretreatment
Year 1 Year 2 Year 3 Year 4 Year 5*
Leebeek et al [ABS043]
4.5-year timepoint, respectively. By Year 5
mean ABR was reduced by 55% and 100%
from the year prior to treatment in cohort
1 and 2 respectively, and FIX replacement
consumption declined by 84% and 100%.
Prophylaxis was discontinued in eight of
nine participants using it prior to infusion.
TRAEs were mainly reported in the first
3.5 months; no participants developed
inhibitors or signs of sustained AAV5
capsid-specific T-cell activation. Durable,
sustained FIX expression and reductions in
ABR and FIX replacement were maintained
up to 5 years. The authors concluded that
these data support the ongoing Phase 3 trial
of etranacogene dezaparvovec (AMT-061),
which encodes the highly active Padua
FIX variant. [ABS043]
The 2-year follow-up data from a Phase 2b,
open-label, single-dose (2x10 13 gc/kg),
single-arm, multicentre trial of etranacogene
dezaparvovec (AMT-061) was presented by
Mean FIX activity over 2 years
FIX activity one-stage aPTT
(% of normal)
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0
0
von Drygalski et al. Etranacogene
dezaparvovec combines the Padua FIX
variant with the AAV5-WT-hFIX from AMT-060.
At baseline all three participants had FIX ≤1%,
needed routine prophylaxis and had
neutralising activity to AAV5. By Week 6
mean FIX activity had increased to 31%
and by Week 52 to 41%, with no relationship
seen between the response to treatment
and the presence of anti-AAV NAbs.
Mean FIX activity at 2 years was 44.2%.
Over 2 years, 1 participant has used a total
of 2 infusions of FIX replacement therapy
(1 suspected and 1 confirmed bleed) on
separate occasions (excluding surgery).
There was no loss of FIX activity over 2 years
and no need for immunosuppression. In
addition, no participant developed inhibitor to
FIX. Sustained FIX activity was demonstrated
in participants with AAV5 NAbs receiving a
single dose of etranacogene dezaparvovec,
and all were able to discontinue routine
prophylaxis. [ABS100]
Participant 1
Participant 2
Participant 3
4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104
Week
No immunosuppression required. † The week 0 time point reflects FIX activity before etranacogene dezaparvovec treatment.
*Samples may include activity from exogenous FIX replacement.
von Drygalski et al [ABS100]
51.6
44.7
36.3
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EAHAD 2021 Congress Review
Overview of FIX activity up to 26 weeks
FIX activity. central one-stage (%)
100
90
80
70
60
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10 11 12
Month 4 Month 5 Month 6
Week
N
52 51 53 48 51 51 47 45 49 52
50 47 54
Mean (SD) FIX activity at Month 6: 37.2% (19.6); change from baseline +36.01% (19.693), p

EAHAD 2021 Congress Review
Results from the Exigency Programme
The Exigency programme explores the expectations of gene therapy in the
UK haemophilia community. Results from sub-studies were presented on
topics including the knowledge and expectation of gene therapy among
parents of young children with haemophilia, why some people have no
interest in gene therapy, and healthcare professionals’ experience of
supporting people undergoing gene therapy.
Fletcher et al presented the results of a
survey exploring parent’s knowledge and
expectations of gene therapy. A total of
63 responses were received with 95%
of respondents aware of gene therapy.
People learnt about gene therapy through
haemophilia social media, treatment
centres, news media, patient groups and
via general social media. A total of 84% were
generally positive about gene therapy, with
28% feeling they had a good understanding
of it; 42% had thought a lot about it for their
child, and 22% of parents reported that their
child had asked if they could have gene
therapy. 88% of parents would consider
gene therapy for their child, although only
11% were aware that it might soon be available
outside of clinical trials, with 37% aware
that it is not available for children. Parents
were aware of the life-changing nature of
gene therapy but demonstrated uncertainty
about outcomes and safety. The authors
summarised that while many respondents
had considered the possibility of gene therapy
for their children, they experienced pressure
to make the right decision, were reluctant to
change existing treatment, and felt confused
and uncertain due to the fragmented nature of
communication on gene therapy. [ABS106]
The results of a sub-study of 10 men with
severe haemophilia who were not interested
in gene therapy were presented by Fletcher
et al. All were receiving prophylaxis and
reported no treatment burden and minimal
bleeding episodes in the previous 12 months.
Five key themes emerged as to why they
would decline gene therapy: 1. Self-identity
as a person with haemophilia, and possible
loss thereof; 2. Concerns over lack of longterm
safety and efficacy data; 3. Lack of
treatment burden on current therapy and
concern over the burden of gene therapy;
4. Ongoing concern over past history of
viruses in the community; 5. Side effects
of immune suppression and loss of gene
expression. The authors concluded that
access to safety and efficacy data as it is
published will be beneficial for the patient
community, as will education to support
informed decision making. The psychological
dynamic around self-identity is considered by
the authors as an area that requires further
exploration to enable appropriate support for
those considering gene therapy. [ABS293]
Pollard et al reported the results of a
sub-study evaluating the experience of
healthcare professionals directly involved
in providing support to participants in gene
therapy clinical trials. A mediated discussion
was held with six haemophilia nurses,
two consultant haematologists, and one
physiotherapist. Challenges communicating
with the research teams were raised. From
a nursing perspective, there was uncertainty
over the ability of participants to adhere to
monitoring requirements following gene
therapy and most felt they lost contact with
their patients during the early trial phase,
which is a key point in their care. Screening
for psychological and emotional health issues
prior to gene therapy and ongoing support
were limited in many cases and nurses
reported that participants can struggle to
adapt to life as a person without haemophilia.
Patient information provided as part of
clinical trials was thought to be too detailed,
however patients lacked understanding that
pre-existing conditions such as arthropathy
would be unaffected by gene therapy and that
they could still pass the condition on. Little
is known about people who were deemed not
eligible for gene therapy. The outcomes of
the study suggest that closer communication
between the HTCs and research teams
would be beneficial, as would addressing
educational gaps and further research into
the mental health implications of inclusion
or exclusion from gene therapy clinical trials.
[ABS292]
Is Integration a Concern in Gene Therapy?
Whether toxicity is a concern after gene therapy was discussed and
integration was investigated in a canine model.
Dr Denise Sabatino spoke on the topic
Is long-term toxicity an issue after AAV
gene therapy? Vector genome integration
events, although rare, have been observed
in mice, NHP and humans. In neonatal
mouse models, dose dependent integration
of viral genomes into the RNA was associated
with HCC. A previous study of haemophilia
A dogs showed two that had a rise in FVIII
expression that was 4 times the steady
state level after approximately 4 years
and continued to rise until the end of the
study. The increase was not associated with
abnormal liver biomarkers, and clinically
the dogs had no evidence of malignancy.
AAV integration and clonal expansion
might have been a potential mechanism
for the observed increase in expression.
DNA analysis identified approximately
1700 unique integration events, distributed
throughout the canine genome, with the
number correlating to the vector copy
number, and with integration favoured in
transcription units and oncogenes. The
structures identified were truncated or
rearranged, however, it is possible that a
full-length integrated event expanded and
may explain the increased FVIII expression.
There was no evidence of tumorigenesis.
The site of integration may be more important
than the number of integration events.
Dr Sabatino concluded that studies using
specific methods of analysis are needed to
better understand integration events.
12 13

EAHAD 2021 Congress Review
Dr Paul Batty presented the Characterisation
of adeno-associated virus vector persistence
after long-term follow up in the haemophilia A
dog model. There are many questions on how
AAV vectors persist and result in transgene
expression, whether predominantly as
non-integrated episomal forms, or integrated
into the host genome. A total of eight dogs
were treated with a wt-BDD canine FVIII AAV
construct administered via a single portal
vein infusion at doses of between 6x10 12 and
2.7x10 13 vg/kg. Follow up was for a mean of
10.7 years. Treatment response was seen
in six, with stable FVIII levels observed
throughout the study and a mean terminal
chromogenic FVIII activity of 5.7%. Persistent
AAV vector genomes were present in the liver
at post-mortem in all dogs. Episomal AAV was
the predominant vector form detected after
8–12 years (95.4%). Integration events were
observed in all dogs and all samples studied.
Mean integration frequency was 9.55x10 -4
integration sites/cell, which is similar to the
frequency reported in shorter follow up in
NHP and humans. This frequency is lower
than that described for lentiviral vectors.
94% of integration occurred in intergenic
regions of the genome, with events clustered
more commonly in some sites than others.
AAV vector insertions were not random and
occurred repeatedly in selected regions, with
KCNIP2, CLIC2, ABCB1 and F8 common sites.
Despite finding common integration events
there was no evidence of liver adenoma or
carcinoma post-mortem. Dr Batty highlighted
the importance of further studies in a research
setting to investigate integration in humans
to begin to understand its relevance.
Symposiums review
There were seven symposiums held at EAHAD 2021, two of which included
content specific to gene therapy, covering experience from the MDT in clinical
trials and addressing the known unknowns.
Thinking differently in haemophilia: considerations
for the multidisciplinary team in gene therapy,
experience from clinical trials
This symposium, sponsored by BioMarin, was chaired by Professor Wolfgang Miesbach and
focused on the role that different members of the MDT play in the gene therapy patient journey,
including the perspectives of a physician, a nurse, a physiotherapist and a psychologist.
Professor Miesbach outlined that the MDT has
specific roles and a shared responsibility in
supporting the gene therapy patient journey,
and that the key to success will be collaboration.
This will be especially important in the
EAHAD-EHC proposed hub-and-spoke model,
which was reviewed. Professor Miesbach
elaborated on the physician’s role prior
to, during and after gene therapy and the
different responsibilities of the physician
at the hub vs the spoke centre. Ensuring
shared, informed decision-making is vital
given that the treatment cannot be reversed.
Key discussions between the physician and
the patient should include how gene therapy
works, the uncertainties of duration, long-term
safety, eligibility and response, the importance
of adherence to follow up, monitoring and
treating ALT elevation, and necessary lifestyle
changes in the short term. One of the main
responsibilities of the physician is coordination,
which, with effective communication between
all members of the MDT across all relevant
centres, will be critical in the gene therapy
patient journey. Some questions remain for
the hub-and-spoke model, such as which
centre is responsible at which stage, who is
responsible for follow up care and guidance
and how decisions relating to lab results
and AEs are made. Over time networking
between hub centres could optimise care,
with sharing of knowledge helping centres
to develop their own service.
Sara García Barcenilla presented the nurse’s
experience. Prior to gene therapy, the role
of the nurse is to support the patient in the
shared decision-making process, including
discussing the variability of FVIII level and
expression, any doubts the patient may
have, planning follow up and ensuring the
patient is aware that an immunosuppression
plan is in place, if necessary. Sara García
Barcenilla discussed appropriate support for
a patient on infusion day, including details
of samples to be taken, the time needed in
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hospital and practical considerations. Home
nursing services and fluent communication
with the HTC can provide support to ensure
participation in gene therapy is as easy and
flexible as possible, with training for patients
to detect early symptoms of increases in
transaminases. Managing patient expectations
and fears is a key role for the nurse, and Sara
García Barcenilla presented interesting data on
managing doubts and complications showing
that patients felt reassured by direct contact
with their physician, nurse or research team.
Dr Sébastian Lobet presented the
physiotherapist’s experience of gene therapy,
with focus on monitoring, education, treatment
and shared decision-making. More sensitive
ways to assess the patient may be needed
after gene therapy, such as gait analysis,
balance or proprioception assessment, or
new tools with better clinimetric properties.
With factor levels heterogenous in different
patients, it is unknown what level of factor is
needed to protect a particular patient during
activities of daily life or during physical activity.
The impact of a constant factor level achieved
by gene therapy may lead a patient to become
overconfident and to take excessive risks.
Physiotherapists will need to educate patients
on what activities they can do with a constant
level of factor. For those with already damaged
joints, continued physiotherapy will be
important after gene therapy. Physiotherapists
know patients well and understand their
personal aspirations and difficulties. There
is an important role for the physiotherapist
in shared decision making when considering
if a patient is an appropriate candidate for
gene therapy, in relation to their levels of
motivation to adhere to follow up.
Dr Gaby Golan gave his insight on the
psychological considerations for gene
therapy including a patient’s motivations,
their compliance and dedication to follow
up, whether their expectations meet reality
and whether they are mentally capable of
going through the process. Patients will likely
require psychological support for adjusting
to a new self-identity, loss of contact with the
haemophilia centre, loss of belonging to the
haemophilia community, and with concerns
about a novel therapy. Uncertainty over the
duration and variability of treatment, fear over
loss of expression and knowing that daughters
will still be carriers of haemophilia may be a
lot for a patient to take on; the psychologist’s
role is to prepare them and ensure they have
the capacity to cope with whatever outcomes
they experience. Dr Golan considered that
psychology teams must be involved in all stages
of gene therapy as part of the coordinated MDT.
Professor Miesbach concluded by stating
that MDT collaboration is key to optimise
an individualised treatment approach in
gene therapy.
Physiotherapist roles in the gene therapy
patient journey
Shared
decision
Monitoring
Treatment
Education
Dr Sébastian Lobet
Addressing the known unknowns: how long-term
follow up is evolving our scientific understanding of
haemophilia gene therapy
This symposium, sponsored by Pfizer, was chaired by Professor Mike Laffan and Ian Winburn
(Pfizer) and addressed the known unknowns of gene therapy including the potential impact on
the liver, the immune response and the psychological considerations for supporting a patient.
Professor Mike Laffan provided an update
on the current status of AAV-mediated gene
therapies in haemophilia. He commented
that future advances may include using
alternative vectors such as lentivirus, targeted
intervention or non-viral vectors such as
liposomes. Professor Laffan discussed the
known unknowns of gene therapy including
efficacy considerations such as the variability
and determinant of response, duration of
effect, whether children can be treated and
whether retreatment is a possibility. From a
safety perspective he stated that outstanding
questions remain as to the nature of the
immune and hepatic responses, whether
it will be safe to treat inhibitor patients,
whether off-target tissues will be affected,
and what the danger of integration is.
Biopsies and improved laboratory animal
models are a potential source for addressing
some of these unknowns.
Professor Heiner Wedemeyer provided a
hepatologist’s view. He commented that
AAV-mediated gene therapy for haemophilia
A may be limited by the ability of hepatocytes
to fully synthesise and secrete FVIII (primarily
synthesised by hepatic sinusoidal endothelial
cells). He outlined three key aspects, from
a hepatology perspective, when considering
a candidate for gene therapy: whether
there is a risk of acute toxicity, if there
is an issue regarding long term safety
and which comorbidities are present
that may impact the efficacy or safety
of gene therapy. Professor Wedemeyer
commented that the risk for acute hepatitis
is not the major concern for hepatologists
as it can be managed with corticosteroids,
and 10-year follow up of dogs receiving
AAV gene therapy did not reveal any late
onset hepatitis. He discussed concerns
over clonal expansion and referenced long
term data in dogs that showed some level
of clonal expansion of transduced liver cells
but no development of HCC. He noted that
the risk of cancer from gene therapy is low
in his opinion, but that underlying liver
diseases need to be considered more
carefully. Professor Wedemeyer concluded
that more data will enable greater
understanding of what is happening in
the liver long term after gene therapy.
Professor Thierry VandenDriessche
addressed the immunological challenges
of gene therapy, in that the immune
system can potentially intervene at all
stages, from neutralising the vector
particles, to clearing the gene-modified
hepatocytes, and recognising the therapeutic
proteins secreted by the cells. He noted
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that pre-existing antibodies can elicit a
greater immune response and interfere
with the efficacy of gene transfer. This may
be avoided by modifying the AAV capsid,
by removing the antibodies, or subjecting
the patient to immune suppression. He
commented that even with vector engineering
and recent advances in antibody degradation
using IgG-specific proteases and IdeS,
if the anti-AAV Ab titer is very high, it will
be challenging to overcome. Professor
VandenDriessche demonstrated evidence
from trials which indicate that a cellular
immune response may account for loss
of hepatocytes, the mechanism for which
is unknown. During the panel discussion
Professor VandenDriessche discussed that it
may be feasible to administer a dose of vector
low enough that T cells do not recognise
the vector and trigger the immune system;
there is rationale for developing more potent
vectors to offset low doses, such as the use
of Padua in AAV-FIX gene therapy.
Dr Nicola Dunn addressed the uncertainties
that may exist for patients who opt for gene
therapy, including duration of expression,
long term safety, and the potential for toxicity,
an immune response or liver complications.
Practical factors with psychological
implications include the significant time
commitment for follow up, the change in
haemophilia management, feelings of risk
associated with not taking factor for physical
activity, and the remaining presence of joint
pain and arthropathy. Dr Dunn addressed the
adjustment that a PwH may need to make
after gene therapy that they are no longer a
person with severe haemophilia and that this
may affect their self-concept and self-esteem.
The impact on partners and children was
discussed as was how feelings of belonging
to the HTC and haemophilia community may
be affected. Dr Dunn concluded by stating
that clear communication is needed with
patients and families at all stages of the
gene therapy patient journey.
LIST OF ABBREVIATIONS
AAV – adeno-associated virus
ABR – annualised bleeding rate
ADA – anti-drug antibodies
ALT – alanine aminotransferase
aPTT – activated partial
thromboplastin time
ATHN – American Thrombosis and
Hemostasis Network
bCG – beta-chorionic gonadotropin
BDD – B-domain deleted
cp/kg – capsid particles/kilogram
EAHAD – European Association for
Haemophilia and Allied Disorders
EHC – European Haemophilia
Consortium
EMA – European Medicines Agency
FDA – US Food and Drug
Administration
gc – genome copies
GTR – gene therapy register
HCC – hepatocellular carcinoma
HTC – Haemophilia Treatment Centre
ISTH – International Society of
Thrombosisand Hemostatis
MOA – mechanism of action
MDT – multidisciplinary team
NAb – neutralising antibody
NHP – non-human primate
PBMCs – peripheral blood
mononuclear cells
PwH – person with haemophilia
TRAE – treatment-related
adverse event
ULN – upper limit of normal
US NHF – US National Hemophilia
Foundation
vg/kg – vector genomes/kilogram
WFH – World Federation of Hemophilia
REFERENCES
1. BioMarin JP Morgan 2021 presentation. https://investors.biomarin.com/events-presentations?item=97
(Accessed 24 February 2021).
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