ACMG 2023 Congress Review

ACHONDROPLASIA.EXPERT
CONGRESS REVIEWS
ACMG 2023
Welcome to the ACMG 2023 congress review.
March 2023 saw the Annual Clinical Genetics Meeting
take place in Salt Lake City, US, attended by delegates
from around the world. Across more than 50 educational
sessions, presenters shared news about the latest
developments in medical genetics.
Year on year the volume of data around achondroplasia
at meetings like this is growing, alongside increasing
awareness and understanding of the condition.
We have chosen a handful of key abstracts presented
in the session on clinical genetics and therapeutics.
This includes data from the Phase 2 and 3 clinical
trials of vosoritide , as well as real-world observational
data that shines a spotlight on quality of life and the
surgical burden associated with achondroplasia.
We hope you will enjoy the selection summarised
for you here.
The Achondroplasia Team
VOSORITIDE: CLINICAL DATA
News from the Phase 2
and 3 trials, including a
look at the persistence of
growth-promoting effects
CLICK TO FIND OUT MORE
REAL-WORLD DATA
An update on early
experience with vosoritide
in clinical practice
JUMP TO THE DATA
ACHONDROPLASIA:
NATURAL HISTORY
Examining QoL, and the
surgical burden associated
with achondroplasia.
READ MORE HERE
The abstracts can be found here.
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All Rights Reserved. EU-VOX-00819 March 2023
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Achondroplasia.expert Congress Reviews: ACMG 2023
VOSORITIDE: CLINICAL DATA
Vosoritide downregulates FGFR3 signalling and is a potent stimulator
of bone growth. It is approved for use in children with achondroplasia
on the basis of a Phase 3 study which demonstrated significant
improvements in AGV versus placebo.*
3-year data from the Phase 3 extension study
were presented by Hoover-Fong et al. After
completion of the placebo-controlled portion of
the study, 119 children were enrolled into the
extension, where they all received open-label
vosoritide 15 μg/kg/day. This created a
population of those with continued vosoritide
treatment (n=58), and those switched from
placebo to vosoritide (n=61). AGV and body
proportion ratio were analysed to assess
efficacy of vosoritide. The results show
that in children randomised to vosoritide,
mean cumulative AGV improved from 4.26
to 5.66 cm/year from baseline to Week 104,
and was maintained at 5.57 cm/year at
Week 156. In 34 children with available
follow-up at Week 182, AGV was maintained
at 5.45 cm/year, and mean upper-to-lower
body segment ratio improved with a change
from baseline of –0.03 at Week 52 to -0.13
after 3.5 years on treatment. In children
who switched from placebo to vosoritide
after 52 weeks, cumulative AGV improved
from 3.77 cm/year to 5.45 cm/year from
baseline to Week 104, and was maintained
at 5.43 cm/year at Week 130. Most adverse
events were mild, and none resulted in
discontinuation. The most common AE
was injection-site reactions, but these
were mostly grade 1 and self-limiting.
One serious adverse event of genu valgum
was reported as related to vosoritide, and
the rate of fractures was comparable to the
background rate reported in the literature
for achondroplasia. There was no evidence
of worsening body proportions, bone mineral
density, bone age, or worsening of spinal
angles. The authors concluded that the effect
of vosoritide on growth was maintained to
3.5 years in children with achondroplasia
aged 5–18 years. The long-term safety profile
remains favourable without treatment-limiting
adverse events. [P193]
An update from the Phase 2 extension
study with vosoritide was also presented by
Hoover-Fong et al., looking at persistence
of growth-promoting effects in children with
achondroplasia over 7 years. After 6 months
in a baseline growth natural history study and
24 months in the open-label dose-ranging
study, 30 children entered the extension study.
Safety, tolerability, AGV, and body proportions
were analysed on a regular basis. As of
February 2022, 20 participants were still
in the study, with 16 on vosoritide; 5 of
those who discontinued had reached final
adult height. The update reports a mean of
76 months’ exposure, representing the longest
clinical experience with vosoritide to date.
Age-specific findings at this data-cut were
compared with those from the natural history
dataset. The results show that vosoritide
continued to be well-tolerated, with no
AGV on treatment with vosoritide is consistently higher compared to age-matched untreated children
Annualized Growth Velocity (cm/yr)
10
9
8
7
6
5
4
3
2
1
0
-1
-2
ACH treated:
AchNH:
Average stature:
Annualized Growth Velocity (cm/yr)
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
ACH treated:
AchNH:
Average stature:
6
10
102
43
6
9
117
37
7
17
82
107
7
21
88
105
AchNH reference derived from CLARITY; 1
average stature reference is non-African American data from Kelly et al. 2
8
23
77
90
8
24
79
85
9
19
72
111
9
20
62
100
10
14
61
140
10
21
62
116
Females
11
Age (years)
15
48
161
Males
11
Age (years)
17
52
144
12
22
37
192
12
17
45
186
13
17
39
187
13
12
35
150
14
10
33
163
14
9
24
151
ACH treated
AchNH
Average stature
15
3
26
171
15
8
20
168
16
1
17
192
ACH treated
AchNH
Average stature
16
4
21
163
Females –
The difference in
the mean integer
AGVs across
each integer
age (6–16 yrs)
between treated
and untreated
= 1.55 (0.78) cm/y
Males –
The difference in
the mean integer
AGVs across
each integer
age (6–16 yrs)
between treated
and untreated
= 1.98 (0.37) cm/y
Hoover-Fong et al. [P193]
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Achondroplasia.expert Congress Reviews: ACMG 2023
evidence of accelerated skeletal maturation
or serious adverse events attributable to
study drug. The growth-promoting effect
was maintained as children aged: mean
age- and sex-specific AGVs (assessed over
successive 1-year intervals) in children
treated with vosoritide were greater than
corresponding mean AGVs in untreated
children of the same integer age and
sex across all integer age groups
(6–14 years old). The mean difference
between integer age groups in treated
versus untreated participants was
1.90 and 1.36 cm/year for boys and girls,
respectively. Expressed in terms of change
No acceleration of bone age with vosoritide treatment
Bone Age / Chronological Age Ratio (years)
1.15
1.10
1.05
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
from baseline height Z-scores, this gave
values of +0.98 at Month 72 (n=18) and
+0.81 at Month 84 (n=12) in relation to
an average-stature population, and
+1.56 at Month 72 and +1.46 at Month 84
in relation to an untreated achondroplasia
population. Upper to lower body segment
ratio changes were particularly marked in
the subset of girls aged

Achondroplasia.expert Congress Reviews: ACMG 2023
any additional procedures. The registry
should collect a more representative
population than was included in the clinical
trials, and better reflect standard clinical
practice and real-life management. It is
hoped that the data collected will provide
important insights into the impact of
long-term vosoritide treatment on safety,
effectiveness, and the use of vosoritide in
context of other interventions. [P338]
Early experience was shared by Semler et al.,
who gathered insights from 20 prescribers in
Europe, the Middle East, and the US on using
vosoritide in clinical practice. The group was
made up of geneticists (n=10), paediatric
endocrinologists (n=6), paediatricians (n=2),
and orthopaedic surgeons (n=2). Current
practice and considerations were discussed,
including the practicalities of training families
to administer vosoritide, the assessments
prior to and during therapy, and how to
manage the expectations of patients and
their families. The results emphasise that
before considering vosoritide, it is crucial to
assess whether adequate multidisciplinary
follow-up is in place. In addition, initial and
ongoing training and support for families
is considered essential, including practical
information on administration, and recognition
and management of injection-site reactions.
Suggested techniques include establishing
a routine, empowering patients by allowing
them to choose injection sites, managing pain,
and timing injections to avoid dizziness. There
were some cases of patients discontinuing
vosoritide, with reasons ranging from inability
to tolerate daily injection, or participation in
a clinical trial. It was found that the protocols
for monitoring patients varied by centre, which
could be influenced by regional differences
in reimbursement and healthcare systems.
The group agreed on the need for core
assessments including clinical exams with
pubertal staging, anthropometry, X-rays to
confirm open physes, and regular review
of adverse events and other medications.
Patients and families should be informed that
response to treatment can vary in magnitude
and timing. Providing ongoing data from
vosoritide clinical trials is encouraged, and
sharing of individual responses to treatment
may motivate families to maintain adherence.
[P339]
ACHONDROPLASIA: NATURAL HISTORY
As further data accumulates on the potential impact of therapies on comorbidities
and surgical interventions in achondroplasia, it is important to understand the
background rates of these events to aid evaluation of potential treatment effects.
Stender et al. completed a review to quantify
the prevalence of achondroplasia related
surgeries by age group. The aim was to
compile a reference to assist in understanding
the risk–benefit of new treatment options and
inform timely management of achondroplasia.
The group defined five age-groups:
infancy (0–2 years), childhood (3–12 years),
adolescence (12–18 years), adulthood
(>18 years), and other (if age at surgery
was undeterminable or ages overlapped).
An a priori decision was made not to use
meta-analysis techniques to pool estimates
as it was important to document the variability
in estimates. Descriptive statistics were used
to summarise estimates by surgery type and
age group. In total, 107 articles were identified,
and 55 included. Most studies were conducted
in the USA (n=29) or Western Europe (n=10),
and were mostly retrospective chart reviews
(n=35) or small cohort or cross-sectional
studies (n=20). While more than one surgical
type could be reported per study, the majority
assessed neurological or ENT surgeries,
followed by spinal and corrective limb
surgery. There was substantial heterogeneity
in study design, clinical setting, populations,
and subgroup definitions. Overall, ENT was
the most frequent surgery, particularly in
infants and children. Neurological surgery
was also highly prevalent in these two
younger groups. Limb surgery was
most often performed in children and
adolescents, and spinal surgery in children,
adolescents, and adults. This review provides
a reference base of current knowledge
of the type and frequency of surgery in
achondroplasia, which not only allows future
contextualisation of new treatments, but
supports clinical decision-making on timely
medical management and intervention.
The work also highlights the severity of this
condition and the frequent need for surgical
management, indicating complex needs
which often involve many different disciplines.
[P337]
Quality of life was captured in the LISA
study, and reported by Llerena et al. This is
a multinational and observational study in
Latin America to quantify the lifetime impact
of achondroplasia by measuring HRQoL in
172 individuals. In children (n=87), QoLISSY
total scores were 71.5 for patients and
63.9 for parent proxies, with the most
impacted domains being physical, social,
effect (parents) and total (child only).
All domains across the PedsQL (n=81)
were lower than the reference population,
particularly the physical domain with scores
of 69.4 (for children and 63.9 for parent
proxies compared to reference population
scores of 87.5 for children and 84.5 for
parent proxies. Overall, 74.1% of patients
aged 8–17 years reported at least one pain
site, and 10.3% reported pain in at least
three sites on the APPT questionnaire.
In adults, the EQ-5D-5L VAS score was
72.7, which was lower than the reference
population (80.1). Moderate or severe
anxiety/depression was reported by 26.6%,
moderate-to-severe pain or discomfort in
25.3%, and moderate-to-severe mobilty
problems in 20.3%. The NHP total score
was 25.8, with the energy, pain, and physical
mobility being the most negatively impacted
domains. Per BPI, 73.4% of subjects reported
experiencing pain not described as everyday
minor aches and pain. The group state that
the LISA study provides the largest set of
data to date from Latin America on HRQoL
of individuals with achondroplasia, and
shows that people with achondroplasia
experience significant burden of illness
across multiple domains. [P233]
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Achondroplasia.expert Congress Reviews: ACMG 2023
LIST OF ABBREVIATIONS
AGV – annualised growth velocity
BPI – Brief Pain Inventory
ENT – ear, nose, and throat
EQ-5D-5L – 5-level 5-dimension EuroQoL
HRQoL – health-related quality of life
NHP – Nottingham Health Profile
PedsQL – Pediatric Quality of Life Inventory
PK – pharmacokinetics
QoLISSY – Quality of Life of Youth Short Stature
VAS – visual analogue scale
FOOTNOTES
* In the EU, VOXZOGO is indicated for the treatment of achondroplasia in patients 2 years of age
and older whose epiphyses are not closed. The diagnosis of achondroplasia should be confirmed
by appropriate genetic testing.
REFERENCES
1. Hoover-Fong J, et al. Orphanet J Rare Dis 2021;16(1):522.
2. Kelly A, et al. J Clin Endocrinol Metab 2014;99(6):2104–12.
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