Long-term follow-up of patients with spinal muscular atrophy Treated with OAV101 IT or OAV101 IV in Clinical Trials

Spinal Muscular Atrophy (SMA) is a neurogenetic disorder caused by a loss or
mutation in the survival motor neuron 1 gene (SMN1) on chromosome 5q13, which
leads to reduced SMN protein levels and a selective dysfunction of motor
neurons. SMA is an autosomal recessive, early childhood disease with an
incidence of approximately 1:10,000 live births (Ogino et al 2004, Sugarman et
al 2012). SMA is the leading cause of infant mortality due to genetic diseases.
Disease severity and clinical prognosis depends on the number of copies of
SMN2. In its most common and severe form (Type 1), hypotonia and progressive
weakness are recognized in the first few months of life, leading to diagnosis
by 6 months of age and then death due to respiratory failure by age 2 years.
Motor neuron loss in SMA Type 1 is profound in the early postnatal period (or
may even start in the pre-natal period), whereas motor neurons in Type 2 and 3
SMA patients adapt and compensate during development and persist into adult
life. The findings from various neurophysiological and animal studies have
shown an early loss of motor neurons in the embryonic and early postnatal
periods (Swoboda et al 2005, Le et al 2011, Farrar et al 2013).

SMN protein depletion is the root cause across all SMA patient phenotypes and
the disease pathogenesis, regardless of age. SMA is caused by abnormally low
levels of the ubiquitously expressed SMN protein, resulting from a combination
of homozygous deletions or mutations of the telomeric copy of the SMN gene
(SMN1) on chromosome 5q and the presence of 1 or more copies of SMN2 (Lefebvre
et al 1995), an almost identical but only partially functional centromeric copy
which is unique to humans (Rochette et al 2001). The relevant difference
between these two genes, a single nucleotide transition at exon 7, affects a
splice site enhancer such that the majority of transcripts of SMN2 lack exon 7
(SMNΔ7), resulting in greatly reduced levels of functional, full-length SMN
protein (Monani et al 1999). When the SMN1 gene is unable to supply SMN protein
to the motor neurons, the only source of SMN protein is the SMN2 gene. The
amount of neuronal SMN protein determines patient phenotype primarily by the
number of SMN2 genes.

In support of the hypothesis that gene copy numbers of SMN2 primarily drive
phenotypic presentation of SMA, a large review examined the association between
SMN2 copy number and SMA phenotype (Calucho et al 2018). The authors showed
that 79% of patients with two copies of SMN2 developed SMA Type I, 16%
developed SMA Type 2 and 5% developed SMA Type 3; 54% of patients with three
copies of SMN2 developed SMA Type 2, 31% developed SMA Type 3 and 16% developed
SMA Type 1; and among patients with four copies of SMN2, most had mild SMA
variants with only 1% developed SMA Type 1 and 11% developed SMA Type 2. In
keeping with the importance of SMN production by SMN2, few individuals with
SMN1 mutations and >=6 copies of SMN2 develop symptoms and those who are
affected develop only mild forms of SMA (Bernal et al 2010, Riessland et al
2017). SMN is part of the machinery which assembles spliceosomal components
(Pellizzoni et al 1998). Ventral spinal cord motor neurons are specifically
sensitive to SMN deficiency and are affected in all types of SMA (Burghes and
Beattie 2009).

Irrespective of phenotypic classification, expert consensus is that all
patients with biallelic pathogenic SMN1 variants and up to 4 SMN2 copies should
receive SMN dependent therapy (Glascock et al 2018, Glascock et al 2020).
Therapeutically increasing SMN levels leads to the most striking results in
patients with SMA Type 1 (Mercuri et al 2018, Pechmann et al 2019, Pane et al
2019, Aragon Gawinska et al 2020). These results are thought to be most
beneficial with early intervention, preventing neurodegeneration and the
associated progressive deterioration that is seen in all Type 1 SMA infants.
These patients now experience improvement in their functional abilities and
attain developmental milestones that had never previously been achieved in this
population (Mercuri et al 2018, Pechmann et al 2018, Pane et al 2019, Aragon
Gawinska et al 2020). A proportion of these infants acquire the ability to sit
independently, and treatment can enable them to stand (usually with support),
depending on how soon treatment is initiated after onset of symptoms. In
children with SMA Type 2, treatment also clearly reduces progression of the
disease compared with the natural history. For these patients, to stand alone
and develop the ability to walk with or without support is a possibility.

SMA is conventionally classified into 4 phenotypes on the basis of age of onset
and highest motor function achieved, with an additional phenotype (Type 0) to
describe the severe forms of antenatal-onset spinal muscular atrophy (Kolb and
Kissel 2011, Mercuri et al 2012). SMA Type 1 patients present with symptoms
within the first 6 months of life, the most prominent being lack of head
control, and by definition never attain independent sitting. SMA Type 1 is the
leading genetic cause of infant death. In contrast, SMA Type 2 manifests within
the first 18 months of life and follows a slower disease progression as
compared to SMA Type 1. Children with SMA Type 2 are able to maintain sitting
unassisted but never walk independently and have a life expectancy of 20-40
years of age. SMA Type 3 patients attain the ability to walk unaided (Type 3a
have onset <3 years of age; Type 3b have onset > 3 years of age). SMA Type 4 is
an adult-onset form of the disease. Figure 1 1 summarizes SMA subtypes and
associated clinical features as well as the relationship of the SMA subtypes to
SMN2 gene copy numbers.

OAV101 gene therapy mechanism of action: OAV101 is a single treatment for
patients with 5q SMA. OAV101 is a non-replicating recombinant adeno*associated
virus serotype 9 (AAV9) containing the human SMN complementary deoxyribonucleic
acid (cDNA) under the control of the cytomegalovirus (CMV) enhancer/chicken-β-
actin-hybrid (CB) promoter (Figure 1 2). One of the two adeno-associated virus
(AAV) inverted terminal repeats has been modified to promote intramolecular
annealing of the transgene, thus forming a double-stranded transgene ready for
transcription.

The mechanism of action of OAV101 is the delivery of a functional copy of the
gene encoding for the SMN protein into target cells, the loss of which is the
root cause of all forms of (5q) SMA. The goal is to increase SMN protein levels
in motor neurons prior to the development of irreversible injury and motor
neuron loss, thereby modifying the patient*s SMA phenotype to a milder course
with improved quality of life and prolonged survival.

Recombinant AAVs are not known to actively integrate into the host genome, but
rather persist episomally within the target cells. Thus, its expression is
eventually lost in a dividing cell population (Hudry and Vandenberghe 2019).
OAV101 is specifically designed to form a circular concatemeric transgene that
harbors even lower potential for deoxyribonucleic acid (DNA) integration or
alteration. Moreover, AAVs cannot replicate within the host cell in absence of
a helper virus, such as adenovirus, herpes simplex virus, human papillomavirus
or vaccinia virus for productive infection.

This study has been transitioned to CTIS with ID 2024-511707-42-00 check the CTIS register for the current data.

The purpose of this study is to collect long-term follow-up safety and efficacy
data on patients with SMA who were treated with OAV101 by IV or IT
administration. Safety and efficacy will be assessed for 15 years following
OAV101 administration.

This is a global, prospective, multi-center study that is designed to assess
the long-term safety and efficacy of OAV101 in participants who participated in
OAV101 clinical trials. The assessments of safety and efficacy in Study
COAV101A12308 will continue for 15 years from the date of OAV101 administration
in the parent study. The number of study visits required in this long-term
follow-up will depend on the length of time since the OAV101 administration.
For example, patients followed for 1 year in the parent study will participate
for up to 14 years following an immediate and seamless transition from the
parent study (End of Study (EOS) Visit) to the Enrollment Visit in Study
COAV101A12308.
The study is comprised of a Baseline Period and 3 Follow-up Periods (Table
8-1). Follow-up Periods 1 and 2 consist of in-person visits and Period 3
consists of tele-visits.
For Follow-up Periods 1 and 2, which includes Baseline through Year 5 visits,
assessments will be performed at the Investigational site. For the first 2
years (Follow-up Period 1), visits will occur every 6 months. For Years 3 to 5
(Follow-up Period 2) follow-up visits will be conducted annually.
During Follow-up Period 3 (Year 6 to up to Year 15 after OAV101
administration), participants/caregivers will be contacted using tele-visits
annually for remote assessments. All patients will enter the study at the
baseline visit and continue until 15 years since OAV101 administration is
reached. Total duration of participation in the study will be dependent upon
time of enrollment relative to OAV101 administration and will vary by
participant.

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