A Double-Blind, Placebo-Controlled, Multicenter Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a rare, fatal degenerative neuromuscular
disease with an X-linked recessive inheritance caused by mutations in the
dystrophin gene that occurs in approximately 1 in every 3500 to 5000 males
worldwide. The mutations that cause DMD typically disrupt the mRNA reading
frame and prevent production of dystrophin, a critically important part of the
protein complex that connects the cytoskeleton of a muscle fiber to the cell
membrane and extracellular matrix. In the absence of dystrophin, the stress of
repeated muscle contraction causes cellular degeneration, regeneration, and
inflammation and over time, myonecrosis. The clinical effect of this disrupted
dystrophin reading frame is dramatic and lethal.

The progression of DMD follows a highly predictable course. Significant motor
deficits may be present during the first year of life, but diagnosis is usually
made between the ages of 3 to 5 years when toddlers begin to show functional
symptoms (eg, waddling gait, toe walking, and difficulty climbing stairs). Over
time, ambulation becomes increasingly abnormal and by 8 years of age, most
patients are losing the ability to rise from the floor and climb stairs, have
an increasingly labored gait, and often fall while walking. By 10 to 14 years
of age, most are wheelchair-dependent. Weakness of the arms and increasingly
limited upper limb function, contractures, decubitus ulcers, and scoliosis
(which often requires surgery) occur frequently.

Boys with DMD have a resting heart rate that is consistently higher than normal
even when cardiac function remains normal. Although elevation in resting heart
rate in this patient population is likely multifactorial, it is associated with
increased risk of cardiomyopathy, which usually manifests after 10 years of age
as dilated cardiomyopathy with reduced left ventricular ejection fraction
(LVEF). The prevalence of cardiomyopathy in patients
with DMD increases with age and disease progression, with the majority of
patients affected by age 18.

Subclinical impairment of respiratory muscle function occurs in ambulatory
patients, but clinical impairment of respiratory function usually only happens
after loss of ambulation (LOA). Respiratory insufficiency typically starts at
night, resulting in disturbed sleep, morning drowsiness and headaches, loss of
appetite, and frequent pulmonary infections. Congestive heart failure or sudden
death occurs in 20% of patients.
In addition to clinical manifestations, patients with DMD typically have
elevated creatine kinase (CK) values due to leakage of the enzyme from
degenerating muscle fibers. In DMD, CK is often 50 to 100 times normal values.
High transaminase levels (alanine aminotransferase [ALT] and aspartate
aminotransferase [AST] up to approximately 22 × upper limit of normal [ULN])
and lactate dehydrogenase levels, originating from
degenerating muscle, are also generally observed in these patients. Creatinine
levels tend to be low or low normal due to decreased muscle mass, thus serum
cystatin C may provide a better measure of renal function than does creatinine.

While pulmonary and cardiac functions are generally normal during early
childhood, cardiac and diaphragmatic muscles progressively weaken during late
childhood and adolescence, leading to eventual dependence on ventilatory
support. Historically, patients typically died from respiratory
or cardiac failure in their late teens or early 20s. Recent research suggests
that use of ventilatory support and steroids may increase life span by several
years; however, DMD still has a mortality rate of 100%. Existing interventions
are largely supportive in nature and include bracing, muscle-stretching
exercises to avoid onset of contractures, tendon-release surgery, and eventual
wheelchair use and assisted ventilation. Current pharmacologic treatments, such
as corticosteroids, focus on alleviation of symptoms, but do not address the
underlying cause of the disease. Corticosteroids may prolong ambulation, delay
the onset of scoliosis, and improve performance on some measures of clinical
function. However, their benefits are only temporary and their use is often
limited by numerous side effects, including growth inhibition, effects on
pubertal changes, weight gain, behavioral changes, osteoporosis, cushingoid
facies and habitus, and cataracts. In December 2019, golodirsen (VYONDYS 53®)
received accelerated approval from the Food and Drug Administration (FDA) for
the treatment of DMD in patients who have a confirmed
mutation in the DMD gene that is amenable to exon 53 skipping. In February
2021, casimersen (AMONDYS 45®) received accelerated approval from the FDA for
patients who suffer from DMD with mutations amenable to exon 45 skipping.

Glucocorticoids, such as deflazacort, are commonly used as treatment of DMD and
have been shown to have some benefits but are associated with well-known side
effects. Moreover, glucocorticoids do not address the cause of DMD (ie, the
absence of dystrophin protein), which results in progressive and irreversible
loss of skeletal and cardiac muscle function that eventually results in death
due to cardiopulmonary decline. The clinical development program of SRP-4045
and SRP-4053 was designed to assess the efficacy and safety in patients
amenable to exon 45 and exon 53 skipping respectively, receiving standard of
care support measures and stable corticosteroid use.

Primary Objective:
Double-blind period : Evaluate the effect of SRP-4045 and SRP-4053
(combined-active group) compared to placebo on ambulation, endurance, and
muscle function, as measured by the 6MWT

Secondary Objectives:
- Double-blind period: Evaluate the effect of SRP-4045 and SRP-4053
(combined-active group) on:
1) Dystrophin protein expression in biopsied muscle tissue as measured by:
* Western blot (quantification)
* Immunohistochemistry (IHC) fiber intensity
2) Functional status as measured by:
* Ability to rise independently from the floor (without external
support)
* Loss of ambulation (LOA)
* North Star Ambulatory Assessment (NSAA)
* Respiratory muscle function as measured by forced vital
capacity (FVC)% predicted
3) Safety and tolerability of SRP-4045 and SRP-4053
- Open-label period:
4) Evaluate the long-term effects of SRP-4045 and SRP-4053 treatment on
functional status up to 144 weeks
5) Evaluate the long-term safety and tolerability of SRP-4045 and SRP-4053
- Pharmacokinetics:
6) Evaluate the PK properties of SRP-4045 and SRP-4053 via a population
PK model

This is a double-blind, placebo-controlled, multicenter study with an OL
extension to evaluate the efficacy and safety of 2 PMOs, SRP-4045 and SRP-4053,
in approximately 222 patients with genotypically confirmed DMD with deletion
mutations amenable to skipping exon 45 and exon 53, respectively.
In the double-blind treatment period, a placebo group will be employed within
each genotype and patients will be randomized by genotype and age (6 to 8.5
years vs > 8.5 to 13 years) in a double-blind fashion in a 2:1 ratio,
combined-active (SRP-4045 or SRP-4053) to matching placebo. Following
completion of the 96-week double-blind period, all patients will begin the OL
period and receive active treatment according to their genotype for up to 48
weeks. After completing the OL extension period, eligible patients may enter
the LTE or Sponsor-offered program for extended treatment..

Double-Blind Treatment Period
Patients will be evaluated for inclusion during a Screening period of up to 8
weeks. Eligible patients who have out-of-frame deletions amenable to exon 45 or
exon 53 skipping will be randomized in a 2:1 ratio between the active group and
the placebo group to receive once weekly intravenous (IV) infusions of study
treatment for up to 96 weeks. Patients with DMD amenable to exon 45 skipping
will be randomized in a 2:1 ratio to receive either SRP-4045 or matching
placebo, and patients with DMD amenable to exon 53 skipping will be randomized
in a 2:1 ratio to receive either SRP-4053 or matching placebo. Thus, SRP-4045
and SRP-4053 will each be administered as monotherapy only, and not
coadministered.

Open-Label Treatment Period
Upon completion of the double-blind portion of this study, patients may
participate in an OL treatment extension period of up to 48 weeks in which they
will receive weekly treatment with 30 mg/kg SRP-4045 or SRP-4053, according to
genotype.

Blood samples: 33 collections, 322 mL of blood in total.
Site visits: weekly, home infusion visits are also foreseen.
Physical examinations or other tests:
- blood draws: pain, light-headedness and fainting, bleeding, bruising,
swelling, or infection at the puncture site
- ECG: redness, rash upon removal of sticky pads
- muscle biopsy: pain, scarring, infection, bruise, numbness near the biopsy
site, or delayed wound healing.
Other potential risks described in the ICFs/Assent Forms.
Questionnaires or diaries which have to be filled in: Fall diary.
All possible discomforts that can occur during the study procedures are
described in the ICFs/Assent Forms.