A Phase 2/3, Multicenter, Double-Blind, Randomized Study to Determine the Efficacy and Safety of Tividenofusp Alfa (DNL310) vs Idursulfase in Pediatric and Young Adult Participants With Neuronopathic or Non-Neuronopathic Mucopolysaccharidosis Type II

Two IV idursulfase replacement therapies are currently marketed for the
treatment of the peripheral manifestation of MPS II. Elaprase (idursulfase;
Shire Human Genetic Therapies, Inc., Lexington, MA) was approved by the Food
and Drug Administration (FDA) and European Medicines Agency (EMA) in 2006 and
2007, respectively, and is the standard of care worldwide (Elaprase US
Prescribing Information [USPI] 2013; Elaprase Summary of Product
Characteristics [SmPC] 2020; Muenzer et al. 2006). Hunterase (idursulfase-β;
GCPharma, Gyeonggi-do, South Korea) has been marketed in South Korea since 2012
and was approved in China in 2020. Extensive clinical experience and clinical
safety data for the administration of these IDS enzymes in MPS II patients,
including children, are available. Elaprase and Hunterase do not adequately
control many aspects of the disease, including skeletal, cardiac, and pulmonary
involvement, and, most importantly, they do not effectively cross the
blood-brain barrier (BBB).

A key area of unmet need is treatment of the CNS manifestations of MPS II
disease, such as developmental delay, disruptive behaviors, and impaired
cognition. Therapeutic approaches that aim to address the neurocognitive
components of MPS II are under development. Two therapeutic approaches were
approved in Japan in 2021: intracerebroventricular (ICV) Hunterase
(idursulfase-β; Clinigen KK, Tokyo, Japan) and Izcargo* (pabinafusp alfa; JCR
Pharmaceuticals Co., Ltd., Ashiya, Japan), an IV administered fusion protein
consisting of human IDS and an anti-human transferrin receptor antibody that
attained Sakigake designation in Japan. DNL310 represents an alternative,
noninvasive approach whereby an IDS fusion protein is administered IV and
carried across the BBB via endogenous receptor-mediated transport mechanisms.

This Phase 2/3, multiregional, two-arm, double-blind, randomized, active
(standard-of-care)-controlled study is designed to determine the efficacy and
safety of DNL310 compared with idursulfase in pediatric participants with
either nMPS II or nnMPS II. A key therapeutic hypothesis of the DNL310 program
and this study is that uniform distribution of IDS throughout the brain will
result in substantially better overall CNS efficacy for patients with MPS II
than the current standard of care treatment, IV-delivered idursulfase, while
also maintaining peripheral benefit.

This study has been transitioned to CTIS with ID 2024-510990-21-00 check the CTIS register for the current data.

The co-primary objectives are: To evaluate the CNS activity of DNL310 vs
idursulfase as measured by the cerebrospinal fluid (CSF) concentration of
heparan sulfate (HS) in participants with the neuronopathic form of
mucopolysaccharidosis type II (nMPS II). And to evaluate the clinical CNS
efficacy of DNL310 vs idursulfase on adaptive behavior as assessed by the
Vineland Adaptive Behavior Scale, Third Edition (Vineland-3), 8-subdomain
Adaptive Behavior Raw Score (ABRS-8) in nMPS II participants.

The secondary objectives are: To evaluate the clinical CNS efficacy of DNL310
vs idursulfase on neurocognitive development, as assessed by the Bayley Scales
of Infant and Toddler Development, Third Edition (BSID-III), cognitive domain
in nMPS II participants.
To evaluate the clinical CNS efficacy of DNL310 vs idursulfase on adaptive
behavior as assessed by the Vineland-3 Adaptive Behavior Composite
(ABC) in nMPS II participants.
To evaluate the efficacy of DNL310 vs idursulfase on neuronal injury in nMPS II
participants.
To evaluate the clinical efficacy of DNL310 vs idursulfase on physical
endurance as measured by the Six-Minute Walk Test (6MWT) in participants with
the non-neuronopathic form of mucopolysaccharidosis type II (nnMPS II).
To evaluate the onset and durability of peripheral efficacy of DNL310 vs
idursulfase as measured by the urine concentration of total glycosaminoglycans
(GAGs) by a mass-spectrometry-based detection method in nMPS II and nnMPS II
participants.
To evaluate the efficacy of DNL310 vs idursulfase on liver volume and spleen
volume as measured by magnetic resonance imaging (MRI) in nMPS II and nnMPS II
participants.
To evaluate the parent*s/caregiver*s assessment of efficacy of DNL310 vs
idursulfase as measured by the Parent/Caregiver Global Impression of Change
(CaGI-C) in nMPS II and nnMPS II participants.

This is a Phase 2/3, multiregional, two-arm, double-blind, randomized, active
(standard-of-care)-controlled study of the efficacy and safety of DNL310, an
investigational CNS-penetrant ERT for MPS II. Approximately 54 participants
aged >= 2 to under 26 years with MPS II will be enrolled in one of the two
following cohorts (Cohort A or Cohort B) according to MPS II phenotype
(neuronopathic vs non neuronopathic): - Cohort A: Approximately 33 participants
aged >= 2 to under 6 years with nMPS II, as determined based on genetic testing
(and cognitive testing or family history, as applicable), will be randomized
2:1 to receive either DNL310 or IV idursulfase through Week 96. Target
enrollment is for at least 50% of the participants to be aged >= 24 and <= 48
months at randomization and for at least 70% of participants aged >48 months to
have a cognitive developmental quotient (DQ) of equal to or higher than 20 as
measured by the BSID-III. Randomization will be stratified by chronological age
(less then or equal to 48 months or more than 48 months) and genotype (presence
or absence of a known severe IDS variant [eg, whole-gene deletion or large
rearrangement]). - Cohort B: Approximately 21 participants aged >= 6 to <26
years with nnMPS II, as determined based on genetic and cognitive testing, will
be randomized 2:1 to receive either DNL310 or IV idursulfase through Week 48.
Randomization will be stratified by chronological age (< 12 years, >= 12 years
to < 17 years, or >= 17 years). The study includes a screening period of
approximately 6 weeks, a baseline period of approximately 3 weeks, and a
96-week (Cohort A) or 48-week (Cohort B) postrandomization treatment period.
For participants who are ERT-nai*ve or ERT-pseudo-nai*ve (ie, have no history
of treatment with idursulfase), a run-in idursulfase treatment period totaling
approximately 4 months (ie, 16 weeks), including an overlapping baseline
period, will be included between screening and the first day of study
intervention administration in the controlled treatment phase.

Name and formulation: DNL310 is supplied in a lyophilized form and is intended
to be administered intravenously after reconstitution and dilution.
Dose: 15 mg/kg dosed once per week
Route of administration: IV infusion

Control Test Product: Idursulfase is to be administered at the recommended dose
(0.5 mg/kg) once per week as an IV infusion.

This is a Phase 2/3, multiregional, two-arm, double-blind, randomized, active
(standard-of-care)-controlled study of the efficacy and safety of DNL310, an
investigational central nervous system (CNS)-penetrant enzyme-replacement
therapy (ERT) for mucopolysaccharidosis type II (MPS II). Approximately 54
participants aged >= 2 to < 26 years with MPS II will be enrolled. For all
participants baseline assessments will include safety, imaging, audiology,
neurocognitive testing, and biomarker sample collections (blood, urine, and
CSF). Results from the Phase 1/2 study with DNL310 (Study DNLI E 0002) informed
the dosage of 15 mg/kg IV once weekly to be used in this Phase 2/3 study. These
data showed that the 15-mg/kg dose provided consistent and sustained reductions
in CSF HS, DS, and GM3 (lysosomal lipid) and urine GAG concentrations (see
DNL310 IB Section 5.2). In order to ensure the continuation of their current
treatment, participants should continue to receive prior ERT with idursulfase
during the baseline period until 1 week prior to Day 1, and will receive their
randomly assigned study intervention starting on Day 1 without a washout
period. All study intervention infusions for this study will be administered at
the study center.