A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the Efficacy, Safety and Tolerability of QR-421a in Subjects with Retinitis Pigmentosa (RP) due to Mutations in Exon 13 of the USH2A Gene with Advanced Vision Loss

The Sponsor is developing an AON, QR-421a, for the treatment of patients with
RP caused by mutations in exon 13 of the USH2A gene. RP is a group of inherited
eye disorders causing photoreceptor degeneration that leads to progressive
vision loss, which ultimately results in complete blindness. Currently there
are no approved therapies for the treatment of RP due to mutations in exon 13
of the USH2A gene and a large unmet medical need exists.
The clinical development program started in the first half of 2019 with the
first-in-human (FIH) clinical study (PQ-421a-001), a Phase 1b/2, double-masked,
sham-controlled, dose-escalation study to evaluate the safety and tolerability
of QR-421a. An interim analysis was performed in March 2021. Available safety
and efficacy data from study PQ-421a-001 support the therapeutic potential
observed in the nonclinical studies.
Study PQ-421a-003 aims to define safety and quantify the treatment effect of
QR-421a administered via IVT injection in subjects with RP due to mutations in
exon 13 of the USH2A gene with advanced loss of vision, relative to masked,
untreated control subjects, at 2 dose regimens of QR-421a.

Primary
• To evaluate the efficacy of QR-421a

Secondary
• To evaluate the safety and tolerability of QR-421a
• To evaluate changes in Patient-Reported Outcome (PRO) measures in subjects
treated with QR-421a
• To evaluate systemic exposure of QR-421a

PQ-421a-003 is a double-masked, randomized, controlled, multiple-dose study to
evaluate the efficacy, safety and tolerability of QR-421a in subjects with RP
due to mutations in exon 13 of the USH2A gene with advanced vision loss. At
study start subjects will be randomized to one of the following treatment
groups:

1) Group 1: QR-421a 180/60 µg (180 µg loading dose administered on Day 1, 60 µg
maintenance dose administered at Month 3 and every 6 months
thereafter; n = 27)
2) Group 2: QR-421a 60/60 µg (60 µg loading dose administered on Day 1,60 µg
maintenance dose administered at Month 3 and every 6 months
thereafter; n = 27)
3) Group 3: Sham-procedure (administered on Day 1, Month 3 and every 6 months
thereafter; n = 27)

After the study eye has been treated for at least 18 months, treatment of the
fellow eye and cross-over of subjects assigned to sham-procedure may be
initiated in eligible eyes (in a masked manner), based on assessment of
benefit-risk

The primary endpoint will be assessed at 18 months of treatment. Analysis of
all other efficacy and safety parameters will also be reported at that time
point. All efficacy and safety parameters will continue to be followed during
the 24-month treatment period.

The current study will evaluate 2 dose levels. Subjects will receive loading
dose administered on Day 1, and maintenance dose administered at Month 3 and
every 6 months. The intended route of administration is intravitreal (IVT)
injection.

The subject is eligible for the study and thus eligible to receive QR-421a or
sham-procedure in the study eye if all the following inclusion criteria apply
at Screening/Day 1. The subject is eligible to receive QR-421a in the fellow
eye after the study eye has been treated for at least 18 months.

Subjects will receive intravitreal injection or Sham injection every 3 months
until M15 (4 times). At month 18 all subjects (in all 3 study arms) could
receive an intravitreal injection with Q-421a in the fellow eye. If this is
found safe by physician. At Month 21 subjects, previously in the sham arm, can
receive intravitreal injection in the study eye. In total subject can receive 6
intravitreal injections, when they are in the active arm and 2 injections when
they are in the sham arm.
Subjects will be followed up to Month 24. In total there are 10 visits to the
research center, with 12 telephone visits (at Day 2 ad Day 8 after
injection) in the period of 24 months.
The study drug will be administered via intravitreal injection. In addition to
the administration of the study drug, various assessments are performed.