Phase 3 Randomized, Controlled Study of AAV5-hRKp.RPGR for the Treatment of X-linked Retinitis Pigmentosa Associated with Variants in the RPGR gene

Retinitis pigmentosa (RP) constitutes a group of inherited diseases of the
retina characterized by a progressive reduction in vision, initially manifest
as nyctalopia (night blindness) that usually becomes apparent in childhood or
early adulthood and is progressive throughout the individual*s
lifetime (Tee 2016).

Currently, there is no approved treatment for XLRP, and the condition is
serious and progressive. There is a real possibility that gene therapy could
offer a significant benefit in terms of markedly slowing or halting progressive
retinal loss thereby preserving central vision and improving sight and quality
of life (QoL). The approval of Voretigene Neparvovec (Luxturna, Spark
Therapeutics) for biallelic RPE65 disease (Russell 2017) provides convincing
proof of concept. This is reinforced by our own experience from the first gene
therapy study for IRD (Bainbridge 2008) and preclinical data demonstrating
improved outcome in animal models of RPGR-XLRP. Preliminary data from the
ongoing Phase 1/2 Study MGT009 has also demonstrated significant improvement in
both visual function (as determined by assessment of visual fields by static
perimetry), and functional
vision (as determined by a visual mobility assessment in low illumination
levels) (see Section 2.2, Background).

Taking into account the measures taken to minimize risk to participants of this
study and the preliminary efficacy results of the MGT009 study, the potential
risks identified in association with AAV5-hRKp.RPGR are justified by the
anticipated benefits that may be afforded to participants
with RPGR-XLRP

Primary:
To assess the effect of bilateral treatment with AAV5-hRKp.RPGR on functional
vision as measured by vision-guided mobility assessment.

Secondary:
To assess changes after treatment administration in retinal function,
functional vision, visual function and to assess the safety and tolerability of
bilateral subretinal delivery of AAV5-hRKp.RPGR

This is a randomized, controlled, multicenter, interventional study of
bilateral subretinal treatment with AAV5-hRKp.RPGR gene therapy in individuals
with RPGR-XLRP.

An Independent Data Monitoring Committee (IDMC) will be commissioned for this
study to provide expert input on safety of the investigational product,
surgical procedure, and related issues.

Participants will be male and female, ages 3 years and older meeting all
eligibility criteria and with a confirmed genetic variant in RPGR.
AAV5-hRKp.RPGR gene therapy will be administered by subretinal injection using
a standardized surgical procedure; all participants will be offered bilateral
treatment, with the second eye treated 7 to 21 days after the first.

The study will be conducted in 3 phases:
1. Screening and Baseline Phase: The screening phase ( up to 6 months) is the
period during which the eligibility of potential participants is assessed and
all baseline procedures/tests are performed prior to study treatment.

2. Core Phase: The core phase of the study is a 52-week period to assess
immediate treatment compared with deferred treatment.

- Immediate treatment group: The 52-week period for the immediate treatment
group begins on the day of treatment administration in the first eye (Day 1)
through the completion of the Week 52 visit. All study visits starting from
Week 4 will be dated from the day of the first treatment (Day 1, Visit 3) in
order to ensure a consistent duration of follow-up.

- Deferred treatment group: The 52-week period for the deferred treatment group
begins on the day of the
final Baseline Visit (Day 1) through the completion of the Week 52 visit.

The primary efficacy and safety outcome assessments will be performed at the
completion of the core phase of the study. The total duration of individual
participation in this protocol will be up to 18 months.

After the IDMC makes a recommendation to continue the study, pediatric
participants can be enrolled. The first pediatric participant randomized to
immediate treatment will be gated similar to the adult safety Cohort 1 adult
participants. This pediatric participant will complete the Week 10 safety
assessments, then the IDMC will be convened to review the relevant pediatric
safety data prior to further enrolment of pediatric aged study participants.
Additional pediatric participants will be enrolled only after the IDMC
completes their review of safety data and makes a recommendation to the sponsor
to continue to enroll further pediatric participants.

3. Long-term Follow-up: Following completion of this study, all participants
will be enrolled in a follow-up study, MGT-RPGR-022; participants must consent
to participate in the follow-up study in order to participate in Study
MGT-RPGR-021.Participants who were randomly assigned to receive immediate
treatment in Study MGT- RPGR-021 will continue directly into the long-term
follow-up phase of Study MGT- RPGR-022 for an additional 48 months of follow-up
with no additional treatment. Participants who were randomly assigned to
deferred treatment in Study MGT-RPGR-021 will be offered bilateral treatment in
MGT-RPGR-022 with 52 weeks of assessment identical to the MGT- RPGR-021 study,
and then transition to the long-term follow-up phase of the MGT- RPGR- 022
study.

Participants will be enrolled and randomized 1:1:1 to immediate bilateral
treatment with the RPGR2e11 dose (in up to 800 µL in each eye), immediate
bilateral treatment with the RPGR4e11 dose (330µl to 800 µL in each eye), or
deferred bilateral treatment (in Study MGT-RPGR-022) given approximately 1 year
after completion of baseline examinations. Participants randomized to deferred
treatment will be re- randomized at Week 52 in a 1:1 ratio to receive the
RPGR2e11 dose or RPGR4e11 dose for their subsequent treatment in Study
MGT-RPGR-022.

All participants will receive bilateral treatment, with surgical delivery to
the 2 eyes performed 7 to 21 days apart. The first eye treated will be the
worse-seeing eye as determined by visual acuity, and the second eye will
receive identical treatment unless there is a contraindication. If visual
acuity is identical in both eyes, static perimetry MRS will be used to
determine the worse-seeing eye. If both visual acuity and MRS are equal in both
eyes, the right eye will be the first eye receiving treatment.

AAV5-hRKp.RPGR gene therapy is injected in the subretinal space of the
treatment eye in the operating room by a retinal surgeon who is trained and
qualified to deliver the investigational product. Delivery of vector liquid to
the subretinal space will be performed following standard surgical vitrectomy.
This will involve a 3-port pars plana vitrectomy followed by injection of
vector liquid using a fine cannula through a retinotomy into the subretinal
space, resulting in a transient retinal detachment. One or more retinotomies
may be used. A pre-bleb (with, eg, balanced salt solution) is not allowed.

Eligible participants will be randomly assigned to immediate bilateral
treatment with the RPGR2e11 dose (300µL to 800 µL in each eye), immediate
bilateral treatment the RPGR4e11 dose (300µL to 800 µL in each eye), or
deferred bilateral treatment given approximately 1 year after completion of all
baseline examinations (in Study MGTR-PGR-022). The total volume of injection
should not exceed 0.8 mL. Previous gene therapy clinical studies have shown
that the bleb of subretinal vector liquid is expected to resolve spontaneously
over the course of approximately the first 24 to 48 hours postoperatively as
the fluid is resorbed by the underlying retinal pigment epithelium.

All participants will receive bilateral treatment, with surgical delivery to
the 2 eyes performed 7 to 21 days apart. The first eye treated will be the
worse-seeing eye as determined by visual acuity, and the second eye will
receive identical treatment. In the event of a significant ocular adverse event
in the first eye, or any other intercurrent issue that persists through Day 21
post first surgery, the investigator will consult with the sponsor*s Medical
Monitor about the risks, benefits, and timing of treatment to the second eye.
If visual acuity is identical in both eyes, static perimetry MRS will be used
to determine the worse-seeing eye. If both visual acuity and MRS are equal in
both eyes, the right eye will be the first eye receiving treatment.

The first 3 participants randomly assigned to immediate therapy, regardless of
dose assignment, will be gated to allow assessment of safety of the second eye
treatment. These first 3 participants will be males aged 18 years or older.
These participants will be followed through the Week 10 visit and safety will
be reviewed with the SAC before additional participants are randomized.

To minimize the occurrence and severity of immune response to the
investigational product, all participants will receive a defined regimen of
local and systemic immune suppression initiated prior to and continued
following the completion of surgery.

For full details see table 1.3 in the protocol (schedule of activities) table
1 and table 2 on page 24-30

The patient participation in this study will last approximately 18 months.
During this time the patient will visit the hospital approximately
16 times in group 1 (immediate treatment) and 6 times in group 2 ( deferred
treatment until 022 study). The visits will take about 2-9 hours.

During these visits the following tests and procedures will take place:
- Physical exam, vital signs, demographic and medical history
- Questionnaires
- Blood and urine tests
- Pregnancy tests in women of childbearing potential
- tears sample and saliva samples
- several eye tests, and images of the eye
- visual mobility assessments
- patients will take part in interviews
- Patients in group 1 will receive the study drug through retinal injection
via Surgical vitrectomy. The second eye will be treated 7-21 days after the
first eye
- Female patients: no breastfeeding allowed. Effective methods of birth control
must be used from the time of signing the ICF, throughout
the entire study and for 40 weeks (9 months) following the last dose of the
study drug.
- Male patients: due to the potential risk of the effect on the sperm
appropriate method of contraception must be used starting at
screening and continuing for at least 40 weeks (9 months) following the last
dose of study drug

Possible side effects that are already known are described in the IB and
patient information letter.