Phase 3 Follow-up 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).

No therapies are approved for any form of RP, 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 inherited
retinal disease (Bainbridge 2008) and pre-clinical data demonstrating improved
outcome in animal models of RPGR-XLRP. Preliminary data from the ongoing 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

This study has been transitioned to CTIS with ID 2024-511411-25-00 check the CTIS register for the current data.

Main objective:

To assess the long-term safety and tolerability of AAV5-hRKp.RPGR in
individuals with RPGR-XLRP
To assess the long-term efficacy of treatment with AAV5-hRKp.RPGR in
individuals with RPGR-XLRP based on assessments of functional vision as
measured by vision-guided mobility assessment (VMA).

Secondary objectives:
To assess changes in all participants after treatment in: retinal
function,functional vision, visual function

This is a long-term, safety follow-up study of participants who participated in
Study MGT-RPGR-021; the study also allows for initial treatment of participants
who were randomly assigned to deferred treatment in MGT-RPGR-021.
Participants will be male and female, aged 3 years and older who participated
in and completed Study MGT-RPGR-021. For participants who are eligible for
treatment in this study, 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.

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.

Follow-up period: All study participants must be followed for a period of 60
months after the treatment:
Participants who were randomly assigned to immediate treatment in Study
MGT-RPGR-021 will transition directly to a long-term follow-up schedule,
beginning with a study visit at Month 18 posttreatment, to complete an
additional 48 months of follow-up.

- Participants who were randomly assigned to deferred treatment in Study
MGT-RPGR-021 will transition to a treatment schedule, including a review of
eligibility criteria and new baseline evaluations within 2 months after
completion of Study MGT-RPGR-021, followed by bilateral treatment. Upon
completion of the 52-week primary treatment period, this cohort will enter the
long-term follow-up schedule, to complete a total of 60 months follow-up.

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 small 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 who were assigned to deferred treatment in Study
MGT-RPGR-021 will be treated bilaterally with either RPGR2e11 dose (in up to
800 µL in each eye) or RPGR4e11 dose (in up to 800 µL in each eye). 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 the first 24 to 48 hours
postoperatively as the fluid is resorbed by the underlying retinal pigment
epithelium.

All treatment-eligible participants will receive bilateral treatment, with
surgical delivery to the 2 eyes performed within 7 to 21 days apart. The first
eye treated will be the worst-seeing eye as determined by visual acuity and
static perimetry, 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, the investigator will consult with the sponsor*s Medical Monitor about the
risks, benefits, and timing of treatment to the second eye.
If both visual acuity and MRS are equal in both eyes, the right eye will be the
first eye
receiving treatment.

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

For full details, see Table 1.3 in the Protocol Table 1 and Table 2 on page
14-18

Patient participation in this study lasts approximately 4 years for group 1 and
5 years for group 2. During this time, the patient in group 1 (immediate
treatment) will visit the hospital approximately 5 times and 15 times in group
2 (delayed treatment until study022 ). The visits last approximately 2-9 hours.
The following tests and procedures are performed during these visits:
- 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
- various eye tests and images of the eye
- visual mobility assessments
- patients participate in interviews
- Patients in Group 2 will receive the study drug via retinal injection via
surgical vitrectomy. The second eye is treated 7-21 days after the first eye
- Female patients: breastfeeding is not allowed. Effective contraceptive
methods should be used during the study and for 6 months after the last dose of
the study drug from the time of signing the ICF.
- Male patients: Due to the potential risk of the effect on sperm, an
appropriate method of contraception should be used from
screening and during the study and for at least 6 months after the last dose of
study drug
Possible side effects that are already known are described in the IB and
patient information letter.