A Randomised, Open Label, Outcomes-Assessor Masked, Prospective, Parallel Controlled Group, Phase 3 Clinical Trial Of Retinal Gene Therapy For Choroideremia Using An Adeno-Associated Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1)

CHM is currently defined as an incurable genetic orphan disease that causes
blindness. The disease is caused by a defect in a certain gene located on the
X-chromosome, and this is why the disease affects men and women differently.
In CHM, this faulty gene results in a progressive degeneration of the retina
(the light sensitive part of the eye responsible for vision, which is like a
camera film that lines the back of the eye). Sight loss in CHM begins with
*night blindness* (i.e. loss of night vision) in adolescence, followed by a
gradual loss of peripheral vision which results in progressively worsening
*tunnel vision*. Ultimately, central vision is lost by the fourth or fifth
decade.
There are currently no effective treatments available for CHM. This clinical
trial will investigate whether a gene therapy, (a technique that involves
putting normal copies of the faulty gene back into the cells of the retina) may
help the cells in the retina affected by this disease, to function normally.
The gene therapy consists of a virus which has been disabled so that it cannot
cause infection. This virus has been specially altered to carry the normal
genes into the cells in the retina. The altered virus is delivered to the
retina during an operation where it will produce multiple copies of the normal
gene.

The objective of the study is to evaluate the efficacy and safety of a single
sub-retinal injection of AAV2-REP1 in subjects with choroideremia (CHM).

Study Design: This is an outcomes-assessor-masked, prospective, randomised,
parallel-controlled group, multi-centre, global, interventional study. The
study consists of 8 visits with a 12-month evaluation period. During the
Screening/Baseline period, each subject will be assessed for eligibility. For
eligible subjects, a study eye will be assigned, and the subjects will be
randomised in a 2:1:2 ratio to receive either AAV2-REP1 high dose (1.0×10^11
genome particles [gp]), AAV2-REP1 low dose (1.0×10^10 gp) or to enter the
untreated Control group.
On the Injection Day Visit (Visit 2, Day 0), subjects in the AAV2-REP1 high-
and low-dose treatment arms will undergo vitrectomy and receive a sub-retinal
injection of the assigned treatment dose of AAV2-REP1 in their study eye; these
subjects will then return to the surgical site for 2 post-operative follow up
visits on Day 1 (Visit 3) and, possibly for Day 7 (Visit 4; Day 7 can occur at
either the surgical site or the home site depending on the clinical status of
the subject). Subjects in the Control group will not undergo surgery, receive
any study drug in their study eye (i.e., Control-study eye) or attend the 2
on-site post-operative visits. Instead, a telephone contact from the site will
occur for the Control group on Day 0 (Visit 2), Day 1 (Visit 3) and Day 7 (± 3
days; Visit 4).
Day 0 (Visit 2) will be defined as the projected surgical day, whether the
subject is randomised to treated or control groups.
All subjects will be followed for 12 months from Visit 2 (Day 0).
Study data will be collected for both eyes of each subject. Since AAV2-REP1
treatment requires an invasive surgical procedure under general anaesthesia,
the sponsor, investigator and the subject will be unmasked to the study
procedure (i.e., vitrectomy and sub-retinal injection), however within the
treated groups, the sponsor, investigator and subject will be masked to the
assigned dose (1.0×10^11 gp or 1.0×10^10 gp). To further minimise the potential
bias of the treated and untreated eye evaluations, all subjective ophthalmic
assessments from the Screening/Baseline Period (Visit 1) and from Month 1
(Visit 5) onwards (including the Month 12 Primary Endpoint evaluation) will be
conducted by a masked assessor.
Subjects will be assessed for efficacy and safety throughout the study as
indicated in the Schedule of Study Procedures. Subjects who develop cataracts
may undergo cataract surgery if deemed clinically necessary; if surgery is
performed, it should be carried out at least 4 weeks before the Month 12
Visit/End of Study (EOS) Visit.

Test product, dosage, and mode of administration:
All subjects receiving active treatment will undergo vitrectomy and receive a
0.1 mL sub-retinal injection of study drug containing 1 × 10e 11 AAV2-REP1
(high dose) or 1 x 10e 10 AAV2-REP1 (low dose) genome particles.

A total of 8 visits is anticipated in one year. Visits may take up to half a
day or more depending on the assessments that are done. The subjects will be
hospitilised for one night after the surgery.

The subject randomized in the AAV2-REP1 group should take oral corticosteroid
medication starting 2 days prior to surgery and 19 days after (a total of 21
days).

The subject will get surgery in the UK and will stay overnight before and after
the surgery (one-two nights). A travel agency will organize the travel and stay
for the subject and a accompanying person. If needed a translator can be
arranged.

The subject will be asked to complete the VFQ- 25 questionnaire (4- times).
Most of the procedures are part of the routine care of the patient with their
treating physician. During the study BCVA, full ophthalmic examination (IOP,
lens opacities, split lamp, dilated ophthalmoscopy, SD-OCT, microperimetry,
contrast sensitivity, colour vision test, 7 field colour fundus photos and
reading speed test performed.

Possible risks and discomforts associated with study procedures:
Risk Associated with the Surgery (Vitrectomy and Subretinal Injection):
All surgical procedures carry a risk of side effects. Your cornea (transparent
front part of the eye) could be scratched during the surgery. Scratches on the
cornea usually get better without treatment but may require patching or a
bandage contact lens. Some potential complications of the new intervention
include vision problems that may be caused by bleeding into the eye,
tears/holes or detachment of the retina: vitreous bleeding, low and elevated
intraocular pressure, choroidal detachment, swelling of the central part of the
retina (macular oedema), thinning of the retina and infection. One occurrence
of retinal artery occlusion (a blockage of one of the blood vessels supplying
the retina) has been observed so far in a subject with advanced stage
choroideremia. A potential long-term complication of the surgical procedure is
formation or worsening of cataracts (lens clouding). Symptoms experienced by
patients with these complications include blurred vision with or without
decreased visual acuity, wavy or distorted vision (metamorphopsia), flashes of
light (photopsias), floaters, pain, tearing, photophobia, glare, and double
vision. Vitrectomy itself is often associated with transient visual impairment.
These complications can be treated effectively by medications or further
surgery but rare instances result in a permanent vision loss, including
complete loss of vision.
The surgery is performed under general anaesthesia, there can arise common and
less serious side effects from it, for example, nausea or vomiting, shivering,
temporary throat pain and hoarse voice. More pronounced, but also more seldom
side effects include sensitivity to the medication used as an anesthetic.
Teeth, vocal cords and soft parts in the mouth can be injured during the use of
instruments in the airways. Stomach contents can, in very rare cases enter the
lungs and cause lung inflammation. These and other side effects of anaesthesia
will be explained further by the anaesthesiologist.

Risks Associated with AAV2-REP1:
The virus carrying the CHM gene is developed from a virus known as
adeno-associated virus (AAV) that does not cause any known diseases in humans,
and which has also been disabled such that it is not expected to cause illness.
There is a possibility however that the virus may cause some inflammation
inside the eye. We intend to minimize any risk of inflammation by asking the
subject to take oral corticosteroid tablets for 2 days prior to the operation
and for a total of 21 days. The possible risks from taking the corticosteroid
medicine is outlined below.

One possible serious side effect, seen in about 5% of patients treated with
AAV2-REP1, was visual acuity reduced (inability to see clearly/read eye chart).

There is a theoretical possibility that the new gene might interfere with the
activity of other genes, posing a potential risk of tumor formation. However,
this effect has not been observed in other trials in subjects treated using
this virus. Routine monitoring procedures are expected to identify this remote
possibility at an early stage to enable prompt and effective treatment.
Tiny amounts of the virus injected may spread along the optic nerve towards the
brain. The intervention has been designed to limit the effect of the new gene
to the retina and any risk of damage to the brain is very small.
Gene therapy can in theory affect the next generation. It is possible that the
gene could be transmitted via semen, however, the risk of the new gene will be
transferred from this study to future children is considered minimal, as only
small amounts of virus are introduced into the eye. Nevertheless, all
participants will be asked to use acceptable prevention in the form of a
barrier method, or abstain from sexual intercourse for the first 3 months
following treatment in order to reduce the potential risk of passing the gene
therapy product on to a partner or unborn child.
Even if gene therapy in the eye is successful, it will not prevent the subjects
daughters from being bearers of the disease (fathers cannot give the disease
further to their sons), and the subjects grandchildren can still be affected by
CHM.

Risks of Corticosteroids:
The use of corticosteroids for prevention or treatment of inflammation can
cause side effects, including raised blood pressure and blood sugar, stomach
ulcers, trouble sleeping and behavioral change like mood swings, irritability,
and depression. These are generally reversible once medication is stopped;
however, the subject will be monitored for these during the surgical period.
There is also a chance that with the use of corticosteroids can suppress the
natural production of hormones made by the adrenal gland. This can cause severe
fatigue, loss of appetite, weight loss, nausea, or muscle weakness.

Risks related to examinations
During ophthalmic examination, SD-OCT, 7-field colour fundus photography,
fundus autofluorescence, fluorescein and indocyanine angiography the subjects
pupils will be dilated using eye drops which will keep the pupils dilated for 4
to 6 hours. This may result in glare in daylight.
In rare cases, the use of numbing eye drops or dilating drops may cause
redness, discomfort or allergic reactions. If the subject has high blood
pressure, an irregular heartbeat or glaucoma, these conditions may get worse
when using the eye drops, however this can be managed. Blood will be drawn
from your arm by using a needle for the immunogenicity (your body*s immune
response) sampling. Risks associated with drawing blood from your arm may
include pain and/or bruising, infection, excess bleeding, clotting or fainting.
The subject should also not donate blood during the 24 month period after the
study.
In the case that air is put into the eye during the surgery, because the
surgeon considered that it is necessary, the subject should avoid air travel,
travelling to high elevations or scuba diving until the air bubble has
completely dissipated from the eye. It may take one week or more following
injection for the air bubble to dissipate. A change in altitude while the air
bubble is still present can result in irreversible vision loss. The
disappearance of the air bubble should be verified through very careful
ophthalmic examination by the study doctor. The doctor will inform the subject
if this restriction applies to them.

The gene therapy (surgery) will take place in Oxford in UK or in Tübingen,
Germany. The subject must travel to UK or Germany 1-2 days before the surgery
and stay there for 1-2 days after the surgery.