Gene therapy for Achromatopsia: CNGB3
Research type
Research Study
Full title
An open label, multi-centre, Phase I/II dose escalation trial of an adeno-associated virus vector (AAV2/8-hCARp.hCNGB3) for gene therapy of adults and children with achromatopsia owing to defects in CNGB3
IRAS ID
207239
Contact name
James Bainbridge
Contact email
Sponsor organisation
MeiraGTx UK II Ltd
Eudract number
2016-002290-35
Duration of Study in the UK
1 years, 7 months, 29 days
Research summary
Research Summary:
Achromatopsia is a non-progressive and hereditary visual disorder which is characterized by decreased vision, light sensitivity, and the absence of color vision.
Achromatopsia is sometimes called ‘Day Blindness’, because affected children see better in subdued light. Children with complete Achromatopsia have impaired sight (20/200 or less) owing to an abnormality of the retina, which is the part of the eye like the film in a camera. They also lack color vision, experience discomfort to light (photophobia) and have nystagmus (shaking of the eyes). In the retina, there are three types of cells called cones that enable color vision; red cones, green cones, and blue cones. A child born with cones that don’t work will have achromatopsia. Achromatopsia is a defect in any of four particular genes. Children with Achromatopsia resulting from defects in the gene called CNGB3 have poor vision from birth or early infancy. The condition is currently untreatable, but there is a possibility that a gene therapy could help improve sight and quality of life. We expect that the gene therapy may offer benefit across a range of ages and we aim to define this range. For this reason, affected people of various ages will be included; children will be included only once we have possessed safety in adults.Lay summary of study results:
Who participated in this study:
People with achromatopsia. Achromatopsia is a hereditary condition that causes vision loss. In some cases, achromatopsia involves a genetic change in the gene CNGB3. Participants were required to have a disease-causing change in that CNGB3 gene to be included in the study.
What treatment did the participants receive:
Study participants were treated with AAV8-hCARp.hCNGB3, which provides functioning copies of the CNGB3 gene to the eye. The functioning copies are delivered to the retina by injection during an eye operation.
What was the aim of this study:
The study's primary purpose was to determine if treatment with the gene therapy is safe and which dose is the best to give.
What was the design of the study:
In this study, 23 participants received a single dose of the therapy at sites in the United Kingdom (UK) and the United States (US). Initially, 11 adults were treated. The first 3 adults received the low dose, then 4 were treated with the intermediate dose, and the next 4 were treated with a high dose. Subsequently, in the expansion phase, 12 children were treated: 8 received the intermediate dose, 3 received an “other” dose (a dose between the intermediate and the high dose), and 1 received the high dose.
Results of the study: The study results demonstrated that treatment with AAV8-hCARp.hCNGB3 had an acceptable safety profile. Since eye inflammation was observed at the highest dose, it was decided that this dose would not be included in future studies.
Full study name: An open-label, multi-center, Phase 1/2 dose escalation trial of a recombinant adeno-associated virus vector (AAV8-hCARp.hCNGB3) for gene therapy of adults and children with achromatopsia owing to defects in CNGB3.1. General Information About the Study
What is achromatopsia:
Achromatopsia is an inherited condition that can be caused by faults in a gene called CNGB3. Symptoms may include reduced or complete loss of color vision, reduced visual acuity, light sensitivity, and involuntary eye movements.
Why the study was done: The study's primary purpose was to determine if treatment with the gene therapy is safe and which dose is the best to give.What was the design of the study:
This was a Phase 1/2 study, meaning that the new treatment was tested on a small number of people with the disease to find one or more safe doses and see if it worked. Initially, 11 adults received a single dose of the therapy. The first 3 adults received the low dose, the next 4 received the intermediate dose, and the last 4 received the high dose. Subsequently, 12 children were treated with a single dose as part of an expansion to the study; 8 received the intermediate dose, 3 received an “other” dose (a dose between the intermediate and the high dose), and 1 received the high dose. The study was open label. This means that both the study participants and the study doctors knew that the therapy was being administered to the study participants. After completing this study, all participants were invited to participate in a follow-up study to assess whether the treatment was still safe after a more extended period (up to 5 years after treatment). This long-term follow-up study is now complete.Where and when the study took place:
The study took place in the United Kingdom and the United States. It started in January 2017 and ended in October 20192. Who Participated in this Study?
Who was allowed to participate in the study:
The study enrolled people 3 years or older with achromatopsia who could undertake the clinical assessments. Participants were required to have a disease-causing fault in the CNGB3 gene to be included in the study.Who was not allowed to participate in the study:
Those who did not have achromatopsia caused by a fault in the CNGB3 gene or had any other condition that made them inappropriate for entry into the study.About the adults and/or children who participated in the study:
A total of 23 participants were enrolled in the study: 11 adults and 12 children. Of the 11 adults, 3 were male and 8 were female. Of the 12 children, 2 were male and 10 were female.3. What treatment did the participants receive? About AAV8-hCARp.hCNGB3:
Participants were treated with AAV8-hCARp.hCNGB3, which provides functioning copies of the CNGB3 gene to the eyeHow was the medicine given:
AAV8-hCARp.hCNGB3 was delivered to the retina by injection during an eye operation.How was it decided which group the participants were in:
Participants were assigned to a treatment group as they enrolled in the study. For the initial adult group, the low dose was first, followed by the intermediate and high doses. In the expansion part of the study, the first child received the high dose as this dose was considered safe in adults. However, as this first child developed eye inflammation, all other children in the expansion part received either the intermediate or “other” dose (i.e., between the intermediate and high doses).4. Results of the Study
A total of 23 participants were administered AAV8-hCARp.hCNGB3, with 3 participants receiving a single low dose, 12 a single intermediate dose, 3 a single other dose, and 5 a single high dose. All 23 participants completed the 6-month study following the intervention of AAV8-hCARp.hCNGB3, and all 23 were subsequently enrolled in the long-term follow-up study, which is now complete. Below are the results through 6 months after treatment. Side effects are health problems a participant experiences after the study starts that the investigator thinks might be related to the study treatment. The study's primary purpose was to determine if treatment with the gene therapy is safe. To assess this, the side effects were checked to see if any met at least one of the following criteria: - A decrease in baseline vision by more than 15 letters on the Early Treatment Diabetic Retinopathy Study chart - Severe inflammation that did not get better with treatment - An infection of the tissues or fluids inside the eyeball (i.e., infective endophthalmitis) - An eye cancer - A severe, serious side effect that is not an eye-related health problem A side effect is considered serious if it: - Is life-threatening or leads to death - Leads to a hospital stay or prolongs a hospital stay - Causes permanent damage - Causes a health problem in the study participant’s (unborn) baby - Is considered an important health problem (putting the participant in danger) Three participants experienced a side effect that met a criterion of the primary safety outcome. All 3 experienced severe inflammation that did not get better within 6 weeks, with treatment. Of these, 1 participant received the intermediate dose, and 2 received the high dose. All 3 cases of inflammation resolved with extended treatment with steroids beyond 6 weeks.How many participants had side effects:
Of the 23 participants, 9 had side effects during the study. Of these, 1 participant received the low dose, 3 the intermediate dose, 2 the other dose, and 3 the high dose.Were there any serious side effects:
Serious side effects were reported for 2 participants during the study. • The first participant was an adult who received the intermediate dose and experienced severe inflammation inside the eye (uveitis) 42 days after the eye operation that required further medication to resolve. • The second participant was a child who received the high dose and experienced severe inflammation inside the eye (uveitis) 18 days after the eye operation that required further medication to resolve. Both side effects of eye inflammation were later reported as resolved.What were the most common side effects:
The most common side effect was eye inflammation, which 7 study participants experienced. Of the 7 who experienced eye inflammation, 2 received the intermediate dose, 3 received the high dose, and 2 received the other dose.5. How has this study helped patients and researchers? The study results demonstrated that AAV8-hCARp.hCNGB3 has an acceptable safety profile, and additional studies of AAV8-hCARp.hCNGB3 can now be performed. The highest dose in this study will not be included in future studies.
6. Where can I learn more about this study? Results of clinical studies may be available to the public in different places. Note that different places may use different methods to display the results.
If you want more information about the study, you can perform an internet search using the product or study identifiers. Below, you can find the list of identifiers used: - MGT006 (Sponsor Study Number) - AAV8-hCARp.hCNGB3 (Sponsor product code) - 2016-002290-35 (EudraCT number) - NCT03001310 (National Clinical Trial number) You can find more information in English about this study or its results on the following websites: - https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=05%7C02%7Cwestlondon.rec%40hra.nhs.uk%7C6ea62696323c49bcec0808dd6633af7d%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638779094353987654%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=PfFkwpGS%2BHqnsoPoCaAZWgsV1ADyDM28F1rqplNNyiQ%3D&reserved=0
7. Who carried out the study? Sponsor: MeiraGTx UK II Ltd How to contact: patients@meiragtx.com
REC name
London - West London & GTAC Research Ethics Committee
REC reference
16/LO/1540
Date of REC Opinion
21 Oct 2016
REC opinion
Further Information Favourable Opinion