Gene therapy of patients with Achromatopsia due to CNGA3 defects

• Research type

  Research Study

• Full title

  An open label, multi-centre, Phase I/II dose escalation trial of a recombinant adeno-associated virus vector (AAV2/8-hG1.7p.cohCNGA3for gene therapy of children with Achromatopsia owing to defects in CNGA3

• IRAS ID

  253450

• Contact name

  Amy De Sa

• Contact email

  CNGA3@meiragtx.com

• Sponsor organisation

  MeiraGTx UK II Ltd

• Eudract number

  2018-003431-29

• Duration of Study in the UK

  1 years, 9 months, 31 days

• Research summary

  Research Summary:
  Achromatopsia is a recessively inherited condition characterised by a lack of cone photoreceptor function resulting in impairment of colour vision and visual acuity, central scotoma often with eccentric fixation, disabling hypersensivity to light (photophobia) and involuntary eye movements (pendular nystagmus).

  Children with CNGA3-related achromatopsia have profound sight impairment from birth or early infancy. The condition is currently untreatable, but there is a real possibility that a gene therapy could offer a significant benefit in
  terms of improved sight and quality of life (QOL), based on our own and others experience of ocular gene therapy trials(Maguire, et al 2008; Cideciyan, AV et al 2008 and 2013; Bainbridge, et al 2015) and pre-clinical data demonstrating improved outcome in CNGB3- related achromatopsia. Possible benefits of improved cone-photoreceptor function include improved visual acuity; improved colour perception; and relief from disabling photophobia.

  Although younger individuals may benefit most from gene supplementation therapy by virtue of their greater visual plasticity, we anticipate that the intervention may offer benefit across a range of ages and we aim to include both older and younger children in this trial.

  Lay summary of study results:
  This is a summary of the results of a clinical study written for the general public.
  A study to evaluate the safety of AAV8-hG1.7p.coCNGA3 in children and adults with achromatopsia owing to defects in CNGA3 Key information about this study:
  Who participated in this study:
  People with achromatopsia. Achromatopsia is a hereditary condition that causes vision loss. In some cases, achromatopsia involves a variant of the CNGA3 gene. Participants were required to have a disease-causing fault in that CNGA3 gene to be included in the study.

  What treatment did the participants receive:
  Study participants were treated with AAV8-hG1.7p.coCNGA3, a gene therapy which provides a functioning version of the CNGA3 gene to the eye. The functioning gene is delivered to the retina by injection during an eye surgery.

  What was the aim of this study:
  The study's main purpose was to determine if treatment with the gene therapy is safe and to help determine the doses to be included in future studies.

  What was the design of the study:
  In this study, 11 participants received a single dose of the therapy at sites in the United Kingdom (UK) and the United States (US). Initially, 9 children were treated in one eye. The first 3 children received the low dose, the next 3 received the intermediate dose, and the last 3 received the high dose. Additionally, 2 adults were each treated with a single high dose at the same time as the 3 children who received the high dose.

  Results of the study:
  The study results demonstrated that treatment with AAV8-hG1.7p.coCNGA3 had an acceptable safety profile at all doses.

  Full study name:
  An Open Label, Multi-center, Phase 1/2 Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV8-hG1.7p.coCNGA3) for Gene Therapy of Children and Adults with Achromatopsia Owing to Defects in CNGA3

  The results mentioned in this document are from a single study. New information or different results may be obtained from other studies with this treatment. These results are for information only.

  1. GENERAL INFORMATION ABOUT THE STUDY
  What is achromatopsia:
  Achromatopsia is an inherited condition that can be caused by faults in a gene called CNGA3. Symptoms may include reduced or complete loss of colour vision, reduced visual acuity, light sensitivity, and involuntary eye movements.

  Why the study was done:
  The study's main purpose was to determine if treatment with the gene therapy is safe and to help determine the doses to be included in future studies.

  What was the design of the study:
  This was a Phase 1/2 study meaning that the new treatment was tested in a small number of people with the disease to find one or more safe doses and to see if it worked.

  Initially, 9 children received a single dose of the therapy in one eye. The first 3 children received the low dose, the next 3 received the intermediate dose, and the last 3 received the high dose. Additionally, 2 adults were each treated with a single high dose at the same time as the 3 children who 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 completion of this study, all participants were invited to take part in a follow-up study to assess whether the treatment was still safe after a longer period (up to 5 years after treatment). This long-term follow-up study is ongoing.

  Where and when the study took place:
  The study took place in the United Kingdom and the United States. It started in August 2019 and ended in June 2021.

  2. WHO PARTICIPATED IN THIS STUDY
  Who was allowed to participate in the study:
  Persons 3 years or older who had achromatopsia as confirmed by a retinal specialist and who were able to undertake the clinical assessments were enrolled in the study. Participants were required to have a disease-causing fault in the CNGA3 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 CNGA3 gene or had any other condition that made them inappropriate for entry into the study.

  About the adults and children who participated in the study:
  A total of 11 participants took part in the study. Of the 9 children who took part, 7 were male and 2 were female. The 2 adults who took part were both males.

  3. WHAT TREATMENT DID THE PARTICIPANTS RECEIVE?
  About AAV8-hG1.7p.coCNGA3:
  Participants were treated with a gene therapy called AAV8-hG1.7p.coCNGA3 which provides a functioning version of the CNGA3 gene to the eye.

  How was the medicine given:
  AAV8-hG1.7p.coCNGA3 was delivered to the retina by injection during an eye surgery.

  How was it decided which group the participants were in:
  Participants were assigned to a treatment group in consecutive order as they enrolled in the study (first the low dose, then the intermediate dose, and lastly the high dose).

  4. RESULTS OF THE STUDY
  A total of 11 participants were administered AAV8-hG1.7p.coCNGA3, with 3 participants receiving a single low dose, 3 participants a single intermediate dose, and 5 participants a single high dose. Below are the results through 6 months after treatment.

  This section contains information on the health problems participants had that might be related to the treatment according to the study investigator. This way of showing the results is according to the method required for this kind of document. Study results may be displayed using a different method in other places available to the public.

  Side effects are health problems that happen to a study participant after the study started and that the study investigator thinks might be related to the study treatment.
  The study's main 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 any of the following criteria:
  - Reduction in vision by more than 15 letters on the Early Treatment Diabetic Retinopathy Study chart that failed to resolve to within 15 letters of baseline in a 4-week period once protective treatment commenced.
  - Severe inflammation that did not get better with treatment
  - An infection of the tissues or fluids inside the eyeball (infective endophthalmitis)
  - An eye condition that has the tendency to become progressively worse
  - 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) No participant had a side effect that met any of the criteria of the main safety outcome.

  How many participants had other side effects (not meeting the above criteria):
  Of the 11 participants, 5 had side effects during the study. Of these, 1 participant received the low dose, 1 participant the intermediate dose, and 3 participants the high dose.

  Were there any serious side effects:
  No participants had a side effect that was considered serious.

  What were the most common side effects:
  The most common side effect was eye inflammation which was experienced by 3 participants (all received the high dose) in the study.

  5. HOW HAS THIS STUDY HELPED PATIENTS AND RESEARCHERS?
  The study results demonstrated that treatment with AAV8-hG1.7p.coCNGA3 has an acceptable safety profile at all doses. Additional studies of AAV8-hG1.7p.coCNGA3 can now be performed.

  6. WHERE CAN I LEARN MORE ABOUT THIS STUDY?
  Results of clinical studies may be available to the public in different places. Note that results presented in different places may use different methods of displaying the results.
  If you want more information on the study, you can perform an internet search using the product or study identifiers. Below you can find the list of identifiers used:
  - MGT012 (Sponsor Study Number)
  - AAV8-hG1.7p.coCNGA3 (Sponsor product code)
  - 2018-003431-29 (EudraCT number)
  - NCT03758404 (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%7C7670ff7bd46f40ef0cee08dd49c8e50a%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638747849363713660%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=ye1GS5wSh%2FeYBLw6%2FO%2Bt88DVvgKZ6fJcotvK8Iwxkac%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

  19/LO/0041

• Date of REC Opinion

  3 May 2019

• REC opinion

  Further Information Favourable Opinion