Gene Therapy for XLRP RPGR

• Research type

  Research Study

• Full title

  An open label, multi-centre, Phase I/II dose escalation trial of a recombinant adeno-associated virus vector (AAV2/5-hRKp.RPGR) for gene therapy of adults and children with X-linked retinitis pigmentosa(XLRP) owing to defects in retinitis pigmentosa GTPase Regulator (RPGR)

• IRAS ID

  218294

• Contact name

  James Bainbridge

• Contact email

  j.bainbridge@ucl.ac.uk

• Sponsor organisation

  MeiraGTx UK II Ltd

• Eudract number

  2016-003967-21

• Duration of Study in the UK

  3 years, 0 months, 1 days

• Research summary

  Research Summary

  X-linked retinitis pigmentosa (XLRP) is the name given to a group of inherited eye diseases that affect the retina (the light-sensitive part of the eye). XLRP is most commonly caused by defects in a gene called RPGR that result in degeneration of the light-sensitive ‘photoreceptor' cells in the retina. Typically night blindness is followed by progressive impairment of sight from childhood or early adulthood.
  
  There is currently no treatment for RP. Gene therapy is considered one the most promising approaches. Provision of a healthy gene may protect the photoreceptor cells and preserve sight. In this trial we aim to establish the safety and possible benefit of injection of the gene RPGR, which is packaged in a vector called 'AAV2/5-hRKp.RPGR’. The first phase of the trial is to establish a safe dose; 18 adult participants will be administered one of 3 different doses, in cohorts of 3 participants at a time. Children may be included once safety has been established in adults.
  
  Once an acceptable safety profile has been established in adults, up to 18 additional participants, who may be children or adults, will be included. The IDMC will agree the maximum tolerated dose in adults before recommending administering this dose to children.

  Summary of Results
  This is a summary of the results of a clinical study written for the general public.

  A study to find a safe dose of AAV5-hRKp.RPGR in adults and children with RPGR-associated X-linked retinitis pigmentosa

  Key information about this study:

  Who participated in this study:
  People with X-Linked (meaning that it occurs on the X chromosome) Retinitis Pigmentosa. Retinitis pigmentosa includes several genetic conditions that cause vision loss. In some cases, retinitis pigmentosa involves a variant of the RPGR gene (Retinitis Pigmentosa GTPase Regulator). Participants needed to have a disease-causing fault in that RPGR gene to be included in the study.

  What treatment did the participants receive:
  Participants were treated with AAV5-hRKp.RPGR which provides a functioning version of the RPGR gene to the eye. The functioning gene is delivered to the retina by injection during an operation.

  What was the aim of this study:
  The main purpose of the study was to determine if treatment with the gene therapy is safe.

  What was the design of the study:
  This study had 3 parts. In the first part, 10 adults received a single dose of the therapy. The first 3 participants received the low dose, the following 4 participants received the intermediate dose, and the last 3 received the high dose. In the second part, 3 children were treated with the intermediate dose based on the data in adults. In the last part of the study, 32 participants were randomly divided in 3 groups; those in the first 2 groups received one of two doses of the therapy immediately (either the low dose or the intermediate dose) and the third group received the therapy after a 6-month waiting period (these participants constitute the control group).

  Results of the study:
  The study results demonstrated that treatment with AAV5-hRKp.RPGR had an acceptable safety profile.

  Full study name:
  An open label, multi-centre, Phase 1/2 dose escalation trial of a recombinant adeno-associated virus vector (AAV5-hRKp.RPGR) for gene therapy of adults and children with X-linked Retinitis Pigmentosa owing to defects in Retinitis Pigmentosa GTPase Regulator (RPGR)

  Do not make a decision based on a single study 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. Therefore, you should not make decisions based on the results of this study alone. These results are for information only

  1 GENERAL INFORMATION ABOUT THE STUDY

  What is X-Linked Retinitis Pigmentosa:
  X-linked retinitis pigmentosa is an inherited condition caused by faults in a gene called RPGR (Retinitis Pigmentosa GTPase Regulator) and gets worse over time. Symptoms usually start in childhood or early adulthood. Those affected first experience difficulty seeing at night. Later, peripheral vision is lost and patients experience “tunnel vision’.

  Why the study was done:
  The main purpose of the study was to determine if treatment with the gene therapy is safe.

  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.

  This study had 3 parts:
  - In the first part, 10 adults received a single dose of the therapy. The first 3 participants received the low dose, the following 4 participants received the intermediate dose, and the last 3 received the high dose.

  - In the second part, 3 children were treated with the intermediate dose. This dose was chosen because it was considered safe based on the results in adults.

  - In the last part of the study, 32 participants were randomly divided in 3 groups. Participants in the first two groups received one of two doses of therapy (either the low dose or the intermediate dose) immediately and the third group received the therapy (either the low dose or the intermediate dose) after a 6-month waiting period (these participants constitute the control group).

  After completion of this study, participants were invited to take part in a follow-up study to make sure the treatment is still safe after a longer time (up to 5 years after treatment).

  Where and when the study took place:
  The study took place in the United Kingdom and the United States. It started in July 2017 and ended in November 2021.

  2 WHO PARTICIPATED IN THIS STUDY

  Who was allowed to participate in the study:
  Males aged 5 years or older who have X-linked retinitis pigmentosa and have a disease-causing fault in the RPGR gene were allowed to take part in the study.

  Who was not allowed participate in the study:
  Those who did not have the condition X-linked retinitis pigmentosa were not allowed to participate in the study. Males with the condition of X-linked retinitis pigmentosa but who were under 5 years of age were not allowed to take part in the study. Females were not allowed to participate irrespective of their age or condition.

  About the adults and children who participated in the study:
  A total of 45 males took part in the study, of whom 42 were adults and 3 were children.

  3 WHAT TREATMENT DID THE PARTICIPANTS RECEIVE

  About AAV5-hRKp.RPGR:
  Participants were treated with AAV5-hRKp.RPGR which provides a functioning version of the RPGR gene to the eye.

  How was the medicine given:
  AAV5-hRKp.RPGR was delivered to the retina by injection during an operation.

  How was it decided which group the participants were in:
  In the third part of the study, participants were assigned to a treatment group by chance (like flipping a coin). Putting people into groups in this way makes the results more reliable.

  4 RESULTS OF THE STUDY
  A total of 45 participants were administered AAV5-hRKp.RPGR, with 32 participants receiving immediate treatment (either in the first, second or third part of the study) and 13 participants in the third part receiving treatment after a 6-month waiting period. These latter participants constitute the control group. Below are the results through 12 months after treatment for the participants receiving immediate treatment and up to the time of treatment for the participants in the control group.

  This section contains information on the health problems that participants had and 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 also be presented in other places available to the public, using a different method of displaying the results.

  Side effects are health problems that happen to a study participant after the study started. These health problems are called side effects if the study investigator thinks they might be related to the study treatment.
  A health problem 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)

  The main purpose of the study was to determine if treatment with the gene therapy is safe. To assess this, the reported 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.
  - Severe inflammation that does 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

  No participant had a side effect that met any of the above criteria.

  How many participants had other side effects (not meeting the above criteria):
  Of the 32 participants who received immediate treatment in the study, 19 had a side effect within 12 months after surgery.

  Were there any serious side effects:
  One participant had 1 side effect that was considered serious. This participant had uveitis, which is inflammation of the middle layer of the eye.

  What were the most common side effects:
  The most common side effects in participants who received immediate treatment, and the number of participants who experienced them, are listed below:
  - Eye inflammation – 7 participants
  - Uveitis (inflammation of the middle layer of the eye) – 5 participants
  - Retinal cyst – 3 participants

  5 HOW HAS THIS STUDY HELPED PATIENTS AND RESEARCHERS?

  The study results demonstrated that treatment with AAV5-hRKp.RPGR had an acceptable safety profile. Additional studies of AAV5-hRKp.RPGR 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 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:
  - MGT009 (Sponsor Study Number)
  - AAV5-hRKp.RPGR (Sponsor product code)
  - 2016-003967-21 (EudraCT number)
  - NCT03252847 (National Clinical Trial number)

• REC name

  London - West London & GTAC Research Ethics Committee

• REC reference

  17/LO/0020

• Date of REC Opinion

  4 May 2017

• REC opinion

  Further Information Favourable Opinion