XIRIUS

• Research type

  Research Study

• Full title

  A Dose Escalation (Phase 1), and Dose Expansion (Phase 2/3) Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using an Adeno-Associated Viral Vector (AAV8) Encoding Retinitis Pigmentosa GTPase Regulator (RPGR)

• IRAS ID

  214620

• Contact name

  Paulo E Stanga

• Contact email

  paulo.stanga@mft.nhs.uk

• Sponsor organisation

  NightstaRx Ltd

• Eudract number

  2016-003852-60

• Clinicaltrials.gov Identifier

  NCT03116113

• Duration of Study in the UK

  2 years, 0 months, 1 days

• Research summary

  Research Summary
  Retinitis pigmentosa is an incurable genetic disease that causes blindness. X-linked retinitis pigmentosa (XLRP) is a very severe form of the disease, which results in rapid disease progression and severe retinal dysfunction.
  XLRP 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. Women have two X-chromosomes and so a normal gene on one X-chromosome can compensate for a defective gene on the other X-chromosome to some extent. Men, however, only have one X-chromosome.

  In XLRP, this defective gene results in a progressive degeneration of the retina. Sight loss in XLRP begins with ‘night blindness’ (i.e. loss of night vision) in the first decade, followed by a loss of peripheral vision which results in progressively worsening ‘tunnel vision’ and severe visual impairment. Ultimately, most patients are legally blind by their forth decade.

  There are currently no effective treatments available for XLRP. This clinical trial will investigate whether gene therapy may help the cells in the retina affected by the 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.

  This is the first time this treatment will have been tested in humans, and therefore the main objective of the study is to assess the safety and tolerability of a range of gene therapy doses.

  Summary of Results
  Research Sponsor: Biogen
  Drug Studied: BIIB112
  Protocol Number: 274RP101 (NSR-RPGR-01) Study Dates: Start: March 16, 2017
  End: November 18, 2020
  Short Study Title: Clinical Trial of an Investigational Gene Therapy for X-linked Retinitis Pigmentosa

  Thank you!

  Thank you to the participants who took part in the study for BIIB112. All participants helped researchers learn more about BIIB112 in people with a specific form of X-linked retinitis pigmentosa, also called XLRP. XLRP is one of many forms of retinitis pigmentosa. Retinitis pigmentosa is a group of genetic, or inherited, diseases that cause vision problems and often leads to blindness.

  NightstaRx Ltd, a Biogen company, sponsored this study and reviewed the results when this study ended. Biogen thinks it is important to share the results with the participants and the public.

  We hope this helps the participants understand and feel proud of their important role in medical research. If you have questions, please speak with the doctor or staff at the study site. Why was this study needed?
  Researchers wanted to learn about the use of BIIB112 as a gene therapy in male participants with XLRP caused by the RPGR gene. In this study, BIIB112 was intended to replace a gene that was not working with a healthy gene in the retina.

  One form of XLRP is caused by a defect in the RPGR gene located on the X-chromosome. This is why the disease is called X-linked retinitis pigmentosa. The X-chromosome is inherited from the mother. Females have two X-chromosomes and males have only one X-chromosome. In females, having a working gene on one X-chromosome can provide some protection from the gene that is not working on their second X-chromosome. If a male has a gene that is not working on his only X-chromosome it means he will be impacted by that gene. As a result, it is mostly males that are impacted by XLRP.

  Most participants living with XLRP become blind by their 40s after progressive vision loss, which occurs over a period of many decades. There are no current treatments that can cure XLRP.

  Researchers wanted to find out if replacing the defective RPGR gene that causes XLRP with a healthy copy of the gene can help the vision of participants living with XLRP.

  What was the purpose of this study?
  The main questions that the researchers wanted to answer were:
  • How many participants in each group had medical problems that were serious enough to prevent an increase in dose of study drug in Part 1?
  • How many participants had a lasting improvement in the visual function of the central retina area in the study eye 1 year after receiving BIIB112 in Part 2 of the study?
  • What medical problems happened during the study in Part 1 and Part 2?

  In Part 2 of the study, there were other questions that the researchers wanted to answer. They were:
  • How many participants had overall improvement in visual function of the study eye 1 year after receiving BIIB112?
  • How many participants had an improvement in visual acuity or night vision of the study eye?
  • How many participants had an improvement in their vision when tested by the Octopus 900, a type of vision test?

  The study included a Part 1 and a Part 2. Part 1 happened before Part 2. Participants from Part 1 did not participate in Part 2.

  Who took part in the study?
  The study included male participants living with XLRP who had a mutation in their RPGR gene.
  • Part 1 of the study included 18 participants between 20 to 50 years old.
  • Part 2 of the study included 32 participants between 17 to 60 years old.

  The study took place at 5 research centers in the United States and 3 research centers in the United Kingdom.

  What happened during the study?
  The study started in March 2017 and ended in November 2020. There were 49 adults and 1 teen who participated in the study. Participants had to have XLRP with a mutation (change in the DNA sequence) in the RPGR gene. They answered questions about their medical history before the study began. When the study ended, the sponsor created a report of the results. This is a summary of that report.

  The doses and number of participants for each group in Part 1 and Part 2 are shown below.

  How was the study done?
  All dosed participants received BIIB112 through an injection into the eye during eye surgery. During the surgery, BIIB112 was injected under the retina of one eye. The eye that received BIIB112 is called the study eye. The other eye did not have surgery and did not receive BIIB112.

  Part 1 Study Design
  Participants were put into 1 of 6 different dose groups, with 3 participants in each group. Researchers gave a low dose of BIIB112 to the 3 participants in Group 1, then checked them to see if they had certain medical problems.

  The medical problems researchers were interested in included:
  • Worsening vision
  • Swelling or redness in the eye
  • Retinal damage (damage to the retina)
  • Other medical problems other than expected vision loss from XLRP

  If the participants in Part 1 did not have any of these medical problems after receiving BIIB112, the researchers then gave a slightly higher dose to the next 3 participants in Group 2. Researchers repeated this process, giving Group 2 through Group 6 slightly higher doses and checking for medical problems each time. There were 3 participants in each group.

  Participants visited the study site 10 times over 24 months after the surgery so that researchers could see if they had any medical problems after receiving BIIB112.

  At the end of Part 1, researchers chose the two doses to use in Part 2.

  Part 2 Study Design
  Participants were randomly put into 1 of 3 different dose groups. There were 3 participants that signed up for the study but did not receive treatment. They are not included in the study results. The number of participants in each group are shown below.

  No treatment group – 9 participants
  BIIB112 low dose group – 10 participants
  BIIB112 high dose group – 10 participants

  Participants visited the study site 8 times over 12 months after the surgery date or the planned start date for the no treatment group. During these visits, study doctors and staff checked participants for any medical problems. Participants also took part in several vision tests.

  What were the study results?
  Below is an overall summary of the results and the key questions researchers asked during the study.

  Part 1
  How many participants in each group had medical problems that were serious enough to prevent an increase in dose of study drug in Part 1 of the study?

  None of the 18 participants in Part 1 had any of the pre-defined medical problems that would stop researchers from giving BIIB112 to the next group of 3 participants. At the end of Part 1, researchers decided it was safe to start Part 2.

  Part 2
  How many participants had a lasting improvement in the visual function of the central retina area in the study eye 1 year after receiving BIIB112 in Part 2 of the study?

  Researchers used Macular Integrity Assessment (MAIA) microperimetry to see if the participants had an improvement in visual function after receiving BIIB112. Microperimetry can measure how sensitive the retina is to light at specific points. Participants were asked to look into a machine and click a button when they saw a light while staring at a fixed point. The light moved around their field of vision. This test makes a map of the sensitivity of their vision in many locations. This can measure if a person has lost any of part of their vision.

  In this study, participants were considered to have a visual function improvement if their retinas were more sensitive to light.

  The number and percent of participants with visual function improvement in central retina of the study eye 1 year after receiving BIIB112 is shown below.

  No treatment group – 9 participants
  There were 2 participants (22%) that had visual function improvement.

  BIIB112 low dose group – 10 participants There were 4 participants (38%) that had visual function improvement.

  BIIB112 high dose group – 10 participants There were 2 participants (25%) that had visual function improvement.

  Researchers found that the differences between the 3 groups were not significant, rather than because of BIIB112.

  What other questions did researchers want to answer?
  Researchers also had other questions they wanted to answer besides the main question for Part 2.

  How many participants had overall improvement in visual function of the study eye 1 year after receiving BIIB112?
  When compared to the group that did not receive treatment, participants in the BIIB112 low dose group had improvement in visual function 1 year after treatment. There was no difference in visual function in the high dose group.

  How many participants had an improvement in clarity of vision or night vision of the study eye?
  Visual acuity tested how clearly a participant can see using the Best-Corrected Visual Acuity Test. To test visual acuity initially researchers had participants read letters at a distance of 4 meters (about 13 feet) from the chart. If participants could not read the chart at this distance, they then tried to read it at a distance of 1 meter (a little over 3 feet). The visual acuity results were reported as number of letters read correctly by the participant. The visual acuity was also tested in low light conditions, also known as night vision. This was done by placing a night vision filter over the front of each eye, then having the participant read the same chart that was used for the best-corrected visual acuity test.

  When compared to the group that did not receive treatment, more participants in the BIIB112 low dose group had a visual acuity increase of 1 line on the chart 1 year after receiving BIIB112. This means that they could read 1 smaller line than they could before receiving BIIB112.

  When compared to the group that did not receive treatment, more participants in the BIIB112 low dose group had a night vision increase of three lines on the chart 1 year after receiving BIIB112. This means that they could read 3 smaller lines than they could before receiving BIIB112.

  When compared to the group that did not receive treatment, more participants in the BIIB112 low and high dose groups showed a night vision increase of 1 line (5 letters) on the chart 1 year after receiving BIIB112.

  How many participants had an improvement in their vision when tested by the Octopus 900, a type of vision test?
  There was no difference between the groups that received either dose of BIIB112 and the group that received no treatment.

  What adverse reactions happened in the study eye during the study?
  This section is a summary of the adverse reactions the participants had during the study. A lot of research is needed to know whether a study drug causes an adverse reaction. An adverse reaction is considered “serious” when it results in death, is life-threatening, causes lasting problems, or requires hospital care. When new drugs are being studied, researchers keep track of all adverse reactions that participants have during the study that they believe were caused by the study drug. Not everyone experiences the same adverse reactions.

  One goal of this study was to learn more about the potential adverse reactions of BIIB112.

  Did any adverse reactions happen during Part 1 of this study?
  The summary of adverse reactions for each group in Part 1 is shown below.

  In Part 1, no participants in BIIB112 dose groups 1 through 3 had any adverse reactions. The number and percent of participants in BIIB112 dose groups 4 through 6 are shown below.

  BIIB112 Dose Group 4 – 3 participants
  3 participants (100%) had an adverse reaction.

  BIIB112 Dose Group 5 – 3 participants
  2 participants (67%) had an adverse reaction

  BIIB112 Dose Group 6 – 3 participants
  1 participant (33%) had an adverse reaction.

  Also, none of the participants in Part 1 had a serious adverse reaction.
  Did any adverse reactions happen during Part 2 of this study?
  The summary of adverse reactions for each group in Part 2 is shown below.

  No Treatment Group – 9 participants
  There were no serious adverse reactions in this group.

  BIIB112 Low Dose Group – 11 participants
  5 participants (46%) had adverse reactions.
  1 participant (9%) had a serious adverse reaction.

  BIIB112 High Dose Group – 12 participants
  6 participants (50%) had adverse reactions.
  2 participants (17%) had serious adverse reactions.

  No participants died in this study from adverse reaction or any other health problems.

  What were the adverse reactions in the study eye?
  What serious adverse reactions did participants have?

  In Part 1 of the study, there were no serious adverse reactions.

  The serious adverse reactions that happened in Part 2 are given below.

  No Treatment Group – 9 participants
  There were no serious adverse reactions in this group.

  BIIB112 Low Dose Group – 11 participants
  1 participant (9%) had a reduction in visual acuity.

  BIIB112 High Dose Group – 12 Participants
  1 participant (8%) had a reduction in visual acuity.
  1 participant (8%) had an inflamed retina.

  What were the common adverse reactions?
  The common adverse reactions for each group in Part 1 is shown below. Only adverse reactions that happened in total of 2 or more participants from all groups in Part 1 are given.

  In Part 1, no participants in BIIB112 dose groups 1 through 3 had any adverse reactions. The number and percent of participants in BIIB112 dose groups 4 through 6 are shown below.

  BIIB112 Dose Group 4 – 3 participants
  1 participant (33%) had an inflamed retina.
  1 participant (33%) had spots in the cornea.
  1 participant (33%) had an inflamed and swollen eye.

  BIIB112 Dose Group 5 – 3 participants
  1 participant (33%) had an inflamed retina.
  1 participant (33%) had spots in the cornea.
  1 participant (33%) had an inflamed and swollen eye.

  BIIB112 Dose Group 6 – 3 participants
  1 participant (33%) had an inflamed retina.

  The most common adverse reactions for each group in Part 2 is shown below. Only adverse reactions that happened in total of 2 or more participants from all groups in Part 2 are shown below.

  No Treatment Group – 9 participants
  There was no common adverse reaction in this group.

  BIIB112 Low Dose Group – 11 participants
  1 participant (9%) had an inflamed retina.
  1 participant (9%) had an inflamed and swollen eye.
  1 participant (9%) had a swollen macula.
  1 participant (9%) had a reduction in visual acuity.
  1 participant (9%) had a presence of cells in the back of the eye.

  BIIB112 High Dose Group – 12 participants
  2 participants (17%) had an inflamed retina.
  2 participants (17%) had an Inflamed and swollen eye.
  1 participant (8%) had a swollen macula.
  1 participant (8%) had a reduction in visual acuity.
  1 participant (8%) had a presence of cells in the back of the eye.

  Where can I learn more about the study?
  You can find more information about the study online at https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrials.gov%2F&data=04%7C01%7Capprovals%40hra.nhs.uk%7C7377a13d94f84415332d08d9e58b8d83%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637793209797570996%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=QkMFXCvwLB2aLKdJifZTg7csSdRr4JLAfp6Ah6aVlQg%3D&reserved=0. Once on the site, type NCT03116113 into the search box and click Search.

  You can also find more information online at Clinical Trials Register. Once on the site, click Home & Search, then type 2016-003852-60 in the search box and click Search.

  If you have questions about BIIB112 or the results of this study, please speak with the doctor or staff at the study research center.

  Official study title: A dose escalation (phase 1), and dose expansion (phase 2/3) clinical trial of retinal gene therapy for X-linked retinitis pigmentosa using an adeno-associated viral vector (AAV8) encoding retinitis pigmentosa GTPase Regulator (RPGR)

  Biogen, the sponsor of this study, has its headquarters in Cambridge, Massachusetts (USA).

  The results presented here are for a single study. You should not make changes to your therapy based on these results without first consulting your doctor.

  Thank you.
  Biogen
  225 Binney Street
  Cambridge, MA 02142
  USA

• REC name

  South Central - Oxford A Research Ethics Committee

• REC reference

  16/SC/0551

• Date of REC Opinion

  22 Dec 2016

• REC opinion

  Further Information Favourable Opinion