RESCUE and REVERSE Long-term Follow-up

• Research type

  Research Study

• Full title

  Long-term Follow-up of ND4 LHON Subjects Treated With GS010 Ocular\nGene Therapy in the RESCUE or REVERSE Phase III Clinical Trials\n

• IRAS ID

  238041

• Contact name

  Patrick Yu Wai Man

• Contact email

  py237@cam.ac.uk

• Sponsor organisation

  GenSight Biologics

• Eudract number

  2017-002153-11

• Clinicaltrials.gov Identifier

  IND Number, 16538

• Duration of Study in the UK

  4 years, 2 months, 29 days

• Research summary

  Research Summary

  This is a Phase III prospective non-interventional (No IMP administered) long-term follow-up clinical study of participants previously enrolled in two Phase III studies—RESCUE and REVERSE. Leber hereditary optic neuropathy (LHON) is an inherited form of blindness caused by pathogenic mutations (spelling mistakes) within the genetic code contained within mitochondria. Mitochondria are the powerhouses within cells and produce most of the energy required for normal cellular function. The majority of patients with LHON carry a specific mutation within the mitochondrial ND4 gene (denoted as G11778A) where due to a mutation the genetic code it now instructs formation of a ND4 protein with a compromised function. During the RESCUE and REVERESE studies participants were administered a single injection with a gene therapy named GS010, aimed at delivering a functional ND4 protein to the deficient mitochondria. This study will monitor these participants over an additional 3 years after the RESCUE and REVERSE studies end. The European Medicines Agency Committee for Medicinal Products for Human Use guideline recommends a monitoring plan to observe participants for potential delayed adverse events (AEs) for up to 5 years post-gene therapy treatment. This is the main rationale for this long-term follow-up study. Approximately 76 participants above the age of 16 years will take part in this study in the UK, Germany, Italy, France and the United States. The long-term follow-up study will include 5 visits at 2, 2.5, 3, 4, and 5 years post injection. Assessments: Safety, efficacy, and Quality of Life variables and blood tests will be assessed during the long-term follow-up study and descriptive summaries and statistical testing will be used for analysis of the data.

  Summary of Results

  "Conclusion of Results
  The improvements in visual acuity (measure of the sharpness or clarity of vision), the high responder rates (a responder is a patient whose visual acuity improves after they received the Investigational Medicinal Product) and Quality of Life positive results found in the initial studies (RESCUE and REVERSE) remained the same and continued in this extension study, which followed patients for up to 5 years after they had received Investigational Medicinal Product. The Investigational Medicinal Product (GS010) had an overall good safety profile with excellent systemic tolerability and a good ocular tolerability over the 5-year follow-up.

  Lay Summary of Results
  Efficacy Results (whether GS010 was effective) were based on the following assessments:
  - Best Corrected Visual Acuity (best possible vision an eye can have with corrective lenses)
  - Contrast Sensitivity (how well the eye can tell the difference between light and dark)
  - Quality of Life questionnaires

  The following efficacy results were found:
  Best Corrected Visual Acuity
  • The Best Corrected Visual Acuity worsened within the first weeks after GS010 was administered then improved up to year 2.5 and remained stable up to year 5. It was similar in both eyes (GS010-treated eye and placebo-treated eye).
  • At year 5 the average change from baseline using Logarithm of the Minimum Angle of Resolution charts (LogMAR) to measure Best Corrected Visual Acuity was -0.08 (0.66) for GS010 treated eyes and -0.03 (0.63) for placebo-treated eyes.
  • At year 5 the average change from nadir (when the patient’s Best Corrected Visual Acuity has been at its worst before they entered the study) using Logarithm of the Minimum Angle of Resolution charts (LogMAR) to measure Best Corrected Visual Acuity was -0.44 (0.46) for GS010 treated eyes (which is the same as reading +22 letters on the vision test chart) and -0.39 (0.36) for placebo treated eyes (which is the same as reading +19.5 letters on the vision test chart).
  • At baseline, 15 (24.19%) GS010-treated eyes and 14 (22.58%) placebo treated eyes were off-chart (their visual acuity could not be tested using the vision test chart as they could not see at least 3 letters on this). At Year 5, 7/15 (46.67%) GS010-treated eyes and 7/14 (50.00%) placebo treated eyes could see at least 3 letters using the vision test chart so their Best Corrected Visual Acuity could be tested using this.
  • At year 5, the proportion of patients with a change from baseline of at least -0.2 LogMAR and -0.3 LogMAR was around 50% and 40%, respectively. The rate of subjects with a Clinically Relevant Recovery from baseline at Year 5 was around 50%. These responder rates versus baseline at Year 5 were higher in patients entered into the REVERSE initial study compared to patients entered into the RESCUE initial study.
  • The proportion of patients with a change from nadir of at least -0.2 LogMAR and -0.3 LogMAR at Year 5 was around 80% and 70%, respectively; approximately 70% of patients had a Clinically Relevant Recovery from nadir in at least 1 eye at Year 5. The proportions of responders from nadir were similar in patients entered into the REVERSE initial study compared to patients entered into the RESCUE initial study.
  • 13 (20.97%) patients had at least 1 eye with LogMAR <1 at baseline, of whom 76.92% had a Clinically Relevant Stabilisation (maintained the Best Correct Visual Acuity at the same level) at Year 5.
  • Clinically Relevant Benefit (patients with Clinically Relevant Stabilisation or Clinically Relevant Recovery from nadir) was observed in 70.97% of patients at Year 5.
  • 29.03% of patients at Year 5 had Best Corrected Visual Acuity of < 1 LogMAR in at least 1 eye, compared to 20.97% of patients at baseline.
  • 35.48% of patients at Year 5 had Best Corrected Visual Acuity of ≤ 1 LogMAR in at least 1 eye, compared to 24.19% of patients at baseline.
  • 82.26% of patients had Best Corrected Visual Acuity ≤ 1.6 LogMAR in at least 1 eye at baseline, and 80.65% at Year 5.
  • The final Best Corrected Visual Acuity was dependent on the relative change (percentage change) from baseline in Ganglion Cell Layer macular volume (Ganglion Cell Layer = a layer of the retina at the back of the eye, which contains nerve cells called ganglions. Macular volume = thickness of the macular layer, which is the area in the centre of the retina containing nerve cells that detect light) and the baseline LogMAR value. The baseline Ganglion Cell Layer macular volume had no statistically significant impact on the final Best Corrected Visual Acuity.

  Contrast sensitivity
  • No relevant changes from baseline in contrast sensitivity were observed in GS010-treated eyes and placebo treated eyes over time. At the patient level, the average change in Log Contrast Sensitivity (LogCS, which is a measure of contrast sensitivity) was +0.15 (0.39) in at least 1 eye at Year 5.
  • At Year 5, the average change in LogCS from nadir was similar in GS010-treated eyes (0.28 [0.29]) and placebo treated eyes (0.24 [0.30]). At the patient level, the average change from nadir was 0.36 (0.34) at Year 5.
  • At Year 5, 33.87% of patients had an improvement from baseline by at least +0.3 LogCS in at least 1 eye.
  • At Year 5, 59.68% of patients had an improvement from nadir by at least +0.3 LogCS in at least 1 eye.
  • At baseline, 20 (32.26%) patients had both eyes off-chart in terms of LogCS. In these patients, 11 (55.00%) had at least 1 eye switching to on-chart at Year 5 (so they could read at least 3 letters on the vision test chart).

  Quality of life
  • At 5 years post-treatment, an average increase from baseline ≥ 4 points (representing an improvement of clinical significance) was observed for most of the metrics of the Visual Function Questionnaire-25:
  o Mental Health (22 points), Role Difficulties (17 points), Dependency (14 points), Near Activities (13 points), General Vision (8 points), Distance Activities (7 points), Composite score (7 points), and Social Functioning (4 points).
  • At 5 years post-treatment, increases from baseline were observed for the emotional well-being score and the social functioning score of the Short Form Survey-36 questionnaire.

  Humphrey visual field
  • The visual field Mean Deviation (which gives an overall value of the total amount of visual field loss) was stable over time in GS010-treated eyes and placebo-treated eyes.
  • At Year 5, 19.61% of eyes had a gain from baseline ≥ 7 dB (ie, clinically meaningful improvement) in visual field Mean Deviation without relevant differences between eye groups. A gain (i.e., improvement) of [3; 4.99] dB and [5; 6.99] dB was observed in 3.92% and 9.80% of eyes, respectively, without relevant differences between eye groups. (dB = decibel and is used to represent how strong the light being shown to the patient is).

  Optical coherence tomography
  • Baseline Ganglion Cell Layer macular volume tended to decrease when the duration of vision loss increased.
  • All measurements were similar in GS010-treated eyes and placebo treated eyes at baseline. After a decrease in thickness between baseline and Year 2, Optical coherence tomography measurements remained stable up to Year 5.

  Safety results summary

  Primary safety endpoints
  • No systemic treatment-emergent adverse events related to the Investigation Medicinal Product or procedure (injection into the eye) were reported during the follow-up study. (Systemic = affecting the entire body rather than a single organ or body part. Treatment-emergent = starting after the Investigational Medicinal Product or procedure has been given. Adverse Event = any untoward medical event which occurs).
  • Ten ocular (eye-related) treatment-emergent adverse events related to the Investigation Medicinal Product or procedure were reported in 5 (8.06%) GS010-treated eyes and 1 (1.61%) placebo treated eye; all were of mild intensity, and none led to the patient(s) having to leave the study.

  Secondary safety endpoints
  • During the follow-up study, 36 ocular treatment-emergent adverse events were reported in 24 (38.71%) GS010-treated eyes and 21 ocular treatment-emergent adverse events were reported in 18 (29.03%) placebo treated eyes. Most were of mild intensity, led to the patient(s) having to leave the study.

  Other safety analyses
  • Ocular treatment-emergent adverse events between baseline and Year 5:
  o Most ocular (eye-related) treatment-emergent adverse events were of mild intensity; 2 severe ocular treatment-emergent adverse were reported, none of which was related to Investigation Medicinal Product or procedure.
  o 1 serious treatment-emergent adverse event (retinal tear) was reported in 1 placebo treated eye.
  o Intraocular inflammation (inflammation of a layer within the eye) was reported more frequently in GS010-treated eyes (124 events in 79.03% of eyes) than in placebo treated eyes (6 events in 9.68% of eyes). Most events were of mild intensity and only occurred in the anterior chamber (the inside of the front of the eye between the cornea and the iris and the ciliary body, which is found in the middle layer of the wall of the eye) and intermediate segment (retina and blood vessels just behind the lens as well as the gel in the centre of the eye (vitreous)); no posterior uveitis was reported (this would affect a layer on the inside of the back of the eye, either the retina or the choroid). Most resolved without treatment.
  o Intraocular pressure (the pressure within the eye) increases were reported more frequently in GS010-treated eyes (24 events in 33.87% of eyes) than in placebo treated eyes (5 events in 8.06% of eyes). Most events were of mild intensity. Most resolved without treatment.
  • Systemic treatment-emergent adverse events between baseline and Year 5:
  o Most systemic treatment-emergent adverse events were of mild intensity; 27 severe systemic treatment-emergent adverse events were reported in 12 (19.35%) patients, none of which was related to Investigation Medicinal Product or procedure.
  o 10 (16.13%) patients experienced 16 serious treatment-emergent adverse events; none was considered related to Investigation Medicinal Product or procedure.
  o There were 2 systemic treatment-emergent adverse events leading to death: 1 patient died from cardiac arrest due to hypertensive (high blood pressure) and atherosclerotic cardiovascular disease (thickening or hardening of the arteries caused by a build-up of plaque in the inner lining of an artery in the heart) and 1 patient died from glioblastoma (brain tumour).

  Other safety assessments
  • Intra Ocular Pressure was stable over time, without differences between GS010-treated eyes and placebo treated eyes.
  • Vital signs were normal and stable over time. No relevant finding was observed regarding physical examination, electrocardiograms (test used to check the heart's rhythm and electrical activity) or laboratory measurements."

• REC name

  South Central - Oxford A Research Ethics Committee

• REC reference

  17/SC/0644

• Date of REC Opinion

  17 Jan 2018

• REC opinion

  Further Information Favourable Opinion