Company: Gensight Biologics (France)
Product: GS010- adeno-associated viral vector containing the human NADH dehydrogenase 4 gene
- gene therapy. GS010 is a gene therapy-based single intravitreal injection in the eye targeting LHON due to the ND4 gene mutation. GS010 uses GenSight’s Mitochondrial Targeting Sequence (MTS) proprietary technology platform, which permits missing mitochondrial proteins to be shuttled into the mitochondrion, enabling the restoration of mitochondrial function.
- GS010 has been granted Orphan Drug Designation both in the United States and in Europe.
- GS010 is currently being investigated in two additional ongoing Phase III trials, RESCUE and REFLECT, while patients in REVERSE continue to be followed for another 4 years. RESCUE is a randomized, double-masked, sham-controlled Phase III trial designed to evaluate the safety and efficacy of a single intravitreal injection of GS010 in subjects affected by LHON with < 6 months of onset of vision loss. GenSight expects to report topline data for RESCUE in the third quarter of 2018. REFLECT is a randomized, double-masked, placebo-controlled Phase III trial evaluating the safety and efficacy of bilateral injections of GS010 in patients with < 1 year of onset of vision loss in LHON. The first patient in REFLECT was treated in March 2018.
Disease: Leber’s hereditary optic neuropathy (LHON)
area: Ophtalmological diseases - Genetic diseases - Rare diseases
Country: France, Germany, Italy, UK, USA
- RESCUE and REVERSE are two separate randomized, double-masked, sham-controlled pivotal Phase III trials designed to evaluate the efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in subjects affected by LHON due to the G11778A mutation in the mitochondrial ND4 gene.
The primary endpoint will measure the difference in efficacy of GS010 in treated eyes compared to sham-treated eyes based on Best Corrected Visual Acuity (BCVA), as measured with the ETDRS at 48 weeks post-injection. The patients’ Log of the Minimal Angle of Resolution, or LogMAR, scores, which are derived from the number of letters they read on the ETDRS chart, will be used for statistical purposes. Both trials have been adequately powered to evaluate a clinically relevant difference of at least 15 ETDRS letters between treated and untreated eyes adjusted to baseline.
The secondary endpoints will involve the application of the primary analysis to best seeing eyes that received GS010 compared to those receiving sham, and to worse seeing eyes that received GS010 compared to those that received sham. Additionally, a categorical evaluation with a responder analysis will be evaluated, including the proportion of patients who maintain vision (< ETDRS 15L loss), the proportion of patients who gain 15 ETDRS letters from baseline and the proportion of patients with Snellen acuity of >20/200. Complementary vision metrics will include automated visual fields, optical coherence tomography, and color and contrast sensitivity, in addition to quality of life scales, bio-dissemination and the time course of immune response. (REVERSE NCT02652780 and RESCUE NCT02652767)
- • On October 18, 2018, GenSight Biologics reported additional results at Week 72 from the REVERSE Phase III clinical trial, which evaluates the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment.
At 72 weeks, a clinically meaningful improvement from baseline in mean visual acuity of +15 letters (-0.294 LogMAR) was observed in GS010-treated eyes, with concomitant contralateral improvement of +12 letters (-0.246 LogMAR) in sham-treated eyes. This improvement, which extends the positive trend that had been reported at Week 48, points to a sustained functional outcome for the trial subjects.
- Continued improvement was also observed in contrast sensitivity as determined by Pelli-Robson low-contrast testing. At 72 weeks, GS010-treated eyes and sham-treated eyes gained on average +0.21 LogCS and +0.15 LogCS versus baseline, respectively. The proportion of treated eyes that achieved a clinically meaningful improvement of at least 0.3 LogCS (45.9%) was statistically significantly higher than that of sham-treated eyes (24.3%; p=0.0047).
- The visual function outcomes were accompanied by evidence that GS010 was engaging its anatomic targets, the ganglion cells. At 72 weeks, high-resolution Spectral-Domain Optical Coherence Tomography (SD-OCT) objectively demonstrated sustained preservation of the retina anatomy relevant to LHON in GS010-treated eyes. The ganglion cell layer macular volume was preserved (+0.000 mm3) in treated eyes, while sham-treated eyes deteriorated from baseline (-0.044 mm3). The difference was statistically significant (p=0.0060). Drug-treated eyes also showed a limited loss in thickness of the temporal quadrant of the retinal fiber layer of -1.6 µm, compared to a loss of -3.6 µm in sham-treated eyes (p=0.0521).
- As per protocol, all 37 subjects will be evaluated again at 96 weeks, and data will be reported in the second quarter of 2019. Topline 48-week data for RESCUE, the second Phase III clinical trial of GS010 in the treatment of LHON, is expected in early Q1 2019.
• On September 13, 2018, GenSight Biologics provided an update on the clinical and regulatory pathways for GS010. The revised regulatory pathway incorporates the findings of the REVERSE (CLIN03B) clinical trial, key results of which were announced in June (see below).
- -At Week 48, GS010-treated eyes demonstrated preserved ganglion cell volume whereas sham-treated eyes lost macular ganglion cell volume; the difference was statistically significant.
- -Likewise, GS010-treated eyes demonstrated preserved retinal nerve fiber layer (NFL) while sham-treated eyes experienced a loss of NFL; the difference in the thickness of the temporal quadrant of the retinal nerve fiber layer at Week 48 was statistically significant.
- -At Week 48, GS010-treated eyes showed improved visual function of contrast sensitivity (CS) as measured via Pelli-Robson testing. Sham-treated eyes showed no improvement of visual function, with their CS remaining stable; the difference was statistically significant.
- -Post-hoc exploratory analyses also suggested subjects with less severe vision loss may benefit most from GS010.
- The unexpected results on BCVA highlighted the importance of gaining more insights into the results observed at Week 48 by obtaining an earlier readout prior to the planned Week 96 analysis. GenSight has therefore added a Week 72 (18-month) readout to planned post-hoc analyses. This readout is expected in early Q4 of this year.
The REVERSE findings have been incorporated in ongoing discussions with regulatory authorities, particularly with the European Medicines Agency (EMA), for whom the REVERSE trial is one of two pivotal trials for GS010. The REVERSE Advisory Panel of Key Opinion Leaders has been discussing the findings ahead of a protocol assistance follow-up meeting with the EMA, which is scheduled in Q4 of this year. Final advice from EMA arising from the Q4 meeting is expected in early Q1 2019.
- The REVERSE findings have also led GenSight to incorporate additional analyses into the statistical analysis plan (SAP) of RESCUE, the second Phase III trial considered pivotal by the EMA. RESCUE enrolled subjects up to six months from onset of visual loss, but otherwise identical disease and demographics enrollment criteria as those in REVERSE. The company conducted a thorough regulatory and clinical assessment of the option of amending the primary efficacy endpoint of RESCUE to CS but concluded that, based on consultations with the EMA and with experts, the expected benefit from such an amendment did not outweigh the risks associated with delaying GS010’s application for marketing authorization. Topline RESCUE results are now expected in early Q1 2019, with full results in mid-Q1.
- All findings will be included in discussions with both EMA and the FDA planned for Q1 next year. The FDA discussions will also feature updates on REFLECT, the third Phase III trial for GS010, which is covered by a Special Protocol Assessment (SPA) with the FDA. The company is currently evaluating options for investigating the bilateral improvement, observed in REVERSE, with an additional supportive ancillary study.
The topline and full results of REVERSE at Week 96 are expected in Q2 next year, providing a fuller picture of the benefits of GS010 for patients up to a year from initial visual loss. Based on ongoing discussions with the EMA, the company is targeting submission for European marketing authorization in Q4 2019. Based on the SPA and interim results of REFLECT, BLA submission in the US is targeted for H2 2020.
- • On June 12, 2018, GenSight Biologics reported additional results from the REVERSE Phase III clinical trial evaluating the safety and efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in 37 subjects whose visual loss due to 11778-ND4 Leber Hereditary Optic Neuropathy (LHON) commenced between 6 and 12 months prior to study treatment.
Topline results, reported in April, showed that the clinically significant improvement of +11 ETDRS letters (-0.218 logMar) in GS010-treated eyes was matched by an unexpected improvement of +10 ETDRS letters (-0.211 LogMAR) in the sham-treated eyes. This caused the study not to meet its primary endpoint predefined as a +15 ETDRS letters difference in visual acuity between GS010- and sham-treated eyes.
- At the same time, the study successfully met secondary endpoints defined by Spectral-Domain Optical Coherence Tomography (SD-OCT) parameters, specifically the change in ganglion cell layer macular volume measured from baseline to week 48 and change in thickness of the temporal quadrant of the retinal nerve fiber layer from baseline to week 48. These results demonstrated a direct biologic and physiological impact of GS010 on the anatomy relevant to LHON.
Further analyses now demonstrate that, although some secondary endpoints did not show significant or meaningful changes, contrast sensitivity as determined by Pelli-Robson low?vision testing almost doubled in the GS010?treated eyes compared to sham?treated eyes. GS010?treated eyes started with lower contrast sensitivity (0.25 LogCS on average) than sham-treated eyes (0.35 LogCs on average). At week 48, GS010?treated eyes gained on average +0.20 LogCS, and the contrast sensitivity in sham-treated eyes remained stable (+0.08 LogCS on average).
- As per protocol, all 37 subjects will be evaluated again at 96 weeks, and data will be reported in the first quarter of 2019.
In addition, post hoc analyses revealed trends that suggest GS010 may have a larger positive impact on the visual acuity of patients at relatively less advanced or severe stages of the disease:
- -Subjects who entered study with better vision (on-chart eyes) tended to have better clinical outcomes. At week 48, in on?chart best-seeing eyes, GS010?treated eyes gained on average +12 ETDRS letters (-0.236 LogMAR) compared to +4 ETDRS letters (-0.075 LogMAR) in sham?treated eyes.
- -Subjects whose vision loss was less than 9 months tended to have better clinical outcomes.75% of GS010-treated eyes that showed a trend in visual acuity improvement at week 48 had vision loss for less than 9 months at time of treatment administration.
-Subjects who were younger (< 21 years) at enrollment tended to have better clinical outcome.
- • On April 3, 2018, GenSight Biologics announced topline results from the REVERSE Phase III clinical trial. Topline results further highlight the favorable safety and tolerability profile of GS010, and demonstrate a clinically meaningful improvement of +11 ETDRS letters (-0.218 LogMAR) in treated eyes at 48 weeks as compared to baseline in all 37 patients. Unexpectedly, untreated contralateral eyes (treated with a sham injection) show a similar improvement of +11 ETDRS letters (-0.211 LogMAR). Due to this improvement in untreated eyes, the trial did not meet its primary endpoint, defined as a difference of improvement in visual acuity in GS010-treated eyes compared to sham-treated eyes at 48 weeks.
- The improvement of visual acuity in sham-treated eyes was unexpected based on the natural history of LHON, for which partial spontaneous recovery is reported in only 8 to 22% of patients with the G11778 ND4 mutation (Lam et al. 2014, Riordan-Eva et al. 1995). “This meaningful improvement of untreated eyes observed at week 48 was totally unexpected given what is known and has been published about the natural history of this devastating disease. We will continue to analyze the data to better understand our results, but they suggest that GS010 benefits both eyes in a way that is still to be understood,” commented Bernard Gilly, Chief Executive Officer of GenSight.
- The graph below shows the mean change from baseline in visual acuity, in both treated (GS010) and untreated (sham) eyes, over time in ETDRS letters:
The objectively measured endpoints were the effects of GS010 on parameters measured with high resolution Spectral-Domain Optical Coherence Tomography (SD-OCT). The critical secondary endpoint of the change in retinal ganglion cell macular volume measured from baseline to week 48 demonstrated a statistically significant difference (p = 0.0189) between all GS010-treated eyes and all sham-treated eyes, with untreated eyes losing 0.038 cubic mm of macular ganglion cell volume while treated eyes preserved their ganglion cell volume (-0.003 cubic mm).
- The secondary endpoint of change in thickness of the temporal quadrant and papillomacular bundle of the retinal nerve fiber layer from baseline to week 48 demonstrated a large statistically significant difference (p = 0.0359) between all GS010-treated eyes and all sham-treated eyes, with untreated eyes showing a loss of 3.4 ?m while treated eyes showed a limited loss of 0.6 ?m.
- Based on preliminary analysis of the safety data, GS010 was well tolerated after 48 weeks. The ocular adverse events most frequently reported in the therapy group were mainly related to the injection procedure, except for the occurrence of intraocular inflammation (accompanied by elevation of intraocular pressure in some patients) that is likely related to GS010, and which was responsive to conventional treatment and without sequelae. There were no withdrawals from the trial.
- • On August 1, 2017, GenSight Biologics announced that enrollment in RESCUE has been successfully completed. RESCUE enrolled 37 patients with an onset of vision loss of less than 6 months. REVERSE, the second trial, completed enrollment in February 2017 of 36 patients with an onset of vision of 7-12 months. Both studies are being conducted in 7 centers in Europe and in the United States. Topline results of REVERSE at 48 weeks of follow-up are expected in Q2 2018, while RESCUE is expected to read out in Q3 2018.
- • On February 21, 2017, GenSight Biologics announced that enrollment in REVERSE, a Phase III clinical trial of GS010 in the treatment of Leber’s Hereditary Optic Neuropathy (LHON), has been successfully completed. REVERSE enrolled 36 patients with an onset of vision loss of 7-12 months, while RESCUE, the second trial, is currently enrolling 36 patients with an onset of vision loss of less than 6 months. Both studies are being conducted in 7 centers in Europe and in the United States. Topline results of REVERSE at 48 weeks are expected at the end of Q1 2018. RESCUE is expected to complete enrollment by the end of H1 2017
- .• On September 8, 2016, GenSight Biologics announced that regulatory agencies and ethics committees in the United States, France and the United Kingdom, have authorized a protocol amendment to include teenage patients (15-18 years) in RESCUE and REVERSE, two ongoing Phase III clinical trials of GS010 in the treatment of Leber’s Hereditary Optic Neuropathy (LHON). The Investigational New Drug (IND) Application had been cleared by the FDA in August 2015, and Clinical Trial Applications (CTAs) had been accepted in France, Germany, Italy and the United Kingdom by national agencies in the first half of 2016, allowing GenSight Biologics to initiate the two Phase III clinical trials in the US and in Europe. The initial protocols were designed to enroll adult patients, whereas this amendment now allows inclusion of patients from the age of 15.
The trials are conducted in parallel in 7 centers across the United States, the UK, France, Germany and Italy. Topline results at 48 weeks are expected early 2018.
- • On February 29, 2016, GenSight Biologics announced enrollment of the first patient in both RESCUE and REVERSE, two parallel pivotal Phase III trials with GS010 for the treatment of Leber’s Hereditary Optic Neuropathy (LHON). The pivotal trials are intended to determine whether GS010 can halt or reverse vision loss associated with LHON due to the NADH dehydrogenase 4 (ND4) mutation or be effective as prophylaxis for vision loss in an eye not yet affected. The trials will also seek to identify the therapeutic window of opportunity for treatment after onset of disease.
As early intervention is potentially a major factor in maximizing therapeutic success, the two clinical trials will focus on treating patients who have manifested visual decline for up to one year. RESCUE is expected to enroll 36 patients with an onset of vision loss up to 6 months in duration, while REVERSE is expected to enroll 36 patients with an onset of vision loss ranging from 7 to 12 months in duration.
GS010 will be administered as a single intravitreal injection to one eye of each subject, while the fellow eye will receive a sham procedure. At the end of the initial 48-week study period, a minimal three-year long term follow-up period will be initiated to determine the sustainability of efficacy outcomes and long-term safety of treatment.
The first patient in the entire program was injected at the Doheny Eye Institute, UCLA Department of Ophthalmology, Pasadena, California (USA) as part of the REVERSE trial, while the first RESCUE trial patient was injected at Wills Eye Hospital, Philadelphia, Pennsylvania (USA). The trials will be conducted in parallel in 7 centers across the United States, the UK, France, Germany and Italy. European sites will open in the coming weeks upon final approval of regulatory agencies. Topline results at 48 weeks are expected by the end of 2017.
- • On September 10, 2015, GenSight Biologics announced that the FDA has cleared its Investigational New Drug (IND) Application for two Phase III clinical trials of GS010 in the treatment of Leber’s Hereditary Optic Neuropathy (LHON). GenSight has also submitted a Clinical Trial Application (CTA) in certain individual European Union countries.