Clinical Trials

Date: 2016-07-03

Type of information: Results

phase: 1-2

Announcement: results

Company: Gensight Biologics (France)

Product: GS010- adeno-associated viral vector containing the human NADH dehydrogenase 4 gene

Action mechanism:

• 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.
• The MTS technology platform is arising from research works conducted at the Institut de la Vision in Paris.

Disease: Leber hereditary optic neuropathy (LHON)

Therapeutic area: Ophtalmological diseases - Genetic diseases - Rare diseases

Country: France

Trial details:

• The purpose of this study is to evaluate the safety and tolerability profile of ascending doses of GS010 in Leber Hereditary Optic Neuropathy (LHON) patients. (NCT02064569)

Latest news:

• • On December 5, 2017, GenSight Biologics reported 2.5 years of follow-up data from its Phase I/II clinical trial with its gene therapy GS010 in patients with Leber Hereditary Optic Neuropathy (LHON). These results confirm longterm sustained gains in visual acuity 2.5 years after a single intravitreal injection of GS010, especially in subjects with less than 2 years of onset of vision loss. In the study, five cohorts of three subjects were administered an increasing dose of GS010 via a single intravitreal injection in the eye more severely affected by the disease. Recruitment of 15 subjects was completed in April 2015 and long-term follow-up is ongoing. Subjects had an average onset of vision loss of 6 years at the time of treatment.
• At baseline, both treated (TE) and untreated (UTE) eyes had an offchart median visual acuity.
• At year 2.5 post-injection, in subjects less than 2 years from onset of vision loss and with relatively better vision at the time of treatment (<2.79 LogMAR), 2 TE had a mean gain of +28 ETDRS letters (-0.55 LogMAR) compared to baseline, while UTE had a mean gain of +13 ETDRS letters (-0.25 LogMAR) compared to baseline. The difference of +15 ETDRS letters in favor of TE is clinically significant, and the magnitude of the improvement, which is similar to the trend observed at Weeks 48, 78, and 96, suggests sustained benefit from GS010.
• The subject group (n=5) with an onset of vision loss of less than 2 years and relatively better vision at the time of injection (<2.79 LogMAR) demonstrated a sustained pharmacological trend in favor of the treated eye, of increasing magnitude from Week 36 onwards, with 60% of subjects showing a clinically significant gain of ? 15 letters in TE at year 2.5.3 The characteristics of this subject group are similar to the baseline characteristics of LHON patients enrolled in ongoing Phase III REVERSE and RESCUE clinical trials. Topline results at 48 weeks for these studies are expected in the second and third quarters of 2018, respectively.
• In all subjects (n=14), the mean change from baseline of visual acuity in TE showed an improvement of +29 ETDRS letters (-0.58 LogMAR) that was both clinically and statistically significant (p = 0.0034), while the mean change in UTE from baseline of visual acuity showed an improvement of +22 ETDRS letters (-0.44 LogMAR), which was not statistically significant. The difference of +7 ETDRS letters was in favor of TE. At year 2.5 post-injection, GS010 continued to demonstrate a favorable tolerability profile, with no reports of worsening vision or ocular sequelae, serious treatment-emergent adverse events (TEAEs), nor systemic adverse events (AEs) related to GS010 or its administration. Consistent with previously reported data, ocular AEs were mostly mild, well-tolerated, and reversible, responding to standard therapy.
• • On June 14, 2017, GenSight Biologics reported additional results after 96 weeks of follow-up in its Phase I/II study with GS010. These results confirm the long-term positive sustained visual acuity gain after 2 years with a single intravitreal injection of GS010 in patients with Leber’s Hereditary Optic Neuropathy, especially in those with less than 2 years of disease onset.
• Each cohort of three patients was administered an increasing dose of GS010 through a single intravitreal injection in the eye most severely affected by the disease. Recruitment was completed in April 2015 and long-term follow-up is ongoing. These patients had an average onset of disease of 6 years at the time of treatment. At baseline, both treated and untreated eyes had an off-chart median visual acuity.
• At week 96 post-injection, in patients with an onset of vision loss of less than 2 years and relatively better vision (<2.79 LogMAR) at the time of treatment, a mean gain of +29 ETDRS letters (-0.57 LogMAR) was observed in TE compared to baseline, with a mean gain of +15 ETDRS letters (-0.30 LogMAR) in UTE, resulting in a difference of +14 ETDRS letters in favor of TE. This improvement is clinically significant, and the magnitude of improvement similar to the observed trend at week 48 and week 78.
• At baseline, treated worse-seeing eyes had a median visual acuity of 2.79 LogMAR (approximately equivalent to hand motion at 1m) and untreated better-seeing eyes had a median acuity of 2.01 LogMAR (approximately equivalent to counting fingers at 50cm).
• The patient group with an onset of vision loss of 2 years or less and relatively better vision (<2.79 LogMAR) at the time of injection (n=5) demonstrated a treatment effect in favor of the treated eye of increasing magnitude from week 36 onwards with 60.0% of patients showing clinically significant ? 15 letters gain on EDTRS visual charts. The characteristics of this patient group are similar to the baseline characteristics of LHON patients enrolled in ongoing Phase III REVERSE and RESCUE clinical trials.
• The mean change of visual acuity from baseline in TE of all patients (n=14) showed an improvement of +21 ETDRS letters (-0.41 LogMAR) and was statistically significant (p = 0.0159). There was no observed difference with the mean change from baseline in the untreated eye. There was a linear correlation between the treated eye and untreated eye in the change from baseline to week 96 that reached 0.67 and was highly significant (p =0.0067). Based on all subjects except one, the improvement in untreated eye was only observed when there was an improvement in treated eye, which was significantly larger than the natural visual recovery. Lastly, the results confirmed the long-term good safety and tolerability of GS010 with no reported vision worsening or ocular sequelae, no serious treatment-emergent adverse events (TEAEs) nor systemic adverse events (AEs) related to study drug or procedure. As expected, mostly mild, well-tolerated, and completely reversible ocular AEs that were responsive to standard therapy occurred.
• The full data from the Phase I/II up to week 96 analyses is pending submission as a peer-reviewed manuscript. Two Phase III clinical studies (RESCUE and REVERSE) are currently ongoing in Europe and the United States to assess the efficacy of GS010 in patients affected with LHON due to the ND4 mutation, with vision loss up to one year at the time of treatment. Recruitment of REVERSE was completed in February 2017, while RESCUE is expected to be completed by the end of July 2017. Topline results at 48 weeks of both studies are expected in the second and third quarters of 2018, respectively.
• • On December 20, 2016, GenSight Biologics reported additional results after 78 weeks of follow-up in its Phase I/II clinical trial. These results confirm the favorable safety and tolerability profile of GS010, while demonstrating sustainable visual acuity improvement in patients with Leber’s Hereditary Optic Neuropathy (LHON). Each cohort of three patients was administered an increasing dose of GS010 through a single intravitreal injection in the eye most severely affected by the disease. Recruitment was completed in April 2015 and long-term follow-up is ongoing. These patients had an average onset of disease of 6 years at the time of treatment. At baseline, both treated and untreated eyes had an off-chart median visual acuity. At 78 weeks post-injection, the mean change of visual acuity from baseline in the treated eyes of all patients* was -0.61 LogMAR (p<0.001), equivalent to a mean improvement of +30 ETDRS letters. For all untreated eyes at week 78, the mean change from baseline was -0.31 LogMAR (p=0.0866), equivalent to a mean improvement of +15 ETDRS letters. This provides a treatment effect (mean difference between treated worse-seeing and untreated best-seeing eyes) of +15 letters (p=0.11) in favor of treated worseseeing eyes. In patients with an onset of vision loss of less than 2 years at the time of treatment, a mean gain of +32 ETDRS letters (-0.63 LogMAR) was observed in treated eyes, while a mean gain of +12 ETDRS letters (-0.23 LogMAR) was observed in untreated eyes, resulting in a difference of 20 ETDRS letters in favor of treated eyes. The patient group with vision loss for 2 years or less at the time of injection demonstrated a treatment effect in favor of the treated eye of increasing magnitude from week 36 onwards. • On June 8, 2016, GenSight Biologics announced additional results of its Phase I/II study, designed to demonstrate the safety and tolerability of GS010 in 15 patients with Leber’s Hereditary Optic Neuropathy. Each cohort of three patients was administered an escalating dose of GS010 through a single intravitreal injection in the eye most severely affected by the disease. Recruitment was completed in April 2015. These patients had an average onset of disease of 6 years. At 48 weeks post-injection, in patients with an onset of disease of less than 2 years, a gain of +30 letters (-0.59 LogMAR) was observed in the treated eye and +13 letters (-0.25 LogMAR) in the untreated eye, a difference of 17 letters in favor of the treated eye. No significant difference was observed in patients with an onset of disease of more than two years. The combined effect of the administered dose and the time from onset is noticeable at 36 weeks and stable after 48 weeks. Gensight Biologics is currently conducting two phase III clinical studies (Rescue and Reverse) in Europe and the United States to assess the efficacy of GS010 in patients affected with LHON due to the ND4 mutation, with an onset of vision loss of less than one year. The top-line results at 48 weeks follow-up are expected in late 2017.

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