GenSight Biologics S.A. announced 4-year efficacy and safety results from the phase 3 REFLECT trial following post-treatment administration of LUMEVOQ (GS010; lenadogene nolparvovec) for Leber Hereditary Optic Neuropathy (LHON).
Start with GenSight.
Founded in 2012 and headquartered in Paris, France, Gensight Biologics is a clinical-stage biotechnology company focused on developing and commercializing gene therapies for neurodegenerative retinal diseases and central nervous system (CNS) disorders.
Aside from gene therapy, its therapeutic pipeline incorporates two core technologies:
- Mitochondrial Targeting Sequence (MTS)
- Delivers nuclear messenger ribonucleic acid (mRNA) directly to the mitochondrial surface and imports newly-synthesized proteins into the mitochondrial matrix
- Intended result: restoration of mitochondrial function
- Also: This is directly involved in the LUMEVOQ (GS010) process.
- Intended result: restoration of mitochondrial function
- Delivers nuclear messenger ribonucleic acid (mRNA) directly to the mitochondrial surface and imports newly-synthesized proteins into the mitochondrial matrix
- Optogenetics
- Transfers gene codes for light-sensitive protein to enable neuronal cells’ response to light stimulation
- The target: to make retinal ganglion cells (RGCs) more sensitive to light
- Also: This is directly involved in the GS030 therapeutic process for retinitis pigmentosa (see here for 1-year data).
- The target: to make retinal ganglion cells (RGCs) more sensitive to light
- Transfers gene codes for light-sensitive protein to enable neuronal cells’ response to light stimulation
Now LUMEVOQ.
Previously referred to as GS010, Lumevoq is an adeno-associated virus (AAV) vector consisting of the ND4 gene (normally located in the mitochondria for synthesization).
The therapeutic payload is delivered via intravitreal injection into retinal cells to mitigate cellular damage—using the MTS platform—whereby it can be replaced and restored, thus potentially leading to vision improvement.
What’s its clinical status in the U.S.?
LUMEVOQ received Orphan Drug Designation from the FDA in November 2013.
Gotcha. Now, talk about this REFLECT study.
The global, multicenter, randomized, double-masked phase 3 trial (NCT03293524) was designed under a special protocol assessment through the FDA.
A total of 98 participants (aged 15+) were enrolled, all with vision loss due to LHON up to 1 year from onset.
And these patients?
Each participant received an intravitreal injection of Lumevoq into one affected eye; the second affected eye was randomized to receive either a second injection of LUMEVOQ (n = 48) or a placebo (n = 50) on the same day as the first eye or the day after.
What was measured?
The original primary endpoint was best-corrected visual acuity (BCVA) reported using LogMAR at 1 year post-treatment in the second affected eye.
Current secondary endpoints included BCVA reported with LogMAR at 2 years post-treatment, measured at each timepoint of the follow-up period (1.5 years) and at 2 years. See here for the complete list, which included responder analysis.
Now this 4-year data.
First, the big picture: Following one injection of LUMEVOQ, visual acuity (VA) improvement remained sustained while also maintaining a favorable safety profile comparable in both bilaterally- and unilaterally-treated patients.
Even further, the company reported that “bilateral injection (of LUMEVOQ) provides an additional effect compared to unilateral treatment,” with the difference being observed at 1.5 years post-treatment.
This was demonstrated across all analyses of VA improvement and responder rates.
How does this compare to last year’s 3-year findings?
GenSight stated that this latest data reinforces the previously-reported data. See here for those findings, which Glance covered last March.
What was the average VA increase?
Among LUMEVOQ-treated eyes—and compared to nadir—average VA increase was beyond the +15 letter threshold used to define clinically meaningful improvement, according to GenSight.
Note: Nadir refers to the worst BCVA recorded from baseline to Year 4.
Give me some more numbers.
Following bilateral injection, GenSight reported that:
- 73% of patient experienced a clinically meaningful improvement of at least -0.3 LogMAR (+15 ETDRS letters) relative to their observed nadir
- 81% of bilaterally-treated patients demonstrated on-chart vision (reading letters on a screen)
Go on …
The company noted that the likelihood of treated patients achieving on-chart vision is “twice as high with bilateral treatment versus a unilateral injection (odds ratio: 2.0 [0.7;5.5]).”
Any adverse reactions?
While there were no serious ocular adverse events (AEs), the most commonly encountered ocular AE was mild intraocular inflammation that was responsive to conventional treatment.
This was consistent with 3-year data.
So what’s next?
Participants of the REFLECT study will continue to be monitored for a 5-year post-injection follow-up period.