GenSight Biologics Reports Positive 96-Week Data from REVERSE Phase III Clinical Trial of GS010 for the Treatment of Leber Hereditary Optic Neuropathy (LHON)
May 15, 2019-
Durable improvement in best-corrected visual acuity (BCVA), as
GS010-treated eyes sustain +15.4 ETDRS letters equivalent improvement
versus baseline and +28.1 ETDRS letters equivalent versus nadir -
Bilateral improvement continues in key visual functions BCVA and
contrast sensitivity -
Responder analyses suggest improved clinical outcomes for
GS010-treated eyes relative to sham-treated eyes - GS010 safety and tolerability established over the course of the trial
-
Briefing packages incorporating findings under preparation for
meetings with regulatory authorities
PARIS–(BUSINESS WIRE)–Regulatory News:
GenSight Biologics (Paris:SIGHT) (Euronext: SIGHT, ISIN: FR0013183985,
PEA-PME eligible), a biopharma company focused on discovering and
developing innovative gene therapies for retinal neurodegenerative
diseases and central nervous system disorders, today reported a first
set of results from Week 96 of the REVERSE Phase III clinical trial. The
trial evaluated 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. Week 96 is
the last of the scheduled readouts for the trial and marks the time when
the data are unmasked, providing access to individual patient profiles.
The results point to continued efficacy of GS010 two years past
injection, with best-corrected visual acuity (BCVA) sustaining a
clinically meaningful improvement over baseline. At Week 96,
GS010-treated eyes showed a mean improvement of -0.308 LogMAR compared
to baseline, equivalent to +15.4 ETDRS letters or 3 lines on the ETDRS
vision chart. This clinically meaningful level of improvement in visual
acuity maintains the gain observed at Week 72 (+14.7 ETDRS letters
equivalent).
As in previous readouts at Week 48 and Week 72, BCVA in sham-treated
eyes evolved on a relatively parallel trajectory, achieving a mean
improvement of -0.259 LogMAR over baseline, or a gain of +12.9 ETDRS
letters equivalent, at Week 96. Although lower in magnitude, the mean
BCVA improvement of sham-treated eyes was not statistically significant
from that of GS010-treated eyes.
Figure 1: Sustained bilateral improvement in BCVA in REVERSE
Notes: A mixed model of analysis of covariance (ANCOVA) was used with
change from baseline as the response, and
subject, eyes of the subject as random factor, treatment and the baseline LogMAR value as covariates in the model.
As in RESCUE and consistent with natural history, subjects experienced
an initial point of low visual acuity, or nadir. Eyes of REVERSE
subjects recovered impressively. By week 96, GS010-treated eyes had
gained +28 more letters relative to their nadir.
Table 1. Recovery of BCVA from Nadir*: RESCUE and REVERSE
(Difference**
from Nadir* in ETDRS Letters Equivalent, Mean and Standard Deviation)
| RESCUE | REVERSE | ||||||||||||||||
| n | Week 48 | n | Week 72 | n | Week 48 | Week 72 | Week 96 | ||||||||||
| GS010-treated eyes | 36 |
+12.9
(17.9) |
34 |
+20.6
(26.4) |
37 |
+24.1
(21.1) |
+27.4
(21.8) |
+28.1
(22.0) |
|||||||||
| Sham-treated eyes | 36 |
+11.8
(16.0) |
33 |
+21.8
(25.1) |
37 |
+20.3
(23.4) |
+22.6
(25.5) |
+23.2
(24.5) |
|||||||||
Note: *Nadir was defined as the lowest post-treatment BCVA
as measured by LogMAR up to week of interest. Light Perception/No
Light Perception, or LP/NLP, vision was not included in the analysis.
**Change from nadir was first calculated using observed LogMAR values;
no data were imputed. The LogMAR values were then converted to the
corresponding ETDRS letters equivalent.
At Week 96, a second key visual function – low-contrast visual acuity,
as measured on the Pelli-Robson chart – showed a similar trend of
improvement for both GS010-treated eyes and sham-treated eyes.
Figure 2: Evolution of contrast sensitivity in REVERSE
Note: An analysis of covariance (ANCOVA), with repeated measures for
eye and covariate adjustment for baseline LogCS, was used to model the
effect of treatment on change in LogCS from baseline. A separate
analysis was performed at each time point.
The trajectories, however, did not track each other as closely as with
BCVA: mean contrast sensitivity for GS010-treated eyes show a more
robust improvement versus baseline over the course of the trial.
Nonetheless, the drop in the mean contrast sensitivity of sham-treated
eyes was not enough to yield a statistically significant difference in
Week 96 mean contrast sensitivity improvement between the two sets of
eyes.
“The data show that both the treated and the sham eye improved in
both high and low contrast, defying the accepted natural history of this
disease and improving upon it, based upon the clinical experiences of
generations of neuro-ophthalmologists,” commented Dr. Robert C.
Sergott, Director, Wills Eye Hospital, Neuro-Ophthalmology and
Director, William H. Annesley, Jr, EyeBrain Center, Thomas Jefferson
University, Philadelphia, PA. “The behavior of the untreated eye must
also make us re-examine what we thought we knew as possibly dogma and be
open to the idea that gene therapy delivered into one eye may be able to
access the contralateral eye.”
Responder analyses suggest various ways in which GS010-treated eyes
achieved better clinical outcomes than sham-treated eyes. The proportion
of GS010-treated eyes that achieved at least a -0.2 LogMAR or +10 ETDRS
letters equivalent improvement versus baseline at Week 96 is
statistically significantly higher than the corresponding proportion of
sham-treated eyes (65% vs. 46%, p-value = 0.0348). GS010-treated eyes
were also significantly more likely than sham-treated eyes to achieve
another measure of treatment success – improving by at least 15 ETDRS
letters at Week 96 from on-chart acuity at baseline, or avoiding the US
legal blindness threshold of 20/200 at Week 96 (32% vs. 16%, p = 0.0196).
Based on a generalized estimating equations (GEE) model, GS010-treated
eyes were 2.8 times more likely to be at or above 20/200 than
sham-treated eyes (p = 0.0094). When only eyes that were strictly above
the threshold were considered, the odds ratio rose to 3.6 (p = 0.0032).
“It is encouraging that GS010-treated eyes were nearly four times
more likely to achieve vision better than 20/200 compared with sham eyes.
The next step, which is to analyze individual longitudinal data on
the visual parameters for each subject recruited into REVERSE, should
further clarify the therapeutic benefit of GS010 in 11778-ND4 LHON,”
noted Dr. Patrick Yu-Wai Man, Senior Lecturer and Honorary
Consultant Ophthalmologist at the University of Cambridge, Moorfields
Eye Hospital, and the UCL Institute of Ophthalmology, London, United
Kingdom.
Another responder analysis provides a useful perspective on the REVERSE
results. In a natural history study conducted by Santhera1,
15% of subjects who had the 11778A mutation achieved the following
definition of spontaneous “clinically relevant recovery” (CRR) from
baseline in at least one eye:
- Improved by at least 10 ETDRS letters from on-chart visual acuity, or
-
Improved from off-chart visual acuity to being able to read at least 5
ETDRS letters
By comparison, 68% of REVERSE subjects achieved this definition of CRR
in at least one eye at Week 96, with GS010-treated eyes significantly
more likely to achieve this than sham-treated eyes (62% vs. 43%, p =
0.0348).
Improvements in visual function were reflected in quality of life scores
in the National Eye Institute Visual Function Questionnaire-25 (NEI
VFQ-25) survey, a validated, vision-specific quality-of-life instrument
completed by REVERSE subjects. Mean composite score and means of
relevant sub-scale scores continued to improve over baseline,
particularly for the ability to carry out near and distance activities.
The increase over baseline of the mean sub-scale scores exceeded those
that have been associated with a 15-letter improvement in BCVA in other
ocular diseases.
Table 2: Meaningful improvements in Quality of Life Scores Reported
by REVERSE Subjects
NEI VFQ-25 Results from REVERSE
Mean
change from baseline (absolute score and percent)
|
Composite |
Near |
Distance |
Dependency |
Role |
General |
Mental |
|||||||||
| Week 48 |
+7.2
+23.2% |
+10.4
+65.1% |
+9.6
+49.8% |
+12.4
+100.6% |
+14.5
+65.0% |
+10.3
+50.9% |
+11.2
+81.9% |
||||||||
| Week 72 |
+8.1
+25.2% |
+9.5
+58.1% |
+8.2
+42.5% |
+18.9
+130.2% |
+15.2
+70.9% |
+11.9
+54.1% |
+15.2
+105.6% |
||||||||
| Week 96 |
+9.5
+28.8% |
+13.3
+78.1% |
+10.7
+47.4% |
+18.5 130.2% |
+15.9
+78.9% |
+6.5
+32.4% |
+16.1
+108.2% |
||||||||
|
Clinically |
+3.90 to |
+4.67 to |
+5.15 to |
+4.72 to |
+3.31 to |
+4.38 to |
+4.70 to |
*Suñer et al. (2009): clinically relevant score
differences based on a clinically significant 15-letter BCVA improvement
at 12 months.
**The composite score is an average of the
vision-targeted sub-scale scores, excluding the general health rating
question.
Note: The mean percent improvement for a sub-score was calculated by
averaging the individual percent improvements.
Structural metrics indicate that GS010-treated eyes maintained the
stability achieved in previous readouts in ganglion cell volume. The
differential effect of therapy was, however, more prominent in previous
readouts.
Initial analyses of subject-level data suggest that the bilateral effect
is common across patients; other analyses of subject-level data are
ongoing. GenSight will hold an investor meeting (in English, to be
simulcast in French) on May 23 in New York City, where invited key
opinion leaders will discuss results in more detail.
Week 96 data further establish the favorable safety profile of GS010.
There have been no discontinuations in the trial and no serious adverse
effects in GS010-treated eyes. The ocular AEs most frequently reported
in the therapy group were mainly related to the injection procedure
itself, along with the occurrence of intraocular inflammation
(accompanied by elevation of intraocular pressure in some patients),
likely related to GS010; these were responsive to conventional treatment
and were without sequelae.
“We are very gratified by these remarkable findings, which
demonstrate the durable and clinically meaningful impact of GS010, while
continuing to establish the safety of our gene therapy,” commented Bernard
Gilly, Co-founder and Chief Executive Officer of GenSight. “We
are moving with speed and determination to build a compelling dossier
from the results of REVERSE and, later this year, RESCUE.”
REVERSE Week 96 results will be included in the briefing materials that
are being prepared for a pre-submission meeting with the EMA and a Type
B meeting with the FDA, both of which are planned for mid-year.
Data from the 96-week readout of the second Phase III trial for GS010,
RESCUE, is expected to be available by the end of Q3 2019.
The third interventional study for GS010, REFLECT, is a randomized,
double-masked, placebo-controlled Phase III trial evaluating the safety
and efficacy of bilateral injections of GS010 in patients up to one year
from onset of vision loss due to LHON. The first patient in REFLECT was
treated in March 2018; treatment of the last patient is expected in Q2
of this year.
GenSight will host a conference call today, May 15, 2019, at 10am CEST
in French, and at 2.30pm CEST (8.30am EST) in English, to discuss these
results.
Webcast & Conference call in French
Dial-in numbers:
United States: +1 212 999 6659
France: +33 (0) 1 7037 7166
United
Kingdom: +44 (0) 20 3003 2666
Password: GenSight
Webcast link: https://channel.royalcast.com/webcast/gensightbiologicsfr/20190514_1/
Webcast & Conference call in English
Dial-in numbers:
United States: +1 212 999 6659
France: +33 (0) 1 7037 7166
United
Kingdom: +44 (0) 20 3003 2666
Password: GenSight
Webcast link: https://channel.royalcast.com/webcast/gensightbiologicsen/20190514_1/
A replay of the calls and webcasts will be available by using the above
links.
Reference:
1. Magda et al (2019), “Natural History of Leber’s Hereditary Optic
Neuropathy (LHON): Findings from a Large Patient Cohort”, Poster
presented at NANOS March 16-21, 2019; Poster Session II: Scientific
Advancements; Poster: 163
About GenSight Biologics
GenSight Biologics S.A. is a clinical-stage biopharma company focused on
discovering and developing innovative gene therapies for retinal
neurodegenerative diseases and central nervous system disorders.
GenSight Biologics’ pipeline leverages two core technology platforms,
the Mitochondrial Targeting Sequence (MTS) and optogenetics, to help
preserve or restore vision in patients suffering from blinding retinal
diseases. GenSight Biologics’ lead product candidate, GS010, is in Phase
III trials in Leber Hereditary Optic Neuropathy (LHON), a rare
mitochondrial disease that leads to irreversible blindness in teens and
young adults. Using its gene therapy-based approach, GenSight Biologics’
product candidates are designed to be administered in a single treatment
to each eye by intravitreal injection to offer patients a sustainable
functional visual recovery.
About GS010
GS010 targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a
mitochondrial targeting sequence (MTS) proprietary technology platform,
arising from research conducted at the Institut de la Vision in Paris,
which, when associated with the gene of interest, allows the platform to
specifically address defects inside the mitochondria using an AAV vector
(Adeno-Associated Virus). The gene of interest is transferred into the
cell to be expressed and produces the functional protein, which will
then be shuttled to the mitochondria through specific nucleotidic
sequences in order to restore the missing or deficient mitochondrial
function.
About Leber Hereditary Optic Neuropathy (LHON)
Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited
mitochondrial genetic disease, characterized by the degeneration of
retinal ganglion cells that results in brutal and irreversible vision
loss that can lead to legal blindness, and mainly affects adolescents
and young adults. LHON is associated with painless, sudden loss of
central vision in the 1st eye, with the 2nd eye
sequentially impaired. It is a symmetric disease with poor functional
visual recovery. 97% of patients have bilateral involvement at less than
one year of onset of vision loss, and in 25% of cases, vision loss
occurs in both eyes simultaneously. The estimated incidence of LHON is
approximately 1,400 to 1,500 new patients who lose their sight every
year in the United States and Europe.
About RESCUE and REVERSE
RESCUE and REVERSE are two separate randomized, double-masked,
sham-controlled 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’ LogMAR (Logarithm of the Minimal Angle of
Resolution) scores, which are derived from the number of letters
patients 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. Readouts for
these endpoints are at 48, 72 and 96 weeks after injection.
The trials are conducted in parallel, in 37 subjects for REVERSE and 39
subjects for RESCUE, in 7 centers across the United States, the UK,
France, Germany and Italy. Week 96 results are expected in 2019 for both
trials, after which patients will be transferred to a long-term
follow-up study that will last for three years.
ClinicalTrials.gov Identifiers:
REVERSE: NCT02652780
RESCUE:
NCT02652767
About REFLECT
REFLECT is a multi-center, randomized, double-masked, placebo-controlled
study to evaluate the safety and efficacy of bilateral injections of
GS010 in subjects with LHON due to the NADH dehydrogenase 4 (ND4)
mutation.
The trial is planned to enroll 90 patients with vision loss up to 1 year
in duration and will be conducted in multiple centers in Europe and in
the US.
In the active arm, GS010 will be administered as a single intravitreal
injection to both eyes of each subject. In the placebo arm, GS010 will
be administered as a single intravitreal injection to the first affected
eye, while the fellow eye will receive a placebo injection.
The primary endpoint for the REFLECT trial is the BCVA reported in
LogMAR at 1-Year post-treatment in the second-affected/not-yet-affected
eye. The change from baseline in second-affected/not-yet-affected eyes
receiving GS010 and placebo will be the primary response of interest.
The secondary efficacy endpoints include: BCVA reported in LogMAR at
2-Years post-treatment in the second-affected/not-yet-affected eye
compared to both placebo and the first-affected eye receiving GS010, OCT
and contrast sensitivity and quality of life scales. The first subject
was treated in March 2018.
ClinicalTrials.gov Identifiers:
REFLECT: NCT03293524
Contacts
GenSight Biologics
Thomas Gidoin
Chief
Financial Officer
[email protected]
+33
(0)1 76 21 72 20
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Media Relations
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Janic
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Trout
US Investor Relations
Chad Rubin
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+1-646-378-2947
James
Palmer
Europe Investor Relations
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