GenSight Biologics Reports Positive Follow-up Results at Week 72 of the RESCUE Phase III Clinical Trial of GS010 in Leber Hereditary Optic Neuropathy (LHON)

  • GS010-treated eyes showed continuous recovery of visual functions from
    nadir (worst vision post-treatment) in both best-corrected visual
    acuity (BCVA) and contrast sensitivity (CS)
  • GS010-treated eyes recovered 21 ETDRS letters from nadir at Week 72
  • Bilateral improvements in visual function corroborate previously
    observed parallel evolution of GS010- and sham-treated eyes in both
    RESCUE and REVERSE trials
  • Mean BCVA in both GS010- and sham-treated eyes improved from off-chart
    values at Week 48 to on-chart values at Week 72
  • 40% of eyes achieved a clinically meaningful BCVA improvement from
    nadir (0.3 LogMAR or 15 ETDRS letters) at Week 72
  • GS010 continued to be safe and well-tolerated through 72 weeks

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 announced results
from the second scheduled readout, at Week 72, of the RESCUE Phase III
clinical trial evaluating the safety and efficacy of a single
intravitreal injection of GS010 (rAAV2/2-ND4) in 39 subjects
whose visual loss due to 11778-ND4 Leber Hereditary Optic
Neuropathy (LHON) occurred up to 6 months prior to study treatment.
These subjects received GS010 in one eye and a sham injection in the
other eye, with drug treatment randomized between best- and
worst-affected eyes.


The key measure of visual function – best-corrected visual acuity (BCVA)
continued to improve at Week 72 compared to Week 48,
demonstrating sustained recovery from the lowest point, or nadir,
experienced in the acute phase of the disease. By Week 72, GS010-treated
eyes improved by -0.413 LogMAR (+21 ETDRS letters equivalent) from
nadir, compared to the Week 48 improvement of -0.257 LogMAR (+13 ETDRS
letters equivalent). This recovery at week 72 could not yet completely
offset deterioration from baseline through the acute phase:
GS010-treated eyes were still below baseline by 0.192 LogMAR (-10 ETDRS
letters equivalent), compared to 0.380 LogMAR (-19 ETDRS letters
equivalent) at Week 48.

Figure 1. Time Course Visual Acuity, Change from Baseline to Week 72
in ETDRS Letters Equivalent in RESCUE

Consistent with all readouts so far in the RESCUE and REVERSE trials,
sham-treated eyes had a BCVA evolution that closely tracked that of
GS010-treated eyes. At Week 72 of RESCUE, sham-treated eyes improved by
-0.435 LogMAR from nadir (+21.7 ETDRS letters equivalent). The U-shaped
curve thus closely matched that of GS010-treated eyes, so a
statistically significant difference in visual acuity between GS010- and
sham-treated eyes could not be shown.

The strength of the bilateral recovery shifted the mean BCVA in both
sets of eyes from being off-chart at Week 48 to on-chart at Week 72. In
addition, 40% of GS010- and sham-treated eyes improved by a clinically
meaningful difference of -0.3 LogMAR (+15 letters ETDRS) from nadir.
Similarly, 58% of GS010-treated and 50% of sham-treated eyes improved by
a clinically meaningful difference of -0.2 LogMAR (+10 lett ETDRS) from
nadir.

Figure 2. Time Course LogMAR Visual Acuity to 72 Weeks in RESCUE

Note: LS Means = Least Squares Means

Table 1. Change from Nadir* in Best-Corrected Visual Acuity
(LogMAR
and ETDRS Letter Equivalents)

    LogMAR Visual Acuity   ETDRS Letter Equivalent
    Week 48   Week 72       Week 48   Week 72
  n   Mean (SD)   n   Mean (SD)

GS010-
Treated eyes

  36   -0.257

(0.358)

  -0.413

(0.527)

  34   +12.8

(17.9)

  +20.6

(26.3)

Sham-
Treated Eyes

  36   -0.236

(0.319)

  -0.435

(0.501)

  33   +11.8

(15.6)

  +21.7

(25.1)

Note: *As per Statistical Analysis Plan (SAP), nadir was
defined as the lowest post-treatment LogMAR value up to
week of

interest. Light Perception/No Light
Perception, or LP/NLP, vision was not included in the analysis.

 

Contrast sensitivity (CS), a second visual function, evolved in a manner
similar to BCVA: while values for GS010-treated eyes and sham-treated
eyes remained below baseline, CS also recovered so that the gap to
baseline diminished at Week 72 compared to Week 48. The two sets of eyes
closely matched each other, so that the difference between their CS
values was not statistically significant.

Figure 3. Time Course LogCS Contrast Sensitivity to 72 Weeks in RESCUE

Note: LS Means = Least Squares Means

Table 2. Change of Contrast Sensitivity from Baseline
(LogCS)

    Week 48   Week 72
  n  

Least-Squares Mean
(Standard Error)

  n  

Least-Squares Mean
(Standard Error)

All GS010-
Treated eyes

  36   -0.34

(0.07)

  38   -0.25

(0.07)

All Sham-
Treated Eyes

  36   -0.32

(0.07)

  38   -0.28

(0.07)

Note: A mixed model of analysis of covariance (ANCOVA) was used
with change from baseline at week 72 as the response.

 

This improvement in visual function from Week 48 to Week 72, both in
visual acuity and contrast sensitivity, strengthens our belief in the
benefits of GS010, looking at the shift of the mean BCVA from off-chart
to on-chart at Week 72. These results show a more favorable trend than
the outcome we usually observe in clinical practice for LHON ND4
patients,
” commented Dr. Catherine Vignal, Head of the
department of Neuro-Ophthalmology at the Rothschild Foundation, and
Principal Investigator at the Department of Ophthalmology at Centre
Hospitalier National d’Ophtalmologie des XV-XX
, Paris.

One difference between results from the REVERSE and RESCUE trials of
GS010 lies in anatomic findings. The data so far do not indicate
differential protection for the anatomy of GS010-treated eyes: in both
drug-treated and sham-treated eyes, the relevant anatomy, as shown by
various OCT measurements (tRNFL thickness, PMB thickness, GCL volume),
continued to thin at Week 72, although the rate of thinning decreased
between Week 48 and Week 72. Among the OCT measures in the trial at Week
72, the ETDRS macular volume showed a difference between GS010-treated
and sham-treated eyes (0.096 mm3, p = 0.0012).

By design, the population in Rescue is very heterogeneous, and the
structure of their retina is also highly variable, from marked atrophy
of nerve fibers to edema.
At unmasking, which happens after week
96, we will separate our subjects by their baseline OCT findings. In the
sub-group with edema, thinning over time will be a good finding.
In
those with baseline atrophy of nerve fibers, increases in thickness will
be a good sign. This mix of OCT findings at entry masks the true OCT
findings at week 72 in Rescue,
” commented Dr. Robert C. Sergott,
Director, Wills Eye Hospital, Neuro-Ophthalmology and Director, William
H. Annesley, Jr, EyeBrain Center, Thomas Jefferson University,
Philadelphia, PA.

Based on preliminary analysis of the safety data, GS010 was
well-tolerated through 72 weeks. There were no serious ocular adverse
events or discontinuations due to ocular issues. The most frequently
seen ocular adverse events were related to the injection procedure
itself. Transient elevations of intraocular pressure were occasionally
seen but secondary to intraocular inflammation likely due to
administration of GS010. Such episodes were without sequelae and
responded to conventional treatment. There were no systemic serious
adverse events or discontinuations related to study treatment or study
procedure.

We are excited and extremely gratified to see a picture of a
sustained recovery of visual function emerge from RESCUE results at Week
72,
” said Bernard Gilly, Co-founder and Chief Executive
Officer of GenSight. “The findings continue to be consistent with
what was observed in REVERSE at 48 and 72 weeks as well as with RESCUE
at 48 weeks, and bolster our confidence in the benefits that GS010 can
deliver to patients and motivate us to work with the authorities to
bring GS010 as early as possible to the market
.”

RESCUE subjects will be evaluated again at 96 weeks, and then data will
be unmasked, allowing more detailed subject-level analyses to be
conducted. Results from RESCUE at Week 96 are expected to be available
by the end of Q3 2019. Week 96 data from the REVERSE trial are expected
earlier, in May 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.

The Company will host a conference call today, April 17, 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:
France: +33 (0) 1 7037 7166
United Kingdom: +44 (0) 20 3003 2666
Password: GenSight

Webcast link: https://channel.royalcast.com/webcast/gensightbiologicsfr/20190417_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/20190417_1/

A replay of the calls and webcasts will be available by using the above
links.

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 affected eyes 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. By protocol,
readouts for these endpoints are at 48, 72 and 96 weeks after injection.

The trials are conducted in parallel, with 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, color 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

tgidoin@gensight-biologics.com
+33
(0)1 76 21 72 20

RooneyPartners
Media Relations
Marion Janic
mjanic@rooneyco.com
+1-212-223-4017

Solebury Trout Group
US Investor Relations
Chad
Rubin

crubin@troutgroup.com
+1-646-398-2947

James Palmer
Europe Investor Relations
j.palmer@orpheonfinance.com
+33
7 60 92 77 74