- Clinically meaningful improvement of 25 ETDRS letters
equivalent versus nadir of BCVA in GS010-treated eyes at 96
weeks
- Results coherent with those of REVERSE: durable bilateral
improvement in vision, despite the intervening acute phase in
RESCUE
- Recovery in BCVA greatly exceeds results from published natural
history studies
- GenSight Biologics now expects to share these findings with
regulatory agencies and file for approval in Europe in Q3 2020
Regulatory News:
This press release features multimedia. View
the full release here:
https://www.businesswire.com/news/home/20190922005072/en/
Figure 1: Time Course of Best-Corrected
Visual Acuity (BCVA) in LogMAR (Photo: Business Wire)
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 the first set of results from Week 96 of the RESCUE
Phase III clinical trial. The trial evaluated the efficacy and
safety 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) commenced up to 6 months prior to study
treatment. Week 96, which marks the time when individual patient
profiles can be analyzed, is the last of the scheduled readouts for
the RESCUE trial and completes the data collection from GS010’s
pivotal trials in Europe.
The results point to continued efficacy of GS010 two years past
injection, with best-corrected visual acuity (BCVA) sustaining a
clinically meaningful improvement over nadir. Having been treated
early in the course of the disease, RESCUE patients’ vision
initially deteriorated to a worst point, or nadir, before beginning
to recover.
Note: 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.
When visual acuity is measured from the post-baseline nadir, the
visual acuity of GS010-treated eyes in fact recovered significantly
from the worst BCVA reading post-baseline.
Table 1: BCVA, Change from Nadir*,
RESCUE
Week 48
Week 72
Week 96
N
Mean (SD)
N
Mean (SD)
N
Mean (SD)
All-GS010 Eyes
36
+12.8 (17.9)
34
+20.6 (26.3)
34
+24.9 (3.8)
All-Sham Eyes
36
+11.8 (15.6)
33
+21.7 (25.1)
34
+22.3 (3.8)
Note: *”Nadir” defined as worst BCVA measured in LogMAR after
baseline, up to the week of interest; baseline reading was excluded
from consideration. Mean change was calculated using observed
values (no data imputation).
GS010-treated eyes regained more than two-thirds of the initial
loss occurring in the most acute phase of the disease. This
improvement from nadir (-0.498 LogMAR mean improvement, or +24.9
ETDRS letters equivalent) corresponds to 5 lines of Snellen acuity
and is far above the 3-line threshold commonly accepted as a
clinically meaningful level of visual improvement. Such recovery of
vision is unprecedented in any gene therapy trial. Moreover, these
results demonstrate the durability of improvement seen in earlier
readouts of this trial.
Vision in sham-treated eyes evolved in parallel fashion,
continuing the bilateral improvement already observed in earlier
Phase III readouts. The picture that has emerged is one of durable,
bilateral recovery from the effects of the acute phase in LHON.
The BCVA results from RESCUE show a remarkable correspondence
with those from the REVERSE trial, which studied the treatment of
subjects at 6 to 12 months after onset of vision loss.
The visual evolution in RESCUE appears to be a phase shift of
the REVERSE curves, with an additional impact from the acute phase.
This coherence will be more rigorously explored in a meta-analysis
of the pooled data from the two trials, which is planned for this
year.
In previous analyses of these trials, LHON clinical experts
confirmed that the visual recovery seen in these trials are at odds
with and much superior to their observations from clinical
practice. That natural history of vision in untreated LHON patients
stands in strong contrast to acuities seen in both RESCUE and
REVERSE.
A natural history study conducted by Santhera1 provides another
way of assessing the results in RESCUE. In that study, 28% of
subjects who had the 11778A mutation achieved the following
definition of spontaneous “clinically relevant recovery” (CRR) from
nadir in at least one eye:
- Improved by at least 10 ETDRS letters from nadir (for on-chart
eyes at nadir), or
- Improved from an off-chart level of visual acuity at nadir to
being able to read at least 5 ETDRS letters
By comparison, 58% of RESCUE subjects achieved this definition
of CRR in at least one eye at Week 96, with GS010-treated eyes as
likely to achieve this as sham-treated eyes (58% vs. 45%, p =
0.0956).
“The results from the RESCUE study are encouraging and
convincing, particularly because we are seeing a similar pattern to
the REVERSE study results,” said Dr. Mark L. Moster,
Neuro-Ophthalmology, Wills Eye Hospital, Professor of Neurology and
Ophthalmology at Thomas Jefferson University, Philadelphia, PA, and
Principal Investigator in the RESCUE and REVERSE trials. “Patients
in RESCUE were treated before the nadir so, as expected, they
continued to worsen early on. But then from week 48 until week 96
they experienced a recovery from the nadir. That is much better
than the natural history in any prior studies.”
Examination of other visual functions and biomarkers, including
Contrast Sensitivity, show that these measures stabilized at Week
96. Based on preliminary analysis of the safety data, GS010 was
well-tolerated after 96 weeks. There were no ocular serious adverse
events or discontinuations that were due to ocular events. 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 systemic serious adverse events or
discontinuations that were related to study treatment or study
procedure.
“These results are remarkable, showing the durable difference
that GS010 can make for patients who would otherwise go blind due
to the onset of LHON,” commented Bernard Gilly, Co-founder
and Chief Executive Officer of GenSight. “These findings, which we
will be discussing at the meetings we have planned with regulatory
authorities, form a compelling core for the clinical and
non-clinical data that support our marketing authorization
application in Europe. GenSight is excited to have reached this
milestone in GS010’s clinical development and energized by the
prospect of pulling it all together for our European dossier.”
GenSight is planning to schedule a pre-submission meeting with
the EMA in early 2020 and expects to submit application for
marketing approval in Europe in the third quarter of 2020.
An End of Phase II meeting with the U.S. Food and Drug
Administration (FDA) has been requested and is expected for
November 2019.
GenSight will host a conference call today, September 23, 2019,
at 10:30am CEST in French, and at 2.30pm CEST (8.30am EST) in
English, to discuss in greater detail these results and the roadmap
to submission.
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/20190923_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/20190923_1/
A replay of the calls and webcasts will be available by using
the above links.
Reference:
- 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 were reported in
2019 for both trials, after which patients were 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 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, and enrolment was completed in July
2019, ahead of schedule.
ClinicalTrials.gov Identifiers: REFLECT: NCT03293524
View source
version on businesswire.com: https://www.businesswire.com/news/home/20190922005072/en/
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 US Investor Relations Chad Rubin
crubin@troutgroup.com +1-646-378-2947
James Palmer Europe Investor Relations
j.palmer@orpheonfinance.com +33 7 60 92 77 74
GenSight Biologics (EU:SIGHT)
Graphique Historique de l'Action
De Fév 2024 à Mar 2024
GenSight Biologics (EU:SIGHT)
Graphique Historique de l'Action
De Mar 2023 à Mar 2024