-
Sustained, clinically meaningful bilateral improvement in visual
functions 96 weeks after injection -
Observed bilateral improvement interpreted as clearly superior to
known natural history -
Improvements in visual function translate to significant increase in
quality of life among LHON patients -
GenSight to move GS010 to regulatory approval, first in Europe then in
the United States
PARIS–(BUSINESS WIRE)–Regulatory News:
GenSight Biologics (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 highlights from its
recent Key Opinion Leader (KOL) panel hosted in New York City on May 23,
2019. The event was dedicated to updates on clinical results for GS010,
in particular findings at Week 96 of the REVERSE Phase III clinical
trial in the treatment of Leber Hereditary Optic Neuropathy (LHON).
The panel of medical experts included David J. Calkins, PhD
1; Sean Donahue, MD, PhD 2; Mark
Moster, MD3; José-Alain Sahel, MD4;
and Robert C. Sergott, MD5. In addition, Andy
Marks, LHON patient and patient advocate, spoke about the patient
experience in LHON.
Dr. Donahue set up the morning’s discussion by providing an overview of
LHON as a genetic disease. Dr. Moster then critically examined the
literature on how vision changes after loss, over the natural history of
the disease. Dr. Moster highlighted differences in the population
studied, in terms of causative mutations, and date of onset in past
studies. His analyses, which attempted to account for the factors above,
indicate a “huge difference” between the results seen in
the REVERSE trial and the outcomes cited in the medical literature.
Just as important, his clinical experience as well as that of his peers
are at odds with the sustained improvements observed in REVERSE. “We
simply do not see the kinds of improvement in our clinical practices
when we follow these patients as have been seen in this trial,”
Dr. Moster concluded. He reminded the audience that REVERSE subjects had
the most severe mutation in terms of rate of spontaneous recovery.
The visual deterioration has profound effects on patients’ lives, Andy
Marks explained. He described having to give up a house that he had just
purchased when he experienced visual loss from LHON, and moving his
residence closer to his office as he adjusted to a lower level of
autonomy. Eventually, he moved from Orlando to the New York City
metropolitan area, where his inability to drive would be less decisive
for his work life. In the community of LHON patients in which he
actively participates, he has yet to encounter someone whose visual
functions recovered to the degree observed in the REVERSE trial after
disease onset.
“We are living in an age of remarkable gene therapies,”
said Dr. Sergott, who reviewed the REVERSE study’s key findings. Among
the efficacy findings, he highlighted the recovery of visual acuity –
+15 ETDRS letters equivalent improvement versus baseline and +28 ETDRS
letters equivalent improvement versus nadir for GS010-treated eyes (+13
and +23, respectively, for sham-treated eyes) – as “extraordinary”.
Dr. Sergott also shared subject-level data, newly available at Week 96,
that showed:
- For most patients, eyes tended to track together;
- Most patients improved in both eyes relative to baseline;
-
Patients with large improvements from baseline and from nadir tended
to have GS010-treated eyes that outperformed their sham-treated eyes;
and -
For a greater number of patients, change from nadir is more pronounced
in GS010-treated eyes.
Bilateral improvement was thus a feature of individual data, not just a
result of aggregation. An explanation for this durable bilateral
improvement, which is at odds with natural history or known clinical
practice, was the focus of Dr. Calkins’ talk. He began with the
provocative observation that he would have been surprised had there been
no effect in the contralateral eye. As he explained, an eye has many
ways to interact with and compensate for a weakness in its fellow eye. “The
fellow eye ought to improve,” he said.
Dr. Calkins’ team studies how stress in one eye can lead the other
(unstressed) eye to share resources via the optic nerve. Dr. Calkins
suggested that a likely mechanism for compensation between the eyes lies
in the networks formed between astrocyte glia and optic nerve fibers in
the retina and optic nerve, which allow sharing of metabolic molecules .
“Resources can travel via astrocyte networks from the treated eye
to the untreated to improve overall performance,” Dr. Calkins
concluded. Recall that GS010 works by restoring the ability of
mitochondria in retinal ganglion cells to generate energy needed for
visual processing.
Dr. Sahel, co-founder of GenSight, summarized the presentations by
reiterating the efficacy findings and rejecting either the “placebo
effect” or “training effect” as an explanation for the results. The
bilateral evolution of subjects’ eyes would be difficult to reconcile
with a “placebo or training effect”, he said. “In which studies would
a placebo or training effect show something similar to the initial
decrease in an efficacy signal [the nadir effect seen in REVERSE and
RESCUE] followed by a sustained increase afterwards? Why would the
placebo or training effect work that way? It would not,” he said. “These
intriguing results represent good news for patients.”
Dr. Donahue concluded by sharing the experience of a teen-aged patient
who was treated with GS010 in a compassionate use program. “He went
from needing to be led by his parents around a room to once again being
able to play basketball,” he said. “It’s the experience of just
one patient, but you can see, it’s very impressive, and the family is
very thankful.”
Following the discussion, Bernard Gilly, co-founder and CEO of GenSight,
underscored GenSight’s determination to bring GS010 to market as early
as possible. “The team is working to prepare the pre-submission
meeting with the EMA and the End of Phase 2 meeting with the FDA in
order to move GS010 through the regulatory process for approval,”
he said.
The presentation is available in replay on the Company’s website at https://www.gensight-biologics.com/2019/05/22/kol-event-to-present-phase-3-reverserescue-results-of-gs010-for-the-treatment-of-leber-hereditary-optic-neuropathy-lhon-new-york-city/.
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
1 O’Day Professor, Vice Chair and Director for Research
Vanderbilt Eye Institute, Vanderbilt University Medical Center,
Nashville, TN
2 Coleman Professor of Ophthalmology,
Neurology and Pediatrics; Vice Chair of Clinical Affairs, Ophthalmology
Vanderbilt University Medical Center, Nashville, TN
3
Neuro-Ophthalmology, Wills Eye Hospital and Professor of Neurology and
Ophthalmology at Thomas Jefferson University, Philadelphia, PA
4
Director of the Institut de la Vision (Sorbonne-Université/Inserm/CNRS),
Paris; Chairman of the Department of Ophthalmology at Centre Hospitalier
National d’Ophtalmologie des XV-XX, Paris; Professor and Chairman of the
Department of Ophthalmology at University of Pittsburgh School of
Medicine and UPMC (University of Pittsburgh Medical Center). Co-founder,
GenSight.
5 Director, Neuro-Ophthalmology, Wills Eye
Hospital; Director, William H. Annesley, Jr, EyeBrain Center, and
Professor of Neurology and Ophthalmology at Thomas Jefferson University,
Philadelphia, PA
Note: Each point in Figures 1 and 2 represents one patient (two eyes)
in REVERSE.
Contacts
GenSight Biologics
Thomas Gidoin
Chief
Financial Officer
tgidoin@gensight-biologics.com
+33
(0)1 76 21 72 20
RooneyPartners
Media Relations
Marion Janic
mailto: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