LUXTURNA would be first gene therapy for a
genetic disease approved in both U.S. and EU
Spark Therapeutics (NASDAQ: ONCE), a fully integrated, commercial
gene therapy company dedicated to challenging the inevitability of
genetic disease today announced that the Committee for Medicinal
Products for Human Use (CHMP) of the European Medicines Agency
(EMA) adopted a positive opinion recommending approval of LUXTURNA®
(voretigene neparvovec), a one-time gene therapy for the treatment
of adult and pediatric patients with vision loss due to inherited
retinal dystrophy caused by confirmed biallelic RPE65 mutations and
who have sufficient viable retinal cells.
“We are encouraged by today’s decision, which
further affirms our pioneering clinical program and brings LUXTURNA
one step closer to patients with inherited retinal disease (IRD)
caused by mutations in both copies of the RPE65 gene in the
European Union,” said Katherine A. High, M.D., president and head
of research & development at Spark Therapeutics. “Along with
Novartis, we look forward to continuing our productive, ongoing
dialogue with EMA toward potential marketing authorization to make
LUXTURNA the first and only treatment for appropriate patients with
this inherited retinal disease (IRD) in the European Union.”
The positive CHMP opinion is based on data from
a Phase 1 clinical trial, its follow-up trial and a Phase 3 trial
that together enrolled 43 participants with inherited retinal
disease caused by mutations on both copies of the RPE65 gene. The
Phase 3 trial was the first randomized, controlled Phase 3 gene
therapy trial for a genetic disease. Spark Therapeutics has
received orphan product designation for LUXTURNA from EMA for the
treatment of inherited retinal dystrophies.
“Inherited retinal diseases are a heterogenous group of
degenerative conditions that represent the major cause of blindness
in childhood and active working life. This opinion represents a
hopeful milestone for current and future patients who may
ultimately benefit from gene therapy,” said Christina Fasser,
president of Retina International, an umbrella organization of more
than 43 patient organizations worldwide promoting research to find
treatments for inherited retinal degenerative diseases.
A marketing authorization decision from the
European Commission is anticipated approximately within two months.
If approved, the authorization will be valid in all 28-member
states of the European Union, as well as Iceland, Liechtenstein and
Norway. In January 2018, Spark Therapeutics entered into a
licensing and supply agreement with Novartis to commercialize
LUXTURNA when and if approved in Europe and all markets outside the
U.S.
LUXTURNA (voretigene neparvovec-rzyl) was
approved by the U.S. Food & Drug Administration (FDA) in
December 2017.
Clinical Trial Overview of LUXTURNA®
(voretigene neparvovec)The safety and efficacy of LUXTURNA
were assessed in one open-label, dose-exploration Phase 1 safety
study (n=12), a second open-label Phase 1 safety study to assess
the safety of injection of the contralateral eye (n=11) and an
open-label, randomized, controlled Phase 3 efficacy and safety
study (n=31) in pediatric and adult participants (range 4 to 44
years) with biallelic RPE65 mutation-associated retinal disease and
sufficient viable retinal cells.
Of the 31 participants enrolled in the Phase 3 study, 21 were
randomized to receive subretinal injection of LUXTURNA and 10 were
randomized to the control (non-intervention) group. One participant
in the intervention group discontinued from the study prior to
treatment and one participant in the control group withdrew consent
and was discontinued from the study. All nine participants
randomized to the control group elected to cross over to receive
LUXTURNA after one year of observation. All participants in these
studies continue to be followed for long-term safety and efficacy.
LUXTURNA Phase 3 clinical trial data, including data from the
intervention group of all randomized participants through the
one-year time point, have been previously reported in The
Lancet.
The efficacy of LUXTURNA in the Phase 3 study was established
based on the binocular multi-luminance mobility test (MLMT) score
change from baseline to one year. MLMT was designed to measure
changes in functional vision as assessed by the ability of a
participant to navigate a course accurately and at a reasonable
pace at seven different levels of illumination, ranging from 400
lux (corresponding to a brightly lit office) to one lux
(corresponding to a moonless summer night). Each light level was
assigned a score ranging from zero to six, with a higher score
indicating that a participant could pass MLMT at a lower light
level. A score of negative one was assigned to participants who
could not pass MLMT at a light level of 400 lux. MLMT score change
was defined as the difference between the score at baseline and the
score at one year with a positive score change indicating that a
participant was able to complete MLMT at a lower light level.
Additional clinical outcomes included white light full-field light
sensitivity threshold (FST) testing and visual acuity, both
averaged over both eyes. Secondary endpoints included white light
full-field light sensitivity threshold (FST) testing averaged over
both eyes, first assigned eye MLMT and visual acuity.
LUXTURNA Phase 3 clinical study results showed a statistically
significant difference between the intervention group (n=21) and
control participants (n=10) at one year in mean binocular MLMT
score change (intervention minus control group difference of 1.6;
95% CI, 0.72, 2.41; p=0.001). After crossing over to receive
LUXTURNA, participants in the control group showed a similar
response to those in the intervention group. This score change has
been sustained for at least three years for the original
intervention group and at least two years in the crossover group in
the Phase 3 clinical study. In addition, participants who received
LUXTURNA showed a statistically significant improvement from
baseline to one year in white light FST (p<0.001) and first
assigned eye MLMT change score (p=0.001) compared to the control
group. The change in visual acuity from baseline to one year was
not significantly different between the intervention and control
participants.
Three ocular serious adverse events (SAEs) were
reported in the clinical program. One SAE related to the surgical
procedure in one eye of a Phase 3 participant, in which there was
foveal thinning and a sustained reduction in VA. One additional
Phase 3 participant reported an SAE of retinal detachment 4 years
after vector administration assessed as related to the
administration procedure. The third ocular SAE was reported in one
eye of a Phase 1 participant in which the treatment for bacterial
endophthalmitis led to elevated intraocular pressure and subsequent
optic atrophy. There were three non-serious AEs of retinal deposits
(subretinal precipitate) in three participants (three eyes) that
were considered to be related to LUXTURNA. All three of these
events were mild in intensity, transient in nature and resolved
without consequences. No deleterious immune responses have been
observed. The most common adverse reactions related to LUXTURNA
reported in 5 percent or greater of the combined Phase 1 and Phase
3 trial participants included conjunctival hyperemia, cataract,
increased intraocular pressure, retinal tear, dellen (thinning of
the corneal stroma), macular hole, subretinal deposits, eye
inflammation, eye irritation, eye pain and maculopathy (wrinkling
on the surface of the macula).
Indication and Important Safety Information for LUXTURNA
in the U.S.LUXTURNA (voretigene neparvovec-rzyl) is an
adeno-associated virus vector-based gene therapy indicated for the
treatment of patients with confirmed biallelic RPE65
mutation-associated retinal dystrophy.
Patients must have viable retinal cells as determined by the
treating physicians.
Warnings and Precautions
- Endophthalmitis may occur following any
intraocular surgical procedure or injection. Use proper aseptic
injection technique when administering LUXTURNA and monitor for and
advise patients to report any signs or symptoms of infection or
inflammation to permit early treatment of any infection.
- Permanent decline in visual acuity may occur
following subretinal injection of LUXTURNA. Monitor patients for
visual disturbances.
- Retinal abnormalities may occur during or
following the subretinal injection of LUXTURNA, including macular
holes, foveal thinning, loss of foveal function,
foveal dehiscence, and retinal hemorrhage. Monitor and manage these
retinal abnormalities appropriately. Do not administer LUXTURNA in
the immediate vicinity of the fovea. Retinal abnormalities may
occur during or following vitrectomy, including retinal tears,
epiretinal membrane or retinal detachment. Monitor patients during
and following the injection to permit early treatment of these
retinal abnormalities. Advise patients to report any signs or
symptoms of retinal tears and/or detachment without delay.
- Increased intraocular pressure may occur after
subretinal injection of LUXTURNA. Monitor and manage intraocular
pressure appropriately.
- Expansion of intraocular air bubbles Instruct
patients to avoid air travel, travel to high elevations or scuba
diving until the air bubble formed following administration of
LUXTURNA has completely dissipated from the eye. It may take one
week or more following injection for the air bubble to dissipate. A
change in altitude while the air bubble is still present can result
in irreversible vision loss. Verify the dissipation of the air
bubble through ophthalmic examination.
- Cataract Subretinal injection of LUXTURNA,
especially vitrectomy surgery, is associated with an increased
incidence of cataract development and/or progression.
Adverse Reactions
- In clinical studies, ocular adverse reactions occurred in 66%
of study participants (57% of injected eyes) and may have been
related to LUXTURNA, the subretinal injection procedure, the
concomitant use of corticosteroids, or a combination of these
procedures and products.
- The most common adverse reactions (incidence ≥ 5% of study
participants) were conjunctival hyperemia (22%), cataract (20%),
increased intraocular pressure (15%), retinal tear (10%), dellen
(thinning of the corneal stroma) (7%), macular hole (7%),
subretinal deposits (7%), eye inflammation (5%), eye irritation
(5%), eye pain (5%), and maculopathy (wrinkling on the surface of
the macula) (5%).
ImmunogenicityImmune reactions and extra-ocular
exposure to LUXTURNA in clinical studies were mild. No clinically
significant cytotoxic T-cell response to either AAV2 or RPE65 has
been observed.
In clinical studies, the interval between the subretinal
injections into the two eyes ranged from 7 to 14 days and 1.7 to
4.6 years. Study participants received systemic corticosteroids
before and after subretinal injection of LUXTURNA to each eye,
which may have decreased the potential immune reaction to either
AAV2 or RPE65.
Pediatric UseTreatment with LUXTURNA is not
recommended for patients younger than 12 months of age, because the
retinal cells are still undergoing cell proliferation, and LUXTURNA
would potentially be diluted or lost during the cell proliferation.
The safety and efficacy of LUXTURNA have been established in
pediatric patients. There were no significant differences in safety
between the different age subgroups.
Please see the full U.S. Prescribing Information for
LUXTURNA here.
About Inherited Retinal Disease
(IRD) Caused by Confirmed Biallelic RPE65
MutationsInherited retinal diseases (also known as
inherited retinal dystrophies) are a group of rare blinding
conditions caused by one of more than 220 different genes, often
disproportionally affecting children and young adults. Based on
Spark Therapeutics’ assessment of available epidemiology data, the
prevalent population in the U.S., Europe and select additional
markets in the Americas and Asia/Pacific is up to approximately
6,000 individuals, in total, with
biallelic RPE65 mutations.
People living with IRD due to
biallelic RPE65 gene mutations nearly all progress to
complete blindness. They often experience night blindness
(nyctalopia) due to decreased light sensitivity in childhood or
early adulthood and involuntary back-and-forth eye movements
(nystagmus). As the disease progresses, individuals may experience
loss in their peripheral vision, developing tunnel vision and
eventually, they may lose their central vision as well, resulting
in total blindness. Independent navigation becomes severely
limited, and vision-dependent activities of daily living are
impaired.
About the Novartis and Spark
Therapeutics Licensing and Supply Agreement In January
2018, Spark Therapeutics entered into a licensing and supply
agreement with Novartis covering development, registration and
commercialization rights to LUXTURNA in markets outside the U.S.
Commercialization rights will be transferred to Novartis upon
successful completion of registration and issuance of marketing
authorization. Novartis has exclusive rights to pursue development,
registration and commercialization in all other countries outside
the U.S., and Spark Therapeutics would supply the gene therapy to
Novartis.
About Gene Therapy Gene therapy is an approach
to treat or prevent genetic disease by seeking to augment, replace
or suppress one or more mutated genes with functional copies. It
addresses the root cause of an inherited disease by enabling the
body to produce a protein or proteins necessary to restore health
or to stop making a harmful protein or proteins, with the potential
of bringing back function in the diseased cells and/or slowing
disease progression. To deliver the functional gene into the cell,
a vector is used to transport the desired gene and is delivered
either intravenously or injected into specific tissue. The goal is
to enable, through the one-time administration of gene therapy, a
lasting therapeutic effect.
About Spark Therapeutics At
Spark Therapeutics, a fully integrated company committed to
discovering, developing and delivering gene therapies, we
challenge the inevitability of genetic
diseases, including blindness, hemophilia and
neurodegenerative diseases. We have successfully applied our
technology in the first FDA-approved gene therapy in the U.S. for a
genetic disease, and currently have three programs in clinical
trials, including product candidates that have shown promising
early results in patients with hemophilia. At Spark, we see
the path to a world where no life is limited by genetic disease.
For more information, visit www.sparktx.com, and follow us on
Twitter and LinkedIn.
Cautionary note on forward-looking
statementsThis release contains "forward-looking
statements" within the meaning of the Private Securities Litigation
Reform Act of 1995, including statements regarding the
company's product LUXTURNA™ (voretigene neparvovec-rzyl). The
words ‘‘anticipate,’’ ‘‘believe,’’ ‘‘expect,’’ ‘‘intend,’’ ‘‘may,’’
‘‘plan,’’ ‘‘predict,’’ ‘‘will,’’ ‘‘would,’’ ‘‘could,’’ ‘‘should,’’
‘‘continue’’ and similar expressions are intended to identify
forward-looking statements, although not all forward-looking
statements contain these identifying words. We may not actually
achieve the plans, intentions or expectations disclosed in our
forward-looking statements, and you should not place undue reliance
on our forward-looking statements. Any forward-looking statements
are based on management's current expectations of future events and
are subject to a number of risks and uncertainties that could cause
actual results to differ materially and adversely from those set
forth in, or implied by, such forward-looking statements. These
risks and uncertainties include, but are not limited to, the risk
that: (i) our MAA submitted for LUXTURNA may not be approved by EMA
when expected, or at all; and (ii) the improvements in functional
vision demonstrated by LUXTURNA in our clinical trials may not be
sustained over extended periods of time. For a discussion of other
risks and uncertainties, and other important factors, any of which
could cause our actual results to differ from those contained in
the forward-looking statements, see the "Risk Factors" section, as
well as discussions of potential risks, uncertainties and other
important factors, in our Annual Report on Form 10-K, our Quarterly
Reports on Form 10-Q and other filings we make with
the Securities and Exchange Commission. All information in
this press release is as of the date of the release, and Spark
undertakes no duty to update this information unless required by
law.
Investor
Relations Contact: |
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Media
Contact: |
Ryan Asay |
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Monique da Silva |
Ryan.asay@sparktx.com |
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communications@sparktx.com |
(215) 239-6424 |
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