Orchard Therapeutics, recently acquired by Kyowa Kirin with the
goal of accelerating the delivery of new gene therapies to patients
around the globe, today announced the U.S. Food and Drug
Administration (FDA) has approved Lenmeldy™ (atidarsagene
autotemcel), formerly known as OTL-200, for the treatment of
children with pre-symptomatic late infantile (PSLI),
pre-symptomatic early juvenile (PSEJ) or early symptomatic early
juvenile (ESEJ)—collectively referred to as
early-onset—metachromatic leukodystrophy (MLD).
“The FDA approval of Lenmeldy opens up
tremendous new possibilities for children in the U.S. with
early-onset MLD who previously had no treatment options beyond
supportive and end-of-life care,” said Bobby Gaspar, M.D., Ph.D.,
co-founder and chief executive officer of Orchard Therapeutics.
“MLD is a rapidly progressing, life-limiting and ultimately fatal
rare disease that has a devastating impact on afflicted children
and their families. This achievement is the culmination of decades
of research and development in partnership with our academic and
clinical collaborators at the San Raffaele-Telethon Institute for
Gene Therapy. I want to express my sincere gratitude to the
patients and families who participated in our clinical trials as
well as to the broader MLD community—we would not be here today
without your contributions and support.”
Dr. Gaspar continued, “I am also incredibly
proud of the entire team at Orchard for their tireless effort to
make this moment possible, and we look forward to ensuring broad
and sustainable access to this remarkable innovation for eligible
patients in need.”
MLD is a rare, fatal genetic disorder caused by
a mutation in the gene responsible for encoding the enzyme
arylsulfatase A (ARSA) leading to neurological damage and
developmental regression due to the accumulation of fats called
sulfatides in the brain and other areas of the body which, when not
broken down, damage the central nervous system over time. In its
most severe form, babies develop normally but in late infancy start
to rapidly lose the ability to walk, talk and interact with the
world around them. These children eventually deteriorate into a
vegetative state, which may require 24-hour intensive care, and the
majority pass away within five years of disease onset, creating an
enormous emotional and financial burden on the family.
Lenmeldy aims to correct the underlying genetic
cause of MLD by inserting one or more functional copies of the
human ARSA gene ex vivo (outside the body) into the genome of a
patient’s own hematopoietic stem cells (HSCs) using a lentiviral
vector. The genetically repaired cells are infused back into the
patient, where, once engrafted, they differentiate into multiple
cell types, some of which migrate across the blood-brain barrier
into the central nervous system and express the functional enzyme.
This approach has the potential to restore enzymatic function to
stop or slow disease progression with a single treatment.
“This is a momentous occasion and I commend the
FDA for recognizing the clinical impact Lenmeldy has on this cruel
disease,” said Barbara Burton, M.D., attending physician, genetics,
genomics and metabolism at the Ann & Robert H. Lurie Children’s
Hospital of Chicago. “For too long, my colleagues and I have
consoled families at their most vulnerable times—usually following
an arduous diagnostic odyssey, coping with a dire prognosis and
being told there were no treatments, and then having to watch their
young child slip away. With this approval, we are now one
significant step closer to ensuring future generations of children,
families and healthcare professionals no longer need to experience
first-hand the terrible manifestations this disease has on
untreated patients.”
“As a mother who lost a child to MLD, it is
difficult to articulate how much of a watershed moment this is for
patients, families and advocates,” said Maria Kefalas, Ph.D.,
co-founder of the Calliope Joy Foundation and a founding member of
Cure MLD. “I, and so many others in our community, have made it our
life’s work to end the horror caused by MLD so other families may
not have to face the same terrible fate as ours. Today, we are
closer than ever to making that vision a reality, but there’s still
more work to be done. With the first therapy for this childhood
disease now approved, we must act urgently and collaboratively to
enable universal newborn screening for MLD in the U.S. so babies
with these pathogenic mutations can be diagnosed and referred for
appropriate treatment before the onset of symptoms.”
Lenmeldy was granted Priority Review in
September 2023. It was previously given both Rare Pediatric Disease
(RPD) and Regenerative Medicine Advanced Therapy (RMAT)
designations from FDA. In connection with the approval, Orchard
Therapeutics received a Priority Review Voucher (PRV), which will
be transferred to GSK in accordance with the terms of the original
licensing agreement.
Orchard Therapeutics will provide more details
about the launch of Lenmeldy in the U.S. through a separate
announcement this week.
Overview of Clinical Development Program
and Results
The FDA approval of Lenmeldy is based on data
from 37 pediatric patients with early-onset MLD, enrolled in two
single-arm, open-label clinical studies or treated under European
expanded access frameworks, who received a one-time administration
of the gene therapy and compared with natural history data. All
treated patients were administered Lenmeldy and subsequently
monitored at Ospedale San Raffaele in Milan, Italy.
With more than 12 years of follow-up in the
earliest treated patients (median 6.76 years), treatment with
Lenmeldy significantly extended overall survival and resulted in
the preservation of motor function and cognitive skills in most
late infantile MLD patients past ages at which untreated patients
showed severe cognitive and motor impairments. Lenmeldy also
resulted in the preservation of motor function and cognitive skills
in some early juvenile MLD patients which is not expected when
compared to untreated patients.
The most common non-laboratory adverse reactions
(incidence ≥ 10%) were: febrile neutropenia (85%), stomatitis
(77%), respiratory tract infections (54%), rash (33%), device
related infections (31%), other viral infections (28%), pyrexia
(21%), gastroenteritis (21%), and hepatomegaly (18%). The most
common laboratory abnormalities were: elevated D-dimer (67%),
neutropenia (28%), and elevated liver enzymes (23%). Please see
below for additional details and Important Safety Information.
About MLDMLD is a rare and
life-threatening inherited disease of the body’s metabolic system
estimated to occur in approximately one in every 100,000 live
births based on existing literature. MLD is caused by a mutation in
the arylsulfatase-A (ARSA) gene that results in the
accumulation of sulfatides in the brain and other areas of the
body, including the liver, gallbladder, kidneys, and/or spleen.
Over time, the nervous system is damaged, leading to neurological
problems such as motor, behavioral and cognitive regression, severe
spasticity and seizures. Patients with MLD gradually lose the
ability to move, talk, swallow, eat and see. In its late infantile
form, mortality at five years from onset is estimated at 50 percent
and 44 percent at 10 years for juvenile patients.i
About LenmeldyLenmeldy™
(atidarsagene autotemcel), formerly known as OTL-200, is the only
approved therapy in the U.S. for the treatment of children
with pre-symptomatic late infantile (PSLI), pre-symptomatic early
juvenile (PSEJ) or early-symptomatic early juvenile (ESEJ)
metachromatic leukodystrophy (MLD).
For additional details about Lenmeldy, please
refer to the full Prescribing Information.
In Europe, Lenmeldy is known as Libmeldy®, where
it has been approved by the European Commission (EC), UK Medicines
and Healthcare products Regulatory Agency (MHRA), and Swiss Agency
for Therapeutic Products (Swissmedic). For more information about
Libmeldy, please see the Summary of Product Characteristics
(SmPC) available on the EMA website.
The program was originated by and developed in
partnership with the San Raffaele-Telethon Institute for Gene
Therapy (SR-Tiget) in Milan, Italy. It was licensed by Orchard
Therapeutics from GSK in 2018.
INDICATION
LENMELDYTM (atidarsagene autotemcel) is an autologous
hematopoietic stem cell-based gene therapy indicated for the
treatment of children with pre-symptomatic late infantile (PSLI),
pre-symptomatic early juvenile (PSEJ), or early symptomatic early
juvenile (ESEJ) metachromatic leukodystrophy (MLD).
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Thrombosis and Thromboembolic Events:Treatment
with LENMELDY may increase the risk of thrombosis and
thromboembolic events. A child with PSEJ MLD died after
experiencing a left hemisphere cerebral infarction secondary to a
thrombotic event in a large blood vessel approximately 1 year after
treatment with LENMELDY. Evaluate the risk factors for thrombosis
prior to and after LENMELDY infusion according to best clinical
practice. Consider monitoring D-dimer levels after LENMELDY
treatment.
Encephalitis:Treatment with LENMELDY may
increase the risk of encephalitis. A child with ESEJ developed a
serious event of encephalitis after treatment with LENMELDY. The
etiology of this event is unclear but attribution to LENMELDY
cannot be ruled out. Treatment with LENMELDY may trigger a
relapsing-remitting pattern of disease progression. No other events
related to encephalitis have been reported during the clinical
development of LENMELDY. Monitor children for signs or symptoms of
encephalitis after LENMELDY treatment.
Serious Infection:In the period between start
of conditioning and within 1 year after LENMELDY treatment, severe
Grade 3 infections occurred in 39% of all children (21% bacterial,
5% viral, 5% bacterial and viral or bacterial and fungal, and 8%
unspecified). Grade 3 febrile neutropenia developed within 1
month after LENMELDY infusion in 82% of children. In the event of
febrile neutropenia, monitor for signs and symptoms of infection
and manage with broad-spectrum antibiotics, fluids, and other
supportive care as medically indicated. Monitor children for signs
and symptoms of infection after myeloablative conditioning and
LENMELDY infusion and treat appropriately. Administer prophylactic
antimicrobials according to best clinical practice.
Veno-Occlusive Disease:Three children (8%)
treated in clinical trials of LENMELDY developed veno-occlusive
disease (VOD) with one Grade 4 SAE and two Grade 3 AEs. None of
these three events met Hy’s Law criteria. Monitor children for
signs and symptoms of VOD including liver function tests in all
children during the first month after LENMELDY infusion. Consider
prophylaxis for VOD with an anti-thrombotic such as defibrotide or
ursodeoxycholic acid based on risk factors for VOD and best
clinical practice.
Delayed Platelet Engraftment (DPE):DPE has been
observed with LENMELDY treatment. Bleeding risk is increased prior
to platelet engraftment and may continue after engraftment in
children with prolonged thrombocytopenia. In clinical trials of
LENMELDY, 4 (10%) children had delayed platelet engraftment after
day 60 (range day 67-109), with 3 children requiring platelet
transfusions until engraftment occurred. Patients should be
informed of the risk of bleeding until platelet recovery has been
achieved. Monitor patients for thrombocytopenia and bleeding until
platelet engraftment and recovery are achieved.
Neutrophil Engraftment Failure: There is a
potential risk of neutrophil engraftment failure after treatment
with LENMELDY. Monitor neutrophil counts until engraftment has been
achieved. If neutrophil engraftment failure occurs in a child
treated with LENMELDY, provide rescue treatment with the
unmanipulated back-up collection of CD34+ cells.
Insertional Oncogenesis: There is a potential
risk of LVV-mediated insertional oncogenesis after treatment with
LENMELDY. Children treated with LENMELDY may develop hematologic
malignancies and should be monitored lifelong. Monitor for
hematologic malignancies with a complete blood count (with
differential) annually and integration site analysis as warranted
for at least 15 years after treatment with LENMELDY. In the event
that a malignancy occurs, contact Orchard Therapeutics at
1-888-878-0185 for reporting and to obtain instructions on
collection of samples for testing.
Hypersensitivity Reactions: The dimethyl
sulfoxide (DMSO) in LENMELDY may cause hypersensitivity reactions,
including anaphylaxis which is potentially life-threatening and
requires immediate intervention. Hypersensitivity including
anaphylaxis can occur in children with and without prior exposure
to DSMO. Monitor for hypersensitivity reactions during infusion and
after infusion.
Anti-Retroviral Use: Children should not
take prophylactic HIV anti-retroviral medications for at least one
month prior to mobilization, or for the expected duration of time
needed for the elimination of the medications. Anti-retroviral
medications may interfere with the manufacturing of LENMELDY. If a
child requires antiretrovirals for HIV prophylaxis, initiation of
LENMELDY treatment should be delayed until confirmation of a
negative test for HIV.
Interference With Serology Testing:
Due to the likelihood of a false-positive test for HIV, children
who have received LENMELDY should not be screened for HIV infection
using a PCR-based assay.
USE IN SPECIFIC POPULATIONS
Females and Males of Reproductive Potential
Pregnancy TestingAs a precautionary measure, a negative serum
pregnancy test must be confirmed prior to the start of
mobilization, and reconfirmed prior to conditioning procedures, and
before administration of LENMELDY in females of childbearing
potential.
Contraception
Consult the Prescribing Information of the mobilization and
conditioning agents for information on the need for effective
contraception. Males capable of fathering a child and females of
childbearing age should use an effective method of contraception
from start of mobilization through at least 6 months after
administration of LENMELDY.
InfertilityThere are no data on the effects of LENMELDY on
fertility.
Data are available on the risk of infertility with myeloablative
conditioning. In clinical trials of LENMELDY, seven children (50%
of females) developed ovarian failure. Advise children of the
option to cryopreserve semen or ova before treatment, if
appropriate.
For additional safety information, please see the full
Prescribing Information.
About Orchard
TherapeuticsOrchard Therapeutics, a Kyowa Kirin company,
is a global gene therapy leader focused on ending the devastation
caused by genetic and other severe diseases by discovering,
developing, and commercializing new treatments that tap into the
curative potential of hematopoietic stem cell (HSC) gene therapy.
In this approach, a patient’s own blood stem cells are genetically
modified outside of the body and then reinserted, with the goal of
correcting the underlying cause of disease with a single
treatment.
Founded in 2015, Orchard’s roots go back to some
of the first research and clinical developments involving HSC gene
therapy. Our team has played a central role in the evolution of
this technology from a promising scientific idea to a potentially
life-transforming reality. Today, Orchard is advancing a pipeline
of HSC gene therapies designed to address serious diseases where
the burden is immense for patients, families and society and
current treatment options are limited or do not exist.
For more information, please
visit www.orchard-tx.com.
About Kyowa KirinKyowa Kirin
aims to discover novel medicines with life-changing value. As a
Japan-based Global Specialty Pharmaceutical Company, we have
invested in drug discovery and biotechnology innovation for more
than 70 years and are currently working to engineer the next
generation of antibodies and cell and gene therapies with
the potential to help patients affected by a severe or
rare disease. A shared commitment to our values, to sustainable
growth, and to making people smile unites us across our four
regions – Japan, Asia Pacific, North America, and
EMEA/International. You can learn more about the business of Kyowa
Kirin
at www.kyowakirin.com.______________________________iMahmood
et al. Metachromatic Leukodystrophy: A Case of Triplets with the
Late Infantile Variant and a Systematic Review of the Literature.
Journal of Child Neurology 2010,
DOI: http://doi.org/10.1177/0883073809341669
Contact
Benjamin Navon
+1 857-248-9454
Benjamin.Navon@orchard-tx.com
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