– OXLUMO is the First Therapeutic Approved for
the Treatment of PH1, and the Only Therapy Proven to Lower Harmful
Oxalate Levels that Drive the Progression of PH1 Disease –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced that the European Commission
(EC) has granted marketing authorization for OXLUMO™ (lumasiran),
an RNAi therapeutic, for the treatment of primary hyperoxaluria
type 1 (PH1) in all age groups.
PH1 is an ultra-rare orphan disease characterized by excessive
oxalate production, which can lead to life threatening end-stage
renal disease (ESRD) and other systemic complications.
Heterogeneity in disease manifestation often contributes to delays
in diagnosis – particularly in adult PH1 patients, with a median
time from symptoms onset to diagnosis of approximately six years.
Untreated PH1 leads to progressive kidney damage; patients with
advanced kidney disease require intensive dialysis to help filter
waste products, including oxalate, from their blood until they are
able and eligible to receive a dual or sequential liver/kidney
transplant, an invasive procedure associated with a high risk of
morbidity and mortality, and life-long immunosuppression.
“Prior to now there have been no approved treatment options for
PH1 in Europe, so this is a potentially life-changing milestone for
people diagnosed with this ultra-rare, debilitating disease - many
of whom are infants and children - and their families. Lumasiran
will address the urgent unmet need that exists for patients with
PH1 and its approval today marks our continued commitment to rare
disease communities,” said John Maraganore, Ph.D., Chief Executive
Officer, Alnylam Pharmaceuticals. “Alnylam has taken lumasiran from
identification of compound to regulatory approval in just six years
and we will progress with the same sense of urgency as we work with
national reimbursement bodies across Europe to bring lumasiran to
patients.”
Lumasiran is an RNAi therapeutic targeting the hydroxyacid
oxidase 1 (HAO1) mRNA that encodes glycolate oxidase (GO) – an
enzyme upstream of the disease-causing defect in PH1. By degrading
the HAO1 mRNA and reducing the synthesis of GO, lumasiran stops the
production of oxalate – the toxic metabolite that directly
contributes to the clinical manifestations of PH1.
“PH1 affects patients of all ages. It is particularly
devastating when infants are born with the condition and develop
kidney failure within the first few months of life. PH1 patients
develop kidney stones from the overproduction of oxalate, and in
many we see a progressive decline in kidney function, which can
ultimately lead to life-threatening end-stage kidney disease. Until
recently the only treatment options available have been combined
liver and kidney transplantation, with vitamin B6 slowing down
kidney failure in a limited number of sensitive patients,” said
Sally-Anne Hulton, M.D., Consultant Paediatric Nephrologist,
Birmingham Women’s and Children’s Hospital NHS Trust, UK. “For the
first time, lumasiran provides those of us treating PH1 children
and adults with a new therapeutic option to tackle the root cause
of this disease and prevent the production of oxalate. The data
show meaningful and sustained reductions in urinary and plasma
oxalate with an encouraging safety and tolerability profile,
providing us with hope for improving care for these patients.”
“In line with our Patient Access Philosophy, Alnylam is
committed to being as innovative commercially as we have been
scientifically,” said Brendan Martin, Acting Head of CEMEA,
Alnylam. “While the ability to enter into innovative agreements
varies by country and local regulations, we intend to work with
health authorities across Europe to achieve responsible and
sustainable access arrangements for lumasiran that address the
diverse patient population affected by PH1, which ranges from
infants to adults, and we will adapt to the local context. Our goal
is to ensure that all patients in need have access to lumasiran
while minimizing budget uncertainty for health services.”
The approval in the European Union is based on efficacy and
safety findings from both the ILLUMINATE-A and ILLUMINATE-B Phase 3
studies of lumasiran. In the ILLUMINATE-A study conducted in adults
and children six years or older, lumasiran achieved the primary
endpoint with a 53 percent mean reduction in urinary oxalate
relative to placebo and showed a 65 percent mean reduction in
urinary oxalate relative to baseline. Eighty-four percent of
patients achieved normal1 or near-normal2 levels of urinary oxalate
and more than half of patients (52 percent) reached normalization,
compared to zero percent in the placebo group. Findings from the
ILLUMINATE-A pivotal study were presented in June 2020 at the
virtual European Renal Association-European Dialysis and Transplant
Association (ERA-EDTA) International Congress. In the ILLUMINATE-B
Phase 3 study, the efficacy results and safety profile of lumasiran
in infants and children under the age of six years were found to be
similar to those observed in ILLUMINATE-A. Results from the
ILLUMINATE-B pediatric study were presented on October 22 at the
virtual American Society of Nephrology (ASN) Annual Congress.
Lumasiran was granted Priority Medicines (PRIME) designation by
the EMA as well as Orphan Designation in the European Union.
Lumasiran was also granted an Accelerated Assessment by the EMA,
which is awarded to medicines deemed to be of major public health
interest and therapeutic innovation and is designed to bring new
treatments to patients more quickly. This approval in the European
Union follows the positive opinion from the Committee for Medicinal
Products for Human Use (CHMP) in October 2020. Alnylam has filed a
New Drug Application (NDA) with the U.S. Food and Drug
Administration (FDA). The FDA has granted a Priority Review for the
NDA and has set an action date of December 3, 2020 under the
Prescription Drug User Fee Act (PDUFA).
Footnotes:
1Normal is defined as urinary oxalate levels at or below the
upper limit of normal (ULN; ≤ 0.514 mmol/24 hr/1.73 m2).
2Near-normal is defined as urinary oxalate levels at or below 1.5 x
ULN (≤ 0.771 mmol/24 hr/1.73 m2).
About OXLUMO™ (lumasiran)
OXLUMO (lumasiran) is an RNAi therapeutic targeting hydroxyacid
oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1
(PH1) to lower urinary oxalate levels in pediatric and adult
patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream
of the disease-causing defect in PH1 and lumasiran works by
degrading HAO1 messenger RNA and reducing the synthesis of GO,
which inhibits hepatic production of oxalate – the toxic metabolite
responsible for the clinical manifestations of PH1. Lumasiran
utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc
conjugate technology designed to increase potency and durability.
In the pivotal ILLUMINATE-A study, lumasiran was shown to
significantly reduce levels of urinary oxalate relative to placebo,
with the majority of patients reaching normal or near-normal
levels. Injection site reactions (ISRs) were the most common
drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase
3 study, lumasiran demonstrated an efficacy and safety profile
consistent to that observed in ILLUMINATE-A. Lumasiran is
administered via subcutaneous injection once monthly for three
months, then once quarterly thereafter at a dose based on actual
body weight. For patients who weigh less than 10 kg, ongoing dosing
remains monthly. OXLUMO should be administered by a healthcare
professional.
About Primary Hyperoxaluria Type 1 (PH1)
PH1 is an ultra-rare disease in which excessive oxalate
production results in the deposition of calcium oxalate crystals in
the kidneys and urinary tract and can lead to the formation of
painful and recurrent kidney stones and nephrocalcinosis. Renal
damage is caused by a combination of tubular toxicity from oxalate,
calcium oxalate deposition in the kidneys, and urinary obstruction
by calcium oxalate stones. Compromised kidney function exacerbates
the disease as the excess oxalate can no longer be effectively
excreted, resulting in subsequent accumulation and crystallization
in bones, eyes, skin, and heart, leading to severe illness and
death. Current treatment options are very limited and include
frequent renal dialysis or combined organ transplantation of liver
and kidney, a procedure with high morbidity that is limited due to
organ availability. Although a small minority of patients respond
to vitamin B6 therapy, there are no approved pharmaceutical
therapies for PH1.
About RNAi
RNAi (RNA interference) is a natural cellular process of gene
silencing that represents one of the most promising and rapidly
advancing frontiers in biology and drug development today. Its
discovery has been heralded as "a major scientific breakthrough
that happens once every decade or so," and was recognized with the
award of the 2006 Nobel Prize for Physiology or Medicine. By
harnessing the natural biological process of RNAi occurring in our
cells, a new class of medicines, known as RNAi therapeutics, is now
a reality. Small interfering RNA (siRNA), the molecules that
mediate RNAi and comprise Alnylam's RNAi therapeutic platform,
function upstream of today’s medicines by potently silencing
messenger RNA (mRNA) – the genetic precursors – that encode for
disease-causing or disease pathway proteins, thus preventing them
from being made. This is a revolutionary approach with the
potential to transform the care of patients with genetic and other
diseases.
Important Safety Information
Contraindications
Severe hypersensitivity to lumasiran or any of the
excipients.
Severe or end-stage renal impairment
Treatment with lumasiran increases plasma glycolate levels,
which may increase the risk of metabolic acidosis or worsening of
pre-existing metabolic acidosis in patients with severe or
end‑stage renal disease. These patients should therefore be
monitored for signs and symptoms of metabolic acidosis.
Moderate or severe hepatic impairment
In patients with moderate or severe hepatic impairment there is
a potential for decreased efficacy. Therefore, efficacy should be
monitored in these patients.
Adverse Reactions
The most common adverse reaction reported was injection site
reaction (32%) and abdominal pain (21%).
About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA
interference (RNAi) into a whole new class of innovative medicines
with the potential to transform the lives of people afflicted with
rare genetic, cardio-metabolic, hepatic infectious, and central
nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning
science, RNAi therapeutics represent a powerful, clinically
validated approach for the treatment of a wide range of severe and
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust RNAi therapeutics platform. Alnylam’s commercial RNAi
therapeutic products are ONPATTRO® (patisiran), approved in the
U.S., EU, Canada, Japan, Brazil, and Switzerland, GIVLAARI®
(givosiran), approved in the U.S., EU, Brazil, and Canada, and
OXLUMO™ (lumasiran) approved in the EU. Alnylam has a deep pipeline
of investigational medicines, including six product candidates that
are in late-stage development. Alnylam is headquartered in
Cambridge, MA.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including, without limitation,
Alnylam’s views with respect to the safety and efficacy of
lumasiran as demonstrated in the ILLUMINATE-A and ILLUMINATE-B
Phase 3 studies and the potential for lumasiran to prevent or
inhibit oxalate over-production in PH1 patients, meet urgent unmet
needs of PH1 patients across all age groups, and have a favorable
impact on PH1 disease manifestations, Alnylam’s plans to progress
with discussions and negotiations with national reimbursement
bodies across Europe and intention to work with health authorities
across Europe to achieve responsible and sustainable access
arrangements for lumasiran that address the diverse patient
population affected by PH1, and to adapt to local requirements, its
goal to ensure that all patients in need have access to lumasiran
while minimizing budget uncertainty for health services, Alnylam’s
expectations with respect to the review timeline for the lumasiran
NDA by the FDA, Alnylam’s plans, assuming regulatory approvals, to
bring lumasiran to patients with PH1 around the world, and
expectations regarding the continued execution on its “Alnylam
2020” guidance for the advancement and commercialization of RNAi
therapeutics, constitute forward-looking statements for the
purposes of the safe harbor provisions under The Private Securities
Litigation Reform Act of 1995. Actual results and future plans may
differ materially from those indicated by these forward-looking
statements as a result of various important risks, uncertainties
and other factors, including, without limitation: the direct or
indirect impact of the COVID-19 global pandemic or any future
pandemic, such as the scope and duration of the outbreak,
government actions and restrictive measures implemented in
response, material delays in diagnoses of rare diseases, initiation
or continuation of treatment for diseases addressed by Alnylam
products, or in patient enrollment in clinical trials, potential
supply chain disruptions, and other potential impacts to Alnylam’s
business, the effectiveness or timeliness of steps taken by Alnylam
to mitigate the impact of the pandemic, and Alnylam’s ability to
execute business continuity plans to address disruptions caused by
the COVID-19 or any future pandemic; Alnylam's ability to discover
and develop novel drug candidates and delivery approaches and
successfully demonstrate the efficacy and safety of its product
candidates; the pre-clinical and clinical results for its product
candidates, which may not be replicated or continue to occur in
other subjects or in additional studies or otherwise support
further development of product candidates for a specified
indication or at all; actions or advice of regulatory agencies,
which may affect the design, initiation, timing, continuation
and/or progress of clinical trials or result in the need for
additional pre-clinical and/or clinical testing; delays,
interruptions or failures in the manufacture and supply of its
product candidates or its marketed products; obtaining, maintaining
and protecting intellectual property; intellectual property matters
including potential patent litigation relating to its platform,
products or product candidates; obtaining regulatory approval for
its product candidates, including lumasiran in other countries, and
maintaining regulatory approval and obtaining pricing and
reimbursement for its products, including ONPATTRO, GIVLAARI and
OXLUMO; progress in continuing to establish an ex-United States
infrastructure; successfully launching, marketing and selling its
approved products globally, including ONPATTRO, GIVLAARI and
OXLUMO, and achieving net product revenues for ONPATTRO within its
revised expected range during 2020; Alnylam’s ability to
successfully expand the indication for ONPATTRO in the future;
competition from others using technology similar to Alnylam's and
others developing products for similar uses; Alnylam's ability to
manage its growth and operating expenses within the ranges of
guidance provided by Alnylam through the implementation of further
discipline in operations to moderate spend and its ability to
achieve a self-sustainable financial profile in the future without
the need for future equity financing; Alnylam’s ability to
establish and maintain strategic business alliances and new
business initiatives; Alnylam's dependence on third parties,
including Regeneron, for development, manufacture and distribution
of certain product candidates, including eye and CNS product
candidates, and Vir for the development of ALN-COV and other
potential RNAi therapeutics targeting SARS-CoV-2 and host factors
for SARS-CoV-2; the outcome of litigation; the risk of government
investigations; and unexpected expenditures; as well as those risks
more fully discussed in the "Risk Factors" filed with Alnylam's
most recent Quarterly Report on Form 10-Q filed with the Securities
and Exchange Commission (SEC) and in other filings that Alnylam
makes with the SEC. In addition, any forward-looking statements
represent Alnylam's views only as of today and should not be relied
upon as representing its views as of any subsequent date. Alnylam
explicitly disclaims any obligation, except to the extent required
by law, to update any forward-looking statements.
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Alnylam Pharmaceuticals, Inc. Fiona McMillan (EU &
Canada Head of Communications) +44 7741655570
Christine Regan Lindenboom (Investors and Media)
+1-617-682-4340
Josh Brodsky (Investors) +1-617-551-8276
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