– Positive Opinion is Based on Results from
ILLUMINATE-A and ILLUMINATE-B Phase 3 Studies –
– European Commission Decision on Approval
Expected in Q4 2020 –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced that the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMA) has adopted a positive opinion recommending approval
of lumasiran, an investigational RNAi therapeutic targeting the
hydroxyacid oxidase 1 (HAO1) mRNA – encoding glycolate oxidase (GO)
– in development for the treatment of primary hyperoxaluria type 1
(PH1). If approved by the European Commission (EC), lumasiran will
be marketed in Europe under the brand name OXLUMO™.
PH1 is an ultra-rare orphan disease characterized by excessive
oxalate production, which can lead to end-stage renal disease
(ESRD) and other systemic complications. PH1 affects approximately
3.5 to 4 individuals per million in Europe and the United States.
Heterogeneity in disease manifestation often contributes to delays
in diagnosis, with a median time to diagnosis of approximately six
years. PH1 leads to progressive kidney damage, and patients with
advanced kidney disease require intensive dialysis to help filter
waste products 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.
“This positive CHMP opinion recognizes the potential of OXLUMO
to address the urgent unmet need that exists for patients of all
ages impacted by primary hyperoxaluria type 1. Since there are no
approved pharmacologic treatment options for PH1, we believe this
is very encouraging news for those living with this ultra-rare,
potentially life-threatening disease and for their families,” said
Brendan Martin, Acting Head of Europe, Canada, Middle East and
Africa (CEMEA), Alnylam Pharmaceuticals.
“People living with PH1 experience a progressive decline in
kidney function due to the overproduction of oxalate, which can
lead to end-stage renal disease. Current treatment approaches aim
to delay progression to renal failure but do not prevent oxalate
overproduction,” said Pushkal Garg, M.D., Chief Medical Officer,
Alnylam Pharmaceuticals. “In clinical trials, OXLUMO has
demonstrated clinically meaningful and sustained reductions in
urinary and plasma oxalate, and an encouraging safety and
tolerability profile. We’re pleased that the CHMP has recognized
the urgent need for new treatments across all age groups with
inclusion of the ILLUMINATE-B results for the initial approval
recommendation.”
The positive opinion is based on efficacy and safety findings of
OXLUMO in PH1 patients, including data from both the ILLUMINATE-A
and ILLUMINATE-B Phase 3 studies. Key primary and secondary
endpoints included the reduction of urinary and plasma oxalate, and
the proportion of patients achieving normalization or
near-normalization of urinary oxalate in response to OXLUMO
relative to placebo. 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. Topline results from the ILLUMINATE-B
pediatric study were reported in September; results from the
primary analysis will be presented at the upcoming virtual American
Society of Nephrology (ASN) Annual Congress on October 22.
OXLUMO was granted Priority Medicines (PRIME) designation by the
EMA as well as Orphan Designation in the European Union. OXLUMO 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. Alnylam 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).
About OXLUMO™ (lumasiran)
OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1
(HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) in
all age groups. HAO1 encodes glycolate oxidase (GO), an enzyme
upstream of the disease-causing defect in PH1. OXLUMO 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. In the pivotal
ILLUMINATE-A study, OXLUMO 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, OXLUMO
demonstrated an efficacy and safety profile consistent to that
observed in ILLUMINATE-A. OXLUMO utilizes Alnylam’s Enhanced
Stabilization Chemistry (ESC)-GalNAc conjugate technology designed
to increase potency and durability. OXLUMO is administered via
subcutaneous injection once monthly for three months, then once
quarterly at a dose based on actual body weight. For patients who
weigh less than 10 kg, maintenance dosing remains monthly. OXLUMO
should be administered by a healthcare professional. The safety and
efficacy of OXLUMO are under evaluation by the FDA.
About ILLUMINATE-A Phase 3 Study
ILLUMINATE-A (NCT03681184) is a six-month randomized,
double-blind, placebo-controlled, global, multicenter Phase 3 study
(with a 54-month extension period) to evaluate the efficacy and
safety of lumasiran in 39 patients, age six and older, with a
documented diagnosis of PH1. Patients were randomized 2:1 to
receive three monthly doses of lumasiran or placebo followed by
quarterly maintenance doses at 3 mg/kg. The primary endpoint was
the percent change in 24-hour urinary oxalate excretion from
baseline to the average of months 3 to 6 in the patients treated
with lumasiran as compared to placebo. Treatment arms were
stratified at randomization based upon mean 24-hour urinary oxalate
during screening (≤ 1.7 or > 1.7 mmol/24hr/1.73m2). Key
secondary and exploratory endpoints were designed to evaluate
additional measures of urinary oxalate, plasma oxalate, estimated
glomerular filtration rate (eGFR), nephrocalcinosis, renal stone
events, safety and tolerability.
About ILLUMINATE-B Phase 3 Study
ILLUMINATE-B (NCT03905694) is a six-month, single arm,
open-label, multicenter Phase 3 trial (with a 54-month extension
period) that enrolled 18 patients with PH1 under the age of six.
Lumasiran was administered according to a weight-based dosing
regimen. Patients below 10 kg of body weight received three monthly
loading doses of lumasiran at 6 mg/kg followed by monthly
maintenance doses at 3 mg/kg; patients at or above 10 kg but lower
than 20 kg of body weight received three monthly loading doses at 6
mg/kg followed by quarterly maintenance doses; patients above the
20 kg body weight received three monthly loading doses at 3 mg/kg
followed by quarterly maintenance doses. The primary efficacy
endpoint of the study was the percent change from baseline to Month
6 in spot urinary oxalate:creatinine ratio averaged across Months 3
to 6. Key secondary and exploratory endpoints were designed to
evaluate additional measures of urinary oxalate, plasma oxalate,
estimated glomerular filtration rate (eGFR), nephrocalcinosis,
renal stone events, safety, and tolerability.
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.
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, and GIVLAARI®
(givosiran), approved in the U.S., Brazil and the EU. Alnylam has a
deep pipeline of investigational medicines, including six product
candidates that are in late-stage development. Alnylam is executing
on its "Alnylam 2020" strategy of building a multi-product,
commercial-stage biopharmaceutical company with a sustainable
pipeline of RNAi-based medicines to address the needs of patients
who have limited or inadequate treatment options. 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 meet urgent
unmet needs of PH1 patients across all age groups and have a
favorable impact on PH1 disease manifestations, Alnylam’s
expectations regarding the implications of the positive opinion
recommending approval of lumasiran by the CHMP and the timeline for
the potential approval of lumasiran by the EC following the
positive CHMP opinion, [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, including lumasiran, 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, and maintaining regulatory approval and obtaining
pricing and reimbursement for its products, including ONPATTRO and
GIVLAARI; progress in continuing to establish a commercial and
ex-United States infrastructure; successfully launching, marketing
and selling its approved products globally, including ONPATTRO and
GIVLAARI, 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 products, including eye and CNS products, Ironwood, for
assistance with the education about and promotion of GIVLAARI, 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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