- ILLUMINATE-A Phase 3 Study Evaluated the
Efficacy and Safety of Lumasiran in Adult and Pediatric Patients
with Primary Hyperoxaluria Type 1 (PH1) -
- Lumasiran Demonstrated a Clinically
Significant Reduction in Urinary Oxalate, a Primary Determinant of
Progression to Renal Failure in PH1, Compared to Placebo -
- Manuscript Marks the Tenth Publication of
Clinical Trial Results for Alnylam Programs in The New England
Journal of Medicine, Highlighting the Impact of RNAi Therapeutics
as a New Class of Medicines -
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today that pivotal trial results
from the ILLUMINATE-A Phase 3 study of lumasiran, an RNAi
therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene
encoding glycolate oxidase (GO) – for the treatment of primary
hyperoxaluria type 1 (PH1), were published online in The New
England Journal of Medicine (NEJM). In November 2020, OXLUMO™
(lumasiran) was approved by the U.S. Food and Drug Administration
for the treatment of PH1 to lower urinary oxalate levels in
pediatric and adult patients, and received marketing authorization
from the European Commission for the treatment of PH1 in all age
groups. OXLUMO is the first-ever treatment approved for PH1 and the
first RNAi therapeutic evaluated in both children and adults. The
full manuscript titled “Phase 3 Trial of Lumasiran, an RNAi
Therapeutic for Primary Hyperoxaluria Type 1,” will appear in the
April 1, 2021 issue of NEJM.
The data reported in the ILLUMINATE-A Phase 3 study publication
demonstrated that RNAi-mediated targeting of liver GO by lumasiran
led to substantial and sustained reductions in urinary oxalate—the
toxic metabolite responsible for the debilitating and
life-threatening clinical manifestations of PH1. Relative to
placebo, treatment with lumasiran resulted in a clinically
significant (53.5 percent) reduction in 24-hour urinary oxalate
excretion from baseline to month 6 – the primary endpoint of the
study.
Improvements were also observed in a number of secondary
endpoints, including the proportion of patients achieving normala
or near-normalb levels of urinary oxalate, with 84 percent of
lumasiran-treated patients meeting this endpoint compared with no
patients (0 percent) on placebo. Patients treated with lumasiran
also experienced favorable effects on exploratory endpoints related
to nephrocalcinosis and the rate of renal stone eventsc compared
with placebo.
Lumasiran administration was associated with an encouraging
safety and tolerability profile, with no serious or severe adverse
events (AEs). The most common AEs that occurred more frequently
with lumasiran than placebo were injection site reactions (38
versus 0 percent). All injection site reactions were mild and
transient and did not result in discontinuation of treatment.
“PH1 often presents in early life, with kidney stones,
nephrocalcinosis, renal failure and, in advanced stages, systemic
spread of oxalate throughout the body with life-threatening
consequences. Oxalate drives disease manifestations and
progression, and is the toxic mediator of end-organ damage in PH1,”
said Prof. Yaacov Frishberg, M.D., Head of Division of Pediatric
Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel, and
lead co-author on the manuscript. “We believe the publication of
the ILLUMINATE-A Phase 3 study results in the NEJM is a testament
to lumasiran as an oxalate-lowering therapy which is expected to
confer significant clinical benefit to children and adults living
with this disease.”
“Publication of the ILLUMINATE-A results in NEJM is an exciting
achievement, highlighting the tremendous unmet need for novel
therapies for this devastating disease and the role lumasiran is
playing to fill this need. We are thrilled by the fact that this is
now the tenth publication in NEJM on results from clinical studies
of Alnylam’s RNAi therapeutics, a noteworthy milestone underscoring
the impact of RNAi on clinical research and the practice of
medicine,” said Pritesh J. Gandhi, PharmD., Vice President and
General Manager, Lumasiran Program at Alnylam. “We look forward to
reporting and publishing additional data from the ILLUMINATE
program including in patients under the age of six and those with
impaired kidney function later this year.”
A total of 38d of 39 patients completed the ILLUMINATE-A 6-month
primary analysis period and all eligible patients transitioned to
the study extension period. Results from the 12-Month extension
period were presented at the American Society of Nephrology (ASN)
virtual congress in October 2020 and demonstrated sustained
efficacy with no safety findings leading to discontinuation in the
study.
IMPORTANT SAFETY INFORMATION
Adverse Reactions
The most common adverse reaction that occurred in patients
treated with OXLUMO was injection site reaction (38%). Symptoms
included erythema, pain, pruritus, and swelling.
Pregnancy and Lactation
No data are available on the use of OXLUMO in pregnant women. No
data are available on the presence of OXLUMO in human milk or its
effects on breastfed infants or milk production. Consider the
developmental and health benefits of breastfeeding along with the
mother’s clinical need for OXLUMO and any potential adverse effects
on the breastfed child from OXLUMO or the underlying maternal
condition.
For additional information about OXLUMO, please see the full
Prescribing Information.
About OXLUMO™ (lumasiran)
OXLUMO 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. 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 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. For more information about OXLUMO, visit
OXLUMO.com.
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 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 Primary Hyperoxaluria Type 1 (PH1)
PH1 is an ultra-rare genetic disease that affects an estimated
one to three individuals per million in the United States and
Europe. PH1 is characterized by oxalate overproduction in the
liver. The excess oxalate 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. PH1 is
associated with a progressive decline in kidney function, which
exacerbates the disease as the excess oxalate can no longer be
effectively excreted, resulting in subsequent accumulation and
deposition of oxalate in bones, eyes, skin, and heart, leading to
severe illness and death. Management options to date were limited
to hyperhydration, crystallization inhibitors and, in a minority of
patients with a specific genotype, pyridoxine (vitamin B6). These
measures do not adequately address oxalate overproduction but
instead help to delay inevitable progression to kidney failure and
the need for intensive dialysis as a bridge to a dual or sequential
liver/kidney transplant. Liver transplantation is the only
intervention that addresses the underlying metabolic defect, but is
associated with high morbidity and mortality, and life-long
immunosuppression. Until today, there were 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), GIVLAARI®
(givosiran), OXLUMO™ (lumasiran), and Leqvio® (inclisiran) being
developed and commercialized by Alnylam’s partner Novartis. Alnylam
has a deep pipeline of investigational medicines, including six
product candidates that are in late-stage development. Alnylam is
executing on its “Alnylam P5x25” strategy to deliver transformative
medicines in both rare and common diseases benefiting patients
around the world through sustainable innovation and exceptional
financial performance, resulting in a leading biotech profile.
Alnylam is headquartered in Cambridge, MA. For more information
about our people, science and pipeline, please visit
www.alnylam.com and engage with us on Twitter at @Alnylam, on
LinkedIn, or on Instagram.
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 OXLUMO
as demonstrated in the ILLUMINATE-A and ILLUMINATE-B Phase 3
studies, the role of OXLUMO as an oxalate-lowering therapy which is
expected to confer significant clinical benefit to children and
adults living with PH1 and its ability to meet an unmet need for
novel therapies for the treatment of PH1, and Alnylam’s ability to
achieve its “Alnylam P5x25” strategy, 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 on Alnylam’s business, results of
operations and financial condition and the effectiveness or
timeliness of Alnylam’s efforts to mitigate the impact of the
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; actions or advice of
regulatory agencies and Alnylam’s ability to obtain and maintain
regulatory approval for its product candidates, as well as
favorable pricing and reimbursement; successfully launching,
marketing and selling its approved products globally;; delays,
interruptions or failures in the manufacture and supply of its
product candidates or its marketed products; obtaining, maintaining
and protecting intellectual property; Alnylam’s ability to
successfully expand the indication for ONPATTRO in the future;
Alnylam's ability to manage its growth and operating expenses
through disciplined investment in operations and its ability to
achieve a self-sustainable financial profile in the future without
the need for future equity financing; Alnylam’s ability to maintain
strategic business collaborations; Alnylam's dependence on third
parties for the development and commercialization of certain
products, including Novartis, Regeneron and Vir; 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 Annual Report on
Form 10-K filed with the Securities and Exchange Commission (SEC)
and in its other SEC filings. 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.
Footnotes:
a Normal is defined as urinary oxalate levels at or below the
upper limit of normal (ULN; ≤ 0.514 mmol/24 hr/1.73 m2); b
near-normal is defined as urinary oxalate levels at or below 1.5 x
ULN (≤ 0.771 mmol/24 hr/1.73 m2); ca renal stone event was defined
as an event which includes at least one of the following: visit to
healthcare provider because of a renal stone, medication for renal
colic, stone passage, macroscopic hematuria due to a renal stone;
done patient discontinued study drug after receiving a single dose
and withdrew from the study after Month 3. Parent/guardian stopped
participation due to patient's inability to comply with
protocol-specific testing.
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version on businesswire.com: https://www.businesswire.com/news/home/20210331005770/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media) +1-617-682-4340 Josh Brodsky (Investors)
+1-617-551-8276
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