– First RNAi Therapeutic Approved in U.S. for
Use in Both Children and Adults, and Third RNAi Medicine to Receive
FDA Approval in Less than Three Years –
– Approval Based on Results from Both
ILLUMINATE-A and ILLUMINATE-B Phase 3 Studies, Demonstrating
Clinically Significant Reductions in Urinary Oxalate and
Encouraging Safety and Tolerability Across a Broad Spectrum of
Patient Ages –
– Alnylam to Host Conference Call Today at 8:00
a.m. ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi
therapeutics company, announced today that the U.S. Food and Drug
Administration (FDA) approved OXLUMO™ (lumasiran) injection for
subcutaneous use, the first-ever therapy available for the
treatment of primary hyperoxaluria type 1 (PH1) to lower urinary
oxalate levels in pediatric and adult patients. PH1 is an
ultra-rare genetic disease characterized by oxalate overproduction.
The excess production of 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,
nephrocalcinosis, progression to kidney failure, and systemic organ
dysfunction. In ILLUMINATE-A – the largest controlled Phase 3 study
ever conducted in PH1 – OXLUMO was shown to significantly reduce
levels of urinary oxalate relative to placebo, with the majority of
patients achieving normal1 or near-normal2 levels. OXLUMO
demonstrated an encouraging safety and tolerability profile, with
injection site reactions (ISRs) as the most common drug-related
adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, the
safety and efficacy of OXLUMO were demonstrated in patients under
the age of six, and results showed reduction of urinary oxalate and
an overall safety and tolerability profile consistent with that
demonstrated in ILLUMINATE-A.
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OXLUMO™ (lumasiran) packaging and product
vial (Photo: Business Wire)
“The approval of OXLUMO is a further testament to the impact
RNAi therapeutics can have in transforming the treatment of severe,
life-threatening diseases like PH1. Results from the ILLUMINATE-A
and ILLUMINATE-B studies demonstrate that OXLUMO addresses the
underlying pathophysiology of PH1 in adults, children and infants,
and we believe this newly approved medicine has the potential to
change the course of this progressive disease,” said Akshay
Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “OXLUMO
marks our third FDA approval in less than three years, positioning
us to meet or exceed our Alnylam 2020 strategy and goals, and
further highlighting the productivity of our RNAi platform and the
speed at which we can bring innovative medicines to patients. For
patients and families impacted by PH1, this is an historic moment,
as OXLUMO represents the first, targeted therapeutic option
available to them. We are grateful to all the investigators, staff
and patients who participated in the ILLUMINATE clinical studies,
and to their families, caregivers and patient advocates. This
moment is what we all had hoped for.”
The FDA approval of OXLUMO was primarily based on positive
results from the randomized, double-blind, placebo-controlled
ILLUMINATE-A Phase 3 study, with results presented in June 2020 at
the 57th European Renal Association – European Dialysis and
Transplant Association Virtual Congress. The FDA also took into
consideration positive interim results from the single-arm,
open-label ILLUMINATE-B Phase 3 pediatric study. Primary analysis
results from the ILLUMINATE-B study were presented in October 2020
at the virtual American Society of Nephrology Annual Congress.
In ILLUMINATE-A, the efficacy and safety of OXLUMO were
evaluated in 39 patients ages six and older with relatively
preserved renal function (estimated glomerular filtration rate
[eGFR] at or above 30 mL/min/1.73m2) and a documented diagnosis of
PH1. The study, conducted in eight countries around the world, is
the largest interventional study conducted specifically in PH1.
Patients were randomized 2:1 to receive three monthly doses of
OXLUMO or placebo at 3 mg/kg followed by a quarterly dosing
regimen. The study showed that OXLUMO met its primary endpoint,
percent change in 24-hour urinary oxalate (corrected for body
surface area and averaged from months three to six). Specifically,
treatment with OXLUMO resulted in a 65 percent mean reduction in
urinary oxalate relative to baseline versus 12 percent reduction
reported in response to placebo, resulting in a mean treatment
difference of 53 percent relative to placebo (p=1.7x10-14). In
addition, OXLUMO achieved statistically significant results for all
six tested secondary endpoints, including the proportion of
patients achieving urinary oxalate levels at or below upper limit
of normal1 (13/25 patients or 52 percent; p=0.001) and at or below
1.5x upper limit of normal2 (21/25 patients or 84 percent; p=8.3 x
10-7), compared with none (0/13) of the patients receiving placebo.
During the primary analysis period, OXLUMO demonstrated an
encouraging safety and tolerability profile, with no serious or
severe adverse events. The most common adverse reaction was ISRs
(reported in at least 20 percent of patients); ISRs occurred at
various time points during the study period and included erythema,
pain, pruritus, and swelling. These symptoms were generally mild
and resolved within one day of the injection and did not lead to
discontinuation of treatment.
In ILLUMINATE-B, a study in PH1 patients under the age of six
with relatively preserved renal function (eGFR above 45
mL/min/1.73m2), OXLUMO was evaluated in 18 patients during the
primary analysis, including infants as young as three months old.
It was administered according to a weight-based dosing regimen
across three body weight categories (less than 10 kg; 10 to less
than 20 kg, and 20 kg or higher). In the primary analysis, OXLUMO
demonstrated a 72 percent mean reduction in spot urinary
oxalate:creatinine ratio from baseline to month six (averaged from
months three to six) – the primary endpoint of the study. The
reduction of oxalate was consistent across all three body weight
categories. In addition, OXLUMO demonstrated positive results
across secondary endpoints, including additional measures of
oxalate. There were no serious or severe adverse events related to
study drug, and the overall safety and tolerability profile of
OXLUMO was consistent with that observed in the ILLUMINATE-A
pivotal study.
“PH1 patients experience progressive and often inevitable
decline in kidney function. As the disease advances, so does the
risk of end-stage kidney disease and systemic spread of oxalate
beyond the kidneys endangering other organs, including the eyes,
bones, skin and heart. This condition, systemic oxalosis, leads to
multi-organ dysfunction and death. The age of onset, rate of
disease progression, and associated clinical manifestations can
vary significantly from patient to patient, even among members of
the same family, making PH1 a particularly challenging condition to
diagnose and treat. Until today, there had been no approved
nonsurgical treatment options available that curb oxalate
overproduction in patients with PH1, with liver transplantation
being the only preemptive treatment approach to address the
underlying metabolic defect in these patients,” said Jeffrey M.
Saland, M.D., Professor and Chief, Pediatric Nephrology and
Hypertension, Jack and Lucy Clark Department of Pediatrics, Mount
Sinai Kravis Children’s Hospital, New York City and Investigator on
the ILLUMINATE-A trial. “The consistent efficacy and safety profile
of OXLUMO demonstrated in the ILLUMINATE-A and -B trials both in
adults and children from as young as a few months old, combined
with an infrequent dosing regimen that leads to rapid and sustained
reduction of oxalate production, make OXLUMO an attractive
therapeutic option to reduce the oxalate burden responsible for the
severe clinical manifestations that individuals suffer due to
PH1.”
“Many people impacted by PH1 face persistent anxiety related to
the unpredictable nature of their condition, in terms of the
uncertainty of how quickly their disease may progress, and the
prospect of needing intensive dialysis and a kidney/liver
transplant that threaten their physical, emotional and financial
health,” said Kim Hollander, Executive Director of the Oxalosis and
Hyperoxaluria Foundation. “The FDA approval of OXLUMO represents a
new path forward for many, providing an effective treatment option
and a sense of hope.”
“PH1 has had a profound impact on my son’s life from a physical,
emotional and social standpoint. As a young boy, it has been
draining for him to be constantly in pain, live through countless
kidney stones – experiencing them on a regular basis – have limited
control of his body, miss out on school and not be able to
participate in sports,” said Amy Bowders, the mother and caregiver
of a 12-year old boy diagnosed with PH1. “With the approval of
OXLUMO, we are truly hopeful and optimistic about the future for
patients affected by PH1.”
OXLUMO is expected to be available for shipment to healthcare
providers in the U.S. by year-end. HCPs can initiate the process
now by visiting www.AlnylamAssist.com and completing and submitting
a Start Form.
OXLUMO was reviewed by the FDA under Priority Review and had
previously been granted Breakthrough Therapy, Orphan Drug, and Rare
Pediatric Disease Designations. With the approval of OXLUMO, the
FDA has granted Alnylam a pediatric rare disease priority review
voucher that entitles the Company to designate a single new drug
application to qualify for a priority review in the future. On
November 19, the European Commission granted marketing
authorization for OXLUMO for the treatment of PH1 in all age
groups, following a positive opinion from the Committee for
Medicinal Products for Human Use (CHMP). Lumasiran was previously
granted Priority Medicines (PRIME) Designation by the European
Medicines Agency (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.
The safety and efficacy of OXLUMO are also being evaluated in
the ongoing ILLUMINATE-C Phase 3 clinical trial in patients of all
ages with advanced PH1, including patients on dialysis. Together,
the ILLUMINATE studies comprise a comprehensive clinical
development program intended to demonstrate the safety and efficacy
of OXLUMO across the full spectrum of patients diagnosed with
PH1.
Visit OXLUMO.com for more information, including full
Prescribing Information.
Conference Call Information:
Alnylam management will discuss the FDA approval via conference
call today, November 24, 2020 at 8:00 a.m. ET. A webcast
presentation will also be available on the Investors page of the
Company’s website, www.alnylam.com. To access the call, please dial
800-239-9838 (domestic) or +1-323-794-2551 (international) five
minutes prior to the start time and refer to conference ID 6976021.
A replay of the call will be available beginning at 11:00 a.m. ET
on the day of the call. To access the replay, please dial
888-203-1112 (domestic) or +1-719-457-0820 (international) and
refer to conference ID 6976021.
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)
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 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), and
OXLUMO™ (lumasiran). 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. For
more information about our people, science and pipeline, please
visit www.alnylam.com and engage with us on Twitter at @Alnylam or
on LinkedIn.
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 and the potential for
OXLUMO to address the underlying pathophysiology of PH1 in adults,
children and, infants and change the course of this progressive
disease, the potential for OXLUMO to be an attractive therapeutic
option that can reduce the oxalate burden responsible for the
severe clinical manifestations associated with PH1, Alnylam’s
expectation regarding the timing for commercial availability of
OXLUMO in the U.S. and Alnylam’s plans, assuming additional
regulatory approvals, to bring lumasiran to patients with PH1
around the world, and expectations regarding the potential for
Alnylam to meet or exceed 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 other marketed products, including
OXLUMO; 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, 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 products, including eye and CNS
products, 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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version on businesswire.com: https://www.businesswire.com/news/home/20201124005407/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media) +1-617-682-4340
Josh Brodsky (Investors) +1-617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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