– Lumasiran Demonstrated a 72 Percent Mean
Reduction in Urinary Oxalate and Improvements in Nephrocalcinosis
in ILLUMINATE-B Phase 3 Study in Children Under the Age of Six and
as Young as Three Months –
– Alnylam Also Presents New Results from the
12-Month Extension Period of the ILLUMINATE-A Pivotal Study,
Showing Sustained Reduction in Urinary Oxalate Levels and Evidence
for a Decrease in the Rate of Renal Stone Events in Patients
Treated with Lumasiran –
– Long-Term Results from the Ongoing Phase 2
Open-Label Extension Study Provide Additional Evidence for
Sustained Reduction in Urinary Oxalate Levels and Acceptable Safety
Profile –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today positive results from the
6-month primary analysis of the ILLUMINATE-B Phase 3 pediatric
study of lumasiran, an investigational, subcutaneously administered
RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) – the gene
encoding glycolate oxidase (GO) – in development for the treatment
of adults and children with primary hyperoxaluria type 1 (PH1).
Results were presented from ILLUMINATE-B, as well as new 12-month
results from the ILLUMINATE-A pivotal Phase 3 study and the ongoing
Phase 2 open-label extension (OLE) study, at the American Society
of Nephrology (ASN) Kidney Week 2020 held as a virtual event on
October 22-25.
Lumasiran is under review by the Food and Drug Administration
(FDA) and received a Positive Opinion from the Committee for
Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMA) on October 16, 2020. If approved, lumasiran will be
marketed as OXLUMOTM.
“We are delighted to present these positive data from
ILLUMINATE-B that reinforce previously reported clinical study
findings for lumasiran and underscore its potential to be an
important treatment option for patients of all ages with PH1, a
devastating and potentially fatal disease with no approved
pharmaceutical treatment options,” said Pritesh J. Gandhi, PharmD.,
Vice President and General Manager, Lumasiran Program at Alnylam.
“Based on longer term follow-up from the ILLUMINATE-A and Phase 2
open-label extension studies, investigators presented data showing
enduring reductions of urinary oxalate – the disease-causing
metabolite in PH1. Moreover, we believe that newly presented
results of exploratory endpoints provide preliminary evidence that
reductions in urinary oxalate may lead to reduced rates of renal
stone events and improve nephrocalcinosis in some patients.”
“Pathologic overproduction of oxalate by the liver is the root
cause of morbidity and mortality associated with PH1. There is
strong evidence in the literature to suggest that levels of urinary
oxalate correlate with clinical outcomes in patients with this
ultra-rare disease. With that in mind, I am pleased to see the
reduction in urinary oxalate levels in response to lumasiran in all
three studies presented at this year’s meeting. More broadly, I am
encouraged by the promise that these findings hold for my patients
living with this condition,” 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. “With the sustained reductions in urinary
oxalate during long-term treatment and the exploratory renal stone
and nephrocalcinosis data presented, I am hopeful about the
potential of lumasiran to have a positive impact on the severe
clinical manifestations that individuals with PH1 suffer.”
ILLUMINATE-B 6-Month Results
Alnylam presented positive efficacy and safety results from the
6-month primary analysis (N=18) of the ILLUMINATE-B Phase 3 study
of lumasiran in infants and children under the age of 6, with the
youngest patient enrolled at 3 months of age. The efficacy results
and safety profile of lumasiran were found to be similar to those
observed in adults and children 6 years or older in the
ILLUMINATE-A study. Treatment with lumasiran in ILLUMINATE-B led to
a 72 percent mean reduction in spot urinary oxalate:creatinine
ratio from baseline to Month 6, averaged across months 3 to 6 – the
primary endpoint of the study. Lumasiran also demonstrated positive
results across secondary endpoints, including proportion of
patients (9/18 or 50 percent) achieving urinary oxalate levels at
or below 1.5 times ULNa.
Preliminary analysis of exploratory endpoints indicated
improvements in nephrocalcinosis in 8 out of 18 patients (44
percent), while estimated glomerular filtration rates (eGFR)
remained stable. At baseline, 14 of 18 patients had
nephrocalcinosis. After 6 months of lumasiran treatment, no
patients worsened, 10 remained stable, and eight showed bilateral
(3 out of 8) or unilateral (5 out of 8) improvements in
nephrocalcinosis. As expected, given the 6-month duration of the
study, there was no change in the rate of renal stone events
(RSEs)b .
Lumasiran had an acceptable safety profile in infants and young
children under the age of six. There were no deaths, severe adverse
events, discontinuations of treatment or withdrawals from the
study. One patient had a serious adverse event (SAE) of viral
infection that was considered not related to lumasiran by the study
investigator. The most common drug-related adverse events (AEs)
were mild and transient injection site reactions (ISRs) reported in
3 of 18 (17 percent) patients. No clinically relevant changes in
laboratory measures (including liver function tests), vital signs,
or electrocardiograms related to lumasiran were observed.
ILLUMINATE-A 12-Month Results
As of the data cut-off date of May 1, 2020, results from the
extension period of the ILLUMINATE-A Phase 3 study showed that
patients initially randomized to lumasiran in the 6-month
double-blind (DB) period who continued treatment with lumasiran
through Month 12 (“lumasiran/lumasiran”; N=24) maintained their
reduction in 24-hour urinary oxalate excretion, with a 64 percent
mean reduction relative to baseline. The majority (88 percent) of
patients in this group reached normal or near-normal levels (at or
below 1.5x ULN)a of urinary oxalate. In patients who were
originally randomized to placebo in the DB period but crossed over
to lumasiran (“placebo/lumasiran”; N=13), treatment with lumasiran
led to a 57 percent mean reduction in 24-hour urinary oxalate
excretion after six months of treatment; 77 percent of these
patients reached urinary oxalate levels at or below 1.5 x ULN.
In an exploratory analysis, reductions in oxalate levels were
associated with lower rates of RSEb in lumasiran treated patients
in both lumasiran/lumasiran and placebo/lumasiran groups.
The safety profile of lumasiran remained consistent with ongoing
dosing (233 doses) and 9.9 months of mean exposure (range 2.8-15.1
months). There were no deaths, SAEs, treatment interruptions or
discontinuations related to lumasiran. One patient had an SAE of
urosepsis that was not related to study drug. Mild ISRs were the
most common drug-related AE reported in at least 10 percent of
patients. Most common ISR symptoms included erythema, pain,
pruritus, or swelling at the injection site. No clinically relevant
changes in laboratory measures (including liver function tests),
vital signs, and electrocardiograms related to lumasiran were
observed.
Phase 2 OLE Results
Additional positive data were also presented from the ongoing
Phase 2 OLE study of lumasiran demonstrating the long-term efficacy
and safety of lumasiran with up to 22 months of exposure (range:
11-22 months; median: 15 months). As of January 30, 2020, data
cut-off date, patients continued to experience sustained reductions
in urinary oxalate excretion, with similar responses across dosage
regimens. Specifically, ongoing treatment with lumasiran resulted
in 74 percent (range: 35.7–88.3 percent) mean maximal reduction in
urinary oxalate relative to Phase 1/2 baseline (N=17), and 17/18
(94 percent) of patients achieved normal or near-normal levels of
urinary oxalate. Mean eGFR levels remained stable over time.
Lumasiran had an acceptable safety profile. There were no
deaths, severe AEs, or AEs leading to discontinuation of treatment.
There were no drug-related SAEs. The most common drug-related AEs
were mild ISRs. No clinically significant laboratory changes
related to lumasiran were reported.
Post-hoc analysis of renal stones showed that long-term
treatment with lumasiran resulted in a decline in the number of
patients experiencing renal stones. In the 12 months prior to study
entry, 6/20 patients (30 percent) reported renal stones. In the
Phase 1/2 Part B study where renal stones were captured as AEs,
4/20 patients (20 percent) reported AEs of renal stones during the
initial 5-month period, and no patients (0/20) reported AEs of
renal stones during the Phase 2 OLE with up to 22 months of
treatment.
Additional findings on real-world disease manifestations and
healthcare resource use among patients with PH1 were also presented
based on a retrospective multinational study of physician chart
reviews.
To view all data presented by Alnylam at ASN Kidney Week, please
visit www.alnylam.com/capella.
Lumasiran has received U.S. and EU Orphan Drug Designations,
Breakthrough Therapy and Rare Pediatric Disease Designations from
the FDA, and a Priority Medicines (PRIME) designation from the EMA.
Alnylam has filed a New Drug Application (NDA) for lumasiran with
the FDA, which 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). Following the recent Positive Opinion from
the CHMP, the Company plans to initiate commercialization of
lumasiran in the EU under the tradename OXLUMO, upon marketing
authorization from the European Commission.
The Company is also conducting ILLUMINATE-C – a global
open-label Phase 3 study of lumasiran in PH1 patients of all ages
with advanced renal disease, including patients on dialysis, with
topline results expected in 2021.
a Upper limit of normal or ULN = 0.514 mmol/24 hr/1.73m2; 1.5 x
ULN = 0.771 mmol/24 hr/1.73 m2 b A renal stone event (RSE) is
defined as an event that includes at least one of the following:
visit to healthcare provider because of a renal stone, medication
for renal colic, stone passage, or macroscopic hematuria due to a
renal stone
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 ILLUMINATE-B Phase 3 Study
ILLUMINATE-B (NCT03905694) is a single arm, open-label,
multicenter Phase 3 trial to evaluate the efficacy and safety of
lumasiran in 18 patients with PH1 under the age of six (range: 3-72
months), with an estimated glomerular filtration rate (eGFR) of
greater than 45 mL/min/1.73 m2 or normal serum creatinine if less
than 12 months old, at nine study sites, in five countries around
the world. Lumasiran was administered according to a weight-based
dosing regimen. 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. At six
months, relative to baseline, lumasiran demonstrated a clinically
meaningful reduction in spot urinary oxalate:creatinine ratio.
Reduction of urinary oxalate relative to baseline was consistent
across all three body weight categories (less than 10 kg; 10 kg to
less than 20 kg, and 20 kg or higher).
About Lumasiran
Lumasiran is an investigational, subcutaneously administered
RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in
development for the treatment of primary hyperoxaluria type 1
(PH1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1
and depleting the GO enzyme, lumasiran inhibits production of
oxalate – the metabolite that directly contributes to the
pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced
Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which
enables subcutaneous dosing with increased potency and durability
and a wide therapeutic index. Lumasiran has received both U.S. and
EU Orphan Drug Designations, Breakthrough Therapy Designation from
the U.S. Food and Drug Administration (FDA), and Priority Medicines
(PRIME) designation from the European Medicines Agency (EMA).
Lumasiran is under review by the U.S. FDA and received a Positive
Opinion from the Committee for Medicinal Products for Human Use
(CHMP) of the EMA.
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
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, EU, and Brazil. 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
lumasiran as demonstrated in the ILLUMINATE-B Phase 3 study in
children under the age of six, including infants, as well as in the
12-Month extension period of the ILLUMINATE-A pivotal study and in
results from the ongoing Phase 2 OLE study, the potential for
lumasiran to have a favorable impact on PH1 disease manifestations
and overall disease progression and management across all ages,
Alnylam's expectations with respect to the review timelines for the
lumasiran NDA by the FDA and expectations regarding EMA approval
following the Positive Opinion from the CHMP, Alnylam’s plans,
assuming favorable regulatory reviews, to bring lumasiran to
patients with PH1 around the world under the tradename OXLUMO,
expectations regarding the timing of topline results from
ILLUMINATE-C, 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, including lumasiran, 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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version on businesswire.com: https://www.businesswire.com/news/home/20201022005596/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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