− Neurofilament Light Chain (NfL) Identified as
a Potential Biomarker of Nerve Damage and Polyneuropathy due to
hATTR Amyloidosis; ONPATTRO® (patisiran) Treatment Found to Reduce
NfL Levels Relative to Placebo in APOLLO Phase 3 Study –
− In Analysis of UK Biobank, Carriers of
Transthyretin (TTR) “Stabilizing” T119M Variant in a General
Population Setting Show No Evidence for Extended Lifespan or
Protection Against Vascular Disease –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today shared new findings at the Second
European Meeting of ATTR Amyloidosis (EU-ATTR) for Doctors and
Patients, being held September 2-3, in Berlin, Germany. The Company
and collaborators presented results from a proteome-wide biomarker
analysis of samples from the APOLLO Phase 3 study of
ONPATTRO® (patisiran), an RNAi therapeutic for the
treatment of the polyneuropathy of hereditary ATTR (hATTR)
amyloidosis in adults. In addition, results were presented from an
analysis of the UK Biobank – a prospective cohort study with
genetic, physical, and health data on approximately 500,000
individuals across the United Kingdom – on clinical outcomes and
medical history of individuals with the non-pathogenic
transthyretin (TTR) “stabilizing” T119M variant.
“These new clinical research findings provide important insights
on a potential biomarker for monitoring polyneuropathy and response
to treatment, and highlight human genetic data showing no evidence
for protection against vascular disease or life-extending
advantages of a ‘stabilizing’ T119M gene variant associated with
elevated TTR plasma levels,” said Eric Green, Senior Vice President
and General Manager, TTR Program at Alnylam. “Notably, our
biomarker study represents the most comprehensive plasma proteomics
analysis in patients with hATTR amyloidosis performed to date and
the first system-wide proteomics interrogation of response to an
RNAi therapeutic in humans. We believe a biomarker such as NfL
could have the potential to allow for an earlier diagnosis of
polyneuropathy in patients with hATTR amyloidosis.”
Biomarker Analysis of APOLLO Patient Samples
A comprehensive proteomics analysis on plasma samples from
patients in the APOLLO Phase 3 study was conducted to interrogate
system-wide changes in the proteome in response to treatment and to
identify potential biomarkers for early detection of disease.
Across greater than 1000 proteins screened, a significant change
was observed in the levels of 66 proteins following patisiran
treatment (p less than 4.18×10–5). Neurofilament light chain (NfL)
– a well-described biomarker of neuroaxonal damage – was identified
as having the greatest statistical significance (p equals
3.95×10–21) for change relative to placebo over the 18-month study
period. A correlation between changes in NfL levels and
polyneuropathy, as determined by the mNIS+7 score, indicated that
decreasing levels of NfL are associated with improvements in
measures of polyneuropathy. Thus, these data support further
evaluation of NfL as a potential biomarker for hATTR amyloidosis
that may facilitate earlier diagnosis of polyneuropathy and enable
monitoring of disease progression and/or regression over time, with
or without treatment. Moreover, upon further evaluation, NfL may
also offer an easy and convenient blood test to detect
polyneuropathy in patients with mutations that predominantly cause
cardiomyopathy, e.g., V122I, but where underlying nerve damage
often occurs and can be overlooked.
UK Biobank Analysis of Transthyretin “Stabilizing” Variant
(T119M)
Results were also presented of an analysis from the UK Biobank
characterizing the association of the T119M genotype with mortality
and vascular disease. The T119M variant encodes a thermodynamically
and kinetically stabilized TTR protein that increases the stability
of wild type and mutant TTR tetramers by slowing tetramer
dissociation – a mechanism that established the therapeutic
rationale for small-molecule TTR tetramer stabilizers. People with
the T119M variant have higher plasma levels of TTR.
A previous Scandinavian study of 68,602 subjects and 321
carriers found an association of the T119M variant with extended
lifespan and reduced vascular disease1. Accordingly, the potential
effect of the TTR T119M variant on vascular disease and mortality
was investigated in the UK Biobank cohort, representing 337,148
subjects and 2,502 carriers of the variant. The analysis showed
that carriers of the TTR T119M variant were not protected against
vascular, cardiovascular, or cerebrovascular disease, or death.
Furthermore, no difference was seen between T119M carriers and
non-carriers in their time to death following a diagnosis of
vascular disease. These findings suggest that stabilization of the
TTR tetramer and/or higher plasma levels of TTR do not confer
protection against vascular disease or death in a general
population setting.
To view the results presented at EU-ATTR please visit
www.alnylam.com/capella.
1. Hornstrup et al. Arteriscler Thromb Vasc Biol
2013;33:1441–7.
Important Safety Information
ONPATTRO is a medicine that treats the polyneuropathy caused by
an illness called hereditary transthyretin-mediated amyloidosis
(hATTR amyloidosis). ONPATTRO is used in adults only.
Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients
treated with ONPATTRO. In a controlled clinical study, 19 percent
of ONPATTRO-treated patients experienced IRRs, compared to 9
percent of placebo-treated patients. The most common symptoms of
IRRs with ONPATTRO were flushing, back pain, nausea, abdominal
pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive
premedication with a corticosteroid, paracetamol, and
antihistamines (H1 and H2 blockers) at least 60 minutes prior to
ONPATTRO infusion. Monitor patients during the infusion for signs
and symptoms of IRRs. If an IRR occurs, consider slowing or
interrupting the infusion and instituting medical management as
clinically indicated. If the infusion is interrupted, consider
resuming at a slower infusion rate only if symptoms have resolved.
In the case of a serious or life-threatening IRR, the infusion
should be discontinued and not resumed.
Reduced Serum Vitamin A Levels and Recommended
Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A
levels. Supplementation at the recommended daily allowance (RDA) of
vitamin A is advised for patients taking ONPATTRO. Higher doses
than the RDA should not be given to try to achieve normal serum
vitamin A levels during treatment with ONPATTRO, as serum levels do
not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they
develop ocular symptoms suggestive of vitamin A deficiency (e.g.
night blindness).
Adverse Reactions
The most common adverse reactions that occurred in patients
treated with ONPATTRO were respiratory-tract infection (29 percent)
and infusion related reactions (19 percent).
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial was a randomized, double-blind,
placebo-controlled, global study designed to evaluate the efficacy
and safety of patisiran in hATTR amyloidosis patients with
polyneuropathy. The primary endpoint of the study was the change
from baseline in modified Neuropathy Impairment Score +7 (mNIS+7)
relative to placebo at 18 months. Secondary endpoints included: the
Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score;
NIS-weakness (NIS-W); Rasch-built Overall Disability Scale (R-ODS);
timed 10-meter walk (10-MWT); modified BMI (mBMI); and the
composite autonomic symptom score-31 (COMPASS-31). In addition,
exploratory cardiac assessments included measurement of N-terminal
pro-brain natriuretic peptide (NT-ProBNP) levels and
echocardiography. The trial enrolled 225 hATTR amyloidosis patients
from 19 countries with 39 genotypes who were randomized 2:1,
patisiran:placebo, with patisiran administered at 0.3 mg/kg once
every three weeks for 18 months. All patients who completed the
APOLLO Phase 3 study were eligible to screen for the Global OLE
study, in which they have the opportunity to receive patisiran on
an ongoing basis.
About ONPATTRO® (Patisiran)
ONPATTRO is an RNAi therapeutic that is approved by the U.S.
Food and Drug Administration (FDA) for the treatment of the
polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also
approved in the European Union for the treatment of hATTR
amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, in
Canada for the treatment of hATTR amyloidosis with polyneuropathy
by Health Canada, and in Japan for the treatment of hATTR
amyloidosis with polyneuropathy by the Japanese Ministry of Health,
Labour and Welfare (MHLW). Based on Nobel Prize-winning science,
ONPATTRO is an intravenously administered RNAi therapeutic
targeting transthyretin (TTR) for the treatment of hereditary ATTR
amyloidosis. It is designed to target and silence TTR messenger
RNA, thereby blocking the production of TTR protein before it is
made. ONPATTRO blocks the production of TTR in the liver, reducing
its accumulation in the body’s tissues in order to halt or slow
down the progression of the disease.
About Transthyretin (ATTR) Amyloidosis
Transthyretin amyloidosis (ATTR) amyloidosis is a rare, serious,
life-threatening, multisystemic disease encompassing hereditary
ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis,
which result from either hereditary (genetic mutation) or
nonhereditary (ageing) causes, respectively. In ATTR amyloidosis,
misfolded TTR proteins accumulate as amyloid fibrils in multiple
organs and tissue types. hATTR amyloidosis can include sensory and
motor, autonomic and cardiac symptoms and is estimated to impact
50,000 people worldwide. wtATTR amyloidosis predominantly manifests
as cardiomyopathy and heart failure symptoms, although patients may
experience other manifestations due to extra-cardiac amyloid
deposition. The disease is estimated to impact 200,000 – 300,000
people worldwide.
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 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 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/ocular diseases. Based on Nobel Prize-winning science, RNAi
therapeutics represent a powerful, clinically validated approach
for the treatment of diseases with high unmet need. Alnylam’s first
commercial RNAi therapeutic is ONPATTRO® (patisiran), approved in
the U.S., EU, Canada, and Japan. Alnylam has a deep pipeline of
investigational medicines, including five product candidates in
Phase 3 studies and one in registration. Looking forward, Alnylam
will continue to execute 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.
Headquartered in Cambridge, MA, Alnylam employs over 1,200 people
worldwide. 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 new clinical research findings
regarding a potential biomarker for monitoring polyneuropathy and
response to treatment and the potential of such biomarker to allow
for an earlier diagnosis of polyneuropathy in patients with hATTR
amyloidosis, its views with respect to human genetic data showing
no evidence for protection against vascular disease or
life-extending advantages of a “stabilizing” T119M gene variant
associated with elevated TTR plasma levels, and expectations
regarding 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, Alnylam's ability to discover and develop novel drug
candidates and delivery approaches, 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, obtaining, maintaining and protecting
intellectual property, Alnylam's ability to enforce its
intellectual property rights against third parties and defend its
patent portfolio against challenges from third parties, obtaining
and maintaining regulatory approval, pricing and reimbursement for
products, progress in establishing a commercial and ex-United
States infrastructure, successfully launching, marketing and
selling its approved products globally, 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, obtain additional funding
to support its business activities, and establish and maintain
strategic business alliances and new business initiatives,
Alnylam's dependence on third parties for development, manufacture
and distribution of products, 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/20190903005279/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media)
617-682-4340
Josh Brodsky (Investors) 617-551-8276
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