— Dose-Dependent Reductions in Serum
Angiotensinogen and 24-hour Ambulatory Blood Pressure Were
Sustained for Six Months After Single Doses of Zilebesiran —
— Acceptable Safety Profile Supporting Further
Development —
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today that results from its Phase 1
study of zilebesiran, an investigational RNAi therapeutic targeting
liver-expressed angiotensinogen (AGT) in development for the
treatment of hypertension, were published in the New England
Journal of Medicine (NEJM). The full manuscript is titled,
“Zilebesiran, an RNA Interference Therapeutic Agent for
Hypertension,” and will appear in the July 20, 2023 issue of NEJM.
The key data reported in the publication showed that in the Phase 1
study, compared to placebo, zilebesiran was associated with
dose-dependent reductions in serum AGT, achieving tonic blood
pressure control with consistent and durable blood pressure
reduction throughout a 24-hour period, sustained up to six months
after single doses of ≥200 mg of zilebesiran. Zilebesiran also
demonstrated an acceptable safety profile supporting continued
clinical development; the most frequent treatment-related adverse
events were mild, transient injection-site reactions.
“Hypertension is the leading cause of premature death,
cardiovascular disease, and chronic kidney disease worldwide, and
the global prevalence is steadily increasing in parallel with
population aging and secular trends in the prevalence of risk
factors including obesity, physical inactivity, and unhealthy diet.
Despite the availability of effective antihypertensive treatments,
nearly half of patients with hypertension fail to achieve
guideline-recommended blood pressure targets, leaving them at
residual risk for myocardial infarction, stroke, kidney disease
progression, and mortality. For clinicians, the challenge in
optimizing treatment of hypertension is frequently compounded by
poor adherence to prescribed medical therapy and substantial
variability in blood pressure between office visits and over the
24-hour cycle,” said Akshay Desai, M.D., the lead author of the
manuscript and Director of the Cardiomyopathy and Heart Failure
Program in the Advanced Heart Disease Section of the Cardiovascular
Division at Brigham and Women’s Hospital. “In this context, the
data we have published in NEJM are exciting, suggesting the
potential role for zilebesiran to treat hypertension in a novel way
via a novel, subcutaneously administered gene silencing approach to
hypertension. This novel approach may provide durable, tonic blood
pressure control with infrequent, office-based dosing and a
favorable safety profile. Additional clinical trials will provide
further insights into the potential of this approach to improve
clinical outcomes in the growing population of patients with
hypertension.”
“The data published in NEJM suggest the potential for
zilebesiran to be an effective and highly-differentiated treatment
that may help people with hypertension achieve sustained blood
pressure control,” said Simon Fox, Ph.D., Vice President,
Zilebesiran Program Lead at Alnylam. “To that end, we are currently
evaluating the safety and efficacy of zilebesiran in our KARDIA
Phase 2 clinical program either as a monotherapy (KARDIA-1) or in
combination with a standard-of-care antihypertensive medication
(KARDIA-2), and we look forward to reporting results from these
programs in mid- and late 2023, respectively.”
Summary of Published Results
The study was conducted in 107* patients (zilebesiran, N=80;
placebo, N=32) with mild-to-moderate hypertension. In Part A,
patients were randomized 2:1 to receive single ascending
subcutaneous doses of zilebesiran (10, 25, 50, 100, 200, 400, or
800 mg) or placebo. Part B of the study assessed the effects of
zilebesiran (800 mg) on blood pressure under low- and high-salt
diet conditions and Part E assessed the effects of zilebesiran (800
mg) coadministration with irbesartan (an angiotensin II receptor
blocker). The study primary endpoint was the frequency of adverse
events (AEs). AEs were reported for 58 patients receiving
zilebesiran (72 percent) and 28 receiving placebo (88 percent). The
most frequent treatment-related adverse events were mild, transient
injection-site reactions reported in five (6 percent) patients who
received zilebesiran. No events of hypotension, hyperkalemia, or
worsening renal function requiring intervention were observed.
Secondary and exploratory endpoints included change from baseline
in serum AGT, pharmacokinetics, and change from baseline in blood
pressure. In Part A, versus placebo, zilebesiran was associated
with dose-dependent reductions in serum AGT that were sustained for
up to six months. Single doses of zilebesiran (≥200 mg) resulted in
reductions in systolic (>10 mm Hg) and diastolic (>5 mm Hg)
blood pressure by Week 8, which were consistent throughout the
diurnal cycle and sustained to six months. At the 800 mg dose,
zilebesiran treatment resulted in mean (± standard error) systolic
and diastolic reductions of 22.5 ± 5.1 mm Hg and 10.8 ± 2.7 mm Hg
at Month 6, respectively. In Parts B and E of the study, blood
pressure changes following zilebesiran treatment could be
attenuated through high dietary salt intake and were augmented by
irbesartan coadministration.
*Five patients receiving placebo in Part A of the study
re-enrolled into Part E of the study and thus transitioned from
placebo to zilebesiran.
About Zilebesiran
Zilebesiran is an investigational, subcutaneously administered
RNAi therapeutic targeting angiotensinogen (AGT) in Phase 2
development for the treatment of hypertension in high unmet need
populations. AGT is the most upstream precursor in the
Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a
demonstrated role in blood pressure (BP) regulation and its
inhibition has well-established anti-hypertensive effects.
Zilebesiran inhibits the synthesis of AGT in the liver, potentially
leading to durable reductions in AGT protein and ultimately, in the
vasoconstrictor angiotensin (Ang) II. Zilebesiran utilizes
Alnylam's Enhanced Stabilization Chemistry Plus (ESC+)
GalNAc-conjugate technology, which enables subcutaneous dosing with
increased selectivity and a wide therapeutic index. The safety and
efficacy of zilebesiran have not been established or evaluated by
the FDA, EMA or any other health authority.
About Hypertension
Uncontrolled hypertension is the chronic elevation of blood
pressure (BP), defined by the 2017 ACC/AHA guidelines as ≥130 mmHg
systolic blood pressure (SBP) and ≥80 mmHg diastolic blood pressure
(DBP). More than one billion people worldwide live with
hypertension.i In the U.S. alone, approximately 47 percent of
adults live with hypertension, with more than half of patients on
medication remaining above the blood pressure (BP) target level.
Despite the availability of anti-hypertensive medications, there
remains a significant unmet medical need, especially given the poor
rates of adherence to existing daily oral medications, resulting in
inconsistent BP control and an increased risk for stroke, heart
attack and premature death.ii In particular, there are a number of
high unmet need settings where novel approaches to hypertension
warrant additional development focus, including patients with poor
medication adherence, difficult-to-treat and resistant
hypertension, and in patients with high cardiovascular risk.
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 Pharmaceuticals (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based
on Nobel Prize-winning science, RNAi therapeutics represent a
powerful, clinically validated approach yielding transformative
medicines. Since its founding in 2002, Alnylam has led the RNAi
Revolution and continues to deliver on a bold vision to turn
scientific possibility into reality. Alnylam’s commercial RNAi
therapeutic products are ONPATTRO® (patisiran), AMVUTTRA®
(vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and
Leqvio® (inclisiran), which is being developed and commercialized
by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of
investigational medicines, including multiple 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, on Instagram,
or on Facebook at @AlnylamPharma.
Alnylam Forward Looking Statements
This press release contains forward-looking statements within
the meaning of Section 27A of the Securities Act of 1933 and
Section 21E of the Securities Exchange Act of 1934. All statements
other than historical statements of fact regarding Alnylam’s
expectations, beliefs, goals, plans or prospects including, without
limitation, Alnylam’s views with respect to the potential role for
zilebesiran as a novel, subcutaneously administered gene silencing
approach to hypertension, its views that zilebesiran has the
potential to be an effective and highly-differentiated treatment;
its expectations regarding its aspiration to become a leading
biotech company and the planned achievement of its “Alnylam P5x25”
strategy, the potential for Alnylam to identify new potential drug
development candidates and advance its research and development
programs, Alnylam’s ability to obtain approval for new commercial
products or additional indications for its existing products, and
Alnylam’s projected commercial and financial performance, should be
considered forward-looking statements. 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 successfully execute on its “Alnylam P5x25” strategy;
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 Alnylam’s product candidates, including patisiran and
vutrisiran; actions or advice of regulatory agencies and Alnylam’s
ability to obtain and maintain regulatory approval for its product
candidates, including patisiran and vutrisiran, as well as
favorable pricing and reimbursement; successfully launching,
marketing and selling Alnylam’s approved products globally; delays,
interruptions or failures in the manufacture and supply of
Alnylam’s product candidates or its marketed products; delays or
interruptions in the supply of resources needed to advance
Alnylam’s research and development programs, including as may arise
from recent disruptions in the supply of non-human primates;
obtaining, maintaining and protecting intellectual property;
Alnylam’s ability to successfully expand the indication for
ONPATTRO or AMVUTTRA 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, Sanofi,
Regeneron and Vir; the outcome of litigation; the potential impact
of a current government investigation and the risk of future
government investigations; and unexpected expenditures; as well as
those risks more fully discussed in the “Risk Factors” filed with
Alnylam’s 2022 Annual Report on Form 10-K filed with the Securities
and Exchange Commission (SEC), as may be updated from time to time
in Alnylam’s subsequent Quarterly Reports on Form 10-Q 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.
i Hypertension. World Health Organization.
https://www.who.int/news-room/fact-sheets/detail/hypertension.
Published September 2019. Accessed November 2021.
ii Carey, R. M., Muntner, P., Bosworth, H. B., & Whelton, P.
K. (2018). Prevention and Control of Hypertension: JACC Health
Promotion Series. Journal of the American College of Cardiology,
72(11), 1278–1293. https://doi.org/10.1016/j.jacc.2018.07.008
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Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom (Investors and Media)
+1-617-682-4340
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Alnylam Pharmaceuticals (NASDAQ:ALNY)
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