– Study Met the Primary Endpoint Demonstrating
Clinically Significant Systolic Blood Pressure Reductions at Month
3 When Zilebesiran Was Added to a Diuretic, Calcium-Channel Blocker
or Angiotensin Receptor Blocker –
– Zilebesiran Demonstrated an Encouraging
Safety and Tolerability Profile When Added to Standard of Care
Antihypertensives –
– Study Results Support Potential for Biannual
Dosing of Zilebesiran –
– Full Study Results to Be Presented as a
Late-Breaking Clinical Trial at the 2024 American College of
Cardiology Annual Scientific Session on April 7 –
– Alnylam and Roche Also Announce Initiation of
the KARDIA-3 Phase 2 Study in Patients at High Cardiovascular Risk
with Uncontrolled Hypertension Despite Standard of Care
Antihypertensive Treatments –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced that the KARDIA-2 Phase 2
study of zilebesiran, an investigational RNAi therapeutic targeting
liver-expressed angiotensinogen (AGT) in development for the
treatment of hypertension, met the primary endpoint showing that
zilebesiran resulted in clinically and statistically significant
additive, placebo-adjusted reductions in 24-hour mean systolic
blood pressure (SBP) at Month 3 as measured by ambulatory blood
pressure monitoring (ABPM) in each of three independent patient
cohorts receiving the standardized background therapies of either a
thiazide-like diuretic (indapamide), calcium channel blocker
(amlodipine) or angiotensin receptor blocker (olmesartan).
Zilebesiran demonstrated an encouraging safety and tolerability
profile when added to these standard of care antihypertensives. The
Company believes these findings support further development.
“We are thrilled that a single dose of zilebesiran achieved
clinically significant, additional reductions in systolic blood
pressure when administered to patients who are not adequately
controlled with commonly prescribed antihypertensives,” said Simon
Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam.
“These KARDIA-2 results, showing durable additional levels of blood
pressure reduction on top of what is achieved by standard of care
first-line antihypertensives with an encouraging safety profile,
reinforce our confidence in zilebesiran’s differentiated profile.
We look forward to sharing the full KARDIA-2 data as a
late-breaking clinical trial at the upcoming American College of
Cardiology Annual Scientific Session.”
The KARDIA-2 Phase 2 study is a randomized, double-blind (DB),
placebo-controlled study designed to evaluate the efficacy and
safety of zilebesiran, when added to standard of care
antihypertensive medications, in adults with mild-to-moderate
hypertension. This global, multicenter study enrolled 672 adults
with hypertension. Patients who met all inclusion criteria and none
of the exclusion criteria during a screening period were first
randomized into three different cohorts to receive open-label
therapy with olmesartan, amlodipine or indapamide as their
protocol-specified background antihypertensive medication during a
run-in period of at least four weeks. Following the run-in period,
eligible patients were randomized 1:1 to receive 600 mg zilebesiran
or placebo in addition to their protocol-specified background
antihypertensive medication for six months.
The primary endpoint is the change from baseline in mean SBP at
Month 3, assessed by 24-hour ABPM. Additional endpoints include the
change in 24-hour mean SBP after six months of treatment assessed
by ABPM, change in office SBP at Month 3 and Month 6, and change in
diastolic blood pressure (DBP) measured by ABPM and office blood
pressure at Month 3 and Month 6. Safety will be assessed throughout
the study.
Alnylam and Roche today also announced the initiation of the
global KARDIA-3 (NCT06272487) Phase 2 study, a randomized, DB,
placebo-controlled, multicenter study designed to evaluate the
efficacy and safety of zilebesiran used as an add-on therapy in
adult patients with high cardiovascular risk and uncontrolled
hypertension despite treatment with two to four standard of care
antihypertensive medications. Patients with estimated glomerular
filtration rate (eGFR) ≥45 mL/min/1.73m2 will be enrolled to cohort
A, and patients with eGFR 30 to <45 mL/min/1.73m2 will be
enrolled to cohort B. Patients who meet all of the inclusion and
none of the exclusion criteria after the screening period will be
randomized to receive 300 or 600 mg zilebesiran or placebo in
cohort A on day 1, or 150, 300, or 600 mg zilebesiran or placebo in
cohort B on day 1, of a 6-month DB treatment period as add-on
therapy to their background antihypertensive medications. After the
6-month DB treatment period, patients will enter the 6-month safety
follow-up period.
The primary endpoint is the change from baseline at Month 3 in
mean seated office SBP. Additional endpoints include change from
baseline at Month 3 in 24-hour mean SBP assessed by ABPM, change
from baseline at Month 6 in mean seated office SBP and in 24-hour
mean SBP assessed by ABPM. Safety will be assessed throughout the
study.
About Zilebesiran
Zilebesiran is an investigational, subcutaneously administered
RNAi therapeutic targeting angiotensinogen (AGT) in 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 infrequent
subcutaneous dosing with increased selectivity and the potential to
achieve tonic blood pressure control demonstrating consistent and
durable blood pressure reduction throughout a 24-hour period,
sustained up to six months after a single dose of zilebesiran. The
safety and efficacy of zilebesiran have not been established or
evaluated by the FDA, EMA or any other health authority.
Zilebesiran is being co-developed and co-commercialized by Alnylam
and Roche.
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 Approximately one in three adults are living with
hypertension worldwide, with up to 80% of individuals remaining
uncontrolled despite the availability of several classes of oral
anti-hypertensive treatments. 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 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 X (formerly Twitter) at @Alnylam, or on LinkedIn,
Facebook, or Instagram.
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 results of the
KARDIA-2 Phase 2 study of zilebesiran or the enrollment or conduct
of the KARDIA-3 Phase 2 study, 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, 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, risks and
uncertainties relating to: 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 vutrisiran, zilebesiran, and ALN-APP;
actions or advice of regulatory agencies and Alnylam’s ability to
obtain and maintain regulatory approval for its product candidates,
including 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; obtaining, maintaining and
protecting intellectual property; Alnylam’s ability to successfully
expand the approved indications for 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; 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; Alnylam’s
ability to maintain strategic business collaborations; Alnylam’s
dependence on third parties for the development and
commercialization of certain products, including Roche, Novartis,
Sanofi, Regeneron and Vir; the outcome of litigation; 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 2023 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20240305182792/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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