- Zilebesiran Met Primary Endpoint
Demonstrating Greater than 15 mmHg Reduction of Systolic Blood
Pressure at Three Months of Treatment Compared to Placebo at Two
Highest Single Doses Evaluated -
- Study Met Key Secondary Endpoints Showing
Consistent and Sustained Reductions of Systolic Blood Pressure at
Six Months, Supporting Quarterly or Biannual Dosing -
- Zilebesiran Demonstrated an Encouraging
Safety and Tolerability Profile in Adult Patients with
Mild-to-Moderate Hypertension -
- Full Study Results to be Presented at an
Upcoming Scientific Conference -
Alnylam Pharmaceuticals, Inc. Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced that the KARDIA-1 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 demonstrating a
dose-dependent, clinically significant reduction in 24-hour mean
systolic blood pressure (SBP) measured by ambulatory blood pressure
monitoring (ABPM) at Month 3, achieving a placebo-subtracted
reduction greater than 15 mmHg (p less than 0.0001) with both 300
mg and 600 mg doses. The study also met key secondary endpoints
including significant change in 24-hour mean SBP as measured by
ABPM at Month 6, as well as significant change in office SBP at
Month 3 and Month 6, for all zilebesiran arms, compared to placebo.
The study results indicate zilebesiran was associated with
dose-dependent, potent and durable knockdown of serum AGT levels
through Month 6. Zilebesiran also demonstrated an encouraging
safety and tolerability profile that the company believes supports
continued development. These findings of robust and tonic blood
pressure control will help determine the optimal dose and regimen
of zilebesiran for future studies.
“Hypertension is a growing global health crisis responsible for
around 10 million deaths worldwide each year. Despite the
availability of several classes of oral anti-hypertensive
treatments, up to 80% of individuals globally remain uncontrolled,
leaving them at an increased risk of cardiovascular,
cerebrovascular and renal disease, which is further exacerbated by
blood pressure variability, lack of nighttime blood pressure
control and poor adherence,” said Professor George L. Bakris, M.D.,
Board-Certified Hypertension Specialist and Director of the
American Heart Association Comprehensive Hypertension Center,
University of Chicago Medicine. “As a physician, I believe these
KARDIA-1 results, which demonstrate clinically significant
reductions in systolic blood pressure of greater than 15 mmHg,
along with the ability to achieve durable tonic blood pressure
control, provide hope that we may one day have access to a novel
therapy with the potential to address the significant unmet needs
of patients with uncontrolled hypertension who are at high risk of
future cardiovascular events.”
Zilebesiran demonstrated an encouraging safety and tolerability
profile. There was one death due to cardiopulmonary arrest in a
zilebesiran-treated patient that was considered unrelated to study
drug. Serious adverse events were reported in 3.6% of
zilebesiran-treated patients and 6.7% of placebo-treated patients.
None were considered related to study drug. Adverse events
occurring in 5% or more of zilebesiran-treated patients in any dose
arm included COVID-19, injection site reaction (ISR), hyperkalemia,
hypertension, upper respiratory tract infection, arthralgia and
headache.
The KARDIA-1 Phase 2 trial is a randomized, double-blind (DB),
placebo-controlled, multi-center global dose-ranging study designed
to evaluate the efficacy and safety of zilebesiran as monotherapy
in adults with mild-to-moderate hypertension. The study enrolled
394 adults representing a diverse patient population with untreated
hypertension or who were on stable therapy with one or more
anti-hypertensive medications. Any patients taking prior
anti-hypertensive medications completed at least a two- to
four-week wash-out before randomization. Patients were randomized
to one of five treatment arms during a 12-month DB period and DB
extension period: 150 mg zilebesiran subcutaneously once every six
months; 300 mg zilebesiran subcutaneously once every six months;
300 mg zilebesiran subcutaneously once every three months; 600 mg
zilebesiran subcutaneously once every six months; or placebo.
Patients who received placebo were randomized to one of the four
initial zilebesiran dose regimens beginning at Month 6.
The primary endpoint is the change from baseline in SBP at Month
3, assessed by 24-hour ABPM. Key secondary and exploratory
endpoints in this study include additional measures of blood
pressure reduction at six months, time-adjusted change in blood
pressure, and change in daytime average and night-time average
blood pressure.
“We are thrilled that the KARDIA-1 Phase 2 results show
zilebesiran’s ability to achieve sustained blood pressure
reductions of greater than 15 mmHg, as well as long-term efficacy
out to six months with infrequent dosing. We believe these results
further validate the differentiated profile we observed in Phase 1.
Moreover, they reinforce the potential for zilebesiran to be a
transformative therapy to reduce cardiovascular risk in patients
with hypertension and to offer new possibilities in a field of
medicine that has seen limited innovation in nearly 20 years,” said
Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at
Alnylam. “We look forward to sharing the full KARDIA-1 results at
an upcoming scientific conference and to reporting topline results
from our KARDIA-2 Phase 2 study of zilebesiran in combination with
one of three standard classes of anti-hypertensive medications in
patients with mild-to-moderate hypertension in early 2024. It is a
very exciting time for Alnylam, as these results build on the
momentum from the recent strategic agreement to co-develop and
co-commercialize zilebesiran with our collaboration partner, Roche,
to potentially transform the landscape for patients with
cardiovascular diseases.”
The KARDIA-2 Phase 2 study of zilebesiran used in combination
with one of three standard classes of anti-hypertensive medications
completed enrollment in June 2023. Topline results are expected in
early 2024.
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-1 Phase 2
dose-ranging study of zilebesiran, 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: 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 Roche, Novartis,
Sanofi, Regeneron and Vir; the outcome of litigation; 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20230907817269/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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