– Zilebesiran Met Primary Endpoint
Demonstrating Up to 16.7 mmHg Placebo-Adjusted Reduction of 24-Hour
Mean Systolic Blood Pressure at Three Months of Treatment –
– Study Met Key Secondary Endpoints Showing
Consistent and Sustained Reductions of Systolic Blood Pressure and
Durable Tonic Blood Pressure Control Through Month 6 –
– Data Support Quarterly or Biannual Dosing
–
– Zilebesiran Demonstrated an Encouraging
Safety and Tolerability Profile in Adult Patients with
Mild-to-Moderate Hypertension –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced positive results from the
KARDIA-1 Phase 2 study of zilebesiran, an investigational RNAi
therapeutic targeting liver-expressed angiotensinogen (AGT) in
development for the treatment of patients with hypertension and
high cardiovascular risk. The study results were presented during
the American Heart Association (AHA) Scientific Sessions being held
in Philadelphia, Pennsylvania from November 11-13, 2023. The
Company previously announced positive topline results from the
KARDIA-1 study in September 2023.
The KARDIA-1 study achieved its primary endpoint, with single
doses of zilebesiran demonstrating clinically significant
reductions in 24-hour mean systolic blood pressure (SBP) measured
by ambulatory blood pressure monitoring (ABPM) at Month 3 across
all doses, with the 150 mg, 300 mg, and 600 mg doses achieving
placebo-adjusted reductions of 14.1 mmHg, 16.7 mmHg, and 15.7 mmHg,
respectively (all p-values less than 0.0001). The study also met
key secondary endpoints across all doses, including demonstration
of durable efficacy out to 6 months. At the 150 mg Q6M, 300 mg Q6M,
300 mg Q3M, and 600 mg Q6M doses, zilebesiran showed
placebo-adjusted reductions in 24-hour mean SBP measured by ABPM of
11.1 mmHg, 14.5 mmHg, 14.1 mmHg, and 14.2 mmHg, respectively, at
Month 6 (all p-values less than 0.0001). Zilebesiran demonstrated
an encouraging safety and tolerability profile that the Company
believes supports continued development.
“These KARDIA-1 results are impressive, showing that in a
diverse group of patients with mild-to-moderate hypertension,
zilebesiran can safely achieve clinically significant reductions in
systolic blood pressure and tonic blood pressure control
administered subcutaneously with either quarterly or bi-annual
dosing,” 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. “I continue to be encouraged and optimistic that
zilebesiran has the potential to become not only a novel treatment
for hypertension but also a transformative therapy to lower
cardiovascular and renal risk in patients with hypertension, an
area where new and innovative therapies are desperately
needed.”
KARDIA-1 Study Results
The KARDIA-1 Phase 2 study is a randomized, double-blind,
placebo-controlled, multi-center global dose-ranging study designed
to evaluate the efficacy and safety of subcutaneously administered
zilebesiran as monotherapy in adults with mild-to-moderate
hypertension.
The study enrolled 394 adults representing a diverse patient
population, of which more than 40% were female and nearly 25% were
Black, with untreated hypertension or who were on stable therapy
with one or more anti-hypertensive medications. Any patients taking
prior antihypertensive medications completed at least a two- to
four-week wash-out before randomization. Patients were randomized
to one of five treatment arms: 150 mg zilebesiran once every six
months (Q6M); 300 mg zilebesiran Q6M; 300 mg zilebesiran once every
three months (Q3M); 600 mg zilebesiran Q6M; or placebo.
The primary endpoint was the change from baseline in 24-hour
mean SBP at Month 3, assessed by ABPM. Key secondary endpoints in
this study include additional measures of blood pressure reduction
at Month 3 and Month 6, and the proportion of patients achieving
treatment response criteria at Month 6, defined as 24-hour mean
ambulatory SBP <130 mmHg and/or reduction ≥20 mmHg without
additional antihypertensive medications.
At six months, the study met its primary endpoint and all key
secondary endpoints. The placebo-adjusted study results presented
today are as follows:
Key Endpoints
150 mg Q6M
300 mg Q6M
300 mg Q3M
600 mg Q6M
Primary Endpoint
Change from Baseline to Month 3 in 24-Hour
Mean Ambulatory SBP
-14.1 mmHg (p less than
0.0001)
-16.7 mmHg (p less than 0.0001)
*
-15.7 mmHg (p less than
0.0001)
Key Secondary
Endpoints
Change from Baseline to Month 6 in 24-Hour
Mean Ambulatory SBP
-11.1 mmHg (p less than
0.0001)
-14.5 mmHg (p less than
0.0001)
-14.1 mmHg (p less than
0.0001)
-14.2 mmHg (p less than
0.0001)
Change from Baseline to Month 3 in Office
SBP
-9.6 mmHg (p less than
0.0001)
-12.0 mmHg (p less than 0.0001)
*
-9.1 mmHg (p less than
0.0001)
Change from Baseline to Month 6 in Office
SBP
-7.5 mmHg (p=0.0025)
-10.5 mmHg (p less than
0.0001)
-12.1 mmHg (p less than
0.0001)
-10.2 mmHg (p less than
0.0001)
* 300 mg Q6M and Q3M groups were pooled
for Month 3 endpoints
- The final key secondary endpoint evaluating the proportion of
patients achieving treatment response criteria at Month 6 was also
met, with the odds of meeting response criteria being significantly
higher across all zilebesiran regimens compared to placebo (p less
than 0.001).
- Reductions in 24-hour mean blood pressure, measured by ABPM,
were maintained over the full diurnal cycle, with consistently
lower hourly, daytime, and nighttime blood pressure across all
zilebesiran regimens compared to placebo through Month 6.
Zilebesiran demonstrated an encouraging safety profile through
Month 6. Serious adverse events were reported in 6.7% of patients
in the placebo group and 3.6% of patients in the zilebesiran
groups. There was one death due to cardiopulmonary arrest in a
zilebesiran-treated patient that was considered unrelated to study
drug. Drug-related adverse events (AEs) reported in more than 5% of
patients in any zilebesiran arm were injection site reaction (ISR)
occurring in 6.3% of patients and hyperkalemia in 5.3% of patients.
No drug-related AEs were classified as serious or severe. ISR and
hyperkalemia AEs were mostly mild and transient. No hyperkalemia
events were associated with acute kidney injury or led to study
drug discontinuation. Four patients had drug-related AEs leading to
an investigator decision to discontinue zilebesiran. These AEs
included orthostatic hypotension (n=2), blood pressure elevation
(n=1), and ISR (n=1). Hypotension AEs were mild or moderate,
non-serious, and transient. A single event in the zilebesiran 300
mg Q3M group was treated with normal saline. Clinically relevant
AEs of acute renal failure, hepatic AEs, hypotension, and
hyperkalemia of any relatedness were reported in 1.3%, 3.0%, 4.3%,
and 6.3% of patients receiving zilebesiran, and 0%, 1.3%, 1.3%, and
2.7% of patients receiving placebo.
“The totality of the data presented at the American Heart
Association Scientific Sessions gives us confidence in
zilebesiran’s potentially differentiated profile and its ability to
transform the treatment landscape for patients with uncontrolled
hypertension who are at high risk of future cardiovascular events,”
said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at
Alnylam. “We look forward to sharing topline results from the
KARDIA-2 Phase 2 study, designed to evaluate the efficacy and
safety of zilebesiran when used in combination with one other
antihypertensive medication in patients with mild-to-moderate
hypertension, in early 2024.”
To view the KARDIA-1 Phase 2 results presented at AHA, please
visit Capella.
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; 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; 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; 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 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; the risks 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20231111731245/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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