– Study Met Primary Endpoint Demonstrating
Clinically Significant Additive Reductions in Ambulatory Systolic
Blood Pressure of Up to 12.1 mmHg Across Three Independent Study
Cohorts at Month 3 –
– A Single Dose of Zilebesiran Resulted in
Clinically Significant Additive Reductions in Office Systolic Blood
Pressure at Month 3 and in Time-Adjusted Office Systolic Blood
Pressure at Month 6 Across Three Independent Study Cohorts –
– Zilebesiran Demonstrated an Encouraging
Safety and Tolerability Profile When Added to Standard of Care
Antihypertensives –
– Alnylam to Host Webcast Investor Event Today
at 7:00 p.m. ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced positive results from the
KARDIA-2 Phase 2 study evaluating the efficacy and safety of a
single subcutaneous dose of zilebesiran when added to one of three
standard of care antihypertensives including a thiazide-like
diuretic (indapamide), calcium channel blocker (amlodipine) or
angiotensin receptor blocker (olmesartan). Zilebesiran is an
investigational RNAi therapeutic targeting liver-expressed
angiotensinogen (AGT) in development for the treatment of
hypertension with the potential for biannual dosing. The results
were presented today as a late-breaking clinical trial at the 2024
American College of Cardiology (ACC) Annual Scientific Session. The
Company previously announced positive topline results from the
KARDIA-2 study in March 2024.
The KARDIA-2 study achieved its primary endpoint demonstrating
clinically and statistically significant additive, placebo-adjusted
reductions of up to 12.1 mmHg in 24-hour mean systolic blood
pressure (SBP) measured by ambulatory blood pressure monitoring
(ABPM) when zilebesiran was added to a thiazide-like diuretic,
calcium channel blocker or angiotensin receptor blocker, measured
independently at Month 3. The study achieved the key secondary
endpoint evaluated at Month 3, demonstrating clinically significant
additive reductions in office SBP across all three independent
cohorts. At Month 6, zilebesiran demonstrated clinically
significant and sustained placebo-adjusted, time-adjusted
reductions in office SBP when added to indapamide, amlodipine and
olmesartan, despite the addition of rescue antihypertensives at
Month 3. In addition, zilebesiran resulted in clinically
significant placebo-adjusted, time-adjusted reductions in 24-hour
mean SBP, assessed by ABPM, when added to indapamide and
amlodipine, sustained to Month 6. A non-statistically significant
result was observed when zilebesiran was added to the maximum dose
of olmesartan when evaluated by time-adjusted change from baseline
in 24-hour mean SBP, assessed by ABPM at Month 6.
“Although many effective oral treatments are available, a large
proportion of patients with hypertension are not managed to
guideline-recommended targets. Inconsistent adherence to complex,
daily, oral medication regimens as well as therapeutic inertia on
the part of clinicians may be important contributors to this
treatment gap,” said Akshay Desai, M.D., Director of the
Cardiomyopathy and Heart Failure Program, Brigham and Women’s
Hospital. “Even in those who are treated, residual blood pressure
variability may ultimately enhance risk for cardiovascular events.
Zilebesiran may help to address many of these limitations of
current treatment options. Although further evidence is needed to
ensure long term efficacy and safety in a broader population, these
data are encouraging and the potential to reduce blood pressure
consistently with two injections a year might be transformative for
clinical practice.”
KARDIA-2 Study Results
The KARDIA-2 study results are as follows:
Key Endpoint
Indapamide (2.5 mg)
Amlodipine (5 mg)
Olmesartan (40 mg)
Primary
Endpoint:
Change from Baseline to Month 3 in 24-Hour
Mean SBP, Assessed by ABPM
- 12.1 mmHg (p<0.001)
- 9.7 mmHg (p<0.001)
- 4.0 mmHg (p=0.036)
Key Secondary
Endpoints:
Change from Baseline to Month 3 in Office
SBP
- 18.5 mmHg (p<0.001)
- 10.2 mmHg (p<0.001)
- 7.0 mmHg (p<0.001)
Time
Adjusted Change from Baseline Through
Month 6 in 24-Hour Mean SBP, Assessed by
ABPM
- 11.0 mmHg (p<0.001)
- 7.9 mmHg (p<0.001)
- 1.6 mmHg (p=0.26)
Time
Adjusted Change from Baseline Through
Month 6 in Office SBP
- 13.6 mmHg (p<0.001)
- 8.6 mmHg (p<0.001)
- 4.6 mmHg (p<0.001)
The final key secondary endpoint evaluated the proportion of
patients with 24-hour mean SBP assessed by ABPM <130 mmHg and/or
reduction ≥20 mmHg without rescue antihypertensive medication at
Month 6. As outlined in the study protocol, after three months of
treatment, all patients were permitted to receive rescue
antihypertensives as needed based on rescue response criteria.
Across all cohorts, a higher percentage of placebo-treated patients
required treatment with rescue antihypertensives compared to
zilebesiran-treated patients. Additionally, the odds of meeting the
SBP response criteria were significantly higher with zilebesiran in
the indapamide and amlodipine cohorts, compared to placebo.
Background Medication
Indapamide (2.5 mg)
Amlodipine (5 mg)
Olmesartan (40 mg)
Placebo
(N=57)
Zilebesiran
(N=53)
Placebo
(N=102)
Zilebesiran
(N=103)
Placebo
(N=134)
Zilebesiran (N=117)
Response Criteria Met
14.0%
64.2%
13.7%
39.8%
17.2%
26.5%
Odds Ratio 95% CI
12.4 (p<0.001)
5.1 (p<0.001)
1.8 (p=0.077)
Zilebesiran demonstrated an encouraging safety and tolerability
profile when added to standard of care antihypertensives.
Safety
Event
Indapamide (2.5 mg)
Amlodipine (5 mg)
Olmesartan (40 mg)
Placebo
(N=64)
Zilebesiran
(N=63)
Placebo
(N=121)
Zilebesiran
(N=118)
Placebo
(N=152)
Zilebesiran
(N=149)
At Least 1 Adverse Event (AE), %
39.1
49.2
47.1
54.2
48.0
58.4
At Least 1 Serious AE (SAE), %
3.1
0
0.8
2.5
2.6
2.7
AEs of Clinical
Interest
Hypotension/Orthostatic Hypotension, %
0
0
3.3
5.9
2.0
4.7
Laboratory Values
Hyperkalemia (potassium >5.5nmol/L),
%
0
3.2
0.8
6.8
2.0
6.7
Confirmed by Repeat Measure, %
0
1.6
0
1.7
0
1.3
Kidney Function Impact (≥30% decrease from
baseline in eGFR (mL/min/1.73m2), %
1.6
12.7
4.1
8.5
2.6
6.7
Confirmed by Repeat Measure, %
0
4.8
1.7
0.8
0.7
2.7
Kidney Function Impact (>2x increase
from baseline in creatinine), %
0
0
0
0
0
2.0
Confirmed by Repeat Measure, %
0
0
0
0
0
0.7
Most laboratory abnormalities of interest were mild, occurred in
the first three months of treatment and resolved upon repeat
measure within one to two weeks without intervention. There were no
deaths reported, and no AEs led to study discontinuation during the
six-month double-blind period.
“The KARDIA program has built a robust body of evidence, with
more than six hundred patients having received zilebesiran in Phase
2 trials, demonstrating clinically significant blood pressure
reductions with encouraging safety as both a monotherapy and as an
add-on therapy, with the potential for both quarterly and biannual
dosing,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program
Lead at Alnylam. “At Alnylam, we are aiming to disrupt
cardiovascular disease, and in collaboration with our partner
Roche, we are committed to moving zilebesiran forward in the hope
of changing the hypertension treatment paradigm for patients. We
are taking that next step with our recently initiated third Phase 2
study, KARDIA-3, designed to evaluate zilebesiran as an add-on
therapy in high cardiovascular risk patients with uncontrolled
hypertension despite receiving two or more antihypertensives.”
The KARDIA-2 Phase 2 study is a randomized, double-blind,
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 indapamide, amlodipine or olmesartan as their
protocol-specified background antihypertensive medication during a
run-in period of at least four weeks. Following the run-in period,
eligible patients with elevated SBP were randomized 1:1 to receive
a single dose of 600 mg zilebesiran or placebo in addition to their
protocol-specified background antihypertensive medication for six
months.
To review the KARDIA-2 study results and the KARDIA-1 subgroup
results presented at ACC, please visit Capella.
Investor Webcast Information
Alnylam management and Akshay Desai, M.D., Director of the
Cardiomyopathy and Heart Failure Program, Brigham and Women’s
Hospital, will discuss the KARDIA-2 results via webcast on April 7,
2024, at 7:00 p.m. ET. The webcast will be available on the
Investors section of the Company’s website at
www.alnylam.com/events. An archived webcast will be
available on the Company’s website approximately two hours after
the event.
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 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 zilebesiran; actions or advice of
regulatory agencies and Alnylam’s ability to obtain regulatory
approval for its product candidates, including zilebesiran, 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 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; 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.
View source
version on businesswire.com: https://www.businesswire.com/news/home/20240407631982/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)
過去 株価チャート
から 4 2024 まで 5 2024
Alnylam Pharmaceuticals (NASDAQ:ALNY)
過去 株価チャート
から 5 2023 まで 5 2024