– Single Doses of Investigational ALN-AGT
Achieved Sustained Reductions in Serum Angiotensinogen (AGT) at 12
Weeks Resulting in Reduced Blood Pressure –
– Durability of AGT Knockdown Supports the
Potential of Once Quarterly or Biannual Dosing –
– ALN-AGT was Generally Well Tolerated, with No
Serious Treatment-Related Adverse Events or Study Withdrawals –
– Data Confirm Potential for AGT Silencing as a
Novel Approach for Treatment of Hypertension and Support Initiation
of Phase 2 KARDIA Studies Mid-Year –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today positive interim results from
the ongoing Phase 1 study of ALN-AGT, a subcutaneous
investigational RNAi therapeutic targeting liver-expressed
angiotensinogen (AGT) for the treatment of hypertension. Results
were presented during a late-breaking oral presentation at the 2021
Joint Meeting of the European Society of Hypertension (ESH) and the
International Society of Hypertension (ISH). ALN-AGT treatment was
associated with dose-dependent knockdown of AGT and reductions in
blood pressure (BP) with a durability that supports the potential
for a once quarterly or biannual dosing regimen, and was found to
be generally safe and well tolerated.
“We face an intractable challenge in controlling hypertension,
which affects an estimated 1.13 billion people worldwide and is a
major risk factor for cardiovascular disease morbidity and
premature mortality.i Despite well-established treatments including
lifestyle modifications and several classes of available
anti-hypertensive medications, fewer than 20 percent of people with
hypertension globally have it under control,”i said Reinhold
Kreutz, M.D., Ph.D., Professor, Charité and Berlin Institute of
Health, Institute of Clinical Pharmacology and Toxicology and
President, ESH. “While several factors contribute to the high rate
of uncontrolled hypertension, inconsistent blood pressure control
and medication adherence in those patients receiving treatment may
play critical roles, and the encouraging early-stage results for
ALN-AGT suggest its potential as a novel therapeutic approach to
address long-standing treatment gaps.”
Eighty-four patients with hypertension were randomized in this
double-blind, placebo-controlled, single ascending dose (SAD) study
evaluating the safety, tolerability and preliminary pharmacokinetic
and pharmacodynamic activity of ALN-AGT. Patients, who were either
treatment naïve or had discontinued other anti-hypertensive
medications prior to study entry, enrolled in ascending dose
cohorts of 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg
ALN-AGT.
Patients treated with single doses of ALN-AGT at 100 mg or
higher experienced durable reductions in serum AGT of more than 90
percent through 12 weeks. In the 800 mg dose cohort, all patients
experienced reductions in serum AGT of 96 – 98 percent at Week 12.
Concomitant reductions in BP were observed with AGT knockdown, with
clinically meaningful mean reductions in 24-hour systolic blood
pressure (SBP) of >10 mm Hg observed at Week 8 after single
doses of 100 mg or higher. At 800 mg, mean reductions in 24-hour
SBP of 17 mm Hg were observed at Week 8 (compared to a mean
increase of 1 mm Hg in the placebo group) and sustained through
Week 12. All data are as of a February 25, 2021 cut-off date.
Suboptimal BP control remains the most common attributable risk
factor for cardiovascular disease and cerebrovascular disease, and
a leading cause of chronic kidney disease progression. These
durable pharmacologic effects of ALN-AGT may support tonic control
of BP with once quarterly and potentially biannual dosing. Less
frequent dosing than available with current treatment options may
help achieve improved medication adherence, an important part of
maintaining BP control.ii
ALN-AGT was shown to be generally well tolerated with an
acceptable safety profile that supports advancement into Phase 2
studies. Most adverse events (AEs) were mild or moderate in
severity and resolved without intervention, with the most common AE
consisting of mild and transient injection site reactions in 5 out
of 56 patients (8.9 percent) receiving ALN-AGT. There were no
clinically significant elevations in serum alanine aminotransferase
(ALT), serum creatinine or serum potassium, and no patient required
intervention for hypotension. There were no treatment-related
serious AEs, deaths or AEs leading to study withdrawal.
“We believe the results for ALN-AGT are highly encouraging and
demonstrate the potential of an RNAi therapeutic to help people
reach and maintain their blood pressure goals,” said Akshay
Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. “We believe
ALN-AGT has the potential to transform the way hypertension is
managed, a disease that has been devoid of new therapeutic
interventions for decades and remains a major contributing risk
factor for stroke, heart attack and sudden death. Based on these
findings, we look forward to advancing the clinical program for
ALN-AGT with the initiation of Phase 2 KARDIA studies planned in
mid-2021.”
To view the data presented at the ESH-ISH 2021 Joint Meeting,
please visit www.alnylam.com/capella.
About ALN-AGT Phase 1 Study
The Phase 1 study is a multi-center, randomized, double-blind,
placebo-controlled, single dose (SD) and active
comparator-controlled multiple dose (MD) trial designed to evaluate
the safety, tolerability, pharmacokinetic, and pharmacodynamic
effects of ALN-AGT in patients with essential hypertension. The
study is being conducted in four parts: single ascending dose (SAD)
phase in hypertensive patients; SD phase in hypertensive patients
with controlled salt intake; MD phase in hypertensive patients who
are obese, with once daily oral doses of irbesartan (angiotensin II
receptor blocker) used as the active comparator; and open-label SD
phase with co-administration of irbesartan in hypertensive
patients. Patients will be randomized 2:1 ALN-AGT to placebo or
ALN-AGT to irbesartan. The planned enrollment for this study,
including optional cohorts, is up to 160 patients.
About ALN-AGT
ALN-AGT 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 regulation and whose inhibition has well-established
anti-hypertensive effects. ALN-AGT inhibits the synthesis of AGT in
the liver, potentially leading to durable reductions in AGT protein
and ultimately, in the vasoconstrictor angiotensin (Ang) II.
ALN-AGT 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 ALN-AGT have not been evaluated by the FDA,
EMA or any other health authority.
About Hypertension
Hypertension is a complex multifactorial disease clinically
defined by most major guidelines as a systolic blood pressure (SBP)
of above 140 mm Hg or a diastolic blood pressure (DBP) greater than
90 mm Hg, though AHA/ACC guidelines have a lower threshold of a SBP
above 130 mm Hg or a DBP greater than 80 mm Hg. More than one
billion people worldwide live with hypertension. 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 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 therapies and peak and trough effects. In particular,
there are a number of high unmet need settings where novel
approaches to hypertension are warranted, including resistant and
refractory hypertension, chronic kidney disease, and heart
failure.
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 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 (Nasdaq: ALNY) is leading 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 genetic, cardio-metabolic, hepatic infectious, and central
nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning
science, RNAi therapeutics represent a powerful, clinically
validated approach for the treatment of a wide range of severe and
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust RNAi therapeutics platform. Alnylam’s commercial RNAi
therapeutic products are ONPATTRO® (patisiran), GIVLAARI®
(givosiran), OXLUMO™ (lumasiran), and Leqvio® (inclisiran) being
developed and commercialized by Alnylam’s partner Novartis. Alnylam
has a deep pipeline of investigational medicines, including six
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, or on Instagram.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including, without limitation,
Alnylam’s views with respect to the effects of treatment with
ALN-AGT in knocking down AGT and reducing BP and the associated
safety profile, the durability of ALN-AGT potentially supporting a
once quarterly or biannual dosing regimen, the potential of ALN-AGT
to transform the way hypertension is managed, expectations
regarding the initiation of Phase 2 studies of ALN-AGT, and
Alnylam’s ability to achieve its “Alnylam P5x25” strategy,
constitute forward-looking statements for the purposes of the safe
harbor provisions under The Private Securities Litigation Reform
Act of 1995. 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 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 its product candidates;
actions or advice of regulatory agencies and Alnylam’s ability to
obtain and maintain regulatory approval for its product candidates,
as well as favorable pricing and reimbursement; successfully
launching, marketing and selling its approved products globally;
delays, interruptions or failures in the manufacture and supply of
its product candidates or its marketed products; obtaining,
maintaining and protecting intellectual property; Alnylam’s ability
to successfully expand the indication for ONPATTRO 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, Regeneron and Vir; the outcome of
litigation; the risk of government investigations; and unexpected
expenditures; as well as those risks more fully discussed in the
“Risk Factors” filed with Alnylam's most recent Annual Report on
Form 10-K filed with the Securities and Exchange Commission (SEC)
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 April 2021. ii Improving
Medication Adherence Among Patients with Hypertension. Million
Hearts.
https://millionhearts.hhs.gov/data-reports/factsheets/adherence.html.
Published April 2020. Accessed April 2021.
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version on businesswire.com: https://www.businesswire.com/news/home/20210411005027/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media) +1 617-682-4340 Joshua Brodsky (Investors) +1
617-551-8276
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