− Patients Receiving Investigational ALN-AGT
Experienced Dose-Dependent Reductions in Blood Pressure, Confirming
Potential for RNAi-Mediated Angiotensinogen (AGT) Silencing as a
Novel Therapeutic Approach for Hypertension –
− Durable AGT Knockdown Through 12 Weeks
Supports a Once Quarterly or Potentially Less Frequent Dosing
Regimen –
− ALN-AGT Generally Well Tolerated, with No
Treatment-Related Serious Adverse Events or Study Discontinuations
–
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today positive interim data 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 in a poster presentation at the American Heart
Association (AHA) Scientific Sessions 2020, taking place virtually
from November 13 – 17, 2020.
Data presented at the AHA Scientific Sessions are from the
ongoing Phase 1 study of ALN-AGT with a data cut-off date of
September 16, 2020. The study is a randomized, double-blind,
placebo-controlled, single ascending dose (SAD) study, evaluating
the safety, tolerability and preliminary pharmacokinetic and
pharmacodynamic activity of ALN-AGT in patients with mild or
moderate hypertension, who were either treatment naïve or had
discontinued other anti-hypertensive medications. Patients (N=60)
had a mean age of 52 years (range 35 – 65) and a mean baseline
24-hour systolic blood pressure (SBP) and diastolic blood pressure
(DBP) of 139 (standard deviation [SD] +/- 8) millimeters of mercury
(mm Hg) and 86 (SD +/- 7) mm Hg, respectively. Patients were
enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg
or 200 mg ALN-AGT (N=12 per cohort; 2:1 randomization of
ALN-AGT:placebo).
Compared to placebo, patients treated with ALN-AGT experienced
dose-dependent reductions in serum AGT — the sole precursor of all
angiotensin peptides, including the potent vasoconstrictor
angiotensin (Ang) II. In the 200 mg dose cohort, the mean reduction
(+/- standard error [SE]) of AGT at 8 weeks was 94.9 +/- 1.6
percent. Reductions of more than 90 percent persisting through 12
weeks after single doses of 100 or 200 mg were observed, with up to
97.6 percent AGT knockdown at 200 mg. The durability of AGT
knockdown supports the potential for once quarterly dosing and
possibly even less frequent dosing.
Suboptimal blood pressure (BP) control is the most common
attributable risk factor for cardiovascular disease and
cerebrovascular disease, and a leading cause of chronic kidney
disease progression. In the Phase 1 study, lowering of BP was
observed concomitantly with AGT knockdown, with a greater than 10
mm Hg reduction of mean 24-hour SBP observed at Week 8 in cohorts
receiving doses of 100 or 200 mg, as measured by ambulatory BP
monitoring (ABPM). At 200 mg, mean BP reductions (+/- SE) at 8
weeks were 11.0 +/- 2.4 mm Hg for systolic and 7.7 +/- 1.1 mm Hg
for diastolic BP. Maximum reductions up to 19.0 mm Hg and 12.3 mm
Hg were observed in SBP and DBP, respectively.
“We believe these initial data for ALN-AGT support the potential
for a fundamentally new approach in the management of hypertension,
a disease where innovation has been lacking for decades. With
approximately half of all hypertensive patients experiencing poor
BP control, there is a significant need for new therapies that
achieve improved patient adherence and sustained BP control between
dosing intervals,” said Lauren Melton, Senior Director, Program
Leader, ALN-AGT Program at Alnylam. “By blocking the source of all
angiotensin peptides through RNAi-mediated AGT silencing, we
believe ALN-AGT has the potential for prolonged pharmacodynamic
effect, infrequent dosing administration and sustained BP
reductions, which could help patients reach and maintain their BP
goal, thereby reducing their risk for cardiovascular disease
without the burden of multiple daily medications.”
ALN-AGT was shown to be generally well tolerated with an
acceptable safety profile for continued development. 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 40 patients (12.5
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.
“Hypertension is recognized to be a modifiable risk factor for
cardiovascular disease and a major contributor to death and
disability worldwide. Despite the availability of effective
antihypertensive therapy, treatment to guideline-recommended blood
pressure targets remains suboptimal in clinical practice. While a
number of factors are likely responsible for this treatment gap,
high patient pill burden and inconsistent adherence to prescribed
therapies may play an important role,” said Akshay Desai, M.D.,
M.P.H., Director of the Cardiomyopathy and Heart Failure Program in
the Cardiovascular Division at Brigham and Women's Hospital and
Associate Professor of Medicine at Harvard Medical School. “The
interim Phase 1 study results of ALN-AGT suggesting a
dose-dependent and sustained reduction in blood pressure persisting
up to 3 months after a single subcutaneous dose are promising and
may offer a novel path to securing better treatment adherence and
improved blood pressure control. Further study to establish the
safety and clinical efficacy of this approach seems warranted.”
To view the data presented by Alnylam at the AHA Scientific
Sessions, 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 subcutaneously administered ALN-AGT in patients with
essential hypertension. The study will be 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 184
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 as a systolic blood pressure of above 130 mm Hg or a
diastolic blood pressure of greater than 80 mm Hg. Approximately 47
percent of U.S. adults live with hypertension with more than half
of patients on medication remaining above the blood pressure target
level. Despite the availability of antihypertensive medications,
there remains an unmet medical need, particularly 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 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 (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), approved in the
U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI®
(givosiran), approved in the U.S., EU, Brazil, and Canada. Alnylam
has a deep pipeline of investigational medicines, including six
product candidates that are in late-stage development. Alnylam is
executing on its “Alnylam 2020” strategy of building a
multi-product, commercial-stage biopharmaceutical company with a
sustainable pipeline of RNAi-based medicines to address the needs
of patients who have limited or inadequate treatment options and
now expects to exceed its “Alnylam 2020” guidance. 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 or on LinkedIn.
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 safety and clinical activity of
ALN-AGT and its potential for to be a fundamentally new approach in
the management of hypertension, the potential for ALN-AGT to
demonstrate prolonged pharmacodynamic effect, infrequent dosing
administration and sustained BP reductions, expectations regarding
the potential for a once quarterly or even less frequent dose
regimen for ALN-AGT due to the durability of AGT knockdown, and
expectations regarding the continued execution on and potential to
exceed its “Alnylam 2020” guidance for the advancement and
commercialization of RNAi therapeutics, 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, such as the scope and duration of
the outbreak, government actions and restrictive measures
implemented in response, material delays in diagnoses of rare
diseases, initiation or continuation of treatment for diseases
addressed by Alnylam products, or in patient enrollment in clinical
trials, potential supply chain disruptions, and other potential
impacts to Alnylam’s business, the effectiveness or timeliness of
steps taken by Alnylam to mitigate the impact of the pandemic, and
Alnylam’s ability to execute business continuity plans to address
disruptions caused by the COVID-19 or any future 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, including ALN-AGT; the
pre-clinical and clinical results for its product candidates,
including ALN-AGT, which may not be replicated or continue to occur
in other subjects or in additional studies or otherwise support
further development of product candidates for a specified
indication or at all; actions or advice of regulatory agencies,
which may affect the design, initiation, timing, continuation
and/or progress of clinical trials or result in the need for
additional pre-clinical and/or clinical testing; delays,
interruptions or failures in the manufacture and supply of its
product candidates, including ALN-AGT, or its marketed products;
obtaining, maintaining and protecting intellectual property;
intellectual property matters including potential patent litigation
relating to its platform, products or product candidates; obtaining
regulatory approval for its product candidates, and maintaining
regulatory approval and obtaining pricing and reimbursement for its
products, including ONPATTRO and GIVLAARI; successfully launching,
marketing and selling its approved products globally, including
ONPATTRO and GIVLAARI, and achieving net product revenues for
ONPATTRO within its revised expected range during 2020; Alnylam’s
ability to successfully expand the indication for ONPATTRO in the
future; competition from others using technology similar to
Alnylam's and others developing products for similar uses;
Alnylam's ability to manage its growth and operating expenses
within the ranges of guidance provided by Alnylam through the
implementation of further discipline in operations to moderate
spend and its ability to achieve a self-sustainable financial
profile in the future without the need for future equity financing;
Alnylam’s ability to establish and maintain strategic business
alliances and new business initiatives; Alnylam's dependence on
third parties, including Regeneron, for development, manufacture
and distribution of certain products, including eye and CNS
products and Vir for the development of ALN-COV and other potential
RNAi therapeutics targeting SARS-CoV-2 and host factors for
SARS-CoV-2; 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 Quarterly Report on Form 10-Q filed with the Securities
and Exchange Commission (SEC) and in other filings that Alnylam
makes with the SEC. 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.
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version on businesswire.com: https://www.businesswire.com/news/home/20201113005290/en/
Alnylam Pharmaceuticals, Inc. Christine Regan Lindenboom
(Investors and Media)
617-682-4340 Joshua Brodsky (Investors) 617-551-8276
Alnylam Pharmaceuticals (NASDAQ:ALNY)
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