– Companies Expect to Initiate Phase 1 Study in
Late 2014 or Early 2015, with Initial Clinical Results Mid-2015
–
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi
therapeutics company, and The Medicines Company (Nasdaq:MDCO), a
global biopharmaceutical company focusing on saving lives,
alleviating suffering and contributing to the economics of
healthcare by focusing on the world’s leading acute/intensive care
hospitals, announced today that Alnylam has filed a Clinical Trial
Application (CTA) with the U.K. Medicines and Healthcare products
Regulatory Agency (MHRA) to initiate a Phase 1 clinical trial with
ALN-PCSsc, an investigational agent for the treatment of
hypercholesterolemia. ALN-PCSsc is a subcutaneously administered
RNAi therapeutic targeting the gene proprotein convertase
subtilisin/kexin type 9 (PCSK9), a target validated by human
genetics that is involved in the metabolism of low-density
lipoprotein cholesterol (LDL-C, or “bad” cholesterol). Per the
filed CTA, the Phase 1 trial of ALN-PCSsc will be conducted in
the U.K. as a randomized, single-blind,
placebo-controlled, single ascending- and multi-dose study,
enrolling up to 76 volunteer subjects with elevated baseline LDL-C
(≥ 100 mg/dL). Following approval of the CTA, the companies expect
to initiate dosing in the Phase 1 trial in late 2014 or early 2015,
with initial data expected to be reported in mid-2015.
“As a first-in-class PCSK9 synthesis inhibitor, we believe that
ALN-PCSsc represents an innovative, differentiated, and
well-validated approach for the treatment of hypercholesterolemia.
First, pre-clinical, non-human primate studies have demonstrated
the potential for a once-monthly, and possibly once-quarterly, low
volume subcutaneous dose regimen. Further, the mechanism of action
for ALN-PCSsc enables LDL-C lowering independent of baseline PCSK9
plasma levels, which we believe could result in additive or even
synergistic activity in combination with statins. Accordingly,
we’re very excited to advance this investigational RNAi therapeutic
to clinical stages with this CTA filing,” said Akshay Vaishnaw,
M.D., Ph.D., Executive Vice President and Chief Medical Officer of
Alnylam. “ALN-PCSsc now becomes our third RNAi therapeutic that
utilizes our proprietary, clinically validated GalNAc conjugate
delivery platform to enter a clinical development stage, and the
second that utilizes our optimized ESC-GalNAc technology. Together
with The Medicines Company, we look forward to the continued
advancement of ALN-PCSsc, including the start of our Phase 1
clinical trial in the coming months, with initial data expected in
mid-2015.”
“Elevated LDL-C remains a major risk factor for coronary artery
disease, and new therapies are needed for patients who are
refractory or intolerant to current approaches for management of
their LDL-C levels. Together with recent progress in our other
efforts, ALN-PCSsc is a key program in our pipeline of innovative
medicines for hypercholesterolemia and atherosclerosis. Based on
its mechanism of action and pre-clinical results, we believe that
ALN-PCSsc has a highly competitive profile as compared with
anti-PCSK9 monoclonal antibodies and a potential for a less
frequent, small volume dosing regimen, and we look forward to
confirming this potential in the clinic,” said David Kallend, MB.BS
(Lon), Vice President and Global Medical Director for the lipid
programs at The Medicines Company. “This new CTA filing is an
important milestone in our collaboration with Alnylam, and we very
much look forward to the start of Phase 1. Assuming positive
results, The Medicines Company will lead the collaborative effort
in subsequent stages of development and commercialization.”
ALN-PCSsc is a subcutaneously administered RNAi therapeutic that
utilizes Alnylam’s proprietary Enhanced Stabilization Chemistry
(ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA
conjugates are designed to achieve targeted delivery of RNAi
therapeutics to hepatocytes through uptake by the
asialoglycoprotein receptor, and enable subcutaneous dosing with
increased potency and durability and a wide therapeutic index.
Recent pre-clinical results in non-human primate (NHP) studies
demonstrated that a single dose of ALN-PCSsc significantly reduced
plasma PCSK9 protein by up to 96%, with mean PCSK9 knockdown at
nadir of 88% at the top dose. Results also showed lowering of LDL-C
of up to 77%, with a mean reduction of 69% at the top dose; these
results were observed in the absence of statin co-administration.
Knockdown of PCSK9 and lowering of LDL-C were rapid and durable,
with maximal effects lasting greater than 90 days and returning to
baseline at approximately 160 days. At the top dose of 10 mg/kg, an
over 50% reduction in LDL-C was maintained for over 90 days.
Moreover, there was sustained and clamped knockdown of PCSK9 and
reduction of LDL-C across this entire time period, which contrasts
with the cyclical variation in LDL-C observed with monthly dose
regimens of anti-PCSK9 monoclonal antibodies (Stein, Curr Opin
Lipidol 2013, 24:510–517). All together, these pre-clinical data
are supportive of a once-monthly, and possibly once-quarterly,
dosing regimen, which could represent a highly competitive target
product profile. In addition, four-week GLP toxicology studies
evaluating doses administered every other week confirmed that
ALN-PCSsc has a wide therapeutic index, with a No Observed Adverse
Effect Level (NOAEL) of greater than 250 mg/kg in rats and NHP.
Alnylam and collaborators previously published complete study
results from a Phase 1 trial with ALN-PCS02 in The Lancet
(Fitzgerald, et al., The Lancet,
doi:10.1016/S0140-6736(13)61914-5). ALN-PCS02 is an intravenously
administered RNAi therapeutic targeting PCSK9. The paper showed
that ALN-PCS02 administration resulted in rapid, dose-dependent
knockdown of plasma PCSK9 of up to 84% relative to baseline and
placebo, with a corresponding reduction in serum levels of LDL-C of
up to 57% relative to baseline and placebo. The knockdown of PCSK9
and lowering of LDL-C were also found to be durable, with effects
lasting for weeks after a single dose. ALN-PCS02 was shown to be
well tolerated in this Phase 1 study and there were no serious
adverse events related to study drug administration.
As per the filed CTA, the Phase 1 trial of ALN-PCSsc will be
conducted as a randomized, single-blind, placebo-controlled, single
ascending- and multi-dose, subcutaneous dose-escalation study. The
study is designed to enroll up to 76 volunteer subjects with
elevated baseline LDL-C (≥ 100 mg/dL), with subjects randomized
3:1, drug:placebo. The study will be performed in two phases: a
single ascending dose (SAD) phase and a multi-dose phase. In the
multi-dose phase, subjects will receive two subcutaneous doses of
either ALN-PCSsc or placebo administered four weeks apart; the
multi-dose phase will also include subjects both on and off statin
co-medication. The primary objective of the Phase 1 study is to
evaluate the safety and tolerability of ALN-PCSsc. Secondary
objectives include assessment of clinical activity as determined by
knockdown of plasma PCSK9 levels and serum LDL-C levels, as well as
pharmacokinetics of ALN-PCSsc.
Alnylam and The Medicines Company are collaborating in the
advancement of ALN-PCSsc per the companies’ agreement formed in
early 2013. Under the terms of the agreement, Alnylam will complete
certain pre-clinical studies and a Phase 1 clinical study of
ALN-PCSsc and The Medicines Company is responsible for leading and
funding development from Phase 2 forward as well as potential
commercialization.
About Hypercholesterolemia
Hypercholesterolemia is a condition characterized by very high
levels of cholesterol in the blood which is known to increase the
risk of coronary artery disease, the leading cause of death in the
U.S. Some forms of hypercholesterolemia can be treated through
dietary restrictions, lifestyle modifications (e.g., exercise and
smoking cessation) and medicines such as statins. However, a large
proportion of patients with hypercholesterolemia are not achieving
adequate LDL-C levels with currently available therapies including
statins, including genetic familial hypercholesterolemia (FH)
patients, acute coronary syndrome patients, high-risk patient
populations (e.g., patients with coronary artery disease,
diabetics, symptomatic carotid artery disease, etc.) and other
patients that are statin intolerant. Severe forms of
hypercholesterolemia are estimated to affect more than 500,000
patients worldwide, and as a result, there is a significant need
for novel therapeutics to treat patients with hypercholesterolemia
whose disease is inadequately managed by existing therapies.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC) GalNAc Conjugates
GalNAc-siRNA conjugates are a proprietary Alnylam delivery
platform and are designed to achieve targeted delivery of RNAi
therapeutics to hepatocytes through uptake by the
asialoglycoprotein receptor. Alnylam’s Enhanced Stabilization
Chemistry (ESC) GalNAc-conjugate technology enables subcutaneous
dosing with increased potency, durability, and a wide therapeutic
index, and is being employed in several of Alnylam’s genetic
medicine programs, including programs in clinical development.
About RNAi
RNAi (RNA interference) is a revolution in biology, representing
a breakthrough in understanding how genes are turned on and off in
cells, and a completely new approach to drug discovery and
development. Its discovery has been heralded as “a major scientific
breakthrough that happens once every decade or so,” and represents
one of the most promising and rapidly advancing frontiers in
biology and drug discovery today which was awarded the 2006 Nobel
Prize for Physiology or Medicine. RNAi is a natural process of gene
silencing that occurs in organisms ranging from plants to mammals.
By harnessing the natural biological process of RNAi occurring in
our cells, the creation of a major new class of medicines, known as
RNAi therapeutics, is on the horizon. Small interfering RNA
(siRNA), the molecules that mediate RNAi and comprise Alnylam's
RNAi therapeutic platform, target the cause of diseases by potently
silencing specific mRNAs, thereby preventing disease-causing
proteins from being made. RNAi therapeutics have the potential to
treat disease and help patients in a fundamentally new way.
About Alnylam Pharmaceuticals
Alnylam is a biopharmaceutical company developing novel
therapeutics based on RNA interference, or RNAi. The company is
leading the translation of RNAi as a new class of innovative
medicines with a core focus on RNAi therapeutics as genetic
medicines, including programs as part of the company’s “Alnylam
5x15™” product strategy. Alnylam’s genetic medicine programs are
RNAi therapeutics directed toward genetically defined targets for
the treatment of serious, life-threatening diseases with limited
treatment options for patients and their caregivers. These include:
patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic
targeting transthyretin (TTR) for the treatment of TTR-mediated
amyloidosis (ATTR) in patients with familial amyloidotic
polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi
therapeutic targeting TTR for the treatment of ATTR in patients
with TTR cardiac amyloidosis, including familial amyloidotic
cardiomyopathy (FAC) and senile systemic amyloidosis (SSA);
ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the
treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5,
an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1, an RNAi
therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for
the treatment of hepatic porphyrias including acute intermittent
porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for
the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic
targeting alpha-1 antitrypsin (AAT) for the treatment of AAT
deficiency-associated liver disease; ALN-HBV, an RNAi therapeutic
targeting the hepatitis B virus (HBV) genome for the treatment of
HBV infection; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for
the treatment of beta-thalassemia and iron-overload disorders;
ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3
(ANGPTL3) for the treatment of genetic forms of mixed
hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi
therapeutic targeting apolipoprotein C-III (apoCIII) for the
treatment of hypertriglyceridemia; ALN-AGT, an RNAi therapeutic
targeting angiotensinogen (AGT) for the treatment of hypertensive
disorders of pregnancy (HDP), including preeclampsia; ALN-GO1, an
RNAi therapeutic targeting glycolate oxidase (GO) for the treatment
of primary hyperoxaluria type 1 (PH1); and other programs yet to be
disclosed. As part of its “Alnylam 5x15” strategy, as updated in
early 2014, the company expects to have six to seven genetic
medicine product candidates in clinical development – including at
least two programs in Phase 3 and five to six programs with human
proof of concept – by the end of 2015. The company’s demonstrated
commitment to RNAi therapeutics has enabled it to form major
alliances with leading companies including Merck, Medtronic,
Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist,
GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In
early 2014, Alnylam and Genzyme, a Sanofi company, formed a
multi-product geographic alliance on Alnylam's genetic medicine
programs in the rare disease field. Specifically, Alnylam will lead
development and commercialization of programs in North America and
Europe, while Genzyme will develop and commercialize products in
the rest of world. In addition, Alnylam and Genzyme will co-develop
and co-commercialize ALN-TTRsc in North America and Europe. In
March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned
subsidiary of Merck. In addition, Alnylam holds an equity position
in Regulus Therapeutics Inc., a company focused on discovery,
development, and commercialization of microRNA therapeutics.
Alnylam scientists and collaborators have published their research
on RNAi therapeutics in over 200 peer-reviewed papers, including
many in the world’s top scientific journals such as Nature, Nature
Medicine, Nature Biotechnology, Cell, New England Journal of
Medicine, and The Lancet. Founded in 2002, Alnylam maintains
headquarters in Cambridge, Massachusetts. For more information,
please visit www.alnylam.com.
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 potential for RNAi
therapeutics, including ALN-PCSsc for the treatment of
hypercholesterolemia, the timing of clinical studies, including the
reporting of data from clinical studies, the potential therapeutic
opportunities for ALN-PCSsc, as well as its expectations regarding
its “Alnylam 5x15” product strategy, and its plans regarding
commercialization of RNAi therapeutics, including ALN-PCSsc,
constitute forward-looking statements for the purposes of the safe
harbor provisions under The Private Securities Litigation Reform
Act of 1995. Actual results may differ materially from those
indicated by these forward-looking statements as a result of
various important factors, including, without limitation, Alnylam’s
ability to discover and develop novel drug candidates and delivery
approaches, successfully demonstrate the efficacy and safety of its
drug candidates, the pre-clinical and clinical results for its
product candidates, which may not support further development of
product candidates, actions of regulatory agencies, which may
affect the initiation, timing and progress of clinical trials,
obtaining, maintaining and protecting intellectual property,
Alnylam’s ability to enforce its patents against infringers and
defend its patent portfolio against challenges from third parties,
obtaining regulatory approval for products, competition from others
using technology similar to Alnylam’s and others developing
products for similar uses, Alnylam’s ability to manage operating
expenses, Alnylam’s ability to obtain additional funding to support
its business activities and establish and maintain strategic
business alliances and new business initiatives, Alnylam’s
dependence on third parties for development, manufacture,
marketing, sales and distribution of products, the outcome of
litigation, 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 to update any forward-looking
statements.
About The Medicines Company
The Medicines Company's purpose is to save lives, alleviate
suffering and contribute to the economics of healthcare by focusing
on 3000 leading acute/intensive care hospitals worldwide. Its
vision is to be a leading provider of solutions in three areas:
serious infectious disease care, acute cardiovascular care, and
surgery and perioperative care. The company operates in the
Americas, Europe and the Middle East, and Asia Pacific regions with
global centers today in Parsippany, NJ, USA and Zurich,
Switzerland.
The Medicines Company Forward-Looking Statements
Statements contained in this press release about The Medicines
Company that are not purely historical, and all other statements
that are not purely historical, may be deemed to be forward-looking
statements for purposes of the safe harbor provisions under The
Private Securities Litigation Reform Act of 1995. Without limiting
the foregoing, the words “believes,” “anticipates” “expects” and
“potential” and similar expressions, are intended to identify
forward-looking statements. These forward-looking statements
involve known and unknown risks and uncertainties that may cause
the Company's actual results, levels of activity, performance or
achievements to be materially different from those expressed or
implied by these forward-looking statements. Important factors that
may cause or contribute to such differences include whether the
Company's products will advance in the clinical trials process on a
timely basis or at all, whether the Company will make regulatory
submissions for product candidates on a timely basis, whether its
regulatory submissions will receive approvals from regulatory
agencies on a timely basis or at all, whether physicians, patients
and other key decision makers will accept clinical trial results
and such other factors as are set forth in the risk factors
detailed from time to time in the Company's periodic reports and
registration statements filed with the Securities and Exchange
Commission including, without limitation, the risk factors detailed
in the Company's Quarterly Report on Form 10-Q filed with the SEC
on August 4, 2014, which are incorporated herein by reference. The
Company specifically disclaims any obligation to update these
forward-looking statements.
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Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations and Corporate
CommunicationsorThe Medicines CompanyRobert F. LavertyVice
President, Global Communications973-290-6162 (office)609-558-5570
(mobile)robert.laverty@themedco.comorMedia:SpectrumLiz Bryan,
202-955-6222 x2526
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