Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has presented new pre-clinical data
from its investigational RNAi therapeutic programs toward genetically
validated targets in development for the treatment of cardiovascular
metabolic diseases, including: ALN-PCSsc targeting PCSK9 for the
treatment of hypercholesterolemia; ALN-AC3 targeting apolipoprotein C3
(apoC3) for the treatment of hypertriglyceridemia; and ALN-ANG targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia. These new
data are being presented at the American Heart Association (AHA)
Scientific Sessions 2014 in a poster presentation titled “Development of
Monthly to Quarterly Subcutaneous Administration of RNAi Therapeutics
Targeting the Metabolic Disease Genes PCSK9, ApoC3 and ANGPTL3.” Among
other data, Alnylam presented new pre-clinical multi-dose data in
non-human primates (NHPs) with over six months of dosing for ALN-PCSsc
showing robust and clamped knockdown of PCSK9 of up to 92% and
reductions in LDL-C of up to 77% with a once-monthly subcutaneous dosing
regimen. Recently, Alnylam filed and received approval for a Clinical
Trial Application (CTA) for ALN-PCSsc, and now expects to start the
Phase 1 trial before year’s end with initial clinical data expected in
mid-2015.
“ALN-PCSsc is a first-in-class PCSK9 synthesis inhibitor that we believe
represents an innovative, differentiated, and well-validated approach
for the treatment of hypercholesterolemia. Our new non-human primate
studies confirm 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. Together with
our partners at The Medicines Company, we look forward to the start of
our Phase 1 clinical trial in the coming weeks, with initial data
expected in mid-2015,” said Rachel Meyers, Ph.D., Vice President,
Research and RNAi Lead Development at Alnylam. “We also presented new
data at AHA on our ALN-AC3 and ALN-ANG programs, which expand our
pipeline of investigational RNAi therapeutics toward genetically
validated targets for cardio-metabolic diseases. Indeed, we see this as
an attractive area for continued investment by Alnylam given the
significant disease burden and unmet need for new medicines, the large
number of liver-expressed disease-causing genes important in
cardio-metabolic disease, and the emerging tolerability, activity, and
durability profile of our GalNAc-conjugate platform.”
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. The new pre-clinical NHP
studies showed that monthly subcutaneous administration of ALN-PCSsc
resulted in PCSK9 knockdown of up to 92% and LDL-C lowering, in the
absence of statin co-administration, of up to 77%; mean maximum
knockdown of PCSK9 was 83.2% +/- 7.2%, and mean maximum LDL-C reduction
was 59.0% +/- 13.3%. As a PCSK9 synthesis inhibitor, ALN-PCSsc showed
rapid, durable, and clamped knockdown of PCSK9 and reduction of LDL-C,
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). Based on current human translational
data with ESC-GalNAC-conjugates, the projected human dose levels are
expected to be less than 1 mg/kg at a subcutaneous injection volume of
less than 1 mL administered once-monthly. In aggregate, these
pre-clinical data are supportive of a once-monthly, and possibly
once-quarterly, dosing regimen for ALN-PCSsc, which the company believes
could represent a highly competitive target product profile.
Alnylam’s CTA for a Phase 1 trial with ALN-PCSsc has been approved and
the company now expects to initiate this study before the end of this
year, with initial data expected to be reported in mid-2015. The Phase 1
trial of ALN-PCSsc will be conducted as a randomized, single-blind,
placebo-controlled, single- and multi-dose, dose-escalation study. The
study is designed to enroll up to 76 healthy 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 multiple dose (MD) phase. In the MD
phase, subjects will receive two doses of either ALN-PCSsc or placebo
administered four weeks apart. The MD 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. In support of the approved
CTA, Alnylam has completed toxicology studies in rodents and NHPs. In
both species, the no observed adverse effect level (NOAEL) was
determined to exceed 250 mg/kg, the top dose in both studies, with no
adverse findings in clinical, hematology, laboratory chemistry, and
histopathology assessments. Alnylam is collaborating with The Medicines
Company on the advancement of ALN-PCSsc.
Alnylam also presented data from its ALN-AC3 program at AHA. ALN-AC3 is
a subcutaneously administered investigational RNAi therapeutic targeting
apoC3 for the treatment of hypertriglyceridemia. ApoC3 is a component of
lipoprotein particles in the blood; it inhibits lipoprotein lipase and
hepatic lipase, reducing hepatic uptake of triglyceride-rich particles.
Polymorphisms in apoC3 have been associated with hypertriglyceridemia;
specifically, a gain-of function phenotype leads to higher apoC3 and
triglyceride levels, and reduced triglyceride clearance. In contrast,
loss-of-function mutations in apoC3 result in greater triglyceride
hydrolysis into free fatty acids and increased triglyceride clearance;
heterozygous individuals have lower triglycerides and lower levels of
very low density lipoprotein (VLDL). Recent studies have identified rare
loss of function variants in apoC3 that appear to be cardioprotective
(Tachmazidou et al., Nat. Comm, 2013; Bochem et.al. Clin Genet.,
2014). The new data presented were from studies conducted in mouse
models that match human genetics. Specifically, a single 3 mg/kg dose of
a GalNAc-conjugated siRNA targeting apoC3 resulted in knockdown of apoC3
levels of up to 94%, with more than 60% knockdown sustained for at least
30 days. In a multi-dose study, results showed that dosing of 3 mg/kg
every other week resulted in 96% knockdown of human apoC3 through day
35, the last time point in the study. Alnylam plans to continue to
conduct additional pre-clinical work in this program to finalize its
Development Candidate.
In addition to ALN-PCSsc and ALN-AC3, Alnylam is also advancing ALN-ANG,
an investigational RNAi therapeutic targeting ANGPTL3 for the treatment
of genetic forms of mixed hyperlipidemia and severe
hypertriglyceridemia. ANGPTL3 is an inhibitor of cellular lipases
involved in the metabolism of lipoproteins. Human genetic as well as
exome sequencing studies have identified a statistically significant
relationship of loss-of-function mutations in ANGPTL3 with decreased
levels of triglycerides and LDL-C (Musunuru et al., N. Engl.
J. Med (2010) 363:2220-2227). New data presented at AHA demonstrated
that a single dose of a GalNAc-siRNA targeting ANGPTL3 led to robust,
dose-dependent knockdown of serum ANGPTL3 protein of up to 99%, with a
single dose ED90 of approximately 1 mg/kg. In studies
performed in an “ob/ob” mouse model of obesity and mixed hyperlipidemia,
ALN-ANG treatment as a single 3 mg/kg dose resulted in a greater than
80% reduction in levels of triglycerides and LDL-C. In addition, total
cholesterol was reduced up to 68%. These data with ALN-ANG support
further advancement of this program for the treatment of genetic forms
of mixed hyperlipidemia and severe hypertriglyceridemia, which are
associated with increased risk of coronary artery disease and/or
recurrent pancreatitis. Alnylam is conducting additional pre-clinical
research to finalize its Development Candidate for the ALN-ANG program.
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 Mixed Hyperlipidemia and Hypertriglyceridemia
Mixed hyperlipidemia is a genetically inherited condition characterized
by very high levels of cholesterol and triglycerides in the blood, both
of which are known to increase the risk of coronary artery disease, the
leading cause of death in the U.S. It is estimated that as many as 1 out
of every 100 individuals have mixed hyperlipidemia and are at increased
risk of developing cardiovascular disease. Some forms of mixed
hyperlipidemia can be treated through dietary restrictions, lifestyle
modifications (e.g., exercise and smoking cessation), and medicines such
as statins or fibrates; however, a large portion of mixed hyperlipidemia
patients are unable to reach either their LDL-C and/or triglyceride
goals with the current standard of care. Patients with severe, inherited
forms of hypertriglyceridemia (e.g., familial chylomicronemia syndrome,
or “FCS”) are at extremely high risk of developing recurrent
pancreatitis. FCS is a rare orphan genetic disease that affects 1 to 2
individuals per million.
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 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) targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR)
in patients with familial amyloidotic polyneuropathy (FAP); revusiran
(ALN-TTRsc) 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 targeting antithrombin
(AT) for the treatment of hemophilia and rare bleeding disorders (RBD);
ALN-CC5 targeting complement component C5 for the treatment of
complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid
synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including
acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the
treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin
(AAT) for the treatment of AAT deficiency-associated liver disease;
ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment
of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of
beta-thalassemia and iron-overload disorders; ALN-ANG targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting
apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia;
ALN-AGT targeting angiotensinogen (AGT) for the treatment of
hypertensive disorders of pregnancy (HDP), including preeclampsia;
ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary
hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus
(HDV) genome for the treatment of HDV infection; ALN-PDL targeting
programmed death ligand 1 (PD-L1) for the treatment of chronic liver
infections; 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
revusiran 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; ALN-AC3
targeting apolipoprotein C-3 (apoC3) for the treatment of
hypertriglyceridemia; and ALN-ANG for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia; including the
timing of beginning clinical studies and reporting data, the potential
therapeutic opportunities for ALN-PCSsc, ALN-AC3, and ALN-ANG, as well
as its expectations regarding its “Alnylam 5x15” product strategy, and
its plans regarding commercialization of RNAi therapeutics, including
ALN-PCSsc, ALN-AC3 and ALN-ANG, 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.
Copyright Business Wire 2014