– Investigational First-in-Class PCSK9
Synthesis Inhibitor Achieves up to 83% Maximal and 64% Mean Maximum
LDL-C Lowering, Comparable to Published Results with Anti-PCSK9
Monoclonal Antibodies, but with Clinically Significant Reductions
in LDL-C Clamped Down for More than 140 Days after Just a Single
Dose –
– ALN-PCSsc Generally Well Tolerated with No
Clinically Significant Drug-Related Adverse Events to Date –
– Program Lead Transitions from Alnylam to The
Medicines Company, who Together Launch “ORION™” Development
Program, with Initial Phase 2 Start Planned by End-2015 and Phase 3
Start Expected in 2017; ORION to Include Comparative Study with
Anti-PCSK9 Monoclonal Antibodies –
– Companies to Host Conference Call Today,
Sunday, August 30th, at 9:30 a.m. ET to Discuss Results –
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 positive initial results from their
ongoing Phase 1 clinical trial with ALN-PCSsc at ESC Congress 2015
held August 29 – September 2, 2015, in London. ALN-PCSsc is an
investigational RNAi therapeutic targeting PCSK9 – a genetically
validated protein regulator of LDL receptor metabolism – being
developed for the treatment of hypercholesterolemia. In contrast to
anti-PCSK9 monoclonal antibodies (MAbs) that bind to PCSK9 in
blood, ALN-PCSsc is a first-in-class investigational medicine that
acts by turning off PCSK9 synthesis in the liver.
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In the Phase 1 study, subcutaneous administration of ALN-PCSsc
resulted in an up to 83% lowering of LDL-C, with an up to 64 ± 5%
mean maximum reduction, comparable to published results for
anti-PCSK9 MAbs (Zhang XL., et al., BMC Med, 2015). Similar
reductions in LDL-C were seen in patients on and off concomitant
statin therapy. The effects of ALN-PCSsc were highly durable, with
clinically significant and clamped reductions in LDL-C maintained
for over 140 days, supportive of a once-quarterly and possibly
bi-annual subcutaneous dose regimen. Maximal lowering effects on
LDL-C were consistently achieved at a dose of 300 mg associated
with a low injection volume of 1.5 mL; this dose was significantly
below the 800 mg top dose studied per the Phase 1 protocol.
Importantly, ALN-PCSsc was generally well tolerated with no
clinically significant drug-related adverse events. The development
leadership of ALN-PCSsc now transitions from Alnylam to The
Medicines Company, who together announce today initiation of the
ORIONTM development program, with an initial Phase 2 study planned
to begin by end-2015 and a Phase 3 study expected to begin by
end-2017. ORION is also expected to include a comparative study of
ALN-PCSsc with anti-PCSK9 MAbs.
“Our initial Phase 1 results with ALN-PCSsc, a first-in-class
investigational PCSK9 synthesis inhibitor, demonstrate robust,
dose-dependent, and durable reductions in LDL-C of up to 83%.
Remarkably, significant and clamped lowering of LDL-C is achieved
for over 140 days after a single dose. At the 300 mg dose – which
we believe is optimal, with fully saturating effects on both LDL-C
lowering and PCSK9 knockdown – an injection volume of 1.5 mL and
possibly lower can be achieved. Accordingly, we believe that these
results support a quarterly, and possibly bi-annual, low volume
subcutaneous dose regimen for further development,” said Akshay
Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and
Chief Medical Officer at Alnylam. “Importantly, ALN-PCSsc was
generally well tolerated with no clinically drug-related
significant adverse events to date. Based on these positive
results, we believe that ALN-PCSsc potentially represents an
innovative, differentiated, and well validated approach for the
treatment of hypercholesterolemia. We very much look forward to our
continued partnership with The Medicines Company as they now take
the lead in developing ALN-PCSsc in the ORION program.”
“Based on these initial Phase 1 results, we believe that
ALN-PCSsc has a highly competitive profile as compared with
anti-PCSK9 monoclonal antibodies that are labeled for twice-monthly
dosing. In particular, we believe that a maximally efficacious and
well tolerated quarterly or potentially bi-annual, low volume
subcutaneous dosing regimen could address the unmet needs for
hypercholesterolemia management in a massive, at-risk, often
non-adherent population worldwide. Moreover, we imagine that
ALN-PCSsc has the potential to open new innovation horizons with
patients, providers, and payers by linking the temporal cycle of
LDL-C monitoring with administration of therapy,” said David
Kallend, MBBS, Vice President and Global Medical Director at The
Medicines Company. “We are now initiating our broad-based ORION
development program to advance ALN-PCSsc toward approval and the
market. We expect to start our initial Phase 2 study by end of this
year, and plan to start our Phase 3 registration studies in 2017.
In addition, we plan on performing studies directly comparing
ALN-PCSsc with anti-PCSK9 MAbs to confirm the important features
and potential benefits of this first-in-class investigational PCSK9
synthesis inhibitor.”
“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. PCSK9 therapies have now emerged as a new class
of drugs for treatment of hypercholesterolemia, and I believe that
these agents have the potential to make a meaningful difference for
patients,” said John J.P. Kastelein, M.D., Ph.D., Professor of
Medicine and Chairman of the Department of Vascular Medicine at the
Academic Medical Center (AMC) of the University of Amsterdam. “I am
very encouraged by these initial clinical data with ALN-PCSsc,
especially the durability of LDL-C lowering effects. If the safety
and efficacy of this novel investigational PCSK9 synthesis
inhibitor can be confirmed in larger studies to support approval,
it may offer an important treatment option for patients,
physicians, and payers.”
The Phase 1 trial of ALN-PCSsc is being conducted in the U.K. as
a randomized, single-blind, placebo-controlled, single ascending-
and multi-dose, subcutaneous dose-escalation study. Enrollment in
the study has been completed, but the study is ongoing with
continued data collection and subject follow up. The study was
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 was performed in two phases: a single ascending
dose (SAD) phase and a multiple dose (MD) phase. The MD phase also
includes 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 lowering of serum LDL-C levels, as well as
pharmacokinetics of ALN-PCSsc.
All results are based on data in the database as of August 4,
2015. A total of 69 subjects were enrolled in the study, with a
mean baseline LDL-C of 146 mg/dL. A total of 24 subjects were
enrolled in five SAD cohorts and received placebo (N=6) or study
drug at fixed doses from 25 mg to 800 mg (N=3, per group; N=6 for
the 800 mg cohort). A total of 45 subjects were enrolled in six MD
cohorts, with subjects receiving: placebo (N=12); four doses of 125
mg once weekly (N=6); two doses of 250 mg once every two weeks
(N=6); two doses of 300 mg once every four weeks (N=6); two doses
of 300 mg once every four weeks with statin co-medication (N=4);
two doses of 500 mg once every four weeks (N=6); and two doses of
500 mg once every four weeks with statin co-medication (N=5).
In the SAD cohorts, ALN-PCSsc administration was associated with
potent, dose-dependent, and highly durable knockdown of PCSK9 and
lowering of LDL-C. An up to 86% maximal knockdown of PCSK9 relative
to baseline was achieved, with an up to 82 ± 2% mean maximum PCSK9
knockdown (p<0.001, compared to placebo). Even in the lowest
dose group of 25 mg, significant knockdown of PCSK9 was observed.
Maximal effects toward PCSK9 were achieved at the 300 mg dose, with
further dose escalation yielding minimal additive effects; the
volume of drug at the 300 mg dose was 1.5 mL. Knockdown of PCSK9
was highly durable, with a 62 ± 5% mean effect (p<0.05, compared
to baseline) in the 300 mg cohort maintained at 140 days after a
single dose.
In the SAD cohorts, an up to 78% maximal lowering of LDL-C was
achieved, with an up to 58 ± 4% mean maximum LDL-C lowering
(p<0.01, compared to placebo); absolute levels of LDL-C as low
as 30 mg/dL were observed. As with PCSK9 knockdown, maximal, fully
saturating effects on LDL-C lowering were achieved at the 300 mg
dose. Reductions in LDL-C were highly durable, with a 44 ± 1% mean
lowering (p<0.001, relative to baseline) in the 300 mg cohort
maintained at 140 days after a single dose; data collection beyond
140 days is ongoing. The least squares mean (LSM) % reduction in
LDL-C from baseline at 12 weeks – a measure used in studies of
anti-PCSK9 MAbs – was 50.1% in the 300 mg cohort; this is
comparable to the 50-60% range of values reported for MAbs, but was
achieved after just a single dose. The durable effects of ALN-PCSsc
support a once quarterly, and possibly bi-annual, low volume
subcutaneous dose regimen for evaluation in further clinical
studies. Results are summarized in the table below.
SAD Group
Maximum %PCSK9Knockdown
MeanMaximum %PCSK9Knockdown#
Mean %PCSK9Knockdownat Day 140^
Maximum %LDL-CLowering
MeanMaximum %LDL-CLowering#
Mean %LDL-CLowering atDay 140^
Placebo (N=6) 38 29 ± 4
N/A 25 19 ± 2 N/A 25 mg
(N=3) 60 54 ± 3 14
44 34 ± 5 15 100 mg (N=3)
73 49 ± 16 -4 ± 41
60 43 ± 9 39 ± 1* 300 mg (N=3)
82 78 ± 2***
62 ± 5*
67 53 ± 7 44 ± 1*** 500
mg (N=3) 86 76 ± 7*** 66
± 9 78 55 ± 12* 39 ± 20
800 mg (N=6) 86 82 ± 2***
Ongoing 69 58 ± 4**
Ongoing
#For mean maximum knockdown/reduction relative to baseline, p
values from pairwise comparisons vs. placebo using ANOVA model^For
mean knockdown/reduction relative to baseline at Day 140, p values
from pairwise t-tests vs. baseline*p less than 0.05**p less than
0.01***p less than 0.001
In the MD cohorts, ALN-PCSsc was associated with potent and
highly durable knockdown of PCSK9 and lowering of LDL-C, with
similar effects to those observed at lower study drug exposure in
SAD cohorts. An up to 94% PCSK9 knockdown and an up to 83% LDL-C
lowering were observed, including absolute levels of LDL-C as low
as 18 mg/dL. The LSM % reduction in LDL-C from baseline at 12 weeks
was 59.4% in the 300 mg once-monthly dose cohort. All MD groups
showed similar levels of PCSK9 knockdown and reductions in LDL-C,
indicating that all doses achieved a fully saturating effect for a
PCSK9 synthesis inhibitor with an approximately 80% knockdown of
PCSK9 and an approximately 60% LDL-C lowering. Also, PCSK9
knockdown and LDL-C lowering were similar in subjects with or
without statin co-administration, suggesting that ALN-PCSsc may be
able to substantially reduce LDL-C in individuals already on a
statin and not at target levels. Data collection beyond 98 days is
ongoing. Results are summarized in the table below.
MD Group
Maximum %PCSK9 Knockdown
Mean Maximum %PCSK9 Knockdown#
Maximum % LDL-CLowering
Mean Maximum %LDL-C Lowering#
Placebo (N=11)^ 63 29 ± 6
43 22 ± 3 125 mg qW x4 (N=6) 86
82 ± 1*** 60 51 ± 2 250 mg q2W
x2 (N=6) 85 81 ± 1*** 70
60 ± 5*** 300 mg qM x2 (N=6) 87
79 ± 3*** 79 64 ± 5*** 300 mg qM
x2 w/ statin (N=3)^ 88 86 ± 1***
69 52 ± 10 500 mg qM x2 (N=6) 86
81 ± 2*** 69 55 ± 7** 500
mg qM x2 w/ statin (N=5) 94 88 ± 2***
83 60 ± 8***
#For mean maximum knockdown/reduction relative to baseline, p
values from pairwise comparisons vs. placebo using ANOVA model*p
less than 0.05**p less than 0.01***p less than 0.001^One subject in
the placebo group received only a single dose; one subject in the
300 mg qM x2 with statin group received a single dose and
discontinued at day 14 due to incarceration; both were excluded
Additional Phase 1 clinical activity results – including further
durability data for PCSK9 knockdown and LDL-C lowering effects, as
well as changes in exploratory biomarkers such as total
cholesterol, apoB, non-HDL-C, and Lp(a) – are planned to be
presented at a future date.
ALN-PCSsc was found to be generally well tolerated, with no
clinically significant drug-related adverse events to date. There
were no serious adverse events (SAEs) or drug-related
discontinuations. All adverse events (AEs) were mild or moderate in
severity. At higher drug exposures of 500 mg or greater, four
subjects receiving ALN-PCSsc reported mild, localized injection
site reactions (ISRs) that resolved without medical intervention.
At or below the lowest maximally effective dose of 300 mg, there
were no ISRs noted in any SAD or MD cohort subjects (0/19). One
subject in the 500 mg MD group developed alanine transaminase (ALT)
elevations approximately 4 times upper limit of normal (ULN)
without change in bilirubin, but this was attributed to concomitant
statin therapy and improved upon statin discontinuation. There were
no clinically significant changes in other laboratory safety
measurements, including cytokine levels, or hematologic parameters.
There were also no clinically significant changes in renal function
tests.
The lead development responsibility for ALN-PCSsc will now
transition from Alnylam to The Medicines Company, who together will
be advancing ALN-PCSsc in the ORION development program, a
comprehensive global clinical development plan designed to support
ALN-PCSsc regulatory approval and market access worldwide. ORION
will begin with an initial Phase 2 study that is expected to start
by end of 2015. Further, the companies expect that Phase 3 clinical
trials will begin in 2017, and that ORION will include a
comparative study of ALN-PCSsc with anti-PCSK9 MAbs.
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.
Conference Call Information
Alnylam and The Medicines Company will host a conference call
today, Sunday, August 30, at 9:30 a.m. ET to discuss these initial
Phase 1 results with ALN-PCSsc and the ORION development program. A
slide presentation will also be available on the Investors page of
the Alnylam website, www.alnylam.com, and on The Medicines Company
website, www.themedicinescompany.com, to accompany the conference
call. To access the call, please dial 877-312-7507 (domestic) or
631-813-4828 (international) five minutes prior to the start time
and refer to conference ID 18857833. A replay of the call will be
available beginning at 12:30 p.m. ET. To access the replay,
please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 18857833.
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 and durability, and a wide
therapeutic index. This ESC-GalNAc-conjugate delivery platform is
being employed in nearly all of Alnylam's pipeline programs,
including ALN-PCSsc and several other 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. Alnylam’s pipeline of investigational RNAi therapeutics
is focused in 3 Strategic Therapeutic Areas (STArs): Genetic
Medicines, with a broad pipeline of RNAi therapeutics for the
treatment of rare diseases; Cardio-Metabolic Disease, with a
pipeline of RNAi therapeutics toward genetically validated,
liver-expressed disease targets for unmet needs in cardiovascular
and metabolic diseases; and Hepatic Infectious Disease, with a
pipeline of RNAi therapeutics that address the major global health
challenges of hepatic infectious diseases. In early 2015, Alnylam
launched its “Alnylam 2020” guidance for the advancement and
commercialization of RNAi therapeutics as a whole new class of
innovative medicines. Specifically, by the end of 2020, Alnylam
expects to achieve a company profile with 3 marketed products, 10
RNAi therapeutic clinical programs – including 4 in late stages of
development – across its 3 STArs. The company’s demonstrated
commitment to RNAi therapeutics has enabled it to form major
alliances with leading companies including Merck, Medtronic,
Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist,
GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and
Genzyme, a Sanofi company. 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 about Alnylam’s pipeline of investigational RNAi
therapeutics, 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 and the potential clinical activity and
durability of ALN-PCSsc, expectations regarding the initiation of
clinical studies, including studies as part of the ORION
development program, expectations regarding the continued
development of ALN-PCSsc by The Medicines Company, expectations
regarding Alnylam’s STAr pipeline growth 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 be replicated or
continue to occur in other subjects or in additional studies or
otherwise 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,
including The Medicines Company, for development, manufacture,
marketing, sales and/or 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,"
“hopes” 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 ALN-PCSsc will advance in the clinical trials process on a
timely basis or at all, whether physicians, patients and other key
decision makers will accept clinical trial results, whether the
Company will make regulatory submissions for ALN-PCSsc on a timely
basis or at all, whether its regulatory submissions will receive
approvals from regulatory agencies on a timely basis or at all, the
Company’s ability to successfully compete with potential
competitors which may discover, develop or commercialize competing
products more successfully than we do, 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 7, 2015, which are
incorporated herein by reference. The Company specifically
disclaims any obligation to update these forward-looking
statements.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20150830005024/en/
Alnylam Pharmaceuticals, Inc.Michael Mason,
617-551-8327Vice President, Finance & TreasurerorSpectrumLiz
Bryan, 202-955-6222 x2526 (Media)orThe Medicines
CompanyNeera Dahiya Ravindran, M.D., 973-290-6044Vice
President, Investor Relations & Strategic
Planningneera.ravindran@themedco.comorBob Laverty, 609-558-5570
(Media)Vice President,
Communicationsrobert.laverty@themedco.com
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