– In Ongoing Phase 1/2 Study, Single
Subcutaneous Doses of ALN-CC5 Achieve Potent, Statistically
Significant, and Highly Durable C5 Knockdown of up to 96% –
– After Single Dose, ALN-CC5 Also Achieves up
to 92% Inhibition of Serum Complement Activity, Including up to 61%
Inhibition of Serum Hemolytic Activity, and was Generally Well
Tolerated –
– Dose Escalation Continues in Multi-Dose
Cohorts, with Additional Data Expected to be Presented in Late 2015
–
– Company to Host Conference Call Today at 7:00
a.m. ET to discuss results –
Alnylam Pharmaceuticals, Inc.
(Nasdaq:ALNY), a leading RNAi therapeutics company, today announced
initial positive results from its ongoing Phase 1/2 clinical trial
with ALN-CC5, an investigational RNAi therapeutic targeting
complement component C5 for the treatment of complement-mediated
diseases. These new clinical data are being presented at the 20th
Congress of the European Hematology Association (EHA) held June 11
– 14 in Vienna, Austria. Initial study results from 12 healthy
volunteer subjects showed that single subcutaneous dose
administration of ALN-CC5 resulted in potent, dose-dependent,
durable, and statistically significant knockdown of serum C5 of up
to 96%. In addition, single dose administration of ALN-CC5 achieved
inhibition of serum complement activity of up to 92%, including an
up to 61% inhibition of serum hemolytic activity. Further, ALN-CC5
has been found to be generally well tolerated to date. The company
is continuing to dose healthy volunteer subjects in both the single
ascending dose (SAD) and multiple ascending dose (MAD) stages of
the study, and expects to present additional data from the trial in
late 2015. Consistent with previous guidance, the company also
plans to begin enrolling patients with paroxysmal nocturnal
hemoglobinuria (PNH) into the trial by the end of 2015.
“We believe that ALN-CC5 – as a first-in-class C5 synthesis
inhibitor – represents an innovative, differentiated, and
well-validated approach for the treatment
of complement-mediated diseases. Our initial single-dose data
from our ongoing Phase 1/2 clinical trial demonstrate clinical
activity for ALN-CC5 with an up to 96% knockdown of serum C5 and up
to 92% inhibition of serum complement activity, including an up to
61% inhibition of serum hemolytic activity. We believe these are
encouraging initial proof-of-concept results, and we expect – based
on our experience in non-human primates, or NHPs – that this level
of single-dose activity should meet our target profile as we
progress in multi-dose cohorts. In addition, we are encouraged that
ALN-CC5 has been generally well tolerated to date,” said Akshay
Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and
Chief Medical Officer at Alnylam. “ALN-CC5 now becomes our fourth
RNAi therapeutic program to demonstrate clinical activity and
excellent translation from NHP to humans, continuing to highlight
the reproducible and modular features of our RNAi therapeutics
platform. Indeed, in the case of ALN-CC5, we appear to observe a
three- to five-fold enhanced potency in humans compared with NHPs.
We are now advancing ALN-CC5 in the multi-dose phase of the Phase
1/2 study, and look forward to reporting additional data from
healthy volunteer subjects in this trial in late 2015. Furthermore,
we remain on track to begin enrolling PNH patients in the trial by
the end of this year.”
“Significant progress has been made in the treatment of
complement-mediated diseases, including PNH, but we continually
strive for even further improvements for our patients. I believe
that a new medicine to treat excessive complement activity that
could be given by infrequent, subcutaneous administration would be
a welcome addition to the treatment landscape,” said Anita
Hill, M.D., Ph.D., MRCP, FRCPath, Consultant Haematologist
for Leeds Teaching Hospitals NHS Trust, UK, and Lead
Clinician for the National PNH Service in England. “I am encouraged
by the emerging initial single dose data from this Phase 1/2 trial,
and I look forward to the continued clinical development of this
novel therapeutic approach.”
The Phase 1/2 trial of ALN-CC5 is being conducted in
the U.K., in three parts. Parts A and B are randomized (3:1,
drug:placebo), double-blind, placebo-controlled, single-dose (Part
A) and multi-dose (Part B), dose-escalation studies, designed to
enroll up to a total of 60 healthy adult volunteers. To mitigate
against the risk of Neisseria meningitides, subjects received
meningococcal vaccination and oral ciprofloxacin. Subjects in Part
A are receiving a single subcutaneous administration of ALN-CC5 at
fixed doses of 50, 200, 400, or 600 mg. Subjects in Part B are
receiving multiple ascending doses of ALN-CC5, at a fixed dose
level of 100 mg in the first cohort, administered once weekly for
up to five weeks; bi-weekly and monthly dosing schedules may also
be evaluated. The primary objective of these first two parts of the
study is to evaluate safety and tolerability of single and multiple
subcutaneous doses of ALN-CC5. Additional objectives include
evaluation of clinical activity for ALN-CC5 as measured by
knockdown of serum C5 and inhibition of serum complement activity,
including measurements of complement alternative pathway (CAP) and
complement classical pathway (CCP) activity by ELISA and serum
hemolytic activity toward sheep erythrocytes. Part C will be an
open-label, multi-dose study in up to eight patients with PNH, and
will assess safety, tolerability, and clinical activity of ALN-CC5,
administered as multiple subcutaneous doses for up to 13 weeks.
This part of the study will include an exploratory evaluation of
the effects of ALN-CC5 on levels of lactate dehydrogenase (LDH), a
measure of endogenous red blood cell hemolysis.
Initial Phase 1/2 study results from 12 healthy volunteer
subjects are being presented in an oral presentation at EHA and
include all available data out to as long as 98 days from the 50,
200, and 400 mg SAD cohorts. Safety data are as of a data cut-off
date of May 26, 2015, and clinical activity data are as of a data
cut-off date of June 4, 2015. In the ongoing study, single doses of
ALN-CC5 were found to be generally well tolerated, with no serious
adverse events (including infections), study discontinuations, or
significant clinical laboratory findings reported to date.
The key additional objectives of the study were to evaluate the
clinical activity of ALN-CC5 as measured toward C5 knockdown and
effects on serum complement activity, including serum hemolytic
activity. Single subcutaneous doses of ALN-CC5 resulted in potent,
dose-dependent, statistically significant, and highly durable
knockdown of serum C5 demonstrating human proof-of-concept.
Specifically, a single ALN-CC5 dose resulted in an up to 96%
knockdown of serum C5. A mean maximum knockdown of 94 +/- 2.0% (p
less than 0.003 compared with placebo) was achieved in the 400 mg
SAD cohort. Nadir C5 knockdown for all treated subjects was
achieved between days 28 and 70 and effects were durable over a
period of months. For example, an up to 94% knockdown of serum C5
was achieved at day 70 after a single dose of drug. The company
believes that the durable and clamped nature of C5 knockdown could
potentially support a once-monthly, fixed dose subcutaneous
regimen. Finally, the level of C5 knockdown in humans after single
dose administration was found to correlate closely (r2=0.83, p less
than 0.0001) with corresponding single dose data in non-human
primates. From these data, there appears to be an approximately
three- to five-fold increased potency for ALN-CC5 in humans as
compared with NHPs.
In addition, single dose administration of ALN-CC5 was
associated with potent, dose-dependent, and durable inhibitory
effects toward complement activity. In particular, single dose
ALN-CC5 administration resulted in an up to 87% inhibition of CAP
activity (mean maximum 75 ± 7.2%), an up to 92% inhibition of CCP
activity (mean maximum 82 ± 6.1%), and an up to 61% inhibition of
serum hemolytic activity (mean maximum 43 ± 9.1%). These effects on
complement activity were statistically significant (p less than
0.005 compared with placebo). In addition, the inhibitory effects
of ALN-CC5 toward complement activity were found to be highly
durable. For example, an up to 82% inhibition of CCP activity was
observed at day 70 following a single dose administration. As seen
in NHP studies with ALN-CC5 and consistent with all other Alnylam
GalNAc-conjugate programs, further increases in inhibitory effects
toward serum complement activity are expected with multi-dose
administration. As reported at the American Society of Hematology
meeting in December 2014, results in NHPs showed that a
twice-monthly subcutaneous dose regimen of ALN-CC5 at 5 mg/kg
achieved inhibition of serum hemolytic activity of over 80%. In
contrast, additional NHP studies show that a single dose of ALN-CC5
at 5 mg/kg (comparable to the 400 mg fixed dose in the Phase 1/2
study) achieved a 49 ± 4.5% mean maximal inhibition of serum
hemolytic activity. The company expects to present initial
multi-dose data from the ongoing Phase 1/2 study in late 2015.
Genzyme Alliance
In January 2014, Alnylam and Genzyme, a Sanofi company,
formed an alliance to accelerate and expand the development and
commercialization of RNAi therapeutics across the world. The
alliance is structured as a multi-product geographic alliance in
the field of rare diseases. Alnylam retains product rights
in North America and Western Europe, while Genzyme
obtained the right to access certain programs in Alnylam's current
and future Genetic Medicines pipeline, including ALN-CC5, in the
rest of the world. In certain defined instances, Genzyme has
co-development/co-commercialization and/or global product rights.
Genzyme's rights are structured as an opt-in that is triggered upon
achievement of human proof-of-principle.
Conference Call Information
Alnylam management will discuss these new Phase 1/2 clinical
results with ALN-CC5 for the treatment of complement-mediated
diseases in a webcast conference call on Friday, June 12
at 7:00 a.m. ET. A slide presentation will also be available
on the Investors page of the company's website, www.alnylam.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
64369692. A replay of the call will be available beginning
at 10:00 a.m. ET. To access the replay, please dial
855-859-2056 (domestic) or 404-537-3406 (international), and refer
to conference ID 64369692.
About ALN-CC5
ALN-CC5 is an investigational RNAi therapeutic targeting the C5
component of the complement pathway for the treatment of
complement-mediated diseases. The complement system plays a central
role in immunity as a protective mechanism for host defense, but
its dysregulation results in life-threatening complications in a
broad range of human diseases including paroxysmal nocturnal
hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS),
myasthenia gravis, neuromyelitis optica, membranous nephropathy,
amongst others. Complement component C5, which is predominantly
expressed in liver cells, is a genetically and clinically validated
target; loss of function human mutations are associated with an
attenuated immune response against certain infections and
intravenous anti-C5 monoclonal antibody (mAb) therapy has
demonstrated clinical activity and tolerability in a number of
complement-mediated diseases. A subcutaneously administered RNAi
therapeutic that silences C5 represents a novel approach to the
treatment of complement-mediated diseases. ALN-CC5 utilizes
Alnylam's ESC-GalNAc conjugate technology, which enables
subcutaneous dosing with increased potency and durability and a
wide therapeutic index.
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 delivery platform is being employed in
nearly all of Alnylam's pipeline 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. 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-CC5 for the treatment of
complement-mediated diseases, expectations regarding the reporting
of data from clinical studies, in particular the ongoing Phase 1/2
clinical trial of ALN-CC5, expectations regarding the durability of
ALN-CC5, the clinical activity that could be achieved with multiple
doses of ALN-CC5 and the market opportunity for ALN-CC5,
expectations regarding its STAr pipeline growth strategy, and its
plans regarding 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 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 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.
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version on businesswire.com: http://www.businesswire.com/news/home/20150612005151/en/
Alnylam Pharmaceuticals, Inc.Michael Mason,
617-551-8327Vice President, Finance and TreasurerorMediaSpectrumLiz
Bryan, 202-955-6222 x2526
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